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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Omecamtiv mecarbil オメカムティブメカビル


Omecamtiv mecarbil.svg

ChemSpider 2D Image | omecamtiv mecarbil | C20H24FN5O3

Image result for OMECAMTIV

Omecamtiv mecarbil

  • Molecular FormulaC20H24FN5O3
  • Average mass401.435 Da
4-[2-fluoro-3-[(6-methyl-3-pyridyl)carbamoylamino]benzyl]piperazine-1-carboxylic acid methyl ester
AMG 423
AMG-423
CK1827452
CK-1827452; CK1827452
Cladribine [BAN] [INN] [JAN] [USAN] [Wiki]
methyl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate
1-Piperazinecarboxylic acid, 4-[[2-fluoro-3-[[[(6-methyl-3-pyridinyl)amino]carbonyl]amino]phenyl]methyl]-, methyl ester
2M19539ERK
オメカムティブメカビル
873697-71-3 [RN]
9088
Methyl 4-(2-fluoro-3-{[(6-methyl-3-pyridinyl)carbamoyl]amino}benzyl)-1-piperazinecarboxylate

In January 2019, Cytokinetics and licensees Amgen and Servier are developing oral modified- and immediate-release formulations of the cardiac myosin activator omecamtiv mecarbil (phase III), the lead from a series of small-molecule, sarcomere-directed compounds, for the treatment of chronic heart diseases including high risk heart failure, stable heart failure and ischemic cardiomyopathy

Omecamtiv Mecarbil has been used in trials studying the treatment and basic science of Heart Failure, Echocardiogram, Pharmacokinetics, Chronic Heart Failure, and History of Chronic Heart Failure, among others.

Omecamtiv mecarbil, a small-molecule activator of cardiac myosin, is developed in phase III clinical trials by originator Cytokinetics and Amgen for the oral treatment of chronic heart failure.

WO2006009726 product patent of omecamtiv mecarbil expire in EU states until June 2025 and expire in the US in September 2027 with US154 extension.

  • Originator Cytokinetics
  • Developer Amgen; Cytokinetics; Servier
  • Class Esters; Heart failure therapies; Organic chemicals; Piperazines; Pyridines; Small molecules
  • Mechanism of Action Cardiac myosin stimulants
  • Phase III Chronic heart failure
  • Phase II Acute heart failure; Heart failure
  • No development reported Angina pectoris; Cardiomyopathies
  • 26 Apr 2018 Amgen and Cytokinetics plan the phase III METEORIC-HF trial in Heart failure by the end of 2018 (NCT03759392)
  • 18 Sep 2017 Pharmacodynamics data from the phase III COSMIC-HF trial Chronic heart failure released by Cytokinetics
  • 08 May 2017 Amgen completes the phase II trial in Heart failure in Japan (NCT02695420)

Omecamtiv mecarbil (INN), previously referred to as CK-1827452, is a cardiac-specific myosin activator. It is being studied for a potential role in the treatment of left ventricular systolic heart failure.[1]

Systolic heart failure involves a loss of effective actin-myosin cross bridges in the myocytes (heart muscle cells) of the left ventricle, which leads to a decreased ability of the heart to move blood through the body. This causes peripheral edema (blood pooling), which the sympathetic nervous system tries to correct[2] by overstimulating the cardiac myocytes, leading to left ventricular hypertrophy, another characteristic of chronic heart failure.

Current inotropic therapies work by increasing the force of cardiac contraction, such as through calcium conduction or modulating adrenoreceptors. But these are limited by adverse events, including arrhythmias related to increased myocardical oxygen consumption, desensitization of adrenergic receptors, and altering intracellular calcium levels.[3] Inotropes are also thought to be associated with worse prognosis.[4] Therefore, the novel mechanism of omecamtiv mecarbil may offer a useful new option for heart failure.

Mechanism of action

Cardiac myocytes contract through a cross-bridge cycle between the myofilaments, actin and myosin. Chemical energy in the form of ATP is converted into mechanical energy which allows myosin to strongly bind to actin and produce a power stroke resulting in sarcomere shortening/contraction.[5] Omecamtiv mecarbil specifically targets and activates myocardial ATPase and improves energy utilization. This enhances effective myosin cross-bridge formation and duration, while the velocity of contraction remains the same.[6]Specifically, it increases the rate of phosphate release from myosin, thereby accelerating the rate-determining step of the cross-bridge cycle, which is the transition of the actin-myosin complex from the weakly bound to the strongly bound state.[7][1] Furthermore, once myosin is bound to actin, it stays bound dramatically longer in the presence of omecamtiv mecarbil.[8][9] The combination of increased and prolonged cross-bridge formation prolongs myocardial contraction. Thus, the overall clinical result of omecamtiv mecarbil is an increase in left ventricular systolic ejection time and ejection fraction.[6][7]

There is a slight decrease in heart rate while myocardial oxygen consumption is unaffected. The increased cardiac output is independent of intracellular calcium and cAMP levels.[3][10] Thus omecamtiv mecarbil improves systolic function by increasing the systolic ejection duration and stroke volume, without consuming more ATP energy, oxygen or altering intracellular calcium levels causing an overall improvement in cardiac efficiency.[6]

Clinical trials

Experimental studies on rats and dogs, proved the efficacy and mechanism of action of omecamtiv mecarbil.[3] Current clinical studies on humans have shown there is a direct linear relationship between dose and systolic ejection time.[1][11][12] The dose-dependent effects persisted throughout the entire trial, suggesting that desensitization does not occur. The maximum tolerated dose was observed to be an infusion of 0.5 mg/kg/h. Adverse effects, such as ischemia, were only seen at doses beyond this level, due to extreme lengthening of systolic ejection time.[1] Thus due to the unique cardiac myosin activation mechanism, omecamtiv mecarbil could safely improve cardiac function within tolerated doses. Omecamtiv mecarbil effectively relieves symptoms and enhances the quality of life of systolic heart failure patients. It drastically improves cardiac performance in the short term; however, the hopeful long-term effects of reduced mortality have yet to be studied.[1][2]

PATENT

WO2006009726

PAPER

Synthesis of unsymmetrical diarylureas via pd-catalyzed C-N cross-coupling reactions
Org Lett 2011, 13(12): 3262

Synthesis of Unsymmetrical Diarylureas via Pd-Catalyzed C–N Cross-Coupling Reactions

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
Org. Lett.201113 (12), pp 3262–3265
DOI: 10.1021/ol201210t

Abstract

Abstract Image

A facile synthesis of unsymmetrical N,N′-diarylureas is described. The utilization of the Pd-catalyzed arylation of ureas enables the synthesis of an array of diarylureas in good to excellent yields from benzylurea via a one-pot arylation–deprotection protocol, followed by a second arylation.

https://pubs.acs.org/doi/suppl/10.1021/ol201210t/suppl_file/ol201210t_si_001.pdf

Methyl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1- carboxylate (Omecamtiv Mecarbil).11 Following general procedure C, a mixture of methyl 4-(3-chloro-2-fluorobenzyl)piperazine-1-carboxylate (143.1 mg, 0.5 mmol), (2- Methylpyridin-5-yl)urea (90.6 mg, 0.6 mmol), Pd(OAc)2 (5 mol %), t-BuBrettPhos (15 mol %), Cs2CO3 (456.2 mg, 0.7 mmol), degassed water (4 mol %) and THF (1 mL) was heated to 65 °C for 6 h. The crude product was purified via flash chromatography (5-10% MeOH/DCM) to provide the title compound as a slightly brownish solid (164 mg, 82%),

mp = 180 °C.

1 H NMR (400 MHz, DMSO-d6 ) δ: 9.13 (s, 1H), 8.59 (d, J = 1.5 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.05 (t, J = 7.6 Hz, 1H), 7.83 (dd, J = 8.4, 2.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.9 Hz, 1H), 7.00 (t, J = 6.7 Hz, 1H), 3.57 (s, 3H), 3.55 (s, 2H), 3.35 (br, 4H), 2.40 (s, 3H), 2.36 (br, 4H) ppm.

13C NMR (101 MHz, DMSO-d6 ) δ: 155.0, 152.3, 151.1, 150.7 (d, J = 242.5 Hz), 139.2, 133.6, 127.3 (d, J = 10.9 Hz), 125.8, 124.1 (d, J = 13.3 Hz), 124.0 (d, J = 4.0 Hz), 123.8 (d, J = 3.8 Hz), 122.8, 119.5, 54.6, 52.2, 52.1, 43.4, 23.2 ppm (observed complexity is due to C–F splitting).

19F NMR (376 MHz, DMSO-d6 ) δ: -135.09.

IR (neat, cm-1 ): 3297, 2920, 2823, 1705, 1638, 1557, 1476, 1450, 1233, 1189, 1129, 779, 765.

Anal. Calcd. for C20H24FN5O3: C, 59.84; H, 6.03. Found: C, 59.64; H, 5.92.

PAPER

Morgan et al. ACS Med. Chem. Lett. 2010, 1, 472

Discovery of Omecamtiv Mecarbil the First, Selective, Small Molecule Activator of Cardiac Myosin

Abstract Image

We report the design, synthesis, and optimization of the first, selective activators of cardiac myosin. Starting with a poorly soluble, nitro-aromatic hit compound (1), potent, selective, and soluble myosin activators were designed culminating in the discovery of omecamtiv mecarbil (24). Compound 24 is currently in clinical trials for the treatment of systolic heart failure.

omecamtiv mecarbil as a white powder (3.64 kg, 90% yield).

IR (KBR) 3292, 2950, 2866, 2833, 1720, 1640, 1550, 1600, 1490, 1455, 1406, 1378, 1352, 1274, 1244, 1191, 1125, 815, 769, 725, 668 cm-1 ;

1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1 H, 2-pyridyl H), 8.59 (d, 1 H, J = 2.5 Hz, Urea N-H), 8.47 (d, 1 H, J = 2.6 Hz, Urea N-H), 8.04 (dt, 1 H, J = 1.5 Hz, 7.8 Hz, phenyl H), 7.83 (dd, 1 H, J = 2.6 Hz, 8.4 Hz, 4-pyridyl H), 7.18 (d, 1 H, J = 8.4 Hz, 5-pyridyl H), 7.10 (app t, 1 H, J = 7.8 Hz, phenyl H), 7.02 (app p, 1 H, J = 1.5 Hz, 6.3 Hz, 7.8 Hz, phenyl H), 3.58 (s, 3 H, OCH3), 3.56 (m, 4 H, piperazine Hs), 2.41 (s, 3 H, pyridineCH3), 2.37 (br m, 4 H, piperazine Hs); 13C NMR (100 MHz, DMSO-d6) δ 155.0,152.3, 151.1 150.7, 139.1, 133.6, 127.3, 127.2, 125.8, 124.1, 123.7, 122.8, 119.5, 54.5, 52.2, 52.0, 43.4, 23.2;

Exact mass calcd for C20H24FN5O3 requires m/z 402.1926. Found m/z 402.1940.

Anal. Calcd. For C20H24FN5O3: C, 59.84; H, 6.03; N, 17.45. Found: C, 59.99; H, 6.07; N, 17.41.

PATENT

WO2016210240

PATENT

WO-2019006231

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019006231&tab=PCTDESCRIPTION&maxRec=1000

Process for the preparation of omecamtiv mecarbil and its new intermediates. Useful for the treatment of heart failure..

Scheme 1 :

Scheme 2

I

Scheme 3

I

Piper 


Scheme 5

Aminopyridine

(APYR) Commercially Available

Scheme 6


IPAc Reaction

.

Scheme 7

Scheme 8

Pi 
(PIPA)

[0043] Thus, provided herein is a method of synthesizing PIPA comprising admixing PIPN (which can comprise PIPN hydrochloride salt), an aqueous solution of an inorganic base, and toluene to form a PIPN freebase solution. The inorganic base can be sodium bicarbonate or sodium hydroxide, for example. In some embodiments, the inorganic base comprises sodium hydroxide. The PIPN freebase solution is then hydrogenated in the presence of a palladium catalyst in toluene and an alcohol solvent to form crude PIPA. The alcohol solvent can comprise ethanol or isopropanol. PIPA is then crystallized from a heptane and toluene solvent mixture.

[0044] In some specific embodiments, to a mixture of 1 equiv. PIPN-HCI and toluene (4V) is added 1 M aq. NaOH (3.3V) at 20 °C. Stirring is continued for 1 hour before the phases are separated. The organic layer is washed twice with a mixture of water (2.4V) and saturated brine (0.6V), then the organic layer is distilled to 3.8V. The solution is filtered, the reactor rinsed with toluene (1V) and the rinse solution filtered before the organic layers are combined. To the toluene layer is added Pd/C (0.7 wt%) and the heterogeneous mixture is charged into a hydrogenation vessel. Ethanol (1V) is added to the mixture. Hydrogenation is performed at 20 °C under 60 psig of hydrogen. After the reaction is complete, the mixture is filtered and rinsed with toluene (1V). The mixture is distilled to 2.4V, seeded with 1 mol% PIPA in heptane (0.1V) at 35 °C and then cooled to 20 °C. The addition of heptane (5.6V) is completed in 3 hours. The mixture is filtered and dried under vacuum and nitrogen to afford PIPA (90% yield, > 97.0 wt%, > 98.0 LCAP).

[0045] In some other specific embodiments, 1 N aqueous sodium hydroxide (3.3 volumes) is added to 1 equiv. of PIPN (hydrochloride salt) suspended in toluene (4 volumes). The biphasic mixture is agitated at 20 °C for 1 hour and the phases are allowed to separate. The organic layer is washed twice with a 0.9 M aqueous sodium chloride solution (3 volumes). The reaction mixture is azeotropically dried by concentration to approximately 3.8 volumes and polish filtered. The transfer line is rinsed with toluene (1 volume) and the rinse solution is combined with the PIPN solution.

Ethanol (1 volume) is added to the PIPN solution and hydrogenation of the starting material is carried out in the presence of 5% Pd/C (on activated carbon sold by BASF as Escat 1421, 0.7 wt% catalyst loading) using a pressure of 4 bars of hydrogen at 15 °C. Upon reaction completion, the mixture is filtered. The hydrogenation autoclave and filtered catalyst are rinsed with toluene (1V) and the rinse solution is combined with the reaction mixture. The solution is concentrated to 2.4 volumes and seeded with 1 mol% PIPA in heptane (0.1 volume) at 38 °C. The mixture is agitated for 30 minutes at 38 °C, cooled to 20 °C over the course of 2 hours, and agitated at that temperature for 30 minutes. Heptane is added (5.6 volumes) over the course of 3 hours and the mixture is agitated for 30 minutes. The mixture is filtered and dried on filter/drier. The cake is washed once with

heptane:toluene (7:3, 2 total volumes) and once with heptane (2 volumes). PIPA is isolated in 88% yield with > 98.0 wt% assay and > 98.0 LC area%.

[0046] Preparation of omecamtiv mecarbil dihvdrochloride hydrate: The prior process to prepare omecamtiv mecarbil dihydrochloride hydrate involved a telescoped procedure by which the

omecamtiv mecarbil is prepared as a solution in THF, and the solvent is subsequently exchanged for isopropanol. However, considering that the solubility of omecamtiv mecarbil in isopropanol at 20°C is about 10 mg/mL and the total volume of isopropanol at the end of the solvent exchange, 95% of the material is out of solution at the end of the solvent exchange, leading to the formation of a slurry that is difficult or impossible to stir. Distillation can no longer be performed once this slurry is formed due to poor mass transfer, leaving behind THF levels in the slurry that are above the in-process control (IPC) specification, e.g., greater than or equal to 1 GC area%. In practice, this leads to delays in the manufacturing due to necessary recharging of isopropanol until the mixture can be stirred, followed by additional distillation and analysis of residual THF. In addition, the ratio of isopropanol and water has to be verified using an in-process control considering the variable amounts of isopropanol at the end of the distillation and the influence of the solvent ratio (isopropanol/water) on the mother liquor losses upon filtration.

Scheme 9

95% yield

[0048] Thus, provided herein is a method of preparing omecamtiv mecarbil dihydrochloride hydrate via admixing PIPA, PCAR, and a trialkylamine (e.g., triethylamine or diisopropylethylamine) in acetonitrile and THF to form omecamtiv mecarbil. The omecamtiv mecarbil is isolated as the free base and then admixed with 2 to 3 molar equivalents of hydrochloric acid in isopropanol and water to form omecamtiv mecarbil dihydrochloride hydrate, which can optionally be crystallized from isopropanol and water. Isolation of the omecamtiv mecarbil free base can be performed via crystallization by addition of water and filtration. PIPA and PCAR can be prepared as disclosed above.

[0049] In some embodiments, PIPA (2.1 kg, 1 equiv) is charged to a reactor, followed by PCAR (1.1 equiv), then THF (2.5 V), and finally acetonitrile (2.5 V). To the resulting slurry is added N,N-diisopropylethylamine (1.2 equiv) and the batch is heated to 55 °C for 16 h. Water (5 V) is then added over 15 minutes and omecamtiv mecarbil freebase seeds (0.05 equiv) are charged to the reactor. The batch is agitated for 15 minutes and water (10 V) is added over 3 h. The batch is cooled to 20 °C over 1 h and filtered. The cake is washed with 3:1 watenacetonitrile (3 V) and then acetonitrile (3 x 3 V). The cake is dried in a filter/drier. Omecamtiv mecarbil freebase is isolated as a solid in 80% yield, with 99.9 LC area%, and 99.3 wt% assay.

[0050] Omecamtiv mecarbil freebase (2.6 kg, 1 equiv) is charged to a reactor followed by 2-propanol (2.6 V) and water (1.53 V). The batch is then heated to 45 °C. 6 M aqueous HCI (2.2 equiv) is added at a rate to keep batch temperature below 60 °C. The batch is heated to 60 °C for 30 minutes and filtered into a clean reactor at 60 °C. The original vessel is rinsed with an

isopropanokwater mixture (1 :1 , 0.1 volume total) and the rinse volume is added to the reaction mixture. The solution is cooled to 45 °C and a slurry of omecamtiv mecarbil dihydrochloride hydrate seed (0.05 or 0.03 equiv) in isopropanol (0.14 or 0.1 V) is charged to the reactor. The suspension is agitated for 1 h. Isopropanol (3.68 V) is charged to the reactor over 2 h. The mixture is warmed to 55 °C over 1 h and held for 30 minutes at that temperature. The mixture is cooled to 45 °C over 1 h. The mixture is agitated for 2 h and then isopropanol (7.37 V) is added to the reactor over 3 h. The mixture is agitated for 1 h and then cooled to 20 °C over 2 h. The mixture is wet milled until d90 specifications are met (e.g., < 110 μιτι) and the suspension is filtered. The wet cake is washed twice with isopropanokwater (95:5, 2V) . The wet cake is dried under vacuum until isopropanol levels are below 1000 ppm. The cake is optionally re-hydrated if necessary using e.g., a stream of humidified nitrogen, until the water content of the solids are between 3.0 and 4.2 wt%. The material can be recrystallized if it doesn’t meet specification. Omecamtiv mecarbil dihydrochloride hydrate is isolated as a solid in 91.3% yield, with 99.96 LC area%, and 100.1 wt% assay.

[0051] Omecamtiv Mecarbil Dihydrochloride Hydrate Preparation using Continuous Manufacturing: Provided herein is a method of preparing omecamtiv mecarbil dihydrochloride hydrate using a continuous manufacturing process. The general synthetic procedure is outlined in Scheme 10 below.

Scheme 10

Conditions For 100 a Demo Run

CH3CN (6 V), 21 °C

Assay Yield = 95.2 %

Conversion = 98.2 %

L-Urea LCAP = 0 %

PIPA Methyl Carbamate LCAP = 1.49 %

Production Rate of Omecamtiv Mecarbil = 15.29 g/h

PATENT

WO2019006235

PATENT

https://patents.google.com/patent/WO2014152270A1

The cardiac sarcomere is the basic unit of muscle contraction in the heart. The cardiac sarcomere is a highly ordered cytoskeletal structure composed of cardiac muscle myosin, actin and a set of regulatory proteins. The discovery and development of small molecule cardiac muscle myosin activators would lead to promising treatments for acute and chronic heart failure. Cardiac muscle myosin is the cytoskeletal motor protein in the cardiac muscle cell. It is directly responsible for converting chemical energy into the mechanical force, resulting in cardiac muscle contraction.

[0004] Current positive inotropic agents, such as beta-adrenergic receptor agonists or inhibitors of phosphodiesterase activity, increase the concentration of intracellular calcium, thereby increasing cardiac sarcomere contractility. However, the increase in calcium levels increase the velocity of cardiac muscle contraction and shortens systolic ejection time, which has been linked to potentially life-threatening side effects. In contrast, cardiac muscle myosin activators work by a mechanism that directly stimulates the activity of the cardiac muscle myosin motor protein, without increasing the intracellular calcium concentration. They accelerate the rate-limiting step of the myosin enzymatic cycle and shift it in favor of the force-producing state. Rather than increasing the velocity of cardiac contraction, this mechanism instead lengthens the systolic ejection time, which results in increased cardiac muscle contractility and cardiac output in a potentially more oxygen-efficient manner. [0005] U.S. Patent No. 7,507,735, herein incorporated by reference, discloses a genus of com ounds, including omecamtiv mecarbil (AMG 423, CK- 1827452), having the structure:

Figure imgf000003_0001

[0006] Omecamtiv mecarbil is a first in class direct activator of cardiac myosin, the motor protein that causes cardiac contraction. It is being evaluated as a potential treatment of heart failure in both intravenous and oral formulations with the goal of establishing a new continuum of care for patients in both the in-hospital and outpatient settings.

Manufacture of Omecamtiv Mecarbil dihydrochloride hydrate Synthetic Route to Omecamtiv Mecarbil

Figure imgf000016_0001

PiE§razine_Nitro^!C Piperazine Aniline

to IPA

Figure imgf000016_0002

omecamtiv mecarbil-2HCI-H20

Synthesis of the API SM Piperazine Nitro-HCl

Figure imgf000016_0003

Piperazine Carboxylate

Figure imgf000016_0004

88% overall [0081] In a 60 L reactor (containing no exposed Stainless steel, Hastelloy®, or other metal parts) equipped with a reflux/return condenser and scrubber charged with a 5N NaOH solution, a mechanically stirred mixture of FN-Toluene (2.0 kg, 12.89 mol, 1.0 equiv.), N- Bromosuccinimide (3.9 kg, 21.92 mol, 1.70 equiv.), benzoyl peroxide (125.0 g, 0.03 equiv., 0.39 mol, containing 25 wt% water), and acetic acid (7.0 L, 3.5 volumes) was heated to 85 °C under an atmosphere of nitrogen for 7 hours. A solution of H3PO3 (106.0 g, 1.29 mol, 0.1 equiv.) and acetic acid (200 mL, 0.1 volume), prepared in separate vessel, was added. The reaction mixture was agitated for 0.5 h and analysis of an aliquot confirmed complete decomposition of benzoyl peroxide (not detected, HPLC254 nm)- The reaction mixture was cooled to 22 °C. DI Water (8.0 L, 4 volumes) and toluene (16.0 L, 8 volumes) were charged, the biphasic mixture was agitated (20 min), and the layers were separated. Aqueous 1.6N NaOH (14.0 L, 7.0 volumes) was added to the organic layer at a rate allowing the batch temperature to stay under 25 °C and the pH of the resultant aqueous phase was measured (> 11). The biphasic mixture was filtered through a 5 μιη Teflon® cartridge line and the layers were separated. The filter line was washed with another 2L of toluene.

[0082] The assay yields were 2.5 % of FN-Toluene, 62.3 % of FN-Bromide and 30.0 % of Di-Bromide. The toluene solution contained no benzoyl peroxide, succinimide, or cc- bromoacetic acid and water content by KF titration was 1030 ppm (This solution could be held under nitrogen at room temperature for > 12 h without any change in the assay yield).

[0083] To this solution at room temperature was added diisopropylethylamine (880.0 g, 6.63 mol, 0.53 equiv.) followed by methanol (460 mL, 11.28 mol, 0.88 equiv.) and heated to 40 °C. A solution of diethylphosphite (820.0 g, 5.63 mol, 0.46 equiv.) in methanol (460 mL, 11.28 mol, 0.88 equiv.) was prepared and added to the reaction mixture at 40 °C through an addition funnel over a period of 1 hour at such a rate that the batch temperature was within 40 + 5 °C. The contents were stirred for a period of 3h at 40 °C from the start of addition and cooled to room temperature and held under nitrogen atmosphere for 12 hours. The assay yield of the reaction mixture was 2.5 % FN-Toluene 92.0% FN-Bromide and 0.2% Di-Bromide. This solution is used as such for the alkylation step.

[0084] Characterization for components of final product mixture (collected for pure compounds).

[0085] 2-Fluoro-3-Nitrotoluene (FN-Toluene): 1H NMR (400 MHz, CHLOROFORM- J) δ ppm 2.37 (s, 1 H), 7.13-7.20 (m, 1 H), 7.45-7.51 (m, 1 H), 7.79-7.85 (m, 1 H). 13C NMR (100 MHz, CHLOROFORM- d) δ ppm 14.3 (d, J = 5 Hz), 123.3 (d, J = 3 Hz), 123.6 (d, J = 5 Hz), 128.2 (d, J = 16 Hz), 136.7 (d, J = 5 Hz), 137.5 (broad), 153.7 (d, J = 261 Hz); 1- (bromomethyl)-2-fluoro-3-nitrobenzene (FN-Bromide): 1H NMR (400 MHz,

CHLOROFORM-J) δ ppm 4.56 (s, 1 H), 7.28-7.34 (m, 1 H), 7.69-7.76 (m, 1 H), 7.98-8.05 (m, 1 H). 13C NMR (100 MHz, CHLOROFORM- J) δ ppm 23.6 (d, / = 5 Hz), 124.5 (d, / = 5 Hz), 126.1 (d, / = 3 Hz), 128.5 (d, / = 14 Hz), 136.5 (d, / = 4 Hz), 137.7 (broad), 153.3 (d, / = 265 Hz). DSC: single melt at 53.59 °C. Exact Mass [C7H5BrFN02 + H]+: calc. = 233.9566, measured = 233.9561; l-(dibromomethyl)-2-fluoro-3-nitrobenzene (Dibromide): 1H NMR (400 MHz, CHLOROFORM- d) δ ppm 6.97 (s, 1 H), 7.39-7.45 (m, 1 H), 8.03-8.10 (m, 1 H), 8.16-8.21 (m, 1 H). 13C NMR (100 MHz, CHLOROFORM-J) δ ppm 29.2 (d, / = 7 Hz), 124.9 (d, / = 5 Hz), 127.1 (d, / = 2 Hz), 132.1 (d, / = 11 Hz), 135.7 (d, / = 2 Hz), 137.2 (broad), 149.8 (d, / = 266 Hz). DSC: single melt at 49.03 °C. Exact Mass [C7H4Br2FN02 + H]+: calc. = 311.8671, measured = 311.8666.

Piperazine Nitro-HCl:

[0086] To a mechanically stirred toluene solution (9 volumes) of FN-Bromide (prepared from previous step) in a 60 L reactor at 22 °C under an atmosphere of nitrogen,

diisopropylethylamine was charged (1.90 kg, 14.69 mol, 1.14 equiv.). To this mixture a solution of piperazine carboxylate methylester (Piperazine Carboxylate) (2.03 kg, 14.05 mol, 1.09 equiv.) in toluene (1.0 L, 0.5 volumes) was added at a rate allowing the batch temperature to stay under 30.0 °C (Exothermic. During the addition, jacket temperature was adjusted to 5 °C in order to maintain batch temperature below 30 °C. The mixture was agitated at 22 °C for 3 hours and analysis of an aliquot confirmed completion of the alkylation reaction (<1.0 LCAP FN-Bromide, HPLC254 nm). The reaction mixture was treated with aqueous NH4C1 (20 wt%, 10.0 L, 5 volumes; prepared from 2.0 kg of NH4C1 and 10.0 L of DI water), the biphasic mixture was agitated (30 min), and the layers were separated. The organic layer was sequentially washed with aqueous NaHC03 (9 wt%, 10.0 L, 5 volumes; prepared from 0.90 kg of NaHC03 and 10.0 L of DI water). The organic layer was filtered through a 5 μιη Teflon® cartridge line and transferred in a drum, washed the filter line with another 1.0 L toluene and the combined toluene solution (10.0 volumes) weighed, and assayed (HPLC) to quantify Piperazine Nitro free base. The assay yield for the Piperazine Nitro-freebase is 89.0%, FN-Toluene 2.5% and FN-Bromide 0.2% with FN-Bromide undetected. The total loss of product to the aqueous washes is < 1.0 %. This solution under nitrogen atmosphere is stable for more than 12h.

[0087] To a mechanically stirred toluene solution of Piperazine Nitro free base, prepared as described above, at 22 °C in a 60 L reactor under an atmosphere of nitrogen, IPA (19.4 L, 9.7 volumes) and DI water (1.0 L, 0.5 volume) were charged. The mixture was heated to 55 °C and 20% of the 1.4 equiv. of cone. HCl (Titrated prior to use and charge based on titer value; 276.0 mL, 3.21 mol) was charged. The contents were agitated for 15 min and

Piperazine Nitro-HCl seed (130.0 g, 0.39 mol, 0.03 equiv.) was charged as slurry in IPA (400 mL, 0.2 volume). The mixture was agitated for 30 min and the remaining cone. HCl (80% of the charge, 1.10 L, 12.82 mol) was added over a period of 4 hours. The mixture was stirred at 55 °C for 1 h, cooled to 20 °C in a linear manner over 1.5 hours, and agitated at this temperature for 12 hours. The supernatant concentration of Piperazine Nitro-HCl was measured (2.8 mg/g). The mixture was filtered through an aurora filter equipped with a 5 μιη Teflon® cloth. The mother liquor were transferred to a clean drum and assayed. The filter cake was washed twice with IPA (11.2 L, 5.6 volumes) and dried to constant weight (defined as < 1.0% weight loss for 2 consecutive TGA measurements over a period of 2 hours) on filter with vacuum and a nitrogen sweep (14 h). The combined losses of Piperazine Nitro- HCl in the mother liquors and the washes were 2.5 %. Piperazine Nitro-HCl was isolated 3.59 kg in 87.6% corrected yield with >99.5 wt% and 99.0% LCAP purity.

[0088] Methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-l-carboxylate hydrochloride

(Piperazine Nitro-HCl): 1H NMR (300 MHz, DMSO-J) δ ppm 3.25 (br. s, 3 H), 3.52-3.66 (m, 8 H), 4.47 (s, 2 H), 7.44-7.63 (t, 1 H, J = 8 Hz), 7.98-8.15 (m, 1 H), 8.17-8.34 (m, 1 H). 13C NMR (75 MHz, DMSO-J) 5 ppm 50.3, 51.4, 52.8, 119.6 (d, J = 14 Hz), 125.1 (d, J = 5 Hz), 127.9, 137.4 (d, J = 8 Hz), 139.8 (d, J = 3 Hz), 152.2, 154.7, 155.7. DSC: melt onset at 248.4 °C. Exact Mass [Q3H16FN3O4 + H]+: calculated = 298.1203, measured = 298.1198. lternative processes for the synthesis of Piperazine Nitro:

Figure imgf000020_0001

2-fluoro-3-nitrobenzoic acid (2-fluoro-3-nitrophenyl)metlianol 2-fluoro-3-nitrobenzy? methanesulfonate

Figure imgf000020_0002

methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-l -carboxylate hydrochloride

[0089] A mixture of NaBH4 ( 1.7 g, 44 mmol) in THF (68 mL) was treated 2-fluoro-3- nitrobenzoic acid (3.4 g, 18.4 mmol) and cooled to 0-5 °C. A solution of iodine (4.7 g, 18.4 mmol) in THF (12 mL) was then added drop wise at a rate to control off-gassing. The progress of the reaction was assessed by HPLC. After 2 hours HPLC assay indicated 4% AUC of 2-fluoro-3-nitrobenzoic acid remained. The mixture was quenched into 1 M HCl (30 mL) and extracted with MTBE (5 mL). The organics were then washed with 20% aqueous KOH solution and 10% sodium thiosulfate. The organics were dried with Na2S04, filtered over Celite and concentrated to afford (2-fluoro-3-nitrophenyl)methanol (2.8 g, 88%, 89% AUC by HPLC).

[0090] A solution of (2-fluoro-3-nitrophenyl)methanol (2.8 g, 16 mmol) in 2-MeTHF (26 mL) was treated with triethylamine (4.5 mL, 32 mmol) and cooled to 0-5 °C. The solution was then treated with methanesulfonyl chloride (1.6 mL, 21 mmol). The progress of the reaction was assessed by HPLC. After 30 minutes at 0-5 °C, the reaction was deemed complete. The mixture was quenched with water (14 mL) and the phases were separated. The organics were washed with brine, dried with Na2S04, filtered over Celite and

concentrated to afford 2-fluoro-3-nitrobenzyl methanesulfonate (3.3 g, 83.1%, 81% AUC by HPLC) as a yellow oil.

[0091] A solution of 2-fluoro-3-nitrobenzyl methanesulfonate (3.3 g, 13 mmol, AMRI lot # 46DAT067B) in toluene (33 mL), was treated with diisopropylethylamine (2.7 mL, 15 mmol) in one portion. A solution of methylpiperazine- 1 -carboxylate (2.1 g, 15 mmol) in toluene (1.1 mL) was added slowly via syringe to maintain between 23-29 °C. The reaction was stirred for 16 hours following the addition. An HPLC assay after this time showed that the reaction was complete. 20% Aqueous NH4C1 (11 mL) was added at 20-25 °C. The biphasic mixture was stirred for 15 minutes, and the phases were separated. This process was repeated using 9% aqueous sodium bicarbonate (11 mL). The toluene layer was then filtered over Celite at 20-25 °C. 2-propanol (50 mL) and water (1.1 mL) were added to the toluene solution and the mixture heated to 55-60 °C. The mixture was then treated with 37wt% HC1 (1.6 mL, 18.7 mmol) over 20 minutes. A precipitate was noted following the addition. When the addition was complete, the mixture was allowed to cool gradually to 20-25 °C and was stirred for hours before filtering and washing with IPA (2 bed volumes).

[0092] The cake was then dried at under vacuum to afford 4-(2-fluoro-3- nitrobenzyl)piperazine-l-carboxylate hydrochloride (2.41 g, 54%, 90% AUC by HPLC, 88 wt% by HPLC).

Piperazine Nitro Freebase:

[0093] In a 60 L reactor equipped with a reflux/return condenser, a mixture of Piperazine Nitro-HCl (2.0 kg, 5.99 mol, 1.0 equiv.) and isopropyl acetate (6.0 L, 3.0 volumes) was mechanically agitated at ambient temperature under an atmosphere of nitrogen. A solution of sodium bicarbonate (629 g, 7.49 mol, 1.25 equiv.) and water (7.5 L, 3.75 volume), prepared in separate vessel, was added. The biphasic mixture was agitated (15 min), and the layers were separated. The upper organic layer (containing product) was transferred to a separate vessel while the reactor was rinsed with water and isopropanol. The organic layer was then transferred through an inline 5 μιη Teflon® cartridge back into the clean 60 L reactor. The filter line was washed with 4.0 L (2.0 volumes) of isopropanol into the 60 L reactor. An additional 12.0 L (6.0 volumes) of isoproponal was added to the 60 L reactor and heated to 40 °C. Under reduced pressure (50 torr) the batch was concentrated down to approximately 6 L (3.0 volumes). The solution was cooled from 27 °C to 20 °C in a linear manner over 10 minutes. Water (4.0 L, 2.0 volumes) was added at 20 °C over 30 minutes followed by Piperazine Nitro Freebase seed (18 g, 0.06 mol, 0.01 equiv). The mixture was aged for 5 minutes and the remaining water (24.0 L, 12.0 volumes) was added over 90 minutes. After holding overnight at 20 °C, the supernatant concentration of Piperazine Nitro Freebase was measured (< 10 mg/mL). The mixture was filtered through an aurora filter equipped with a 12 μιη Teflon® cloth. The filter cake was washed with a mixture of water (3.3 L, 1.65 volumes) and isopropanol (700 mL, 0.35 volumes) and dried to constant weight (defined as < 1.0% weight loss for 2 consecutive TGA measurements over a period of 2 hours) on filter with vacuum and a nitrogen sweep (48 h). The combined losses of Piperazine Nitro Freebase in the mother liquors and the wash were aproximately 7.5 %. Piperazine Nitro Freebase was isolated 1.67 kg in 92.5% corrected yield with 100.0 wt% and 99.4% LCAP purity.

Synthesis of the API SM Phenyl Carbamate-HCl

Figure imgf000022_0001

Amino Pyridine Phenyl Carbamate-HCl

[0094] A 60 L, glass-lined, jacketed reactor set at 20 °C under nitrogen atmosphere and vented through a scrubber (containing 5N NaOH) was charged with 2.5 kg of Amino

Pyridine (1.0 equiv, 23.1 moles), followed by 25 L (19.6 kg, 10 vol) acetonitrile. After initiating agitation and (the endothermic) dissolution of the Amino Pyridine, the vessel was charged with 12.5 L of N-methyl-2-pyrolidinone (12.8 kg, 5 vol). An addition funnel was charged with 1.8 L (0.6 equiv, 13.9 moles) phenyl chloroformate which was then added over 68 minutes to the solution of the Amino Pyridine keeping the internal temperature < 30°C. The reaction was agitated for > 30 minutes at an internal temperature of 20 ± 5 °C. The vessel was then charged with 61 ± 1 g of seed as a slurry in 200 mL acetonitrile and aged for > 30 min. The addition funnel was charged with 1.25 L (0.45 equiv, 9.7 moles) of phenyl chloroformate which was then added over 53 minutes to the reaction suspension while again keeping the temperature < 30°C. The contents of the reactor were aged > 30 hours at 20 ± 5°C. After assaying the supernatant (< 15mg/g for both product and starting material), the solids were filtered using an Aurora filter equipped with a 12μιη Teflon cloth. The mother liquor was forwarded to a 2nd 60 L, glass-lined, jacketed reactor. The reactor and cake were rinsed with l x lO L of 5: 10 NMP/ ACN and 1 x 10 L ACN. The washes were forwarded to the 2nd reactor as well. The cake was dried under vacuum with a nitrogen bleed for > 24 hours to afford 5.65 kg (90.2% yield) of the product, Phenyl Carbamate-HCl as an off-white solid in 98.8 wt% with 99.2% LCAP purity.

[0095] Phenyl (6-methylpyridin-3-yl)carbamate hydrochloride (Phenyl Carbamate-HCl) 1H NMR (400 MHz, DMSO-J6) 5 ppm 11.24 (s, 1 H), 8.81 (s, 1 H), 8.41 (d, 1 Η, / = 8.8 Hz), 7.85 (d, l H, / = 8.8 Hz), 7.48 – 7.44 (m, 2 H), 7.32 – 7.26 (m, 3 H), 2.69 (s, 3 H); 13C NMR (100 MHz, DMSO- ) δ ppm 151.66, 150.01, 147.51, 136.14, 133.79, 129.99, 129.49, 127.75, 125.87, 121.70, 18.55: HR-MS : Calculated for Cuii W . 228.0899, M + H+ = 229.0972; Observed mass: 229.0961

Alternative Synthesis of Phenyl Carbamate HC1

[0096] 5-Amino-2-methylpyridine (53.2 kg, 1.0 equiv) and acetonitrile (334 kg, 8.0 mL/g) were charged to a nitrogen flushed glass-lined reactor. The contents of the reactor were stirred while warming to 25-30 °C. The mixture was then recirculated through a filter packed with activated carbon (11 kg, 20 wt ) for 3 h intervals while maintaining 25-30 °C.

Following each 3 h interval, a sample of the mixture was analyzed for color by comparison to a color standard and UV Absorbance at 440nm. Once a satisfactory result was achieved, the filter was blown out into the reactor and the filter was rinsed with acetonitrile (85 kg, 2.0 mL/g). The acetonitrile rinse was transferred into the reaction mixture. l-Methyl-2- pyrrolidinone (274 kg, 5.0 mL/g) was charged to the reaction mixture in the glass-lined reactor. Phenyl chloroformate (46.6 kg, 0.6 equiv) was slowly added to the mixture while maintaining 15-30 °C (typically 60-70 min). The reaction mixture was stirred for approximatly 60 minutes while maintaining 20-25 °C. Phenyl(6-methylpyridin-3- yl)carbamate hydrochloride (0.58 kg, 0.010 equiv) seed crystals were charged to the stirring mixture. The slurry was then stirred for approximatly 4 h at 20+ 5°C. Phenyl chloroformate (33.4 kg, 0.45 equiv) was slowly added to the slurry while maintaining 15-30 °C. The mixture was then allowed to age while stirring for 8+1 h whereupon concentration of 5- amino-2-methylpyridine (target <15 mg/mL) and phenyl (6-methylpyridin-3-yl)carbamate hydrochloride (target <15 mg/mL) were checked by HPLC. The batch was then filtered under vacuum and washed with a mixture of acetonitrile (112 kg, 2.68 mL/g) and l-methyl-2- pyrrolidinone (72 kg, 1.32 mL/g) followed by washing thrise with acetonitrile (167 kg, 4.0 mL/g). The solids were deliquored followed by transfering to a tray dryer maintained between 20-40°C and 1.3-0.65 psia until an LOD of <lwt was achieved, whereupon phenyl(6-methylpyridin-3-yl)carbamate hydrochloride 106.3 kg (81.6% yield) was isolated from the dryer. Methyl 4-(3-amino-2-fluorobenzyl)piperazine-l-carboxylate (Piperazine Aniline)

Neutralization

Figure imgf000024_0001

Piperazine NitrcHCI

+ NaCI (1 equiv)

+ C02 (1 equiv)

+ H20 (1 equiv)

+ NaHC03 (0.25 equiv)

Figure imgf000024_0002

[0097] To a 100-L jacketed glass-lined reactor were added methyl 4-(2-fluoro-3- nitrobenzyl)piperazine-l-carboxylate hydrochloride (2.00 kg, 1.00 equiv) and isopropyl acetate (6.00 L, 3.00 Vol with-respect to starting material). The resulting slurry was agitated under a nitrogen sweep. To the mixture was added dropwise over 45 + 30 min: 7.7 % w/w aqueous sodium bicarbonate solution (629 g, 1.25 equiv of sodium bicarbonate dissolved in 7.50 L water), maintaining an internal temperature of 20 + 5 °C by jacket control (NOTE: addition is endo thermic, and may evolve up to 1 equiv of carbon dioxide gas). The mixture was stirred for > 15 min, resulting in a clear biphasic mixture. Agitation was stopped and the layers were allowed to settle.

[0098] The bottom (aqueous) layer was drained and analyzed by pH paper to ensure that the layer is pH > 6. Quantititative HPLC analysis of the upper (organic) layer revealed 97- 100% assay yield of the methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-l-carboxylate freebase (1.73 – 1.78 kg). The upper (organic) layer was transferred through an in-line filter into a 20- L Hastelloy® hydro genator, and the 100-L reactor and lines were rinsed with an additional aliquot of isopropyl acetate (2.00 L, 1.00 Vol). The hydrogenator was purged with nitrogen and vented to atmospheric pressure. To the reaction mixture was added a slurry of 5.0 wt% palladium on carbon (20.0 g, Strem/BASF Escat™ 1421, approx 50% water) in isopropyl acetate (400 mL), followed by a 400 mL rinse. The resulting reaction mixture was diluted with an additional aliquot of isopropyl acetate (1.2 L; total isopropyl acetate amount is 10.0 L, 5.00 Vol). The hydrogenator was purged three times with nitrogen (pressurized to 60 + 10 psig, then vented to atmospheric pressure), then pressurized to 60 + 5 psig with hydrogen. The reaction mixture was stirred at < 100 rpm at 30 + 5 °C while maintaining 60 + 5 psig hydrogen, for >2 hours until reaction was deemed complete. This temperature and pressure correspond to a measured kLa value of approx 0.40 in a 20-L Hydrogenator. End of reaction is determined by dramatic decrease in hydrogen consumption accompanied by a relief in the heat evolution of the reaction. To control potential dimeric impurities, the reaction is continued for at least 30 minutes after this change in reaction profile, and HPLC analysis is performed to confirm that >99.5% conversion of the hydroxyl-amine to the aniline is achieved.

[0099] At the end of reaction, the hydrogenator was purged with nitrogen twice

(pressurized to 60 + 10 psig, then vented to atmospheric pressure). The crude reaction mixture was filtered through a 5 μιη filter followed by a 0.45 μιη filter in series, into a 40-L glass-lined reactor. The hydrogenator and lines were washed with an additional aliquot of isopropyl acetate (2.00 L). Quantitative HPLC analysis of the crude reaction mixture revealed 95-100% assay yield (1.52 – 1.60 kg aniline product). The reaction mixture was distilled under reduced pressure (typically 250 – 300 mbar) at a batch temperature of 50 + 5 °C until the total reaction volume was approximately 8.00 L (4.00 Vol). The batch was subjected to a constant-volume distillation at 50 + 5 °C, 250 – 300 mbar, by adding heptane to control the total batch volume. After approximately 8.00 L (4.00 Vol) of heptane were added, GC analysis indicated that the solvent composition was approximately 50 % isopropyl acetate, 50% heptane. Vacuum was broken, and the internal batch temperature was maintained at 50 + 5 °C. To the reaction mixture was added a slurry of seed (20.0 grams of product methyl 4-(3-amino-2-fluorobenzyl)piperazine-l-carboxylate, in a solvent mixture of 80 mL heptane and 20 mL isopropyl acetate). The resulting slurry was allowed to stir at 50 + 5 °C for 2 + 1 hours, then cooled to 20 + 5 °C over 2.5 + 1.0 h. Additional heptane (24.0 L, 12.0 Vol) was added dropwise over 2 hours, and the batch was allowed to stir at 20 + 5 °C for > 1 hours (typically overnight). Quantitative HPLC analysis of this filtered supernatant revealed < 5 mg/mL product in solution, and the product crystals were 50 – 400 μιη birefringent rods. The reaction slurry was filtered at 20 °C onto a filter cloth, and the cake was displacement-washed with heptane (6.00 L, 2.00 Vol). The cake was dried on the filter under nitrogen sweep at ambient temperature for > 4 hours, until sample dryness was confirmed by LOD analysis (indicated <1.0 wt% loss). The product methyl 4-(3-amino-2- fluorobenzyl)piperazine-l-carboxylate (1.56 kg) was isolated as a pale-yellow powder in 86% yield at 99.8 wt% by HPLC with 100.0 LCAP2i0. [Analysis of the combined filtrates and washes revealed 108 grams (7.0%) of product lost to the mother liquors. The remaining mass balance is comprised of product hold-up in the reactor (fouling).] 1H NMR (DMSO-Jg, 400 MHz) δ: 6.81 (dd, J = 7.53, 7.82 Hz, 1H), 6.67 (m, 1H), 6.49 (m, 1H), 5.04 (s, 2H), 3.58 (s, 3H), 3.45 (m, 2H), 3.34 (m, 4H), 2.33 (m, 4H). 19F NMR (d6-DMSO, 376 MHz) δ: – 140.2. 13C NMR (d6-DMSO, 125 MHz) δ: 155.0, 150.5, 148.2, 136.2 (m), 123.7 (m), 117.6, 115.1, 73.7, 54.9 (m), 52.1 (m), 43.4. mp = 89.2 °C.

Alternate route to Piperazine Aniline

[00100] To a jacketed glass-lined reactor were added methyl 4-(2-fluoro-3- nitrobenzyl)piperazine-l-carboxylate hydrochloride (46.00 kg, 1.00 equiv) and isopropyl acetate (200 kg, 5.0 mL/g). The resulting slurry was agitated under a nitrogen sweep. To the mixture was added 7.4 % w/w aqueous sodium bicarbonate solution (1.25 equiv) while maintaining an internal temperature of 25 + 5 °C. The mixture was agitated for > 30 min, resulting in a clear biphasic mixture. Agitation was stopped and the bottom (aqueous) layer was discharged. Analysis of aqueous layer indicates pH >6. Water (92 kg, 2.0 mL/g) was charged the organic layer and agitated for >15 min. Agitation was then stopped and the bottom (water wash) layer was discharged. Water (92 kg, 2.0 mL/g) was charged the organic layer and agitated for > 15 min. Agitation was then stopped and the bottom (water wash) layer was discharged. The batch was distilled under reduced pressure while maintaining the batch temperature between 40-50 °C. The batch volume was held constant throughout the distillation by the continuous addition of isopropyl acetate. Once the water content of the batch was < 1,500 ppm, the solution was passed through an inline filter into a Hastelloy reactor containing 5.0 wt% palladium on carbon (BASF Escat 1421, 0.69 kg, 1.5 wt%). The jacketed glass-lined reactor was rinsed with isopropyl acetate (100 kg, 2.5 mL/g) and added to the Hastelloy reactor though the inline filter.

[00101] The batch was adjusted to approximately 25-35 °C (preferably 30 °C) and hydrogen gas was added to maintain about 4 barg with vigorous agitation. Hydrogenation was continued for 1 h after hydrogen uptake has ceased, and >99.0% conversion by HPLC were achieved. The palladium on carbon catalyst was collected by filtration and the supernatant was collected in a reactor. Isopropyl acetate (40 kg, 1.0 mL/g) was charged to the Hastelloy reactor and transferred through the filter and collected in the jacketed glass-lined reactor.

[00102] The batch was concentrated under reduced pressure while maintaining the batch temperature between 35-55 °C until the final volume was approximately 4.0 mL/g. Heptane (219 kg, 7.0 mL/g) was added to the jacketed glass-lined reactor while maintaining the batch between 50-60 °C, until 20-25% isopropyl acetate in heptane was achieved as measured by GC. The solution was cooled to between 40-50 °C and seeded with methyl 4-(3-amino-2- fluorobenzyl)piperazine-l-carboxylate (0.46 kg, 1.0 wt%) as a slurry in heptane (6.4 kg, 0.20 mL/g). The slurry was aged for approximately 2 h, whereupon, the batch was distilled under reduced pressure while maintaining the batch temperature between 35-45 °C. The batch volume was held constant throughout the distillation by the continuous addition of heptane (219 kg, 7.0 mL/g). The batch was then cooled to between 15-25 °C over approximately 3 h. Concentration of the supernatant was measured to be <5 mg/mL methyl 4-(3-amino-2- fluorobenzyl)piperazine-l-carboxylate by HPLC.

[00103] The batch was filtered and the resulting solids were successively washed with heptane (63 kg, 2.0 mL/g) then heptane (94 kg, 3.0 mL/g). The solids were dried on the filter with a stream of dry nitrogen with vacuum until an LOD of <_lwt% was achieved whereupon 33.88 kg (90.7% yield) was isolated from the filter dryer.

Omecamtiv Mecarbil Dihydrochloride Hydrate procedure

f lu

Figure imgf000027_0001

1) 2-PrOH (11 V)

2) Distill to 4V

3) Water (2.30 V)

4) 6N HCI (2.4 equiv)

5) 2-PrOH (16.5V)

6) Wet Mill

Figure imgf000027_0002

[00104] To a 15L glass lined reactor were charged methyl 4-(3-amino-2-fluoro- benzyl)piperazine-l-carboxylate (1,202 g, 4.50 mol), phenyl (6-methylpyridin-3- yl)carbamate hydrochloride (1,444 g, 5.40 mol), and tetrahydrofuran (4.81 L). The resulting slurry was agitated under a nitrogen sweep and N,N-diisopropylethylamine (1,019 L, 5.85 mol) was then charged to the slurry which resulted in a brown solution. The temperature of the solution was increased to 65 °C and agitated for 22 h, until <1% AUC piperazine aniline remained by HPLC analysis.

[0100] The batch was cooled to 50 °C and distilled under reduced pressure while maintaining the internal temperature of the vessel below 50 °C by adjusting vacuum pressure. 2-Propanol was added with residual vacuum at a rate to maintain a constant volume in the 15 L reactor. A total of 10.5 kg of 2-propanol was required to achieve <5% THF by GC. Water (2.77 kg) was then charged to the reactor followed by the addition of 6N HC1 (1.98 kg) at a rate to maintain the internal temperature below 60 °C. The reactor was brought to ambient pressure under a nitrogen sweep. The solution was then heated to 60 °C, and transferred to a 60L glass lined reactor through an inline filter. The 15L reactor was then rinsed with 1: 1 water/2-propanol (1.2L) which was sent through the inline filter to the 60L reactor.

[0101] The 60L reactor was adjusted to 45 °C and a slurry of seed (114 g, 0.23 mol) in 2- propanol (0.35 L) was added to the reactor resulting in a slurry. The batch was aged at 45 °C for 1 h, followed by the addition of 2-propanol (3.97 kg) through an inline filter over 2 h. The batch was heated to 55°C over 1 h and held for 0.25 h, then cooled back to 45°C over 1 h and held overnight at 45 °C. 2-propanol (11.71 kg) was then added through an inline filter to the batch over 3 h. The batch was aged for 1 h and then cooled to 20°C over 2 h and held at 20 °C for 0.5 h. The batch was then recirculated though a wet mill affixed with 1-medium and 2- fine rotor-stators operating at 56 Hz for 2.15 h, until no further particle size reduction was observed by microscopy.

[0102] The batch was then filtered through a 20″ Hastelloy® filter fitted with a 12 urn filter cloth under 500 torr vacuum. A wash solution of 95:5 2-propanol:water (1.82 L) was charged through an inline filter to the 60L reactor, then onto the filter. A second wash of 2- propanol (2.85L) was charged through an inline filter to the 60L reactor, then onto the filter. The batch was then dried under 5 psi humidified nitrogen pressure until <5,000 ppm 2- propanol, and 2.5-5% water remained. The final solid was discharged from the filter to afford 2.09 kg of methyl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-l- carboxylate as an off-white crystalline solid in 89% yield at 99.88 wt% by HPLC, 100.0% AUC. Total losses to liquors was 0.10 kg (4.7%).

[0103] DSC: Tonset = 61.7 °C, Tmax = 95.0 °C; TGA = 2.2%, degradation onset = 222 °C; 1H HMR (D20, 500 MHz) δ 8.87 (s, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.83 (t, J = 1.5 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.35-7.29 (m, 2H), 4.48 (s, 2H), 4.24 (br s, 2H), 3.73 (s, 3H), 3.31 (br s, 6H), 2.68 (s, 3H); 13C HMR (D20, 150 MHz) δ 156.8, 154.2, 153.9 (J = 249 Hz), 147.8, 136.3, 136.1, 130.1, 129.4, 128.0, 127.2, 125.5 (J = 11.8 Hz), 125.1 (J = 4.2 Hz), 116.1 (J = 13.5 Hz), 53.54, 53.52, 53.49, 50.9, 40.5, 18.2.

Figure imgf000029_0001

[0104] A reaction vessel was charged methyl 4-(3-amino-2-fluorobenzyl)piperazine-l- carboxylate (2.5 g, 1.0 equiv), acetonitrile (25.0 mL, 10.0 mL/g) and l-methyl-2- pyrrolidinone (12.5 mL, 5.0 mL/g). The batch was cooled to 0 °C whereupon phenyl chloroformate (1.20 mL, 1.02 equiv) was added over approximately 5 min. After 45 minutes the resulting slurry resulted was allowed to warm to 20 °C. The solids were collected by filtration and rinsed twice with acetonitrile (10.0 mL, 4.0 mL/g). The solids were dried under a stream of dry nitrogen to afford methyl 4-(2-fluoro-3-

((phenoxycarbonyl)amino)benzyl)piperazine- l -carboxylate hydrochloride 2.8 g (71 % yield) as a white solid.

[0105] 4-(2-fluoro-3-((phenoxycarbonyl)amino)benzyl)piperazine-l-carboxylate hydrochloride: 1H NMR (400 MHz, DMSO-J6) δ ppm 3.08 (br. s., 2 H), 3.24 – 3.52 (m, 4 H), 3.62 (s, 3 H), 4.03 (d, J=11.25 Hz, 2 H), 4.38 (br. s., 2 H), 7.11 – 7.35 (m, 4 H), 7.35 – 7.49 (m, 2 H), 7.49 – 7.66 (m, 1 H), 7.80 (s, 1 H), 10.12 (br. s, 1 H), 11.79 (br. s, 1 H); HRMS = 388.1676 found, 388.1667 calculated. [0106] A reaction vessel was charged methyl 4-(2-fluoro-3-

((phenoxycarbonyl)amino)benzyl)piperazine-l-carboxylate hydrochloride (0.50 g, 1.0 equiv), 6-methylpyridin-3-amine (0.15 g, 1.2 equiv), tetrahydrofuran (2.0 mL, 4.0 mL/g) and

N,N-diisopropylethylamine (0.23 mL, 1.1 equiv). The batch was heated to 65 °C for 22 h, whereupon quantitative HPLC analysis indicated 0.438 g (92% assay yield) of omecamtiv mecarbil.

Alternative Omecamtiv Mecarbil Dihydrochloride Hydrate procedure

[0107] Omecamtiv Mecarbil, free base (3.0 kg, 1.0 equiv) was charged to a nitrogen purged jacketed vessel followed by water (4.6 L, 1.5 mL/g) and 2-propanol (6.1 L, 2.60 mL/g). The slurry was agitated and heated to approximately 40 °C, whereupon 6N HC1 (2.6 L, 2.10 equiv) was charged to the slurry resulting in a colorless homogenous solution. The solution was heated to between 60-65 °C and transferred through an inline filter to a 60L reactor pre -heated to 60 °C. The batch was cooled to 45 °C whereupon Omecamtiv Mecarbil dihydrochloride hydrate (150 g, 5.0 wt%) was charged to the vessel as a slurry in 95:5 (v/v) 2-Propanol/Water (600 mL, 0.20 mL/g). The resulting slurry was maintained at 45 °C for 0.5 h followed by cooling to approximately 20 °C then held for 3-16 h. 2-Propanol (33.0 L, 11.0 mL/g) was added over >2h followed by a >1 h isothermal hold at approximately 20 °C.

(Supernatant pH <7).

[0108] The batch was recirculated through a wet mill for 5-10 batch turnovers until sufficient particle reduction was achieve as compared to offline calibrated visual microscopy reference. The slurry was filtered by vacuum and the resulting solids were washed with two washes of 95:5 (v/v) 2-Propanol/Water (3.0 L, 1.0 mL/g) and a final cake wash with 2- Propanol (6.0 L, 2.0 mL/g). The cake was dried on the filter by pushing humidified nitrogen through the cake until <5,000 ppm 2-propanol and 2.5-5% water were measured by GC and KF analysis, respectively. Omecamtiv Mecarbil dihydrochloride hydrate was isolated as a colorless crystalline solid (3.40 kg, 93% yield). pH dependent release profiles

CLIP

J Am Chem Soc. 2012 July 11; 134(27): 11132–11135. doi:10.1021/ja305212v.

CLIP

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CLIP
PATENTS
Patent ID

Title

Submitted Date

Granted Date

US2017267638 COMPOUNDS, COMPOSITIONS AND METHODS
2017-04-06
US9643925 COMPOUNDS, COMPOSITIONS AND METHODS
2015-08-27
2016-04-28
US2016016906 SALT OF OMECAMTIV MECARBIL AND PROCESS FOR PREPARING SALT
2014-03-14
2016-01-21
US2016015628 HETEROCYCLIC COMPOUNDS AND THEIR USES
2014-03-14
2016-01-21
US9150564 COMPOUNDS, COMPOSITIONS AND METHODS
2014-09-18
2015-01-01
Patent ID

Title

Submitted Date

Granted Date

US8445495 Certain Chemical Entities, Compositions and Methods
2010-02-04
US2009247544 Certain Chemical Entities, Compositions and Methods
2009-10-01
US2007208000 Certain chemical entities, compositions and methods
2007-09-06
US2007161617 Certain chemical entities, compositions and methods
2007-07-12
US2007197505 Certain chemical entities, compositions and methods
2007-08-23
Patent ID

Title

Submitted Date

Granted Date

US7989455 Compounds, compositions and methods
2007-08-23
2011-08-02
US7507735 Compounds, compositions and methods
2006-01-19
2009-03-24
US2016186141 SMALL MOLECULE CELLULAR REPROGRAMMING TO GENERATE CARDIOMYOCYTES
2016-03-10
2016-06-30
US2014309235 HETEROCYCLIC COMPOUNDS AND THEIR USES
2014-03-14
2014-10-16
US8513257 Ureas and their use in the treatment of heart failure
2011-12-30
2013-08-20
Patent ID

Title

Submitted Date

Granted Date

US8871769 Ureas and their use in the treatment of heart failure
2013-07-19
2014-10-28
US8871768 Certain chemical entities, compositions and methods
2013-05-17
2014-10-28
US2009192168 Compounds, Compositions and Methods
2009-07-30
US8101617 Disubstituted ureas and uses thereof in treating heart failure
2009-04-16
2012-01-24
US8110595 Ureas and their use in the treatment of heart failure
2009-02-05
2012-02-07
Omecamtiv mecarbil
Omecamtiv mecarbil.svg
Clinical data
Synonyms CK-1827452
Routes of
administration
Intravenous infusion
ATC code
  • None
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
KEGG
Chemical and physical data
Formula C20H24FN5O3
Molar mass 401.43 g/mol
3D model (JSmol)

/////////////Omecamtiv mecarbil, オメカムティブメカビル  , AMG 423, AMG-423, CK1827452, CK-1827452, K1827452, Cladribine, PHASE 3

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SELETALISIB, селеталисиб , سيلستاليسيب , 司来利塞 ,


Image result for SELETALISIB

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ChemSpider 2D Image | Seletalisib | C23H14ClF3N6O

DB12706.png

SELETALISIB

CAS 1362850-20-1

UCB-5857 , Plaque psoriasis,Sjoegren’s syndrome,Immunodeficiency disorders

PHASE 3 UCB

23H14ClF3N6O , 482.85

Phosphatidylinositol 3 kinase delta (PI3Kδ) inhibitors

10023
1362850-20-1 [RN]
N-{(1R)-1-[8-Chlor-2-(1-oxido-3-pyridinyl)-3-chinolinyl]-2,2,2-trifluorethyl}pyrido[3,2-d]pyrimidin-4-amine
N—{(R)-1-[8-Chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}N-(1-oxypyrido-[3,2-d]pyrimidin-4-yl)amine
Pyrido[3,2-d]pyrimidin-4-amine, N-[(1R)-1-[8-chloro-2-(1-oxido-3-pyridinyl)-3-quinolinyl]-2,2,2-trifluoroethyl]-

3-{8-chloro-3-[(1R)-2,2,2-trifluoro-1-({pyrido[3,2-d]pyrimidin-4-yl}amino)ethyl]quinolin-2-yl}pyridin-1-ium-1-olate

селеталисиб [Russian] [INN]
سيلستاليسيب [Arabic] [INN]
司来利塞 [Chinese] [INN]
N-[(1R)-1-[8-chloro-2-(1-oxidopyridin-1-ium-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl]pyrido[3,2-d]pyrimidin-4-amine

Seletalisib has been used in trials studying the treatment and basic science of Primary Sjogren’s Syndrome.

  • Originator UCB
  • Class Anti-inflammatories; Small molecules
  • Mechanism of Action Immunomodulators; Phosphatidylinositol 3 kinase delta inhibitors
  • Phase III Immunodeficiency disorders
  • Phase II Sjogren’s syndrome
  • No development reported Plaque psoriasis
  • 05 Dec 2017 UCB Celltech terminates a phase II trial in Sjogren’s syndrome in France, Spain, United Kingdom, Greece, Sweden, Italy, due to enrolment challenges (PO) (NCT02610543) (EudraCT2014-004523-51)
  • 04 Nov 2017 No recent reports of development identified for phase-I development in Plaque-psoriasis in United Kingdom (PO, Capsule)
  • 14 Jun 2017 Pharmacokinetics and pharmacodynamics data from Preclinical and Clinical studies in Immunodeficiency disorders presented at the 18th Annual Congress of the European League Against Rheumatism (EULAR-2017)

SYN

US 9029392

https://patents.google.com/patent/US9029392B2/en

Example 27 N—{(R)-1-[8-Chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}N-(1-oxypyrido-[3,2-d]pyrimidin-4-yl)amine

A stirred solution of Example 1 (955 mg, 2.05 mmol) in DCM (40 mL) was cooled to 0° C. MCPBA (410 mg, 1.84 mmol) was added and the mixture was allowed to warm slowly to r.t. over 3 h. The reaction mixture was partitioned between DCM and saturated aqueous NaHCOsolution. The aqueous phase was extracted with further DCM and the combined organic fractions were washed with brine, dried Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO2, 3-60% MeOH in EtOAc) to give the title compound (39 mg, 4%) as a yellow solid. δ(DMSO-d6) 9.64-9.52 (m, 1H), 9.30 (s, 1H), 9.06 (dd, J 4.2, 1.3 Hz, 1H), 8.78-8.71 (m, 2H), 8.67 (dd, J 4.9, 1.6 Hz, 1H), 8.64 (s, 1H), 8.16-8.01 (m, 4H), 7.75-7.69 (m, 1H), 7.52 (ddd, J 7.8, 4.9, 0.7 Hz, 1H), 6.65-6.52 (m, 1H). LCMS (ES+) 483 (M+H)+, RT 1.87 minutes.

AND

PATENT

WO 2012032334

PATENT

WO 2015181053

WO 2015181055

WO 2016170014

PATENT

WO 2017198590

A SPECIFIC TRIFLUOROETHYL QUINOLINE ANALOGUE FOR USE IN THE TREATMENT OF APDS

The present invention relates to the new therapeutic use of a known chemical compound. More particularly, the present invention concerns the use of a specific substituted quinoline derivative comprising a fluorinated ethyl side-chain in the treatment of activated phosphoinositide 3 -kinase delta syndrome (APDS).

N- {(R)- 1 -[8-Chloro-2-(l -oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifiuoroethyl} -pyrido[3,2-JJpyrimidin-4-ylamine is specifically disclosed in WO 2012/032334. The compounds described in that publication are stated to be of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.

There is no specific disclosure or suggestion in WO 2012/032334, however, that the compounds described therein might be beneficial in the treatment of APDS.

Activated phosphoinositide 3-kinase delta syndrome (APDS), also known as

PASLI (pi ΙΟδ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency), is a serious medical condition that impairs the immune system.

APDS patients generally have reduced numbers of white blood cells (lymphopenia), especially B cells and T cells, compromising their propensity to recognise and attack invading microorganisms, such as viruses and bacteria, and thereby prevent infection. Individuals affected with APDS develop recurrent infections, particularly in the lungs, sinuses and ears. Recurrent respiratory tract infections may gradually lead to bronchiectasis, a condition which damages the passages leading from the windpipe to the lungs (bronchi) and can cause breathing problems. APDS patients may also suffer from chronic active viral infections, including Epstein-Barr virus infections and cytomegalovirus infections.

APDS has also been associated with abnormal clumping of white blood cells, which can lead to enlarged lymph nodes (lymphadenopathy). Alternatively, the white blood cells can build up to form solid masses (nodular lymphoid hyperplasia), usually in the moist lining of the airways or intestines. Whilst lymphadenopathy and nodular lymphoid hyperplasia are benign (noncancerous), APDS also increases the risk of developing a form of cancer called B cell lymphoma.

APDS is a disorder of childhood, typically arising soon after birth. However, the precise prevalence of APDS is currently unknown.

Phosphoinositide 3-kinase delta (ΡΒΚδ) is a lipid kinase which catalyses the generation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) from phosphatidylinositol 4,5-bisphosphate (PIP2). PI3K5 activates signalling pathways within cells, and is specifically found in white blood cells, including B cells and T cells. PI3K5 signalling is involved in the growth and division (proliferation) of white blood cells, and it helps direct B cells and T cells to mature (differentiate) into different types, each of which has a distinct function in the immune system.

APDS is known to occur in two variants, categorised as APDSl and APDS2.

APDSl is associated with a heterozygous gain-of- function mutation in the PIK3CD gene encoding the PI3K5 protein; whereas APDS2 is associated with loss-of-function frameshift mutations in the regulatory PIK3R1 gene encoding the p85a regulatory subunit of class I phosphoinositide 3-kinase (PI3K) peptides. Both mutations lead to hyperactivated PI3K signalling. See I. Angulo et ah, Science, 2013, 342, 866-871; C.L. Lucas et ah, Nature Immunol, 2014, 15, 88-97; and M-C. Deau et al, J. Clin. Invest., 2014, 124, 3923-3928.

There is currently no effective treatment available for APDS. Because of the seriousness of the condition, and the fact that it arises in infancy, the provision of an effective treatment for APDS would plainly be a highly desirable objective.

It has now been found that N-{(R)-l-[8-chloro-2-(l-oxypyridin-3-yl)quinolin-3-yl]- 2,2,2-trifluoroethyl}pyrido[3,2-(i]pyrimidin-4-ylamine is capable of inhibiting the elevation of PI3K signalling in T cells (lymphocytes) from both APDSl and APDS2 patients in the presence or absence of T cell receptor activation.

The present invention accordingly provides N-{(R)-l-[8-chloro-2-(l-oxypyridin-3-yl)quinolinB-yl]-2,2,2-trifluoroethyl}pyrido[3,2-JJpyrimidin-4-ylamine of formula (A):

or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of APDS.

The present invention also provides a method for the treatment and/or prevention of APDS, which method comprises administering to a patient in need of such treatment an effective amount of N-{(R)-l-[8-chloro-2-(l-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoro-ethyl}pyrido[3,2-(i]pyrimidin-4-ylamine of formula (A) as depicted above, or a pharmaceutically acceptable salt thereof. The present invention also provides the use of N-{(R)-l-[8-chloro-2-(l-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido[3,2-JJpyrimidin-4-ylamine of formula (A) as depicted above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of APDS.

PAPER

Journal of Pharmacology and Experimental Therapeutics (2017), 361(3), 429-440.

http://jpet.aspetjournals.org/content/361/3/429

///////////////SELETALISIB, PHASE 3, UCB, селеталисиб سيلستاليسيب 司来利塞 

[O-][N+]1=CC(=CC=C1)C1=NC2=C(Cl)C=CC=C2C=C1[C@@H](NC1=NC=NC2=CC=CN=C12)C(F)(F)F

 

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ANTHONY MELVIN CRASTO

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NDA

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Lumateperone


ChemSpider 2D Image | Lumateperone | C24H28FN3O

ITI-007.svg

Lumateperone

  • Molecular FormulaC24H28FN3O
  • Average mass393.497 Da

4-((6bR,10aS)-3-Methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one

1-Butanone, 1-(4-fluorophenyl)-4-(2,3,6b,9,10,10a-hexahydro-3-methyl-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-
1-(4-fluorophenyl)-4-{4-methyl-1,4,12-triazatetracyclo[7.6.1.0⁵,¹⁶.0¹⁰,¹⁵]hexadeca-5,7,9(16)-trien-12-yl}butan-1-one
313368-91-1 [RN]
70BSQ12069, Lumateperone, PHASE 3, ITI-007
Image result for Lumateperone
Image result for Lumateperone

4- methylbenzenesulfonate. SALT

Molecular Formula: C31H36FN3O4S
Molecular Weight: 565.704 g/mol

(6bR,10aS)-8-[4-(4-Fluorophenyl)-4-oxobutyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-ium 4-methylbenzenesulfonate

1187020-80-9 [RN]

1-Butanone, 1-(4-fluorophenyl)-4-[(6bR,10aS)-2,3,6b,9,10,10a-hexahydro-3-methyl-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl]-, 4-methylbenzenesulfonate (1:1)
ITI-007 tosylate
JIE88N006O
Lumateperone tosylate [USAN]
UNII:JIE88N006O

ITI 007

  • Originator Bristol-Myers Squibb
  • Develope rIntra-Cellular Therapies
  • Class Antidepressants; Antipsychotics; Pyrroles; Quinoxalines; Sleep disorder therapies
  • Mechanism of Action Dopamine receptor modulators; NR2B N-Methyl D-Aspartate receptor modulators; Serotonin 2A receptor antagonists; Serotonin plasma membrane transport protein inhibitors; Serotonin uptake inhibitors
  • 07 Nov 2018 Intra-Cellular Therapeutics completes enrolment in the phase III Study 401 trial for Bipolar depression (Monotherapy) in USA
  • 16 Oct 2018 Intra-Cellular Therapies plans to launch lumateperone for Schizophrenia in USA
  • 02 Aug 2018 Intra-Cellular plans a clinical trial for Depressive disorders in 2H of 2018

Highest Development Phases

  • Preregistration Schizophrenia
  • Phase III Behavioural disorders; Bipolar depression
  • Phase II Sleep maintenance insomnia
  • Preclinical Mental disorders
  • No development reported Mood disorders

Lumateperone (INN; developmental code names ITI-007ITI-722) is an investigational atypical antipsychotic which is currently under development by Intra-Cellular Therapies, licensed from Bristol-Myers Squibb, for the treatment of schizophrenia.[1][2] It is also being developed by Intra-Cellular Therapies for the treatment of bipolar disorderdepression, and sleep and behavioral disturbance in dementiaautism, and other neuropsychiatric disorders.[3] As of September 2015, lumateperone has passed the first of two phase IIIclinical trials for schizophrenia.[4] In November 2017 the US FDA awarded Intra-Cellular Therapies Fast Track designation for lumateperone.[5]

Pharmacology

Pharmacodynamics

Relative to presently-available antipsychotics, lumateperone possesses a unique and novel mechanism of action.[6][7] It acts as a 5-HT2A receptor antagonist (Ki = 0.54 nM), a partial agonist of presynaptic D2 receptors and an antagonist of postsynaptic D2 receptors (Ki = 32 nM), and a serotonin transporter blocker (Ki = 61 nM).[6][8] It also possesses affinity for the D1 receptor (Ki = 52 nM) and lower affinity for the α1A and α1B-adrenergic receptors (Ki = 73 nM at α1), 5-HT2C receptor (Ki = 173 nM), and D4 receptor.[6] Lumateperone does not significantly bind to the 5-HT2BH1 (Ki > 1,000 nM), muscarinic acetylcholine receptors, or many other sites (Ki > 100 nM).[6]

Lumateperone shows a 60-fold difference in its affinities for the 5-HT2A and D2 receptors, which is far greater than that of most or all existing atypical antipsychotics, such as risperidone (12-fold), olanzapine (12.4-fold), and aripiprazole (0.18-fold).[6][9] It is thought that this property may improve the effectiveness and reduce the side effect profile of lumateperone relative to currently-available antipsychotics, a hypothesis which is supported by the observation of minimal catalepsy in mice treated with the drug.[6][9] Moreover, it has been expressed that this property could result in full occupancy and blockade of the 5-HT2A at low doses, with dose-dependent adjustable modulation of the D2 receptor, as well as the SERT, possible with increasing doses, which would uniquely allow for clinical optimization of efficacy and side effect incidence.[6][9]

Unlike most current antipsychotics, such as haloperidol, risperidone, and olanzapine, lumateperone does not disrupt striatal dopamine signaling, a property which is likely due to its partial agonism of presynaptic D2 receptors.[6] In accordance, similarly to aripiprazole, which is also a partial agonist of presynaptic D2 receptors, lumateperone showed no striatum-based motor side effects (i.e., catalepsy) in animals.[6]

Clinical studies

In phase II clinical trials, lumateperone showed statistically-significant efficacy in improvement of psychosis at a dose of 60 mg daily.[2] In addition, it distinguished itself from its comparator risperidone in reducing negative symptoms, including improvement in social function, as well as in alleviating depressive symptoms in schizophrenia patients with comorbid depression, whereas risperidone had no effect.[2][10] Lumateperone also distinguished itself from risperidone in that it produced little or no weight gain, did not negatively affect metabolic parameters (i.e., insulinglucosetriglyceride, and cholesterol levels), did not increase prolactin levels, and did not show a rate of the side effect of akathisia that differed from placebo.[2][10] In addition, lumateperone did not produce any changes in cardiovascular function, such as QTc prolongation, and unlike risperidone, it did not produce a measurable increase heart rate.[7] Due to its favorable influence on metabolic parameters, it was concluded that lumateperone, unlike many other available antipsychotics such as risperidone, may not cause an increase in the risk of diabetes or cardiovascular disease, and hence may prove to be a significant improvement relative to many existing antipsychotic drugs in terms of long-term safety and tolerability.[2]

Lumateperone, at a dose of 60 mg per day, was not found to be associated with any statistically significant treatment-emergent side effects relative to placebo.[10] At a dose of 120 mg daily, the most frequent adverse effect observed was sedation/somnolence, reported by 32.5% of patients.[10] There was no evidence of extrapyramidal symptoms or increase in suicidal ideation or behavior.[10]

SYNTHESIS

MEDCHEM

PAPER

https://pubs.acs.org/doi/abs/10.1021/jm401958n

dx.doi.org/10.1021/jm401958n | J. Med. Chem. 2014, 57, 2670−2682

5 (367 mg, 53%yield) as a gray solid.

1H NMR (DMSO-d6, 500 MHz) δ 9.10 (br, 1H),8.10−8.01 (m, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.42−7.33 (m, 2H), 7.11 (d, J = 7.8 Hz, 2H), 6.65−6.57 (m, 1H), 6.51 (d, J = 7.3 Hz, 1H), 6.42 (d, J = 7.9 Hz, 1H), 3.59 (dd, J = 12.2, 6.5 Hz, 1H), 3.52−3.37 (m, 3H), 3.37−3.28 (m, 2H), 3.25−3.20 (m, 1H), 3.18−2.99 (m, 5H), 2.81 (s, 3H), 2.71 (td, J = 10.2, 3.0 Hz, 1H), 2.63−2.52 (m, 1H), 2.28 (s, 3H), 2.27−2.22 (m, 1H), 2.15−1.93 (m, 3H).

13C NMR (DMSOd6, 126 MHz) δ 197.2, 165.1 (d, JCF = 252 Hz), 145.6, 137.6, 137.3, 135.2, 133.1, 130.9 (d, JCF = 10 Hz), 128.1, 126.7, 125.5, 120.6, 115.7 (d, JCF = 22 Hz), 112.5, 109.3, 62.2, 55.5, 52.5, 49.8, 47.8, 43.7, 38.6, 37.0, 34.9, 21.7, 20.8, 18.0.

MS (ESI) m/z 394.2 [M + H]+.

HRMS (ESI) m/z calcd for C24H29FN3O [M + H]+, 394.2295; found, 394.2292. UPLC purity, 97.7%; retention time, 2.06 min (method A).

str1

PATENT

WO 2000077002

WO 2000077010

US 20040220178

WO 2008112280

WO 2009114181

WO 2011133224

PATENT

WO 2017172811

0003] l-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH,7H- pyrido[3′,4′:4,5]pyrrolo[l,2,3-de]quinoxalin-8-yl)-butan-l-one (sometimes referred to as 4- ((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH-pyrido[3′,4′:4,5]pyrrolo[l,2,3- de]quinoxalin-8(7H)-yl)-l-(4-fluorophenyl)-l-butanone, or as ITI-007), has the following structure:

Figure imgf000002_0001

[0004] ITI-007 is a potent 5-HT2A receptor ligand (Ki=0.5 nM) with strong affinity for dopamine (DA) D2 receptors (Ki=32 nM) and the serotonin transporter (SERT) (Ki=62 nM) but negligible binding to receptors (e.g., HI histaminergic, 5-HT2C, and muscarinic) associated with cognitive and metabolic side effects of antipsychotic drugs. ΠΊ-007 is currently in clinical trials, i.a., for treatment of schizophrenia. While ITI-007 is a promising drug, its production and formulation present challenges. In free base form, ITI-007 is an oily, sticky solid, with poor solubility, not only in water but also in many organic solvents. Making salts of the compound has proven to be unusually difficult. A hydrochloride salt form of ITI-007 was disclosed in US 7183282, but this salt is hygroscopic and shows poor stability. A toluenesulfonic acid addition salt (tosylate) of ITI- 007 was finally identified and described in WO 2009/114181.

[0005] There is a need for alternative stable, pharmaceutically acceptable solid forms of ITI-007, which can be readily incorporated into galenic formulations.

XAMPLES

[0027] The following equipment and methods are used to isolate and characterize the exemplified co-crystal forms:

[0028] X-ray powder diffraction (XRPD): The X-ray powder diffraction studies are performed using a Bruker AXS D2 PHASER in Bragg-Brentano configuration, equipment #1549 / #2353. The equipment uses a Cu anode at 30kV, 10 mA; sample stage standard rotating; monochromatization by a Κβ-filter (0.5% Ni). Slits: fixed divergence slits 1.0mm (=0.61°), primary axial Soller slit 2.5°, secondary axial Soller slit 2.5°. Detector: Linear detector LYNXEYE with receiving slit 5° detector opening. The standard sample holder (0.1 mm cavity in (510) silicon wafer) has a minimal contribution to the background signal. Measurement conditions: scan range 5 – 45° 2Θ, sample rotation 5 rpm, 0.5s/step, 0.010°/step, 3.0mm detector slit; and all measuring conditions are logged in the instrument control file. As system suitability, corundum sample A26- B26-S (NIST standard) is measured daily. The software used for data collection is Diffrac. Commander v2.0.26. Data analysis is done using Diffrac.Eva vl.4. No background correction or smoothing is applied to the patterns.

[0029] Simultaneous thermogravimetry (TGA) and differential scanning calorimetry (DSC) or TGA/DSC analysis: The TGA/DSC studies are performed using a Mettler Toledo TGA/DSC 1 Stare System, equipment #1547, auto-sampler equipped, using pin-holed Al- crucibles of 40 μΐ. Measurement conditions: 5 min 30.0 °C, 30.0 – 350.0 °C with 10 °C/min., N2 flow of 40 ml/min. The software used for instrument control and data analysis is STARe vl2.10.

[0030] Differential scanning calorimetry (DSC): The DSC studies are performed using a Mettler Toledo DSC1 STARe System, equipment #1564. The samples are made using Al crucibles (40 μΐ; pierced). Typically 1 – 8 mg of sample is loaded onto a pre- weighed Al crucible and is kept at 30°C for 5 minutes, after which it is heated at 10°C/min from 30°C to 350 °C and kept at 350°C for 1 minute. A nitrogen purge of 40 ml/min is maintained over the sample. As system suitability check Indium and Zinc are used as references. The software used for data collection and evaluation is STARe Software vl2.10 build 5937. No corrections are applied to the thermogram.

[0031] Polarized light microscopy (PLM): The microscopy studies are performed using an Axio Vert 35M, equipped with an AxioCamERc 5s, equipment #1612. The microscope is equipped with four lenses: Zeiss A-Plan 5x/0.12, Zeiss A-Plan lOx/0.25, LD A-Plan 20x/0.30 and Achros TIGMAT 32x/0.40. Data collection and evaluation is performed using Carl Zeiss Zen Axio Vision Blue Edition Lite 2011 vl.0.0.0 software. A small amount of sample is loaded on an object glass and carefully spread until a thin layer is obtained.

[0032] Dynamic Vapour Sorption (DVS): The Dynamic Vapour Sorption studies are performed using a Surface Measurement Systems Ltd. DVS-1 No Video, equipment #2126. The sample is loaded into a balance pan, typically 20-30 mg, and equilibrated at 0% RH. After the material was dried, the RH is increased with 10% per step for 1 hour per increment, ending at 95% RH. After completion of the sorption cycle, the sample was dried using the same method. The software used for data collection is DVSWin v3.01 No Video. Data analysis is performed using DVS Standard Analysis Suite v6.3.0 (Standard).

[0033] Particle size distribution (PSD): The particle size distribution studies are performed using a Malvern Instruments Mastersizer, equipment #1712. The Mastersizer uses a 300RF lens range of 0.05 μηι – 900 mm. Polydisperse is used as analysis model. Measurement conditions: before each sample measurement a background measurement is performed, the background scan time is 12 seconds (12000 snaps). Each sample is dispersed in Multipar G, refractive index of 1.42. The obscuration range on sample dispersion is between 10%-30%. Each sample is measured 6 times at t=0 and t=30 minutes and the measurement scan time is 10 seconds (10000 snaps). The targeted stirring speed of the sample dispersion unit is 2000+10 rpm. Data collection and evaluation is performed using Mastersizer S Version 2.19 software. [0034] Capillary Melting Point: The capillary melting point is determined on a Biichi Melting Point B-545, equipment #000011, conform USP guidelines.

[0035] X-ray fluorescence (XRF): The X-ray fluorescence studies are performed using a Bruker AXS S2 RANGER, equipment #2006. Using an end-window X-ray tube with Palladium anode and an ultra-thin Beryllium window (75 μιη) for superior light element analysis. As detector the Xflash V5 detector with Cr, Ti, Al, Ta collimator (energy resolution < 129 eV FWHM at 100 000 cps Mnka) is used. The S2 Ranger is equipped with an autosampler with integrated 28 position X- Y automatic sample changer with exchangeable tray, which allows maximum sample diameter of 40 mm. Samples are mounted in steel rings of 51.5 mm diameter for automatic operation. Measurement conditions: disposable liquid cups (35 mm inner diameter, 40 mm outer diameter) with polypropylene foil 5 μιη. As system suitability check a copper disk is measured daily and a glass disk, containing several elements, is measured weekly. The software used for data collection is S2 Ranger Control Software V4.1.0. Data analysis is performed using SPECTRA EDX V2.4.3 evaluation software. No background correction or smoothing is applied to the patterns.

[0036] Fourier transform infrared spectroscopy (FT-IR): The FT-IR studies are performed using a Thermo Scientific Nicolet iS50, equipment # 2357. An attenuated total reflectance (ATR) technique was used with a beam splitter of KBr. Experiment setup of the collected sample is used number of scans 16 with a resolution of 4from 400 cm“1 to 4000 cm“1. The software OMNIC version 9.2 is used for data collection and evaluation.

[0037] Thermogravimetric analysis (TGA) with infrared spectroscopy (TGA-IR):

In TGA-IR, the off-gassing materials are directed through a transfer line to a gas cell, where the infrared light interacts with the gases. The temperature ramp and first derivative weight loss information from the TGA is shown as a Gram-Schmidt (GS) profile; the GS profile essentially shows the total change in the IR signal relative to the initial state. In most cases, the GS and the derivative weight loss will be similar in shape, although the intensity of the two can differ. For this experiment are two devices coupled to each other. The TGA studies are performed using a Mettler Toledo TGA/DSCl STARe System with a 34-position auto sampler, equipment #1547. The samples are made using Al crucibles (100 μΐ; pierced). Typically 20-50 mg of sample is loaded into a pre- weighed Al crucible and is kept at 30°C for 5 minutes after which it is heated at 10°C/min from 30°C to 350°C. A nitrogen purge of 40 ml/min is maintained over the sample. The TGA-IR module of the Nicolet iS50 is coupled to the TGA/DSCl. The IR studies were performed using a Thermo Scientific Nicolet iS50, equipment # 2357. Experiment setup of the collected series, the profile Gram-Schmidt is used number of scans 10 with a resolution of 4. The software OMNIC version 9.2 is used for data collection and evaluation.

[0038] High performance liquid chromatography (HPLC): The high performance liquid chromatography analyses are performed on LC-31, equipped with an Agilent 1100 series G1322A degasser equipment #1894, an Agilent 1100 series G1311A quaternary pump equipment #1895, an Agilent 1100 series G1313A ALS equipment #1896, an Agilent 1100 series G1318A column equipment #1897 and an Agilent 1100 series G1314A VWD equipment #1898 / LC-34, equipped with an Agilent 1200 series G1379B degasser equipment #2254, an Agilent 1100 series G1311A quaternary pump equipment #2255, Agilent 1100 series G1367A WPALS equipment #1656, an Agilent 1100 series G1316A column equipment #2257 and an Agilent 1100 series G1315B DAD equipment #2258. Data is collected and evaluated using Agilent ChemStation for LC systems Rev. B.04.02[96]. Solutions are prepared as follows: Mobile phase A: Add 800 ml of MilliQ water to a 1L volumetric flask. Add 1 ml of TFA and homogenize. Fill up to the mark with MilliQ; Mobile phase B: Add 800 ml of Acetonitrile to a 1L volumetric flask. Add 1 ml of TFA and homogenize. Fill up to the mark with Acetonitrile; Diluent: 50/50 MeOH/ACN.

Example 1: Co-crystal screen

[0039] Solubility of free base in various solvents is evaluated, and based on the results of the solubility range, suitable solvents are selected for the co-crystal screen. Co-crystal formation is based on hydrogen bonding and stacking of the molecules, meaning the co-former selection is based on active groups. Grinding is a method to form co-crystals, however the free base itself is an oil/ sticky solid and therefore not suitable for this method. The free base and counter ion are added to a solution in a certain ratio to give the chance to form a co-crystal, similar to salt formation. We found the best method is to add a saturated solution of the co-former to that of the free base to find an optimal ratio for co-crystal formation.

[0040] Three different experiments are performed with each of 26 candidate co-formers, which include sugar alcohols, amino acids, and other compounds identified as having potential to for co- crystals; adding solutions stepwise, slurry experiments and cooling crystallization experiments. The free base and co-former are dissolved prior to adding to each other. Co-formers are added in a 1 : 1 , 2: 1 and 1 :2 ratio to the free base. All experiments are performed using four different solvents, methanol, acetonitrile, ethyl acetate and toluene. All solids are characterized by XRPD. Two different ITI-007 free base co-crystals formed, with nicotinamide and with isonicotinamide. Both co-crystals were obtained by slurry experiments in methanol.

Example 2: Isonicotinamide co-crystal

[0041] Isonicotinamide forms a possible co-crystal with ITI-007 free base by slurrying the mixture in methanol and ethyl acetate, appearing as a red/brown and yellow solid respectively. TGA-DSC analysis of the experiment using isonicotinamide in methanol results in two endothermic events,

Figure imgf000013_0001

Both endothermic events do not correspond to the free base or the co-former, which means ITI-007 free base-isonicotinamide co-crystal is formed. HPLC and Ή-ΝΜΡ analyses confirm both of the free base and the co-former to be present. Using isonicotinamide in ethyl acetate, however, does not result in a co-crystal and, no endothermic event is present in the TGA/DSC analysis.

[0042] The slurry experiment in methanol is repeated at a gram scale. First, ITI-007 free base and isonicotinamide are each dissolved in methanol. Subsequently, the obtained solutions are mixed in a 1: 1 ratio and the resulting mixture is stirred at room temperature for 2 hours. The mixture remains a clear solution, which is evaporated under vacuum to give a brown sticky solid. XRPD analysis shows the brown sticky solid to be crystalline, as shown in Figure 1, ITI-007 free base-isonicotinamide co-crystal has formed. The corresponding peak list is showing in Table 1. The XRPD shows clustered peaks which is likely due to preferred orientation.

PATENT

WO 2018189646

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=B7967631262D0B0FD9D0AE25DA9CE085.wapp1nC?docId=WO2018189646&tab=PCTDESCRIPTION&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=&recNum=1824&maxRec=71295115

The present application relates to solid state forms of Lumateperone p-Tosylate and processes for preparation thereof.

The drug compound is having the adopted name “Lumateperone” and it has chemical name: l-(4-fluorophenyl)-4-[(6bR,10aS)-2,3,6b,9,10,10a-hexahydro-3-methyl-lH-pyrido[3′,4′:4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl] 1-Butanone; and a structure depicted by Formula I.

Formula I

International Patent Application Publication Nos. WO2000077002A1, WO2009145900 A 1 and WO2013155504A1 which are incorporated herein in their entirety reported Lumateperone and its related compounds. These compounds have been found to be useful as 5-HT2 receptor agonists and antagonists used in treating disorders of the central nervous system including a disorder associated with 5HT2C or 5HT2A receptor modulation selected from obesity, anorexia, bulemia, depression, a anxiety, psychosis, schizophrenia, migraine, obsessive -compulsive disorder, sexual disorders, depression, schizophrenia, migraine, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, sleep disorders, conditions associated with cephalic pain, social phobias, gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility. International Patent Application Publication No. WO2008112280A1 disclose process(es) for preparing Lumateperone and its salts.

International Patent Application Publication No. WO2009114181A2 disclose crystalline forms of the p-Tosylate salt of compound of Formula (I), WO 2017172784 Al disclose oxalate, aminosalicylate, cyclamate salts of Lumateperone, WO 2017172811 Al

disclose co-crystal of Lumateperone with iso-nicotinamide, nicotinatinamide, WO 2018031535 Al disclose crystalline Form Fl of Lumateperone ditosylate.

Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form. For some therapeutic indications, one bioavailability pattern may be favored over another. Therefore, it is desirable to have amorphous forms of drugs with high purity to meet the needs of regulatory agencies and also highly reproducible processes for their preparation.

In view of the above, it is therefore, desirable to stable amorphous form of Lumateperone j?-tosylate. The amorphous form provided herein is at least stable under ordinary stability conditions with respect to purity, storage and is free flowing powder.

Amorphous solid dispersions of drugs are generally known to improve the stability and solubility of drug products. However, some of such amorphous solid dispersions are found to be unstable over time. Amorphous solid dispersions of drugs tend to convert to crystalline forms over time, which can lead to improper dosing due to differences of the solubility of crystalline drug material compared to amorphous drug material. The present invention, however provides stable amorphous solid dispersions of Lumateperone j?-tosylate with improved solubility. Moreover, the present invention provides solid dispersions of Lumateperone j?-tosylate which may be reproduced easily and is amenable for processing into a dosage form

EXAMPLE 1 : PREPARATION OF AMORPHOUS LUMATEPERONE p-TOSYLATE

Lumateperone j?-tosylate (500 mg) was dissolved in methanol (25 mL) at room temperature for clear solution and filtered to remove undissolved particles. The resultant filtrate was subjected to fast solvent evaporation using rotavapor at about 55°C to afford the solid compound. The said solid was dried under vacuum at about 45°C to afford the amorphous Lumateperone p-tosylate according to Figure 1.

References

  1. Jump up^ Sylvain Celanire; Sonia Poli (13 October 2014). Small Molecule Therapeutics for Schizophrenia. Springer. pp. 31–. ISBN 978-3-319-11502-3.
  2. Jump up to:a b c d e Intra-Cellular Therapies, Inc. (2015). “Intra-Cellular Therapies Announces Further Analyses of the Phase 2 Clinical Trial of ITI-007 in Schizophrenia at the 168th Annual Meeting of the American Psychiatric Association”. GlobeNewswire, Inc.
  3. Jump up^ Intra-Cellular Therapies. “Product Pipeline – Intra-Cellular Therapies”. Archived from the original on 2015-05-11. Retrieved 2015-05-19.
  4. Jump up^ Intra-Cellular Therapies. “Intra-Cellular Therapies Announces Positive Top-Line Results From the First Phase 3 Trial of ITI-007 in Patients With Schizophrenia and Confirms the Unique Pharmacology of ITI-007 in a Separate Positron Emission Tomography Study”intracellulartherapies. Archived from the original on 2016-03-21.
  5. Jump up^ “Intra-Cellular Therapies Receives FDA Fast Track Designation for Lumateperone for the Treatment of Schizophrenia | Intra-Cellular Therapies Inc”Intra-Cellular Therapies Inc. Retrieved 2017-11-25.
  6. Jump up to:a b c d e f g h i Snyder GL, Vanover KE, Zhu H, Miller DB, O’Callaghan JP, Tomesch J, Li P, Zhang Q, Krishnan V, Hendrick JP, Nestler EJ, Davis RE, Wennogle LP, Mates S (2015). “Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission”Psychopharmacology232 (3): 605–21. doi:10.1007/s00213-014-3704-1PMC 4302236PMID 25120104.
  7. Jump up to:a b Nancy A. Melville (2015). “Novel Drug Promising for Schizophrenia”. Medscape Medical News.
  8. Jump up^ Li P, Zhang Q, Robichaud AJ, Lee T, Tomesch J, Yao W, Beard JD, Snyder GL, Zhu H, Peng Y, Hendrick JP, Vanover KE, Davis RE, Mates S, Wennogle LP (2014). “Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders”. J. Med. Chem57 (6): 2670–82. doi:10.1021/jm401958nPMID 24559051.
  9. Jump up to:a b c Davis RE, Vanover KE, Zhou Y, Brašić JR, Guevara M, Bisuna B, Ye W, Raymont V, Willis W, Kumar A, Gapasin L, Goldwater DR, Mates S, Wong DF (2015). “ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D 2 receptors and serotonin transporters using positron emission tomography in healthy volunteers”. Psychopharmacology232 (15): 2863–72. doi:10.1007/s00213-015-3922-1hdl:10044/1/24121PMID 25843749.
  10. Jump up to:a b c d e Intra-Cellular Therapies, Inc. (2013). “Intra-Cellular Therapies Announces Positive Topline Phase II Clinical Results of ITI-007 for the Treatment of Schizophrenia”. PRNewswire.

External links

Lumateperone
ITI-007.svg
Clinical data
Synonyms ITI-007; ITI-722
Routes of
administration
By mouth
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C24H28FN3O
Molar mass 393.496
3D model (JSmol)
Patent ID

Title

Submitted Date

Granted Date

US8648077 SUBSTITUTED HETEROCYCLE FUSED GAMMA-CARBOLINES SOLID
2011-05-12
US9371324 ORGANIC COMPOUNDS
2015-02-20
2015-06-18
US8993572 ORGANIC COMPOUNDS
2011-04-22
2013-08-08
US9586960 SUBSTITUTED HETEROCYCLE FUSED GAMMA-CARBOLINES SOLID
2015-11-30
2016-07-07
US9199995 SUBSTITUTED HETEROCYCLE FUSED GAMMA-CARBOLINES SOLID
2014-02-11
2014-10-30

////// Lumateperone, PHASE 3, ITI-007, ITI-722

Molidustat, Bay 85-3934


Molidustat structure.png

Molidustat

UNII-9JH486CZ13, cas no 1154028-82-6, MW: 314.3076

2-(6-morpholin-4-ylpyrimidin-4-yl)-4-(triazol-1-yl)-1H-pyrazol-3-one

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors

  • Originator Bayer Schering Pharma
  • Developer Bayer HealthCare Pharmaceuticals
  • Class Antianaemics; Morpholines; Pyrazoles; Pyrazolones; Pyrimidines; Small molecules; Triazoles
  • Mechanism of Action Hypoxia-inducible factor-proline dioxygenase inhibitors
  • Phase III Anaemia
  • 24 Jun 2018 Biomarkers information updated
  • 23 Jun 2018 Bayer initiates enrolment in the MIYABI HD-M phase III trial for Anaemia in Japan (PO) (NCT03543657)
  • 05 Jun 2018 Bayer plans a phase III trial for Anaemia (renal) in Japan in June 2018 (NCT03543657)

For the cardio-renal syndrome, a Phase IIb program with the investigational new drug Molidustat (BAY 85-3934) is under initiation in patients with anemia associated with chronic kidney disease and/or end-stage renal disease. Molidustat is a novel inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) which stimulates erythropoietin (EPO) production and the formation of red blood cells. Phase I data have shown that inhibition of HIF-PH by Molidustat results in an increase in endogenous production of EPO.

About Bayer HealthCare

The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.6 billion (2012), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 54,900 employees (Dec 31, 2012) and is represented in more than 100 countries. More information at www.healthcare.bayer.com.

molidustat

Molidusat sodium

2D chemical structure of 1375799-59-9

RN: 1375799-59-9
UNII: CI0NE7C96T

Molecular Formula, C13-H13-N8-O2.Na, Molecular Weight, 336.2897

Sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-olate

Molidustat sodium is an orally-available hypoxia-inducible factor prolyl hydroxylase inhibitor in phase I clinical trials at Bayer for the treatment of patients suffering from renal anemia due to chronic kidney disease.

Molidustat (INNBay 85-3934) is a drug which acts as a HIF prolyl-hydroxylase inhibitor and thereby increases endogenous production of erythropoietin, which stimulates production of hemoglobin and red blood cells. It is in Phase III clinical trials for the treatment of anemia secondary to chronic kidney disease.[1][2] Due to its potential applications in athletic doping, it has also been incorporated into screens for performance-enhancing drugs.[3]

WO 2008067871

WO 2012065967

WO 2013167552

2-Heteroaryl-4-aryl-1,2-dihydropyrazolones having a bactericidal and/or fungicidal action are disclosed in EP 165 448 and EP 212 281. The use of 2-heteroaryl-4-aryl-1,2-dihydropyrazolones as lipoxygenase inhibitors for treatment of respiratory tract, cardiovascular and inflammatory diseases is claimed in EP 183 159. 2,4-Diphenyl-1,2-dihydropyrazolones having a herbicidal activity are described in DE 2 651 008.

The preparation and pharmacological properties of certain 2-pyridyl-1,2-dihydropyrazolones are reported in Helv. Chim. Acta 49 (1), 272-280 (1966). WO 96/12706, WO 00/51989 and WO 03/074550 claim compounds having a dihydropyrazolone partial structure for treatment of various diseases, and hydroxy- or alkoxy-substituted bipyrazoles for treatment of neuropsychiatric diseases are disclosed in WO 2006/101903.

Heteroaryl-substituted pyrazole derivatives for treatment of pain and various CNS diseases are furthermore described in WO 03/051833 and WO 2004/089303. WO 2006/114213 has meanwhile disclosed 2,4-dipyridyl-1,2-dihydropyrazolones as inhibitors of HIF prolyl 4-hydroxylases.

The x-ray crystal structure of the compound 3-methyl-1-(pyridin-2-yl)-4-(1-pyridin-2-yl-3-methyl-1H-pyrazol-5-yl)-2H-3-pyrazolin-5 (114)-one (other name: 5,5′-dimethyl-2,2′-di-pyridin-2-yl-1′,2′-dihydro-2H,3′H-3,4′-bipyrazol-3′-one) is reported inActa Crystallogr., Section E: Structure Reports Oμline E57 (11), o1126-o1127 (2001) [Chem. Abstr. 2001:796190].

The synthesis of certain 3′,5-dimethyl-2-phenyl-1′-(1,3-thiazol-2-yl)-1′H,2H-3,4′-bipyrazol-5′-ol derivatives is described inIndian J. Heterocyclic Chem. 3 (1), 5-8 (1993) [Chem. Abstr. 1994:323362].

The preparation and tautomerism of individual 4-(pyrazol-5-yl)-pyrazolin-5-one derivatives is reported in J. Heterocyclic Chem. 27 (4), 865-870 (1990) [Chem. Abstr. 1991:428557]. A therapeutic use has not hitherto been described for the compounds mentioned in these publications. The compound 2-tert-butyl-1′-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]-3′,5-dimethyl-1′H,2H-3,4′-bipyrazol-5′-ol is listed as a test example in WO 2007/008541.

SYN

WO 2013167552

CLIP

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cmdc.201700783

Image result for molidustat

1-[6-(Morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1Hpyrazol-5-ol (molidustat, BAY 85-3934, 45): Method A (gram-scale): Ethyl 3-(dimethylamino)-2-(1H-1,2,3-triazol-1-yl)acrylate (73, 1.98 g, 9.43 mmol) and 4-(6-hydrazinopyrimidin-4-yl)morpholine (78, 1.89 g, 9.70 mmol) were introduced into ethyl acetate (25 mL) and TFA (502 mg, 4.4 mmol) was added at RT. The mixture was stirred under reflux for 18 h, then cooled to 0–58C and subsequently stirred for a further 2 h. The solid formed was filtered off, washed with cold ethyl acetate and dried first in air and thereafter under a high vacuum. Yield: 2.13 g (71%);

1H NMR (400 MHz, [D6 ]DMSO): d=8.42 (s, 1H), 8.38 (s, 1H), 8.01 (s, 1H), 7.73 (s, 1H), 7.70 (s, 1H), 3.71–3.65 (m, 4H), 3.57–3.51 ppm (m, 4H);

13C NMR (125 MHz, [D6 ]DMSO): d=44.3, 65.6, 85.6, 102.8, 123.7, 132.9, 135.8, 152.4, 154.1, 154.7, 162.0 ppm;

IR (KBr): n˜ =3441, 3135–3108, 2965–2884, 1636–1345, 1257 cm@1 ;

UV/Vis (acetonitrile/water 1:1): lmax (e)= 249 nm (34928 L (mol cm)@1 );

MS (EI+) m/z: 315 [M+H]+ ;

Anal. calcd for C13H14N8O2 : C 49.7, H 4.5, N 35.7, O 10.2, found: C 49.5, H 4.4, N 35.5, O 12.6.

Method B (kilogram-scale): Inastirred vessel, 4- (6-hydrazinopyrimidin-4-yl)morpholine (78, 42.0 kg, 215.1 mol) and methyl 3-(dimethylamino)-2-(1H-1,2,3-triazol-1-yl)acrylate (83, 44.0 kg, 224.2 mol) were suspended in ethyl acetate (378 kg), admixed with TFA (12.1 kg, 106.1 mol) and heated under reflux (from 788C to 81 8C) at a jacket temperature of 908C for 26 h. The suspension obtained was cooled to 0 8C, stirred at 08C for 1 h and filtered. The filter cake was washed with ethyl acetate (53 kg) and dried under reduced pressure at up to 458C. The filter cake was admixed with a mixture of water (355 kg) and acetic acid (11.7 kg), then suspended and stirred at 50–548C for 1 h. After cooling to 248C, the suspension was filtered. The filter cake was washed first with water (90 kg), then twice with methanol (50 kg each time) and finally dried at 35–458C under reduced pressure. Yield: 57.4 kg (85%)

Synthesis of molidustat sodium (84)

Sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1 H-1,2,3-triazol1-yl)-1H-pyrazol-5-olate (molidustat sodium, 84): Kilogram scale: In a stirred vessel, compound 45 (55 kg, 175.0 mol) was suspended in a mixture of methanol (200 kg) and water (30 kg), admixed with triethylamine (17.8 kg, 175.9 mmol), heated at 608C, stirred further for about 1 h and filtered hot to separate off undissolved constituents. The filter cake was washed with methanol (15 kg, 608C). Sodium hydroxide solution (18.7 kg, 210.4 mmol, 45% strength) was slowly introduced at 608C and methanol (5 kg) was added. Sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)- 1H-pyrazol-5-olate (84, 0.12 kg) was added as seed crystals and the mixture was stirred at 608C for another 1 h and cooled to 248C over a period of about 2 h. The mixture was stirred for 8 h at this temperature, subsequently cooled to 08C over a period of about 1 h and filtered in portions by means of a centrifuge. The filter cake was washed with a mixture of water (24 kg) and methanol (168 kg) and also methanol (about 23 kg in each case) and dried all together at 40 8C under reduced pressure in a dryer for 8 h. Yield: 57.6 kg (98%);

1H NMR (500 MHz, [D6 ]DMSO): d=8.98 (d, J= 1.4 Hz, 1H), 8.72 (s, 1H), 8.68 (s, 1H), 8.64 (d, J=1.4 Hz, 1H), 7.77 (s, 1H), 4.25–4.00 ppm (m, 8H);

13C NMR (125 MHz, [D6 ]DMSO): d= 48.2, 67.8, 91.5, 107.0, 129.6, 130.9, 138.0, 151.7, 152.0, 157.4, 159.9 ppm;

IR (KBr): n˜ =3153–3006, 2976–2855, 1630–1439, 1241, 1112, 987 cm@1 ;

UV/Vis (acetonitrile/water 1:1): lmax (e)=284 nm (16855 L [mol cm]@1 );

MS (EI+) m/z: 337 [M+Na]+ , 315 [M+H]+ ;

Anal. calcd for C13H13N8O2Na: C 46.4, H 3.9, N 33.3, found: C 46.1, H 4.0, N 33.1.

PATENT

RM 1

Example 3A 3-(Dimethylamino)-2-(1H-1,2,3-triazol-1-yl)acrylic acid ethyl ester

Figure US20100305085A1-20101202-C00024

The preparation of the starting compound is carried out analogously to 2A starting from 1.00 g (6.45 mmol) 2-(1H-1,2,3-triazol-1-yl)acetic acid ethyl ester.

Yield: 1.4 g (100% of th.)

1H-NMR (400 MHz, DMSO-d6): δ=8.10 (d, 1H), 7.78 (d, 1H), 7.65 (s, 1H), 4.03 (q, 2H), 3.06 (br. s, 3H), 2.10 (br. s, 3H), 1.12 (t, 3H).

LC-MS (Method 5): Rt=1.40 min; MS (ESIpos): m/z=211 [M+H]+.

 …………

RM 2

Example 16A 4-(6-Hydrazinopyrimidin-4-yl)morpholine

Figure US20100305085A1-20101202-C00043

Stage a):

4-(6-Chloropyrimidin-4-yl)morpholine

Figure US20100305085A1-20101202-C00044

45.0 g (302.1 mmol) 4,6-dichloropyrimidine are initially introduced into 450 ml water. 26.3 g (302.1 mmol) morpholine are added and the mixture is stirred at 90° C. for 16 h. Thereafter, it is cooled to 0° C. and the precipitate formed is filtered off. The precipitate is washed once with 50 ml water and dried in air.

Yield: 51.0 g (85% of th.)

LC-MS (Method 4): Rt=1.09 min; MS (ESIpos): m/z=200 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.35 (s, 1H), 6.95 (s, 1H), 3.62 (s, 8H).

Stage b)

4-(6-Hydrazinopyrimidin-4-yl)morpholine

Figure US20100305085A1-20101202-C00045

53.0 g (2.7 mmol) 4-(6-chloropyrimidin-4-yl)morpholine are initially introduced into 260 ml ethanol. 132.9 g (2.7 mol) hydrazine hydrate are added and the mixture is stirred under reflux for 16 h. Thereafter, it is cooled to RT and approx. half of the solvent is removed by distillation. The mixture is cooled to 0° C. and the solid formed is filtered off. It is rinsed with cold ethanol and the solid is dried first in air and then in vacuo.

Yield: 35.0 g (68% of th.)

LC-MS (Method 1): Rt=0.17 min; MS (ESIpos): m/z=196 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=7.94 (s, 1H), 7.70 (s, 1H), 5.91 (s, 1H), 4.15 (s, 2H), 3.66-3.60 (m, 4H), 3.45-3.37 (m, 4H).

 ………..

Example 71

2-(6-Morpholin-4-ylpyrimidin-4-yl)-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one

Figure US20100305085A1-20101202-C00156

1.9 g (8.8 mmol) of the compound from Example 3A and 1.9 g (9.7 mmol) of the compound from Example 16A are initially introduced into 25 ml ethyl acetate and 504 mg (4.4 mmol) TFA are added at RT. The mixture is stirred under reflux for 16 h, then cooled to 5° C. and subsequently stirred for a further 2 h. The solid formed is filtered off, washed with ethyl acetate and dried first in air and thereafter under a high vacuum. 1.7 g of product are obtained.

The mother liquor is combined with the wash solution and the solvent is removed. According to LC-MS, the residue (2.4 g) still contains the intermediate 3-[2-(6-morpholin-4-ylpyrimidin-4-yl)hydrazino]-2-(1H-1,2,3-triazol-1-yl)prop-2-enoic acid ethyl ester (intermediate stage of the cyclization), which is used directly for the preparation of Example 72 (see there).

Yield: 1.7 g (61% of th.)

LC-MS (Method 9): Rt=0.90 min; MS (ESIpos): m/z=315 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.42 (s, 1H), 8.38 (s, 1H), 8.01 (s, 1H), 7.73 (s, 1H), 7.70 (s, 1H), 3.71-3.65 (m, 4H), 3.57-3.51 (m, 4H).

………..

Hydrochloride

Example 72

2-(6-Morpholin-4-ylpyrimidin-4-yl)-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one hydrochloride

Figure US20100305085A1-20101202-C00157

Batch 1: 7.5 ml of a 4 N solution of hydrogen chloride in dioxane are added to 1.7 g (5.4 mmol) of the compound from Example 71. The mixture is stirred at RT, 5 ml dioxane are added and the mixture is stirred at RT for 16 h. The solid is filtered off and washed with 5 ml dioxane. The mixture is dried under a high vacuum for 16 h, 10 ml methanol are then added and the mixture is stirred at RT for 1 h. The solid is filtered off, washed with 4 ml methanol and dried under a high vacuum. 1.6 g of the title compound are obtained.

Batch 2: A further amount of the title compound is obtained as follows: The residue (2.4 g) obtained from the mother liquor during the synthesis of Example Compound 71, which contains the open-ring intermediate state of the cyclization, 3-[2-(6-morpholin-4-ylpyrimidin-4-yl)hydrazino]-2-(1H-1,2,3-triazol-1-yl)prop-2-enoic acid ethyl ester, is dissolved in 12 ml ethanol and 1.5 ml 30% strength sodium methylate solution in methanol are added at RT, while stirring. The mixture is subsequently stirred at RT for 45 min, then adjusted to pH 5 with 2 N hydrochloric acid and subsequently stirred at RT for a further 16 h. The mixture is cooled to 10° C. and the solid is filtered off and washed with 3.5 ml dioxane. The mixture is dried under a high vacuum for 16 h, 5 ml methanol are then added and the mixture is subsequently stirred at RT for 1 h. The solid is filtered off, washed with 2 ml methanol and dried under a high vacuum to give a further 997 mg of the title compound in this way.

Yield: together 2.6 g (83% of th.)

LC-MS (Method 6): Rt=0.89 min; MS (ESIpos): m/z=315 [M+H]+;

1H-NMR (400 MHz, DMSO-d6): δ=8.54 (s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 7.88 (s, 1H), 7.42 (s, 1H), 3.71 (s, 8H).

References

  1. Jump up^ Flamme, I; Oehme, F; Ellinghaus, P; Jeske, M; Keldenich, J; Thuss, U (2014). “Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects”PLoS ONE9 (11): e111838. Bibcode:2014PLoSO…9k1838Fdoi:10.1371/journal.pone.0111838PMC 4230943PMID 25392999.
  2. Jump up^ Gupta, Nupur; Wish, Jay B (2017). “Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients with CKD”. American Journal of Kidney Diseases69 (6): 815. doi:10.1053/j.ajkd.2016.12.011PMID 28242135.
  3. Jump up^ Dib, Josef; Mongongu, Cynthia; Buisson, Corinne; Molina, Adeline; Schänzer, Wilhelm; Thuss, Uwe; Thevis, Mario (2017). “Mass spectrometric characterization of the hypoxia-inducible factor (HIF) stabilizer drug candidate BAY 85-3934 (molidustat) and its glucuronidated metabolite BAY-348, and their implementation into routine doping controls”. Drug Testing and Analysis9 (1): 61–67. doi:10.1002/dta.2011PMID 27346747.
Patent ID

Title

Submitted Date

Granted Date

US8653111 Substituted dihydropyrazolones for treating cardiovascular and hematological diseases
2012-01-23
2014-02-18
US8653074 Substituted sodium 1H-pyrazol-5-olate
2011-11-08
2014-02-18
US8389520 SUBSTITUTED DIHYDROPYRAZOLONES FOR TREATING CARDIOVASCULAR AND HEMATOLOGICAL DISEASES
2010-12-02
US2016015786 MOBILIZING AGENTS AND USES THEREFOR
2013-11-04
2016-01-21
US2015087827 METHOD FOR THE PREPARATION OF TRIAZOLE COMPOUNDS
2013-05-06
2015-03-26
Molidustat
Molidustat structure.png
Clinical data
Synonyms Bay 85-3934
ATC code
  • None
Identifiers
CAS Number
PubChem CID
UNII
Chemical and physical data
Formula C13H14N8O2
Molar mass 314.31 g·mol−1
3D model (JSmol)

//////////MolidustatBay 85-3934

Revefenacin, ревефенацин , ريفيفيناسين , 瑞维那新 ,


Revefenacin.png

Revefenacin; 864750-70-9; TD-4208; UNII-G2AE2VE07O; G2AE2VE07O; TD-4208; GSK-1160724;

160724; GSK 1160724; TD-4028; YUPELRI

Molecular Formula: C35H43N5O4
Molecular Weight: 597.76 g/mol

[1-[2-[[4-[(4-carbamoylpiperidin-1-yl)methyl]benzoyl]-methylamino]ethyl]piperidin-4-yl] N-(2-phenylphenyl)carbamate

TD-4208
UNII:G2AE2VE07O
ревефенацин [Russian] [INN]
ريفيفيناسين [Arabic] [INN]
瑞维那新 [Chinese] [INN]

Revefenacin is under investigation for the treatment of Chronic Obstructive Pulmonary Disease (COPD).

  • Originator Theravance
  • Developer Theravance Biopharma
  • Class Antiasthmatics; Biphenyl compounds; Carbamates; Piperidines
  • Mechanism of Action Muscarinic receptor antagonists
  • Preregistration Chronic obstructive pulmonary disease
  • 17 Sep 2018 Efficacy data from two replicate 12-week phase III trials and a 12-month safety trial in Chronic obstructive pulmonary disease (COPD) presented at the European Respiratory Society International Congress (ERS-2018)
  • 31 May 2018 Theravance Biopharma in collaboration with Theravance Biopharma initiates enrolment in a phase III trial for Chronic obstructive pulmonary disease in USA (NCT03573817)
  • 18 May 2018Efficacy and adverse events data from a phase I trial in Chronic obstructive pulmonary disease presented at the 114th International Conference of the American Thoracic Society

The compound was licensed to GlaxoSmithKline by Theravance for the inhalation treatment of chronic obstructive pulmonary disease in 2004. The rights were returned in 2009. In 2014, Theravance Biopharma spun-off from Theravance. In 2015, Theravance Biopharma and Mylan enter in a co development agreement for the global development and commercialization of the once-daily nebulizer for the treatment of chronic obstructive pulmonary disease and other respiratory diseases.

SYN

WO 2012009166

SYN OF INT

STR1

FINAL

STR1

PAPER
Discovery of (R)-1-(3-((2-Chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl)piperidin-4-yl (1,1′-biphenyl)-2-ylcarbamate (TD-5959, GSK961081, batefenterol): First-in-class dual pharmacology multivalent muscarinic antagonist and 2 agonist (MABA) for the treatment of chronic obstructive pulmonary disease (COPD)
J Med Chem 2015, 58(6): 2609

Discovery of (R)-1-(3-((2-Chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl)piperidin-4-yl [1,1′-Biphenyl]-2-ylcarbamate (TD-5959, GSK961081, Batefenterol): First-in-Class Dual Pharmacology Multivalent Muscarinic Antagonist and β2 Agonist (MABA) for the Treatment of Chronic Obstructive Pulmonary Disease (COPD)

Departments of Medicinal Chemistry, Pharmacology, §Drug Metabolism and Pharmacokinetics, and Molecular and Cellular Biology, Theravance Biopharma, Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States
J. Med. Chem.201558 (6), pp 2609–2622
DOI: 10.1021/jm501915g
*Phone: 650-808-3737. E-mail: ahughes@theravance.com
Abstract Image

Through application of our multivalent approach to drug discovery we previously reported the first discovery of dual pharmacology MABA bronchodilators, exemplified by 1. Herein we describe the subsequent lead optimization of both muscarinic antagonist and β2 agonist activities, through modification of the linker motif, to achieve 24 h duration of action in a guinea pig bronchoprotection model. Concomitantly we targeted high lung selectivities, low systemic exposures and identified crystalline forms suitable for inhalation devices. This article culminates with the discovery of our first clinical candidate 12f (TD-5959, GSK961081, batefenterol). In a phase 2b trial, batefenterol produced statistical and clinically significant differences compared to placebo and numerically greater improvements in the primary end point of trough FEV1 compared to salmeterol after 4 weeks of dosing in patients with moderate to severe chronic obstructive pulmonary disease (COPD).

PATENT

WO 2006099165

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006099165

FIG. 18 shows a PXRD pattern of Form I of the crystalline freebase of the compound of formula I. This crystalline freebase is further characterized by the DSC trace in FIG. 19, the TGA trace in FIG. 20, the DMS trace in FIG. 21, and the micrographic image in FIG. 22.
FIG. 23 shows a PXRD pattern of Form II of the crystalline freebase of the compound of formula I. This crystalline freebase is further characterized by the DSC trace in FIG. 24, the TGA trace in FIG. 25, and the DMS trace in FIG. 26.

PREPARATION 1
Biphenyl-2-ylcarbamic Acid Piperidin-4-yl Ester
Biphenyl-2-isocyanate (97.5 g, 521 mmol) and 4-hydroxy-N-benzylpiperidine (105 g, 549 mmol) were heated together at 70 0C for 12 hours. The reaction mixture was then cooled to 50 0C and ethanol (1 L) was added and then 6M HCl (191 mL) was added slowly. The resulting mixture was then cooled to ambient temperature and ammonium formate (98.5 g, 1.56 mol) was added and then nitrogen gas was bubbled through the solution vigorously for 20 minutes. Palladium on activated carbon (20 g, 10 wt% dry basis) was then added and the reaction mixture was heated at 40 0C for 12 hours, and then filtered through a pad of Celite. The solvent was then removed under reduced pressure and IM HCl (40 mL) was added to the crude residue. The pH of the mixture was then adjusted with IO N NaOH to pH 12. The aqueous layer was extracted with ethyl acetate (2 x 150 mL) and the organic layer was dried (magnesium sulfate), filtered and the solvent removed under reduced pressure to give 155 g of the title intermediate (100% yield). HPLC (10-70) Rt = 2.52; m/z: [M + H+] calc’d for C18H20N2O2 297.15; found 297.31
PREPARATION 2
iV-Benzyl-iV-methylaminoacetaldehvde
To a 3-necked 2-L flask was added N-benzyl-N-methylethanolamine (30.5 g, 0.182 mol), DCM (0.5 L), DIPEA (95 mL, 0.546 mol) and DMSO (41 mL, 0.728 mol).

Using an ice bath, the mixture was cooled to about -10 °C and sulfur trioxide pyridine-complex (87 g, 0.546 mol) was added in 4 portions over 5 minute intervals. The reaction was stirred at -10 0C for 2 hours. Before removing the ice-bath, the reaction was quenched by adding water (0.5 L). The aqueous layer was separated and the organic layer was washed with water (0.5 L) and brine (0.5 L) and then dried over magnesium sulfate and filtered to provide the title compound which was used without further purification.
PREPARATION 3
Biphenyl-2-ylcarbamic Acid l-[2-(Εenzylmethylammo)ethyllpiperidin-4-yl Ester
To a 2-L flask, containing the product of Preparation 2 in DCM (0.5 L) was added the product of Preparation 1 (30 g, 0.101 mol) followed by sodium triacetoxyborohydride (45 g, 0.202 mol). The reaction mixture was stirred overnight and then quenched by the addition of 1 N hydrochloric acid (0.5 L) with vigorous stirring. Three layers were observed and the aqueous layer was removed. After washing with IN NaOH (0.5 L)3 a homogenous organic layer was obtained which was then washed with a saturated solution of aqueous NaCl (0.5 L), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by dissolving it in a minimal amount of isopropanol and cooling this solution to 0 °C to form a solid which was collected and washed with cool isopropanol to provide 42.6 g of the title compound (95% yield). MS m/z: [M + H+] calc’d f for C28H33N3O2444.3; found 444.6. Rf=3.5l min (10-70 ACN:H2O, reverse phase HPLC).
PREPARATION 3 A
Biphenyl-2-ylcarbamic Acid l-f2-(Benzylmethylammo)ethyllpiperidin-4-yl Ester
The title compound was prepared by mesylation of iV-benzyl-N-methyl
ethanolamine, which was then reacted with biphenyl-2-ylcarbamic acid piperidin-4-yl ester in an alkylation reaction.
A 500 mL flask (reactor flask) was charged with N-benzyl-iV-methylethanolamine (24.5 mL), DCM (120 mL), NaOH (80 mL; 30wt%) and tetrabutylammonium chloride. Mixing at low speed throughout the reaction, the mixture was cooled to -10 °C (cooling bath), and the addition funnel charged with DCM (30 mL) and mesyl chloride (15.85 mL), which was added drop wise at a constant rate over 30 minutes. The addition was exothermic, and stirring was continued for 15 minutes while the temperature equilibrated back to -10 0C. The reaction was held for at least 10 minutes to ensure full hydrolysis of the excess mesyl chloride.
A 250 mL flask was charged with biphenyl-2-ylcarbamic acid piperidin-4-yl ester (26 g; prepared as described in Preparation 1) and DCM (125 mL), stirred for 15 minutes at room temperature, and the mixture chilled briefly to 10 0C to form a slurry. The slurry was then charged into the reactor flask via the addition funnel. The cooling bath was removed and the reaction mixture was warmed to 5 °C. The mixture was transferred to a separatory funnel, the layers allowed to settle, and the aqueous layer removed. The organic layer was transferred back to the reactor flask, stirring resumed, the mixture held to room
temperature, and the reaction monitored by HPLC for a total of 3.5 hours.
The reactor flask was charged with NaOH (IM solution; 100 mL), stirred, and the layers allowed to settle. The organic layer was separated, washed (NaCl satd. solution), its volume partially reduced under vacuum, and subjected to repeated IPA washings. The solids were collected and allowed to air-dry (25.85 g, 98% purity). Additional solids were obtained from further processing of the mother liquor (volume reduction, EPA, cooling).
PREPARATION 4
Biphenyl-2-ylcarbamic Acid l-(2-Methylaminoethyl)piperidin-4-yl Ester
To a Parr hydrogenation flask was added the product of Preparation 3 (40 g, 0.09 mol) and ethanol (0.5 L). The flask was flushed with nitrogen gas and palladium on activated carbon (15g, 10 wt% (dry basis), 37% wt/wt) was added along with acetic acid (20 mL). The mixture was kept on the Parr hydrogenator under a hydrogen atmosphere (-50 psi) for 3 hours. The mixture was then filtered and washed with ethanol. The filtrate was condensed and the residue was dissolved in a minimal amount of DCM. Isopropyl acetate (10 volumes) was added slowly to form a solid which was collected to provide 22.0 g of the title compound (70% yield). MS m/z: [M + H+] calc’d for C21H27N3O2 354.2; found 354.3. R/=2.96 min (10-70 ACNrH2O, reverse phase HPLC).
PREPARATION 5
Biphenyl-2-ylcarbamic Acid l-{2-[(4-Formylbenzoyr)
methylaminol ethyll piperidin-4- yl Ester
To a three-necked 1-L flask was added 4-carboxybenzaldehyde (4.77 g,
31.8 mmol), EDC (6.64 g, 34.7 mmol), HOBT (1.91 g, 31.8 mmol), and DCM (200 mL). When the mixture was homogenous, a solution of the product of Preparation 4 (10 g, 31.8 mmol) in DCM (100 mL) was added slowly. The reaction mixture was stirred at room temperature for approximately 16 hours and then washed with water (1 x 100 mL), IN HCl (5 x 60 mL), IN NaOH (1 x 100 mL) brine (1 x 5OmL)3 dried over sodium sulfate, filtered and concentrated to afford 12.6 g of the title compound (92% yield; 85% purity based on HPLC). MS m/z: [M + H+] calc’d for C29H31N3O4 486.2; found 486.4. i?y=3.12 min (10-70 ACNiH2O, reverse phase HPLC).
EXAMPLE 1
Biphenyl-2-ylcarbamic Acid 1 -(2- { |4-(4-Carbamoylpiperidin- 1 -ylmethvD
benzoylimethylamino) ethyl’)piperidin-4-vl Ester

To a three-necked 2-L flask was added isonipecotamide (5.99 g, 40.0 mmol), acetic acid (2.57 mL), sodium sulfate (6.44 g) and isopropanol (400 mL). The reaction mixture was cooled to 0-10 0C with an ice bath and a solution of biphenyl-2-ylcarbamic acid l-{2-[(4-formylbenzoyl)methylamino]ethyl}piperidin-4-yl ester (11 g, 22.7 mmol; prepared as described in Preparation 5) in isopropanol (300 mL) was slowly added. The reaction mixture was stirred at room temperature for 2 hours and then cooled to 0-10 0C. Sodium triacetoxyborohydride (15.16 g, 68.5 mmol) was added portion wise and this mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure to a volume of about 50 mL and this mixture was acidified with IN HCl (200 mL) to pH 3. The resulting mixture was stirred at room temperature for 1 hour and then extracted with DCM (3 x 250 mL). The aqueous phase was then cooled to 0-5 °C with an ice bath and 50% aqueous NaOH solution was added to adjust the pH of the mixture to 10. This mixture was then extracted with isopropyl acetate (3 x 300 mL) and the combined organic layers were washed with water (100 mL), brine (2 x 50 mL), dried over sodium sulfate, filtered and concentrated to afford 10.8 g of the title compound (80% yield. MS m/z: [M + H+] calc’d for C35H43N5O4 598.3; found 598.6. Rj=232 min (10-70 ACNiH2O, reverse phase HPLC).

EXAMPLE 2
Crystalline Diphosphate Salt of Biphenyl-2-ylcarbamic Acid l-(2-{[4-(4- Carbamoylpiperidin-l-ylmethyl)benzoyl1methylamino>ethyDpiperidin-4-yl Ester
500 mg of biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiρeridin-l-ylmethyl) benzoyl]methylamino}ethyl)piperidin-4-yl ester (0.826 mmol of 96% pure material;
prepared as described in Example 1) was taken up in 5 ml of water and 1.5 ml of IM phosphoric acid. The pH was adjusted to approximately pH 5.3 with an additional 0.25ml of IM phosphoric acid (equaling 2.1 molar equivalents). The clear solution was filtered through a 0.2 micron filter, frozen and lyophilized to dryness to yield an amorphous diphosphate salt.
20 mg of the amorphous diphosphate salt was dissolved in 2 ml of IPA: ACN (1:1). 0.1 ml of water was added and the mixture heated to 60 °C under stirring. Almost all of the solids dissolved. The suspension was allowed to cool to ambient temperature, under stirring, overnight. The resulting crystals were collected by filtration and air-dried for 20 minutes to give the title compound (18.5 mg, 93% yield) as a white crystalline solid.
When examined under a microscope using polarized light, the crystals exhibited some birefringence.
EXAMPLE 3
Crystalline Diphosphate Salt of Biphenyl-2-ylcarbamic Acid l-(2-{|4-(4- Carbamoylpiperidin-l-vhτiethyl)benzoyl]methylamino}ethyl)piperidin-4-yl Ester
5.0 g of biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (freebase; prepared as described in Example 1) was combined with 80 ml of IPA:ACN (1:1). 4.0 ml of water was added and the mixture heated to 50 °C under stirring, forming a clear solution. To this was added dropwise at 50 °C, 16 ml IM phosphoric acid. The resulting cloudy solution was stirred at 50 °C for 5 hours, then allowed to cool to ambient temperature, under slow stirring, overnight. The resulting crystals were collected by filtration and air-dried for 1 hour, then under vacuum for 18 hours, to give the title compound (5.8 g, 75% yield) as a white crystalline solid (98.3% purity by HPLC).

EXAMPLE 4
Crystalline Monosulfate Salt of Biphenyl-2-ylcarbamic Acid l-(2-{[4-(4- Carbamoylpiperidm-l-ylmethvπbenzoyllmethylamino>ethyl)piperidm-4-yl Ester
442 mg of biphenyl-2-ylcarbamic acid l-(2-{[4-(4-Carbamoylpiperidin-l-ylmethyl) benzoyl]methylamino} ethyl)piperidin-4-yl ester (0.739 mmol of 96% pure material;
prepared as described in Example 1) was taken up in 5 ml of H2OrACN (1 : 1) and 1.45 ml of IN sulfuric acid was added slowly, while monitoring the pH. The pH was adjusted to approx. pH 3.3. The clear solution was filtered through a 0.2 micron filter, frozen and lyophilized to dryness to yield a monosulfate salt.
30.3 mg of the monosulfate salt was dissolved in 1.65 ml of IPA:ACN (10:1). The suspension was heated by placing the vial in a pre-heated 60 °C water bath for 30 minutes. A viscous material was formed and the heat increased to 70 °C for 30 minutes. Since the material remained viscous, the heat was lowered to 60 0C and the mixture heated for an additional hour. The heat was turned off and the mixture was allowed to cool to room temperature. After 4 days, the material appeared to be solid, and the sample was allowed to sit for an additional nine days. The solid was then filtered and dried using a vacuum pump for 1 hour to give the title compound (23 mg, 76% yield).
EXAMPLE 5
Crystalline Monosulfate Salt of Biphenyl-2-ylcarbamic Acid l-(2-{[~4-(4- Carbamoylpiperidin-l-ylmethyl)benzoyl]methylamino>ethyl)piperidin-4-yl Ester
161 g of the monosulfate salt (prepared as described in Example 4) was dissolved in 8.77 ml of IPA:ACN (10:1). The suspension was heated by placing the vial in a pre-heated 70 °C water bath for 1.5 hours. Oil droplets formed within 5 minutes. The heat was lowered to 60 °C and the mixture heated for an additional 1.5 hours, followed by heating at 50 °C for 40 minutes, at 40 °C for 40 minutes, then at 30 0C for 45 minutes. The heat was turned off and the mixture was allowed to slowly cool to room temperature. The next day, the material was viewed under a microscope and indicated needles and plates. The material was then heated at 40 °C for 2 hours, at 35 0C for 30 minutes, and then at 30 °C for 30 minutes. The heat was turned off and the mixture was allowed to slowly cool to room temperature. The solid was then filtered and dried using a vacuum pump for 1 hour to give the title compound (117 mg, 73% yield).

EXAMPLE 6
Crystalline Dioxalate Salt of Biphenyl-2-ylcarbamic Acid l-(2-{|4-(4-Carbamoylpiperidin- 1 -ylmethyl)benzoyl]methylamino> ethyl)piperidin-4-yl Ester
510 mg of biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l-ylmethyl)benzoyl]methylamino} ethyl)piperidin-4-yl ester (0.853 mmol of 96% pure material; prepared as described in Example 1) was taken up in 5 ml of H2O:ACN (1:1) and 1.7 ml of IM aqueous oxalic acid was added slowly, while monitoring the pH. The pH was adjusted to approx. pH 3.0. The clear solution was filtered through a 0.2 micron filter, frozen and lyophilized to dryness to yield a dioxalate salt.
31.5 mg of the dioxalate salt was dissolved in 2.76 ml of 94%IPA/6%H20. The mixture was stirred in a pre-heated 60 °C water bath for 2.5 hours. After 25 minutes, all of the sample was in solution. The heat was turned off and the mixture was allowed to cool to room temperature. The next day, a small amount of viscous material was present. The vial was refrigerated at 4 °C. After 4 days, the viscous material was still present. The vial was then placed at room temperature and observed one month later. The material appeared to be solid, and was observed to be crystalline under a microscope. The solid was then filtered and dried using a vacuum pump for 1 hour to give the title compound (20 mg, 63.5% yield).
EXAMPLE 7
Crystalline Dioxalate Salt of Biphenyl-2-ylcarbamic Acid l-(2-{T4-(4-Carbamoylpiperidin- 1 -ylmethyl)benzoyl]methylammo) ethvDpiperidin-4-yl Ester
150 mg of the dioxalate salt (prepared as described in Example 6) was dissolved in 13.1 ml of 94%IPA/6%H20. The mixture was stirred in a pre-heated 60 °C water bath for 2.5 hours. The heat was turned off and the mixture was allowed to cool to room
temperature. The vial was refrigerated at 4 °C. After 6 days, an oily material was observed with what appeared to be a crystal on the side of the vial. The vial was then allowed to reach room temperature, at which point seeds (crystalline material from Example 6) were added and allowed to sit for 16 days. During this time, more crystals were observed to come out of solution. The solid was then filtered and dried using a vacuum pump for 14 hours to give the title compound (105 mg, 70% yield).

EXAMPLE 8
Crystalline Freebase Biphenyl-2-ylcarbamic Acid l-(2-(f4-(4-Carbamoylpiperidin-l- ylmethvDbenzoyl]methylaniino}ethyl)piperidin-4-yl Ester (Form T)
109 mg of biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (prepared as described in
Example 1) was dissolved in 0.56 ml of H2O: ACN (1:1). The suspension was left in a vial (cap loosely placed on top) to allow for a slower evaporation time. The vial was placed under a nitrogen flow environment, although the nitrogen was not used for evaporation, only for the environment. A precipitate was visible within 1 day, which was observed to be crystalline under a microscope. The solid was then placed on a high vacuum line to remove all solvent to give the title compound. Quantitative recovery, 97.8% pure by HPLC.

In an alternate procedure, after dissolving in H2O: ACN (1:1) (approximately 350 mg/mL), the vial was stored at 5 0C, and the precipitate was visible at day 2. The solid was filtered, rinsed with water, and dried on high vacuum overnight. Recovery was 55%, with the solid having 98.2% purity and the liquid having 92.8% purity.
EXAMPLE 9
Crystalline Freebase Biphenyl-2-ylcarbamic Acidl-(2-{J4-(4-Carbamoylpiperidin- l-yhiaethyl)benzoyllmethylammo|ethvDpiperidin-4-yl Ester (Form T)
50.4 mg of biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (prepared as described in
Example 1) was dissolved in 0.144 ml of H2O:ACN (1:1). The suspension was left in vial (cap loosely placed on top) to allow for a slower evaporation time. The vial was refrigerated at 4 0C for 6 days. A precipitate was visible after 2 days. The solid was filtered and placed on a high vacuum line to remove all solvent and give the title compound as a white solid (27.8 mg, 55.2 % yield).
EXAMPLE 10
Crystalline Freebase Biphenyl-2-ylcarbamic Acid l-(2-{[4-(4-Carbamoylpiperidin- l-vhnethvDbenzoyl]methylamino>ethvDpiperidin-4-yl Ester (Form T)
230 mg of biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l-yhnethyl)benzoyl]methylamino}ethyl)piρeridin-4-yl ester (prepared as described in
Example 1) was dissolved in 0.2 ml of H2O:ACN (1:1), using slight heat. The mixture was then heated in a 70 °C water bath for 2 hours. The heat was turned off and the mixture was allowed to cool to room temperature, then refrigerated at 4 °C for 1 hour. 50 μl of water was then added (oiled out), followed by the addition of 40 μl of ACN to get the sample back into solution. Seeds (crystalline material from Example 8) were added under slow stirring at room temperature. Crystals started to form ,and the mixture was allowed to sit overnight, with slow stirring. The next day, a heat cool cycle was applied (30 °C for 10 minutes, 40 0C for 10 minutes, then 50 °C for 20 minutes). The heat was turned off and the mixture allowed to cool overnight, with slow stirring. The next day, a second heat/cool cycle was applied (60 0C for 1 hour, with dissolving observed at 70 °C). The heat was turned off and the mixture allowed to cool overnight, with slow stirring. The next day, crystals were present and a third heat cool cycle was applied (60 0C for 3 hours). The heat was turned off and the mixture allowed to cool overnight, with slow stirring. The next day, a heat cool cycle was applied (60 °C for 3 hours, slow cool, then 60 °C for 3 hours). The heat was turned off and the mixture allowed to cool overnight, with slow stirring. After 3 days, the solid was filtered and placed on a high vacuum line to remove all solvent and give the title compound.
EXAMPLE 11
Crystalline Freebase Biphenyl-2-ylcarbamic Acid l-(2-{[4-(4-Carbamoylpiperidin- l-ylmethyl)benzoyl]methylamino|ethyl)piperidin-4-yl Ester (Form JD
70 mg of biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l-yhnethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (prepared as described in
Example 1) was dissolved in 0.1 mL ACN. After addition of 0.3 ml MTBE, the solution appeared cloudy. An additional 50 μl of ACN was added to clarify the solution (155 mg/ml ACN:MTBE = 1 :2). The mixture was left in the vial and capped. Crystals appeared by the next day. The solid was then filtered and placed on a high vacuum line to remove all solvent and give the title compound.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011008809

U.S. Patent Publication No. 2005/0203133 to Mammen et al. discloses novel biphenyl compounds that are expected to be useful for treating pulmonary disorders such as chronic obstructive pulmonary disease (COPD) and asthma. In particular, the compound biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l-ylmethyl) benzoyl]methylamino}ethyl)piperidin-4-yl ester is specifically described in this application as possessing muscarinic receptor antagonist or anticholinergic activity.

The chemical structure of biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoyl piperidin- 1 -ylmethyl)benzoyl]methylamino } ethyl)piperidin-4-yl ester is represented by formula I:

I

The compound of formula I has been named using the commercially-available AutoNom software (MDL, San Leandro, California).

Therapeutic agents useful for treating pulmonary or respiratory disorders are advantageously administered directly into the respiratory tract by inhalation. In this regard, several types of pharmaceutical inhalation devices have been developed for administering therapeutic agents by inhalation including dry powder inhalers (DPI),

metered-dose inhalers (MDI) and nebulizer inhalers. When preparing pharmaceutical compositions and formulations for use in such devices, it is highly desirable to have a crystalline form of the therapeutic agent that is neither hygroscopic nor deliquescent and which has a relatively high melting point thereby allowing the material to be micronized without significant decomposition. Although crystalline freebase forms of the compound of formula I have been reported in U.S. Patent Publication No. 2007/0112027 to Axt et al. as Form I and Form II, the crystalline freebase forms of the present invention have different and particularly useful properties, including higher melting points

One aspect of the invention relates to crystalline freebase forms of biphenyl-2-ylcarbamic acid 1 -(2- { [4-(4-carbamoylpiperidin- 1 -ylmethyl)benzoyl]methy lamino } ethyl) piperidin-4-yl ester characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2Θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1.

Another aspect of the invention relates to a crystalline freebase of biphenyl-2-ylcarbamic acid 1 -(2- { [4-(4-carbamoylpiperidin- 1 -ylmethyl)benzoyl]methy lamino } ethyl) piperidin-4-yl ester, designated as form III, which is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2Θ values of 6.6±0.1, 13. l±O.l,

18.6±0.1, 19.7±0.1, and 20.2±0.1; and further characterized by having five or more additional diffraction peaks at 2Θ values selected from 8.8=1=0.1, 10. l±O.l, 11.4±0.1, l l.β±O.l, 14.8±0.1, 15.2±0.1, lβ.l±O.l, 16.4±0.1, 16.9±0.1, 17.5±0.1, 18.2±0.1, 19.3±0.1, 19.9±0.1, 20.8±0.1, 21. l±O.l, 21.7±0.1, and 22.3±0.1.

Still another aspect of the invention relates to a crystalline freebase of biphenyl-2-ylcarbamic acid 1 -(2- { [4-(4-carbamoylpiperidin- 1 -ylmethyl)benzoyl]methy lamino } ethyl) piperidin-4-yl ester, designated as form IV, which is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2Θ values of 6.6±0.1 , 13. l±O.1 ,

18.6=1=0.1, 19.7=1=0.1, and 20.2±0.1; and further characterized by having five or more additional diffraction peaks at 2Θ values selected from 10.6±0.1, 15.0=1=0.1, lβ.O±O.l, 17.3±0.1, 17.7±0.1, 20.9±0.1, 21.4±0.1, 22.6±0.1, 24.6±0.1, and 27.8±0.1.

Preparation 1

Biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l- ylmethvDbenzovHmethylaminol ethyDpiperidin-4-yl Ester The diphosphate salt of biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (16 g) was dissolved in a biphasic mixture of water (100 mL) and EtOAc (200 mL). NaOH (2 N, 75 mL) was added over a period of 5 minutes. The mixture was then stirred for 30 minutes. The phases were separated and the aqueous phase was extracted with EtOAc (200 mL). The combined organic phases were concentrated. DCM (100 mL) was added, and the mixture evaporated to dryness. The solids were dried in an oven for about 48 hours to yield the title compound (9.6 g).

EXAMPLE 1

Crystalline Freebase of Biphenyl-2-ylcarbamic Acid l-(2-{r4-(4-Carbamoylpiperidin-l- ylmethyl)benzoyllmethylamino|ethyl)piperidin-4-yl Ester (Form III) Biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (102.4 mg) was dissolved in MeCN (500 μL). The solution was stirred at room temperature for 80 minutes and a white solid precipitate formed. The mixture was placed in the shaker block to thermocycle (0-40 0C in one hour blocks) for 48 hours. A white, dense, immobile solid was observed. MeCN (500 μL) was added to mobilize the slurry. The mixture was then placed back in the shaker block for 2 hours. The solids were isolated by vacuum filtration using a sinter funnel, then placed in the piston dryer at 40 0C under full vacuum for 15.5 hours, to yield 76.85 mg of the title crystalline compound.

EXAMPLE 2

Crystalline Freebase of Biphenyl-2-ylcarbamic Acid l-(2-{r4-(4-Carbamoylpiperidin-l- ylmethyl)benzoyllmethylamino|ethyl)piperidin-4-yl Ester (Form III) Diphosphate salt of biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoyl-piperidin-l-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (C3sH43NsO4»2H3PO4; MW 793.75; 632.9 g) was slurried in isopropyl acetate (11.08 L) and water (6.33 L) at room temperature under nitrogen. The suspension was warmed to 53±3 0C and 1OM NaOH (317 mL) was added to the stirred mixture, while maintaining the temperature of the mixture above 50 0C. The mixture was stirred for approximately 5 minutes at 53±3 0C before allowing the layers to settle. The layers were then separated and the aqueous layer was removed. Water (3.16 L) was added to the organic layer while maintaining the temperature of the mixture above 50 0C. The mixture was stirred for 5 minutes at 53±3 0C before allowing the layers to settle. The layers were separated and the water layer was removed. Isopropyl acetate (6.33 L) was added and then about 10 volumes of distillate were collected by atmospheric distillation. This step was repeated with additional isopropyl acetate (3.2 L). After the second distillation, the temperature of the clear solution was reduced to 53±3 0C, then seeded with a suspension of the biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester crystalline freebase (Form III; 3.2 g) in isopropyl acetate (51 mL). The resulting suspension was stirred at 53±3 0C for 2 hours, then cooled to 10±3 0C over 4 hours. The suspension was stirred at 10±3 0C for at least 2 hours and then the solids were collected by filtration. The resulting filter cake was washed with isopropyl acetate (2 x 1.9 L) and the product was dried in vacuo at 50 0C to yield the title crystalline compound (C3SH43NsO4; MW 597.76; 382.5 g, 80.3% yield).

EXAMPLE 3

Recrystallization of Crystalline Freebase of Biphenyl-2-ylcarbamic Acid l-(2-{[4-(4- Carbamoylpiperidin- 1 -ylmethyDbenzoyllmethylaminol ethyl)piperidin-4-yl Ester (Form

III)

Crystalline freebase of biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (Form III; C35H43N5O4; MW 597.76; 372.5 g) was slurried in toluene (5.6 L) at 20±3 0C under nitrogen. The suspension was warmed to 82±3 0C, and held at this temperature until complete dissolution was observed. The solution was then clarified into the crystallizer vessel, followed by rinsing with toluene (373 μL). Solids were observed in the crystallizer vessel, and the vessel was re-heated to 82±3 0C to effect dissolution, then cooled to 58±3 0C and seeded with a pre-sonicated (approximately 1 minute) of crystalline freebase (Form III; 1.9 g) in toluene (8 μL). The resulting suspension was allowed to stand at 58±3 0C for at least 4 hours, then cooled to 20±3 0C over 2 hours (approximate cooling rate of 0.33 °C/min). The suspension was stirred at 20±3 0C for at least 1 hour, then the solids were collected by filtration. The resulting filter cake was washed with toluene (2 x 1.2 L) and the product was dried in vacuo at 52±3 0C to yield the title crystalline compound (345.3 g, 92.7% yield).

EXAMPLE 4

Crystalline Freebase of Biphenyl-2-ylcarbamic Acid l-(2-{r4-(4-Carbamoylpiperidin-l- ylmethyl)benzoyllmethylamino|ethyl)piperidin-4-yl Ester (Form IV) Biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (prepared as described in Preparation 1; 2.5 g) was dissolved in MeCN (10 mL) to yield a viscous oily pale yellow material. Additional MeCN (5 mL) was added to dilute the material. The solution was seeded with crystalline freebase (20 mg; Form III prepared as described in Example 1) and stirred at room temperature for 90 minutes. A large amount of white precipitate (small crystals) was observed. The slurry was analyzed under a polarized light microscope and found to be birefringent.

Additional MeCN (3 mL) was added and the slurry was placed in a Metz SynlO block to thermocycle (0-40 0C in one hour blocks) at 800 rpm overnight. The Metz SynlO is a 10 position parallel reaction station that is static. Agitation of the solution/slurry was by a cross magnetic stirrer bar. The shaker block was a separate piece of equipment that was heated and cooled by an external Julabo bath. The material was removed at 0 0C. It was observed that the slurry had settled out, leaving a pale yellow solution above the white precipitate. The slurry was stirred and placed back in the shaker block to thermocycle.

The material was removed at 40 0C, and stirred at a high agitation rate at room temperature for 80 minutes. The slurry was again analyzed and found to be birefringent. The filter cake was isolated by vacuum filtration using a sinter funnel. MeCN (3 mL) was used to wet the filter paper and the filter cake was washed with MeCN prior to filtration. The cake was deliquored under vacuum for 40 minutes to yield 2.3 g of a flowing white powder. The material was placed in a piston dryer at 400C for 65 hours, to yield 2.2 g of the title crystalline compound as a white powder (99.6% purity).

PATENT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=0049F6A3F9FB8C7273B825D49F2465F6.wapp1nA?docId=WO2005087738&tab=PCTDESCRIPTION&maxRec=1000

Example 1
Biphenyl-2-ylcarbamic Acid l-(2-{[4-(4-Carbamoylpiperidin-l- ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl Ester

To a three-necked 2-L flask was added isonipecotamide (5.99 g, 40.0 mmol), acetic acid (2.57 mL), sodium sulfate (6.44 g) and LPA (400 mL). The reaction mixture was cooled to 0-10°C with an ice bath and a solution ofthe product of Preparation 5 (11 g, 22.7 mmol) in LPA (300 mL) was slowly added. The reaction mixture was stined at room temperature for 2 hours and then cooled to 0-10°C. Sodium triacetoxyborohydride (15.16 g, 68.5 mmol) was added portion wise and this mixture was stined at room temperature for 16 h. The reaction mixture was then concentrated under reduced pressure to a volume of about 50 mL and this mixture was acidified with IN HCl (200 mL) to pH 3. The resulting mixture was stined at room temperature for 1 hour and then extracted with DCM (3 x 250 mL). The aqueous phase was then cooled to 0-5°C with an ice bath and 50% aqueous NaOH solution was added to adjust the pH ofthe mixture to 10. This mixture was then extracted with isopropyl acetate (3 x 300 mL) and the combined organic layers were washed with water (100 mL), brine (2 x 50 mL), dried over sodium sulfate, filtered and concentrated to afford 10.8 g ofthe title compound (80% yield. MS m/z: [M + H“1”] calcd for C35H43N5O4, 598.3; found, 598.6. Rf = 2.32 min (10-70 ACN: H2O, reverse phase HPLC).

Example 1A
Biphenyl-2-ylcarbamic acid l-(2- {[4-(4-carbamoylpiperidin-l-ylmethyl)benzoyl] methylamino} ethyl)piperidin-4-yl ester was also prepared as a diphosphate salt using the following procedure :
5.0 g ofthe product of Example 1 was combined with 80 ml of IPA:ACN (1:1). 4.0 ml of water was added and the mixture heated to 50°C under stining, forming a clear solution. To this was added dropwise at 50°C, 16 ml 1M phosphoric acid. The resulting cloudy solution was stined at 50°C for 5 hours, then allowed to cool to ambient temperature, under slow stirring, overnight. The resulting crystals were collected by filtration and air-dried for 1 hour, then under vacuum for 18 hours, to give the diphosphate salt ofthe title compound (5.8 g, 75% yield) as a white crystalline solid (98.3% purity by HPLC).

Example IB
Biphenyl-2-ylcarbamic acid 1 -(2- { [4-(4-carbamoylpiperidin- 1 -ylmethyl)benzoyl] methylamino }ethyl)piperidin-4-yl ester was also prepared as a monosulfate salt using the following procedure.
442 mg ofthe product of Example 1 (0.739 mmol of 96% pure material) was taken up in 5 ml of H2O:ACN (1:1) and 1.45 ml of IN sulfuric acid was added slowly, while monitoring the pH. The pH was adjusted to approx. pH 3.3. The clear solution was filtered through a 0.2 micron filter, frozen and lyophilized to dryness. 161 g of the lyophilized material was dissolved in 8.77 ml of IPA:ACN (10:1). The suspension was heated by placing the vial in a pre-heated 70°C water bath for 1.5 hours. Oil droplets formed within 5 minutes. The heat was lowered to 60°C and the mixture heated for an additional 1.5 hours, followed by heating at 50°C for 40 minutes, at 40°C for 40 minutes, then at 30°C for 45 minutes. The heat was turned off and the mixture was allowed to slowly cool to room temperature. The next day, the material was viewed under a microscope and indicated needles and plates. The material was then heated at 40°C for 2 hours, at 35°C for 30 minutes, and then at 30°C for 30 minutes. The heat was turned off and the mixture was allowed to slowly cool to room temperature. The solid was then filtered and dried using a vacuum pump for 1 hour to give the monosulfate salt ofthe title compound (117 mg, 73% yield).

Example IC
Biphenyl-2-ylcarbamic acid l-(2- {[4-(4-carbamoylpiperidin-l-ylmethyl)benzoyl] methylamino} ethyl)piperidin-4-yl ester was also prepared as a dioxalate salt using the following procedure.
510 mg ofthe product of Example 1 (0.853 mmol of 96% pure material) was taken up in 5 ml of H2O:ACN (1:1) and 1.7 ml of 1M aqueous oxalic acid was added slowly, while monitoring the pH. The pH was adjusted to approx. pH 3.0. The clear solution was filtered through a 0.2 micron filter, frozen and lyophilized to dryness. 150 mg ofthe lyophilized material was dissolved in 13.1 ml of 94%IPA/6%H20. The mixture was stined in a pre-heated 60°C water bath for 2.5 hours. The heat was turned off and the mixture was allowed to cool to room temperature. The vial was refrigerated at 4°C. After 6 days, an oily material was observed with what appeared to be a crystal on the side ofthe vial. The vial was then allowed to reach room temperature, at which point seeds (synthesis described below) were added and allowed to sit for 16 days. During this time, more crystals were observed to come out of solution. The solid was then filtered and dried using a vacuum pump for 14 hours to give the dioxalate salt ofthe title compound (105 mg, 70% yield).
Seed Synthesis
510 mg ofthe product of Example 1 (0.853 mmol of 96% pure material) was taken up in 5 ml of H2O:ACN (1:1) and 1.7 ml of 1M aqueous oxalic acid was added slowly, while monitoring the pH. The pH was adjusted to approx. pH 3.0. The clear solution was filtered through a 0.2 micron filter, frozen and lyophilized to dryness to yield a dioxalate salt. 31.5 mg of this dioxalate salt was dissolved in 2.76 ml of 94%IPA/6%H20. The mixture was stined in a pre-heated 60°C water bath for 2.5 hours. After 25 minutes, all of the sample was in solution. The heat was turned off and the mixture was allowed to cool to room temperature. The next day, a small amount of viscous material was present. The vial was refrigerated at 4°C. After 4 days, the viscous material was still present. The vial was then placed at room temperature and observed one month later. The material appeared to be solid, and was observed to be crystalline under a microscope. The solid was then » filtered and dried using a vacuum pump for 1 hour to give the dioxalate salt (20 mg, 63.5% yield).

Example ID
Biphenyl-2-ylcarbamic acid 1 -(2- { [4-(4-carbamoylpiperidin- 1 -ylmethyl)benzoyl] methylamino} ethyl)piperidin-4-yl ester was also prepared as a freebase crystal using the following procedure.
230 mg ofthe product of Example 1 was dissolved in 0.2 ml of H O:ACN (1:1), using slight heat. The mixture was then heated in a 70°C water bath for 2 hours. The heat was turned off and the mixture was allowed to cool to room temperature, then refrigerated at 4°C for 1 hour. 50 μl of water was then added (oiled out), followed by the addition of 40 μl of ACN to get the sample back into solution. Seeds (synthesis described below) were added under slow stirring at room temperature. Crystals started to form ,and the mixture was allowed to sit overnight, with slow stirring. The next day, a heat cool cycle was applied (30°C for 10 minutes, 40°C for 10 minutes, then 50°C for 20 minutes). The heat was turned off and the mixture allowed to cool overnight, with slow stirring. The next day, a second heat/cool cycle was applied (60°C for 1 hour, with dissolving observed at 70°C). The heat was turned off and the mixture allowed to cool overnight, with slow stirring. The next day, crystals were present and a third heat cool cycle was applied (60°C for 3 hours). The heat was turned off and the mixture allowed to cool overnight, with slow stirring. The next day, a heat cool cycle was applied (60°C for 3 hours, slow cool, then 60°C for 3 hours). The heat was turned off and the mixture allowed to cool overnight, with slow stirring. After 3 days, the solid was filtered and placed on a high vacuum line to remove all solvent and give a freebase crystal ofthe title compound.

Seed Synthesis
109 mg ofthe product of Example 1 was dissolved in 0.56 ml of H2O:ACN (1:1). The suspension was left in a vial (cap loosely placed on top) to allow for a slower evaporation time. The vial was placed under a nitrogen flow environment, although the nitrogen was not used for evaporation, only for the environment. A precipitate was visible within 1 day, which was observed to be crystalline under a microscope. The solid was then placed on a high vacuum line to remove all solvent to give the freebase crystal.
Quantitative recovery, 97.8% pure by HPLC.

Example IE
Biphenyl-2-ylcarbamic acid 1 -(2- { [4-(4-carbamoylpiperidin- 1 -ylmethyl)benzoyl] methylamino} ethyl)piperidin-4-yl ester was also prepared as a freebase crystal using the following alternate procedure.
70 mg ofthe product of Example 1 was dissolved in 0.1 mL ACN. After addition of 0.3 ml MTBE, the solution appeared cloudy. An additional 50 μl of ACN was added to clarify the solution (155 mg/ml ACNMTBE = 1 :2). The mixture was left in the vial and capped. A solid appeared by the next day. The solid was then filtered and placed on a high vacuum line to remove all solvent and give a freebase crystal ofthe title compound.

PATENT

https://patents.google.com/patent/WO2012009166A1/en

U.S. Patent No. 7,228,657 to Mammen et al. discloses novel biphenyl compounds that are expected to be useful for treating pulmonary disorders such as chronic obstructive pulmonary disease and asthma. In particular, the compound biphenyl-2-ylcarbamic acid 1- (2- {[4-(4-carbamoylpiperidin-l-ylmethyl)benzoyl]methylamino}-ethyl)piperidin-4-yl ester is specifically described in this application as possessing muscarinic receptor antagonist or anticholiner ic activity, and is represented by formula I:

Figure imgf000002_0001

The compound of formula I is synthesized from the compound 8, which is described as being prepared from the oxidation of 2-(benzylmethylamino)ethanol to the aldehyde intermediate followed by reductive amination with biphenyl-2-yl-carbamic acid piperidin- 4-yl ester and debenzylation:

Figure imgf000003_0001
Figure imgf000003_0002

However, while this procedure performs well on small scale, the aldehyde intermediate is difficult to scale up due to its instability, and low yields were typically observed.

Thus, a need exists for an efficient process of preparing compound 8 as a pure material with high chemical purity and good overall yield, without having to isolate intermediates. This invention addresses those needs.

Therapeutic agents useful for treating pulmonary or respiratory disorders are advantageously administered directly into the respiratory tract by inhalation. In this regard, several types of pharmaceutical inhalation devices have been developed for administering therapeutic agents by inhalation including dry powder inhalers, metered- dose inhalers, and nebulizer inhalers. When preparing pharmaceutical compositions and formulations for use in such devices, it is highly desirable to have a crystalline form of the therapeutic agent that is neither hygroscopic nor deliquescent and which has a relatively high melting point thereby allowing the material to be micronized without significant decomposition.

A crystalline diphosphate of the compound of formula I has been reported in U.S. Patent No. 7,700,777 to Axt et al, and a crystalline freebase (identified as Form III) is described in U.S. Patent Application Publication No. 201 1/0015163 to Woollham. All of the aforementioned disclosures are incorporated herein by reference.

The compound of formula I is described as being prepared by reacting compound 8 with 4-carboxybenzaldehyde to form the aldehyde core 10:

Figure imgf000004_0001

which is then isolated prior to being combined with isonipicotamide in the presence of a reducing agent to form the compound of formula I. The crystalline diphosphate is prepared by contacting the separated and purified compound of formula I with phosphoric acid. The crystalline freebase (Form III) can then be prepared from the crystalline diphosphate.

A need also exists for an efficient process of preparing the crystalline freebase (Form III). It is desirable to develop a process that does not first require preparation of the crystalline diphosphate. This invention addresses those needs.

Figure imgf000011_0001
Figure imgf000013_0001
Figure imgf000014_0001

Preparation 1

Biphenyl-2-yl-carbamic acid piperidin-4-yl Ester

Figure imgf000018_0001

Biphenyl-2-isocyanate (97.5 g, 521 mmol) and 1 -benzylpiperidin-4-ol (105 g, 549 mmol) were heated together at 70°C for 12 hours. The mixture was then cooled to 50°C and EtOH (1 L) was added, followed by the slow addition of 6M HC1 (191 mL). The resulting mixture was then cooled to ambient temperature. Ammonium formate (98.5 g, 1.6 mol) was added and then nitrogen gas was bubbled through the solution vigorously for 20 minutes. Palladium on activated carbon (20 g, 10 wt% dry basis) was added and the mixture was heated at 40°C for 12 hours, and then filtered. The solvent was removed under reduced pressure and 1M HC1 (40 mL) was added to the crude residue. The pH of the mixture was adjusted with 10 N NaOH to pH 12. The aqueous layer was extracted with EtOAc (2×150 mL), and the organic layer was dried over MgS04, filtered and the solvent removed under reduced pressure to yield the title compound (155 g). HPLC (10-70) ¾ = 2.52; m/z: [M + H+] calcd for Ci8H2202 297.15; found 297.3.

EXAMPLE 1

Step A: (2,2-Dimethoxyethyl)methylcarbamic Acid Benzyl Ester

Figure imgf000018_0002

K2CO3 (13.8 g, 100 mmol, 1.76 eq.) and H20 (46 mL) were mixed to form a homogeneous solution. The solution was cooled to 20°C. N-methylaminoacetaldehyde dimethylacetal (12.8 mL, 100 mmol, 1.8 eq) and MeTHF (50 mL) were added. The resulting mixture was cooled to 2°C. Benzyl chloroformate (8.1 mL, 56.7 mmol, 1.0 eq.) was added by syringe over 10 minutes (addition was exothermic). The mixture was maintained at room temperature until completion of the reaction. The layers were separated and the organic layer was washed with IN HC1 (50 mL) and used directly in the next step.

Step B: Methyl-(2-oxoethyl)carbamic Acid Benzyl Ester

Figure imgf000019_0001

The mixture from the previous step was combined with a 3N HC1 solution (70 mL), and the resulting mixture was stirred for 18 hours at 22°C to yield a clear homogeneous pale yellow solution. Solid aHC03 was added to the solution to bring the pH to neutral. The layers were separated and the aqueous layer was back-extracted with MeTHF (20 mL). The organic layers were combined and washed with a saturated aHC03 solution (50 mL). The layers were separated and the organic layer was dried over Na2S04, filtered and concentrated to dryness to afford the title compound (1 1.9 g) as a pale yellow oil.

Step C: Biphenyl-2-yl-carbamic acid l-[2-(benzyloxycarbonyl

methylamino)ethyl]piperidin-4-yl Ester

Figure imgf000019_0002

Biphenyl-2-yl-carbamic acid piperidin-4-yl ester (31.1 g, 105 mmol, 1.0 eq.) and MeTHF (150 mL) were mixed. A solution of methyl-(2-oxoethyl)carbamic acid benzyl ester (23 g, 113.4 mmol, 1.05 eq.) in MeTHF (150 mL) was prepared and added to the ester mixture. The resulting mixture was heated to 30°C for a few minutes, then cooled to room temperature over 1 hour. The mixture was then cooled to 3°C and the temperature maintained for 1 hour. NaHB(OAc)3 (35.1 g, 170 mmol, 2.0 eq.) was added portion-wise while maintaining the internal temperature at 7±1°C. After addition, the mixture was allowed to warm to room temperature until the reaction was complete. A saturated solution of aHC03 (3000 mL) was added, stirred for 20 minutes, and the layers separated. This was repeated, after which the organic layer was dried over a2S04. The material was filtered, concentrated and dried under high vacuum to afford the title compound (43 g) as a thick colorless to pale yellow oil, which was used directly in the next step without purification.

Step D: Biphenyl-2-yl-carbamic acid l-(2-methylaminoethyl)piperidin-4-yl Ester

Figure imgf000020_0001

Biphenyl-2-yl-carbamic acid l-[2-(benzyloxycarbonyl methylamino)ethyl] piperidin-4-yl ester (53 g, 105 mmol, 1 eq.), MeOH (250 mL), and MeTHF (50 mL) were combined under nitrogen. 10% palladium on carbon (0.8 g) was added and hydrogen was bubbled into the mixture for 1 minute. The reaction vessel was sealed and stirred under hydrogen at atmospheric pressure for three hours. The mixture was then filtered, and the solids were washed MeTHF (10 mL).

The filtrate and washes were combined and concentrated under reduced pressure (250 mL removed). MTBE (100 mL) was added, and the solution again concentrated under reduced pressure (100 mL removed). MTBE (200 mL) was added and the solution was seeded with a few milligrams of biphenyl-2-yl-carbamic acid l-(2-methylaminoethyl) piperidin-4-yl ester, and the mixture was maintained for 3 hours. The solids were collected and the vessel and filter cake were washed with MTBE (2×15 mL). The material was dried to yield 13.2 g of the title compound (99.5% pure). This process was repeated to yield the title compound (12.5 g, 98.6% pure). The filtrate and washes were combined and concentrated under reduced pressure. MTBE (150 mL) was added and the solution was seeded with a few milligrams of biphenyl-2-yl-carbamic acid l-(2-methylaminoethyl) piperidin-4-yl ester, and the mixture was maintained for 20 hours. The solids were collected and the vessel and filter cake were washed with MTBE (2×15 mL). The material was dried to yield the title compound (5 g, 90% pure).

A portion of the three crops (13 g , 12 g, 4.5 g, respectively) were combined taken up in IPA (90 mL). The resulting slurry was heated to 45°C, then cooled to room temperature over 1 hour. The slurry was stirred for 5 hours at 25°C. The solids were collected and washed with IPA (2×15 mL). The solids were then dried for 1 hour to yield the title compound (25 g, >99% pure).

EXAMPLE 2

All volumes and molar equivalents are given relative to biphenyl-2-yl-carbamic acid piperidin-4-yl ester.

Step A: (2,2-Dimethoxyethyl)methylcarbamic Acid Benzyl Ester K2C03 (8.4 kg, 60 mol, 1.8 eq.) and H20 (49.3 kg, 2.6 volumes) were placed in the reaction vessel and stirred. N-methylaminoacetaldehyde dimethylacetal (6.5 kg, 54 mol, 1.6 eq) and MeTHF (20.2 kg, 2.9 volumes) were added. The resulting mixture was cooled to 5°C. Benzyl chloroformate (6.8 kg, 37.6 mol, 1.1 eq.) was added over a period of about 30 minutes, while maintaining the temperature below 10°C. The feed line was rinsed with MeTHF (4.3 kg). The mixture was then maintained at 5°C and stirred for 1 hour. The layers were separated and the organic layer was washed with IN HC1 (14.3 kg, 1 1.7 mol, 1.4 volumes) and used directly in the next step.

Step B: Methyl-(2-oxoethyl)carbamic Acid Benzyl Ester

The mixture from the previous step was combined with water (23.4 kg,

2.9 volumes) and 30% hydrochloric acid (13.1 kg, 107.7 mol, 1.1 volumes). Water (5.1 kg) was used to rinse the feed line. The temperature was adjusted to 25-30°C, and the reaction was run for 16-24 hours. A 25% NaOH solution (1 1.8 kg, 71.1 mol, 2.2 eq.) was added to the solution to adjust the pH and obtain phase separation.

The layers were separated and the aqueous layer was back-extracted with MeTHF

(10.0 kg, 1.1 volumes). The aqueous layer was discarded and the organic layers were combined. MeTHF (4.4 kg) was used to rinse the feed line. The organics were washed with a saturated aHC03 solution (14.6 kg, 15.6 mol, 1.1 volumes). The layers were separated and the organic layer was dried over a2S04 (2.5 kg, 17.6 mol) for 60-90 minutes. The drying agent was filtered off and the remaining solids were washed with

MeTHF (8.8 kg, 1 volume). The reaction vessel was washed with water and MeOH before continuing with the next step.

Step C: Biphenyl-2-yl-carbamic acid l-[2-(benzyloxycarbonyl

methylamino) ethyl Jpiperidin-4-yl Ester

The product from the previous step (in MeTHF) and biphenyl-2-yl-carbamic acid piperidin-4-yl ester (10.0 kg, 32.6 mol, 1.0 eq.) in MeTHF (28.5 kg) were placed in the reaction vessel and heated to 30°C for one hour. The mixture was then cooled to 5°C. NaHB(OAc)3 (10.0 kg, 45.8 mol, 1.4 eq.) was added portion wise over a period of 40 minutes while maintaining the temperature below 20°C. The mixture was then stirred for 30 minutes. Additional NaHB(OAc)3 (0.5 kg) was added the reaction allowed to progress to completion. A saturated solution of NaHCC^ (14.3 kg, 15.3 mol, 1.1 volumes) was added and stirred for 10 minutes. The aqueous phase was separated and discarded. A 33% NaOH solution (15.8 kg, 129.9 mol, 4.0 eq.) was added to the reaction mixture to adjust the H to be in the range of 8-12. Water (40 kg) was added in two portions, after which phase separation occurred. A saturated NaHCC (7.1 kg, 7.6 mol, 0.7 volumes) was added to the reaction mixture and stirred for 10 minutes. The aqueous phase was separated and discarded. Additional water (4.9 kg) was added to dissolve any remaining salts and a vacuum distillation was conducted at a maximum temperature of 45°C to remove part of the solvent (7.2 volumes). MeOH (56.1 kg, 7.2 volumes) was added to the reaction mixture before continuing with the next step.

Step D: Biphenyl-2-yl-carbamic acid l-(2-methylaminoethyl)piperidin-4-yl Ester

10% palladium on carbon (0.4 kg, 0.03 wt%, Degussa type 101 NE/W) was added to the reaction mixture. A hydrogenation reaction was performed to remove the benzyloxycarbonyl protective group, with reaction conditions at 30±5°C and 4 bar pressure. The reaction was run until completion. The mixture was then filtered and the filter cake was washed with MeOH (8.0 kg, 1.0 volume). The reaction was continued in a clean vessel, which was charged with the product solution (in MeTHF/MeOH) from the hydrogenation reaction. 3-Mercaptopropyl silica (0.6 kg, 0.07 wt%, Silicycle) was added. MeOH (4.8 kg) was used to rinse the feed line. The reaction mixture was stirred for 14-72 hours at 25±5°C. Activated carbon (0.7 kg, 0.07 wt%) was added and the mixture stirred for 30 minutes. The mixture was filtered and the filter cake was washed with MeOH (1.0 volume). The reaction was continued in a clean vessel, which was charged with the product solution (in MeTHF/MeOH), and MeOH (4.2 kg) was used to rinse the feed line. The mixture was heated to 40-45°C and a vacuum distillation was performed to bring the final volume to 5.6 volumes (removal of methanol).

2-propanol (40.2 kg, 5.0 volumes) was added and distillation continued until the volume was reduced to 2.5 volumes. The solids were then isolated by filtration and washed with MTBE (1.5 volumes) to yield the product as a wet cake (8.6 kg, 96.8% purity). The cake was charged to the reaction vessel and additional 2-propanol

(1.9 volumes) was added. The mixture was warmed to 40±5°C, and maintained at that temperature for 2 hours. The mixture was then slowly cooled over a minimum of 4 hours to 20°C, then actively cooled to 5-10°C, followed by stirring for 2 hours. The product was filtered and the resulting cake washed with MTBE (1.0 volume). The solids were then dried under atmospheric conditions to yield the title compound (6.6 kg, 98.5% purity).

EXAMPLE 3

Crystalline Freebase of Biphenyl-2-yl-carbamic Acid l- {2-r(4-carbamoylbenzoyl) methylaminolethyllpiperidin-4-yl Ester (Form III)

Biphenyl-2-yl-carbamic acid l-{2-[(4-formylbenzoyl)

methylamino ] ethyl }piperidin-4-yl Ester

Figure imgf000023_0001

4-Carboxybenzaldehyde (9 g, 60 mmol, 1.0 eq.) and biphenyl-2-yl-carbamic acid 1-

(2-methylaminoethyl)piperidin-4-yl ester (21.2 g, 60 mmol, 1.0 eq.) were combined in MeTHF (115 mL). The mixture was stirred for 0.5 hours, forming a thick slurry.

Additional MeTHF (50 mL) was added to form a free-flowing slurry. 4-(4,6-dimethoxy- l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (18 g, 63 mmol, 1.1 eq., 97% pure) was added in two portions and the funnel rinsed with additional MeTHF (50 mL). The mixture was stirred at room temperature overnight. MeCN (50 mL) was added and the mixture was filtered. The solids were washed with MeTHF (30 mL). The filtrate and washes were combined and a saturated aHC03 solution (100 mL) was added and stirred for 10 minutes. The layers were separated and a saturated NaCl solution (100 mL) was added and stirred for 10 minutes. The layers were separated and the aqueous layer discarded. The resulting solution was concentrated under reduced pressure and held at room temperature for three days, then used directly in the next step.

Step B: Biphenyl-2-yl-carbamic acid l-{2-[(4-carbamoylbenzoyl)

meth lamino] ethyl}piperidin-4-yl ester (non-isolated form)

Figure imgf000023_0002

Isonipecotamide (15.4, 120 mmol, 2.0 eq.) and IPA (200 mL) were added to the solution of biphenyl-2-yl-carbamic acid l-{2-[(4-formylbenzoyl)methylamino]ethyl} piperidin-4-yl ester from the previous step. Liquid (200 mL) was distilled off and additional IPA (400 mL) was added under reduced pressure at 60°C. Liquid (400 mL) was distilled off over a period of 1.5 hours and additional IPA (600 mL) was added. Liquid (100 mL) was distilled off and the remaining solution was cooled to 30°C to yield a hazy white mixture, which was then added to Na2S04 (18 g). The flask was rinsed with IPA (100 mL) and added to the solution. The resulting mixture was cooled to room

temperature and AcOH (20 mL, 360 mmol, 6.0 eq.) was added. The mixture was cooled to 18°C with an ice bath and NaHB(OAc)3 (38.2 g, 180 mmol, 3.0 eq.) was added over 5 minutes. The mixture was allowed to warm up to 25°C and was maintained at that temperature for 2 hours. Solvent was removed under reduced pressure, and the remaining material was used directly in the next step.

Step C: Biphenyl-2-yl-carbamic acid l-{2-[(4-carbamoylbenzoyl)

methylamino]ethyl}piperidin-4-yl ester (isolated solid)

iPrOAc (300 mL) was added to the material, followed by the addition of water (200 mL). The pH of the solution was adjusted to pH 1 with 3N HC1 (-150 mL). The layers were separated and the organic layer was discarded. The aqueous layer was collected, and iPrOAc (300 mL) was added. The pH of the solution was adjusted to basic pH with 50 wt% NaOH (-100 mL). The resulting mixture was stirred for 15 minutes and the layers were separated. The organic layer was filtered and seeded with micronized crystalline freebase of biphenyl-2-yl-carbamic acid l- {2-[(4-carbamoylbenzoyl) methylamino]ethyl}piperidin-4-yl ester (Form III; prepared as described in U.S. Patent Application Publication No. 201 1/0015163 to Woollham) and stirred overnight at room temperature to yield a white slurry. Stirring was continued for 8 hours at room temperature and for 16 hours at 5°C (cold room). The mixture was slowly filtered under pressure. The cake was washed with cold iPrOAc (2×20 mL) and dried under nitrogen to yield a white solid (27.5 g). The material was further dried in a vacuum oven at 30°C for 24 hours to yield 25.9 g.

Step D: Crystalline Freebase of Biphenyl-2-yl-carbamic Acid l-{2-[ ( 4- carbamoylbenzoyl)methylamino]ethyl}piperidin-4-yl Ester (Form III) The white solid (5 g, 60 mmol, 1.0 eq.) was dissolved in toluene (75 mL) and the resulting mixture was heated to 82°C to yield a clear solution. The solution was filtered. The solids were washed with toluene (2 x 5 mL), and the filtrate and washes were combined. The mixture was cooled to 60°C and seeded with micronized crystalline freebase of biphenyl-2-yl-carbamic acid l-{2-[(4-carbamoylbenzoyl)methylamino]ethyl} piperidin-4-yl ester (Form III; prepared as described in Example 3 in U.S. Patent

Application Publication No. 201 1/0015163 to Woollham). The mixture was maintained at 55°C for 2 hours, then cooled to room temperature on an oil bath overnight (~16 hours). The resulting slurry was then filtered and the cake was dried for 3 hours to yield a solid while material (4.6 g). The material was further dried in a vacuum oven at 30°C for 24 hours (exhibited no further weight loss) to yield the title compound (4.6 g).

The product was analyzed by powder x-ray diffraction, differential scanning calorimetry and thermal gravimetric analysis, and was determined to be the crystalline freebase (Form III) of biphenyl-2-ylcarbamic acid l-(2-{[4-(4-carbamoylpiperidin-l- ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester described in U.S. Patent Application Publication No. 201 1/0015163 to Woollham.

US20050113417A1 *2003-11-212005-05-26Mathai MammenCompounds having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity
WO2006099165A1 *2005-03-102006-09-21Theravance, Inc.Crystalline forms of a biphenyl compound
US7228657B22003-07-102007-06-12Controlled Environments LimitedClimate control for a greenhouse
US20110015163A12009-07-152011-01-20Grahame WoollamCrystalline freebase forms of a biphenyl compound
Family To Family Citations
JP4555283B2 *2003-02-142010-09-29セラヴァンス, インコーポレーテッドβ2 adrenergic receptor agonist activity and biphenyl derivatives having muscarinic receptor antagonist activity
CN1930125B *2004-03-112010-07-21施万制药Biphenyl compounds useful as muscarinic receptor antagonists
US7659403B2 *2005-03-102010-02-09Theravance, Inc.Biphenyl compounds useful as muscarinic receptor antagonists
Patent ID

Title

Submitted Date

Granted Date

US9226896 CRYSTALLINE FREEBASE FORMS OF A BIPHENYL COMPOUND
2014-11-19
2015-06-18
US9656993 CRYSTALLINE FORMS OF A BIPHENYL COMPOUND
2015-12-18
2016-06-16
US7700777 Crystalline forms of a biphenyl compound
2007-12-27
2010-04-20
Patent ID

Title

Submitted Date

Granted Date

US9415041 Crystalline freebase forms of a biphenyl compound
2015-12-01
2016-08-16
US9249099 CRYSTALLINE FORMS OF A BIPHENYL COMPOUND
2014-11-25
2015-06-04
US8921396 Crystalline freebase forms of a biphenyl compound
2013-08-22
2014-12-30
US7521041 Biphenyl compounds useful as muscarinic receptor antagonists
2008-04-24
2009-04-21
US2007112027 Crystalline forms of a biphenyl compound
2007-05-17
Patent ID

Title

Submitted Date

Granted Date

US8017783 Biphenyl compounds useful as muscarinic receptor antagonists
2008-03-20
2011-09-13
US7550595 Biphenyl compounds useful as muscarinic receptor antagonists
2007-12-20
2009-06-23
US9283183 BIPHENYL COMPOUNDS USEFUL AS MUSCARINIC RECEPTOR ANTAGONISTS
2014-11-12
2015-06-18
US2010048622 CRYSTALLINE FORMS OF A BIPHENYL COMPOUND
2010-02-25
US9452161 Biphenyl compounds useful as muscarinic receptor antagonists
2016-02-05
2016-09-27
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Title

Submitted Date

Granted Date

US8754225 PROCESS FOR PREPARING A BIPHENYL-2-YLCARBAMIC ACID
2012-01-19
US8921395 Crystalline forms of a biphenyl compound
2014-03-19
2014-12-30
US8716313 Crystalline forms of a biphenyl compound
2013-01-14
2014-05-06
US8557997 Biphenyl compounds useful as muscarinic receptor antagonists
2012-08-23
2013-10-15
US8541451 CRYSTALLINE FREEBASE FORMS OF A BIPHENYL COMPOUND
2011-01-20
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Title

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US8377965 CRYSTALLINE FORMS OF A BIPHENYL COMPOUND
2010-10-07
US8242137 CRYSTALLINE FORMS OF A BIPHENYL COMPOUND
2010-01-28
2012-08-14
US2017204061 BIPHENYL COMPOUNDS USEFUL AS MUSCARINIC RECEPTOR ANTAGONISTS
2016-08-30
US9765028 CRYSTALLINE FREEBASE FORMS OF A BIPHENYL COMPOUND
2016-07-11
US9035061 PROCESS FOR PREPARING A BIPHENYL-2-YLCARBAMIC ACID
2013-11-26
2014-05-01
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US7803812 BIPHENYL COMPOUNDS USEFUL AS MUSCARINIC RECEPTOR ANTAGONISTS
2009-09-10
2010-09-28
US7910608 Biphenyl compounds useful as muscarinic receptor antagonists
2009-01-15
2011-03-22
US7491736 Biphenyl compounds useful as muscarinic receptor antagonists
2007-12-20
2009-02-17
US7585879 Biphenyl compounds useful as muscarinic receptor antagonists
2007-11-15
2009-09-08
US7288657 Biphenyl compounds useful as muscarinic receptor antagonists
2005-09-15
2007-10-30
Patent ID

Title

Submitted Date

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US8912334 Biphenyl compounds useful as muscarinic receptor antagonists
2013-09-11
2014-12-16
US8273894 Biphenyl compounds useful as muscarinic receptor antagonists
2012-04-03
2012-09-25
US8173815 BIPHENYL COMPOUNDS USEFUL AS MUSCARINIC RECEPTOR ANTAGONISTS
2011-12-29
2012-05-08
US8053448 BIPHENYL COMPOUNDS USEFUL AS MUSCARINIC RECEPTOR ANTAGONISTS
2011-06-02
2011-11-08
US8034946 BIPHENYL COMPOUNDS USEFUL AS MUSCARINIC RECEPTOR ANTAGONISTS
2010-09-30
2011-10-11

/////////TD-4208, UNII:G2AE2VE07O, ревефенацин ريفيفيناسين 瑞维那新 , GSK 1160724, revefenacin, PHASE 3

CN(CCN1CCC(CC1)OC(=O)NC2=CC=CC=C2C3=CC=CC=C3)C(=O)C4=CC=C(C=C4)CN5CCC(CC5)C(=O)N

Vericiguat, ベルイシグアト


Vericiguat.pngImage result for vericiguatImage result for vericiguat

Vericiguat

BAY 102; BAY-1021189; MK-1242

1350653-20-1
Chemical Formula: C19H16F2N8O2

Molecular Weight: 426.3878

Vericiguat; 1350653-20-1; UNII-LV66ADM269; Methyl (4,6-diamino-2-(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)carbamate; BAY-1021189; LV66ADM269

Methyl (4,6-diamino-2-(5-fluoro-1-((2-fluorophenyl)methyl)-1H-pyrazolo(3,4-b)pyridin-3-yl(pyrimidin-5-yl)carbamate

methyl N-[4,6-diamino-2-[5-fluoro-1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]carbamate

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridi- n-3-yl]pyrimidin-5-yl}carbamate

  • Originator Bayer HealthCare Pharmaceuticals
  • Developer Bayer HealthCare Pharmaceuticals; Merck & Co
  • Mechanism of Action Guanylate cyclase stimulants
  • Phase III Chronic heart failure
  • Phase I Coronary artery disease
  • 28 May 2018 Phase II VITALITY HFpEF trial for Chronic heart failure in Austria, USA, Belgium, Portugal, Canada, Spain, Hungary and Greece (PO) (EudraCT2018-000298-65) (NCT03547583)
  • 17 May 2018 Phase-I clinical trials in Coronary artery disease (In adults, In the elderly) in Moldova and Germany (PO) (NCT03504982)
  • 20 Apr 2018 Bayer in collaboration with Merck Sharp & Dohme Corp. plans a phase I trial for Coronary Artery Disease in the Netherlands, Moldova and Germany (NCT03504982)

Vericiguat, also known as BAY1021189 or BAY10-21189, is a potent and orally active sGC stimulator (Soluble Guanylate Cyclase Stimulator). Direct stimulation of soluble guanylate cyclase (sGC) is emerging as a potential new approach for the treatment of renal disorders. sGC catalyzes the formation of cyclic guanosine monophosphate (cGMP), deficiency of which is implicated in the pathogenesis of chronic kidney disease (CKD).

Vericiguat, discovered at Bayer, is the first soluble guanylate cyclase (sGC) stimulator. Vericiguat is currently being studied in a Phase III clinical program for the treatment of heart failure with reduced ejection fraction (HFrEF)

ベルイシグアト
Vericiguat

C19H16F2N8O2 : 426.38
[1350653-20-1]

Vericiguat hydrochloride.png

Vericiguat hydrochloride

cas 1350658-96-6

PHASE 3 MERCK/BAYER

Chemical Names: UNII-5G76IGF54K; 5G76IGF54K; ; 1350658-96-6; Carbamic acid, N-(4,6-diamino-2-(5-fluoro-1-((2-fluorophenyl)methyl)-1H-pyrazolo(3,4-b)pyridin-3-yl)-5-pyrimidinyl)-, methyl ester, hydrochloride (1:1); Methyl (4,6-diamino-2-(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridin-3-yl)pyrimidin-5-yl)carbamate hydrochloride
Molecular Formula: C19H17ClF2N8O2
Molecular Weight: 462.846 g/mol

Image result for DRUG FUTURE Vericiguat

Clip

https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0036-1590758.pdf

Image result for vericiguat

Significance: Vericiguat (BAY 1021189) is an orally available soluble guanylate cyclase (sGC) stimulator that has entered phase-three trials for the once-daily treatment of chronic heart failure. Key steps in the synthesis depicted are (1) construction of the 5-fluoro-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate C by condensation of the 5-amino-1H-pyrazole-3-carboxylate A with the aldehyde B and (2) construction of the pyrimidine-4,5,6-triamine derivative H through reaction of [(E)-phenyldiazenyl]malononitrile (G) with amidine F.

Comment: Experimental details are provided for the noteworthy four-step synthesis (not shown) of the crystalline 2-fluoro-(3-morpholin-4-yl)acrylaldehyde B from commercially available 2,2,3,3- tetrafluoro-1-propanol. The synthesis of pyrazole A is described in a patent (A. Straub et al. WO 2000/006569 A1). The [(E)-phenyldiazenyl]malononitrile (G) was generated in situ by reaction of phenyldiazonium chloride with malononitrile.

M. FOLLM ANN * E T AL. (BAYER AG, WUPPERTAL , GE RMANY) Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure J. Med. Chem. 2017, 60, 5146–5161
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24. Yield 2.2 g (70%). 1 H NMR (400 MHz, DMSO-d6): δ = 8.89 (dd, J = 9.0, 2.8 Hz, 1H), 8.66 (m, 1H), 7.99 and 7.67 (2 br s, 1H), 7.32−7.40 (m, 1H), 7.19−7.26 (m, 1H), 7.10−7.19 (m, 2H), 6.22 (br s, 4H), 5.79 (s, 2H), 3.62 (br s, 3H). LC-MS (method d): tR (min) = 0.79. MS (ESI +): m/z = 427 [M + H]+
PATENT
US 8,802,847

Example 13

Methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridi- n-3-yl]pyrimidin-5-yl}carbamate

Method A:

4.0 g (77.0% by weight, 8.36 mmol) of the compound from Example 12 in 37.9 ml of isopropanol were heated to 35.degree. C. and then 0.84 ml (10.87 mmol) of methyl chloroformate was added dropwise. The mixture was stirred at 35.degree.-40.degree. C. for 20 h and heated to 50.degree. C., and 9.5 ml of methanol were added. Subsequently, 1.9 ml of triethylamine were added dropwise within 0.5 h and rinsed in with 1.3 ml of methanol, and the mixture was stirred at 50.degree. C. for 1 h. Thereafter, the reaction mixture was cooled to RT and stirred at RT for 1 h, and the solids were filtered off with suction, washed three times with 8 ml each time of ethanol, suction-dried and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 3.4 g of crude product. 3.0 g of the crude product were stirred in 8 ml of DMSO for 5 min, 13.0 ml of ethyl acetate and 50 mg of activated carbon were added, and the mixture was heated at reflux (84.degree. C.) for 15 min. The suspension was hot-filtered and the filter residue was washed with 1.9 ml of ethyl acetate.sup.1). 60 ml of ethyl acetate and 16 ml of ethanol were heated to 60.degree. C., and the combined filtrates were added dropwise and stirred at 60.degree. C. for 1.5 h. The suspension was cooled to RT within 25 min, stirred for a further 1.5 h, cooled further to 0.degree.-5.degree. C. and stirred for a further 1 h. The solids were filtered off with suction, washed twice with 6.4 ml each time of ethyl acetate, suction-dried and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 2.2 g (70.0% of theory) of the title compound. 1) According to the preparation process described, the di-dimethyl sulphoxide solvate is obtained at this point, and this is characterized in Tables 2 and 4 by the reflections in the x-ray diffractogram and bands in the IR spectrum.

MS (ESIpos): m/z=427 (M+H).sup.+

.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=3.62 (br s, 3H), 5.79 (s, 2H), 6.22 (br s, 4H), 7.10-7.19 (m, 2H), 7.19-7.26 (m, 1H), 7.32-7.40 (m, 1H), 7.67 and 7.99 (2 br s, 1H), 8.66 (m, 1H), 8.89 (dd, 1H) ppm.

The di-dimethyl sulphoxide solvate of the compound of the formula (I) has the advantage of much better filterability than the substance in the prior art. Furthermore, the preparation process via the di-dimethyl sulphoxide solvate of the compound of the formula (I) leads to a very high purity of the compound of the formula (I).

Method B:

4.0 g (10.8 mmol) of the compound from Example 12 Method B in 37.9 ml of isopropanol were heated to 35.degree. C. and then 1.1 ml (14.1 mmol) of methyl chloroformate were added dropwise. The mixture was stirred at 35.degree.-40.degree. C. for 16.5 h and cooled to RT, and 2.1 ml of aqueous ammonia (28%) were added. Subsequently, 4.2 ml of water were added and the mixture was stirred for 2.5 h. The solids were filtered off with suction, washed twice with 5 ml each time of water, suction-dried and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 4.4 g of crude product.

Method C:

4.0 g (10.8 mmol) of the compound from Example 12 Method B in 37.9 ml of isopropanol were heated to 35.degree. C. and then 1.1 ml (14.1 mmol) of methyl chloroformate were added dropwise. The mixture was stirred at 35.degree.-40.degree. C. for 16.5 h, and 9.5 ml of methanol were added at 50.degree. C. Subsequently, 2.42 ml of triethylamine were added dropwise within 20 min and rinsed in with 1.3 ml of methanol, and the mixture was stirred at 50.degree. C. for 1 h. Thereafter, the reaction mixture was cooled to RT and stirred at RT for 1 h, and the solids were filtered off with suction, washed three times with 8 ml each time of methanol, suction-dried and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 4.3 g of crude product.

Method D:

6.9 g of the crude product were stirred in 18.4 ml of DMSO for 5 min, 30.0 ml of ethyl acetate and 115 mg of activated carbon were added, and the mixture was heated at reflux (84.degree. C.) for 15 min. The suspension was hot-filtered and the filter residue was washed with 4.4 ml of ethyl acetate. 138 ml of ethyl acetate were heated to 50.degree. C., and the combined filtrates were added dropwise and stirred at 45-50.degree. C. for 1 h. The suspension was cooled to 0.degree.-5.degree. C. within 1.5 h and stirred for a further 1 h. The solids were filtered off with suction, washed twice with 14.8 ml each time of ethyl acetate and suction-dried for 1 h. 6.4 g of the di-dimethyl sulphoxide solvate were obtained as a moist product.sup.1).

Method E:

2.0 g of the di-dimethyl sulphoxide solvate were stirred at reflux temperature in 40 ml of ethyl acetate and 11.1 ml of ethanol for 17 h, cooled to RT and stirred for a further 1 h. The solids were filtered off with suction, washed four times with 1.4 ml each time of ethyl acetate and dried in a vacuum drying cabinet at 50.degree. C. under a gentle nitrogen stream. This gave 1.4 g of the title compound present in polymorph I.

Method F:

0.5 g of the di-dimethyl sulphoxide solvate were stirred at reflux temperature in 12.5 ml of solvent for 17 h, cooled to RT and stirred for a further 1 h. The solids were filtered off with suction, washed with 2 ml of solvent and suction-dried for 30 min. This gave 0.3 g of the title compound present in polymorph I.

The following solvents were used:

1.) 9 ml of ethyl acetate/3.5 ml of ethanol/0.3 ml of water

2.) 12.5 ml of isopropanol

3.) 12.5 ml of isopropanol/0.3 ml of water

4.) 12.5 ml of methanol

5.) 12.5 ml of methanol/0.3 ml of water

6.) 12.5 ml of acetonitrile

7.) 12.5 ml of acetone

8.) 12.5 ml of tetrahydrofuran,

9.) 12.5 ml of methyl tert-butyl ether

Table 1 indicates the reflections of the x-ray diffractogram. Table 3 shows the bands of the IR spectrum.

The compound (I) in crystalline polymorph I is notable for higher stability and more particularly for the fact that it is stable in the micronization process and hence no conversion and recrystallization takes place.

The compound of the formula (I) can be prepared by processes described above. This affords the compound of the formula (I) in a crystal polymorph referred to hereinafter as polymorph I. Polymorph I has a melting point of 257.degree. C. and a characteristic x-ray diffractogram featuring the reflections (2 theta) 5.9, 6.9, 16.2, 16.5, 24.1 and 24.7, and a characteristic IR spectrum featuring the band maxima (in cm.sup.-1) 1707, 1633, 1566, 1475, 1255 and 1223 (Tables 1 and 3, FIGS. 1 and 5).

Surprisingly, four further polymorphs, a monohydrate, a dihydrate, a DMF/water solvate and a di-dimethyl sulphoxide solvate, and also a triacetic acid solvate of the compound of the formula (I) were found. The compound of the formula (I) in polymorph II melts at approx. 253.degree. C.; the compound of the formula (I) in polymorph III has a melting point of approx. 127.degree. C. Polymorph IV of the compound of the formula I melts at a temperature of 246.degree. C., while polymorph V has a melting point of 234.degree. C. The monohydrate contains approx. 4.1% water, the dihydrate contains 7.8% water, the DMF/water solvate contains 13.6% dimethylformamide and 0.9% water, the di-DMSO solvate contains 26.8% dimethyl sulphoxide and the triacetic acid solvate contains 29.7% acetate. Each of the crystalline forms mentioned has a characteristic x-ray diffractogram and IR spectrum (Tables 2 and 3, FIGS. 1-4, 6-14).

TABLE 1
X-ray diffractometry for polymorphs I to V

FIGURES

FIG. 1: IR spectrum of the compound of the formula (I) in polymorphs I, II and III

FIG. 2: IR spectrum of the compound of the formula (I) in polymorphs IV, V and as the triacetic acid solvate

FIG. 3: IR spectrum of the compound of the formula (I) as the di-DMSO solvate, DMF/water solvate and monohydrate

FIG. 4: IR spectrum of the compound of the formula (I) as the dihydrate

FIG. 5: X-ray diffractogram of the compound of the formula (I) in polymorph I

FIG. 6: X-ray diffractogram of the compound of the formula (I) in polymorph II

FIG. 7: X-ray diffractogram of the compound of the formula (I) in polymorph III

FIG. 8: X-ray diffractogram of the compound of the formula (I) in polymorph IV

FIG. 9: X-ray diffractogram of the compound of the formula (I) in polymorph V

FIG. 10: X-ray diffractogram of the compound of the formula (I) as the triacetic acid solvate

FIG. 11: X-ray diffractogram of the compound of the formula (I) as the di-DMSO solvate

FIG. 12: X-ray diffractogram of the compound of the formula (I) as the DMF-water solvate

FIG. 13: X-ray diffractogram of the compound of the formula (I) as the monohydrate

FIG. 14: X-ray diffractogram of the compound of the formula (I) as the dihydrate

PATENT

Example 11A

2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine

      Variant A: Preparation Starting from Example 7A:
      In pyridine (30 ml), 378 mg (0.949 mmol) of the compound from Example 7A were introduced and then 143 mg (0.135 mmol) of palladium (10% on carbon) were added. The mixture was hydrogenated overnight at RT under standard hydrogen pressure. The suspension was then filtered through kieselguhr and the filtercake was washed with ethanol. The filtrate was concentrated and yielded 233 mg (81% purity, 51% of theory) of the desired compound, which was reacted without further purification.
      Variant B: Preparation Starting from Example 10A:
      In DMF (800 ml), 39.23 g (85.75 mmol) of the compound from Example 10A were introduced and then 4 g of palladium (10% on carbon) were added. The mixture was hydrogenated with stirring overnight under standard hydrogen pressure. The batch was filtered over kieselguhr and the filter product was washed with a little DMF and then with a little methanol, and concentrated to dryness. The residue was admixed with ethyl acetate and stirred vigorously, and the precipitate was filtered off with suction, washed with ethyl acetate and diisopropyl ether and dried under a high vacuum over Sicapent.
      Yield: 31.7 g (100% of theory)
      LC-MS (method 2): R t=0.78 min
      MS (ESIpos): m/z=369 (M+H) +

Working Examples

Example 1

Methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate

      In pyridine (600 ml), 31.75 g (86.20 mmol) of the compound from Example 11A were introduced under argon and cooled to 0° C. Then a solution of 6.66 ml (86.20 mmol) of methyl chloroformate in dichloromethane (10 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h. Thereafter the reaction mixture was brought to RT, concentrated under reduced pressure and co-distilled repeatedly with toluene. The residue was stirred with water/ethanol and then filtered off on a frit, after which it was washed with ethanol and ethyl acetate. Subsequently the residue was again stirred with diethyl ether, isolated by filtration with suction and then dried under a high vacuum.
      Yield: 24.24 g (65% of theory)
      LC-MS (method 2): R t=0.79 min
      MS (ESIpos): m/z=427 (M+H) +
       1H NMR (400 MHz, DMSO-d 6): δ=3.62 (br. s, 3H), 5.79 (s, 2H), 6.22 (br. s, 4H), 7.10-7.19 (m, 2H), 7.19-7.26 (m, 1H), 7.32-7.40 (m, 1H), 7.67 and 7.99 (2 br. s, 1H), 8.66 (m, 1H), 8.89 (dd, 1H).
Patent ID

Title

Submitted Date

Granted Date

US2016324856 USE OF SGC STIMULATORS FOR THE TREATMENT OF NEUROMUSCULAR DISORDERS
2015-01-13
US2016158233 SGC STIMULATORS OR SGC ACTIVATORS AND PDE5 INHIBITORS IN COMBINATION WITH ADDITIONAL TREATMENT FOR THE THERAPY OF CYSTIC FIBROSIS
2014-07-21
2016-06-09
US2013158028 USE OF STIMULATORS AND ACTIVATORS OF SOLUBLE GUANYLATE CYCLASE FOR TREATING SICKLE-CELL ANEMIA AND CONSERVING BLOOD SUBSTITUTES
2011-06-21
2013-06-20
US9845300 PROCESS FOR PREPARING SUBSTITUTED 5-FLUORO-1H-PYRAZOLOPYRIDINES
2017-02-17
US9604948 PROCESS FOR PREPARING SUBSTITUTED 5-FLUORO-1H-PYRAZOLOPYRIDINES
2015-07-10
2016-01-14
Patent ID

Title

Submitted Date

Granted Date

US2017273977 SUBSTITUTED 5-FLUORO-1H-PYRAZOLOPYRIDINES AND THEIR USE
2016-11-10
US8921377 Substituted 5-fluoro-1H-pyrazolopyridines and their use
2013-03-27
2014-12-30
US8420656 Substituted 5-fluoro-1H-pyrazolopyridines and their use
2012-01-26
US9096592 BICYCLIC AZA HETEROCYCLES, AND USE THEREOF
2011-08-31
2014-05-29
US2014038956 Use of sGC stimulators, sGC activators, alone and combinations with PDE5 inhibitors for the treatment of systemic sclerosis (SSc).
2011-05-24
2014-02-06

////////////////Vericiguat,  BAY 102, BAY-1021189, MK-1242, ベルイシグアト , PHASE 3,  MERCK, BAYER

COC(=O)NC1=C(N=C(N=C1N)C2=NN(C3=NC=C(C=C23)F)CC4=CC=CC=C4F)N

RG7440, Ipatasertib, アイパタセルチブ;


1001264-89-6.png

Ipatasertib.svg

Ipatasertib

GDC-0068 , RG7440

CAS 1001264-89-6, C24H32ClN5O2, 457.9962

アイパタセルチブ;
イパタセルチブ;

Antineoplastic, AKT serine/threonine kinase inhibitor

2(S)-(4-Chlorophenyl)-1-[4-[7(R)-hydroxy-5(R)-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]piperazin-1-yl]-3-(isopropylamino)propan-1-one

(2S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta(d)pyrimidin-4-yl)piperazin-1-yl(-3-((propan-2-yl)amino)propan-1-one

1-Propanone, 2-(4-chlorophenyl)-1-(4-((5R,7R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopentapyrimidin-4-yl)-1-piperazinyl)-3-((1-methylethyl)amino)-,  (2S)-

2D chemical structure of 1396257-94-5

Ipatasertib dihydrochloride
1396257-94-5

Ipatasertib (RG7440) is an experimental cancer drug in development by Roche. It is a small molecule inhibitor of Akt. It was discovered by Array Biopharma and is currently in phase II trials for treatment of breast cancer.[1]

In vitro, ipatasertib showed activity against all three isoforms of Akt.[2]

Ipatasertib is an orally-available protein kinase B (PKB/Akt) inhibitor in phase III clinical development at Genentech for the treatment of metastatic castration-resistant prostate cancer in combination with abiraterone and prednisone.

In 2014, orphan drug designation was assigned in the U.S. for the treatment of gastric cancer including cancer of the gastro-esophageal junction.

Ipatasertib. An orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) with potential antineoplastic activity. Ipatasertib binds to and inhibits the activity of Akt in a non-ATP-competitive manner, which may result in the inhibition of the PI3K/Akt signaling pathway and tumor cell proliferation and the induction of tumor cell apoptosis. Activation of the PI3K/Akt signaling pathway is frequently associated with tumorigenesis and dysregulated PI3K/Akt signaling may contribute to tumor resistance to a variety of antineoplastic agents. Check for active clinical trials using this agent.

PROBLEM 

It has been found that ipatasertib exhibits a very high solubility (>1 g/g water; >2 g/g water/ethanol 1:1) and a very high hygroscopicity (˜6% at 50% RH, >35% at 95% RH). Whereas poor solubility is often a limiting factor in the development of galenical formulations of other API’s (active pharmaceutical ingredient), a high solubility can equally be problematic for the process performance. Due to this very high intrinsic hygroscopicity of the API, ipatasertib drug substance tends to auto-dissolve to a honey-like viscous liquid at increased humidity. Such high solubility and hygroscopicity may pose serious problems for processing as well as for stability and shelf-life of the final product. Therefore, conventional pharmaceutical compositions comprising ipatasertib and processes for the manufacture of pharmaceutical compositions comprising wetting (e.g. wet granulation) are difficult due to the high solubility and high hygroscopicity of the API.

SYN

 Ipatasertib pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=691990

Bromination of (+)-(R)-pulegone (I) with Br2 in the presence of NaHCO3 in Et2O, followed by ring contraction via Favorskii rearrangement with NaOEt in EtOH, and treatment with semicarbazide hydrochloride and NaOAc in refluxing EtOH/H2O gives rise to cyclopentanecarboxylate (II) (1). Subsequent ozonolysis of olefin (II) by means of O3 in EtOAc at -78 °C, and reductive treatment with Zn in AcOH provides beta-ketoester (III). Reaction of ketoester (III) with ammonium acetate (IVa) in MeOH/CH2Cl2 yields enamine (V), which upon cyclization with ammonium formate (IVb) and formamide (VI) at 150 °C provides cyclopentapyrimidinol (VII). Chlorination of pyrimidinol (VII) using POCl3 in refluxing CH2Cl2 results in 4-chloro-5(R)-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (VIII), which is condensed with N-Boc-piperazine (IX) in the presence of DIEA in refluxing BuOH to produce piperazinyl cyclopentapyrimidine (X). Oxidation of compound (X) using mCPBA and NaHCO3 in CHCl3 furnishes N-oxide (XI). Subsequent rearrangement of N-oxide (XI) using Ac2O in CH2Cl2 at 100 °C yields acetate (XII). This compound (XII) is hydrolyzed with LiOH in H2O/THF to give alcohol (XIII), which upon Swern oxidation with (COCl)2, DMSO and Et3N in CH2Cl2 at -78 °C affords ketone (XIV) (1-6). Asymmetric transfer hydrogenation of ketone (XIV) in the presence of RuCl[(R,R)-TsDPEN(p-cymene)], HCOOH and Et3N in CH2Cl2, followed by protection with PNBCl in the presence of Et3N in CH2Cl2, and hydrolysis with LiOH in H2O/THF gives rise to alcohol (XV) (1-6). Also, intermediate (XV) can be produced by enzymatic reduction of ketone (XI) using KRED-101 in the presence of GDH, NADP, KOH and PEG-400, KRED-X1.1-P1F01 in the presence of glucose and NAD in DMSO/i-PrOH or KRED-X1.1-P1B06, KRED-X1.1-P1F01 or KRED-X1.1-P1H10 in the presence of NADP in DMSO/i-PrOH or i-PrOH (11,12). In an alternative method, asymmetric transfer hydrogenation of ketone (XIV) in the presence of RuCl[(R,R)-MsDPEN(p-cymene)], HCOOH and Et3N in CH2Cl2, followed by O-protection of the resultant cis/trans mixture of alcohols with PNBCl and Et3N or protection with pivaloyl chloride in the presence of DIEA in CH2Cl2, followed by separation of the resulting cis/trans mixture of esters by means of HPLC. Hydrolysis of trans ester with LiOH in THF yields alcohol (XV) (11). N-Deprotection of piperazine derivative (XV) by means of HCl in CH2Cl2, i-PrOH or toluene at 62 °C provides amine dihydrochloride (XVI) (1-7,11,12), which is then coupled with aminoacid derivative (XVIIa) (1-7,11) or its sodium salt (XVIIb) (12,13) in the presence of DIEA and HBTU in CH2Cl2 or NMM and T3P in i-PrOH or toluene to produce amide (XVIII) (1-7,11-13). Finally, Boc-deprotection of precursor (XVIII) by means of HCl in MeOH/Et2O, PrOH, i-PrOH or toluene at 57 °C furnishes the target GDC-0068

 Ipatasertib pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=691990

Synthesis of intermediate (XVII): Condensation of methyl (4-chlorophenyl)acetate (XIX) with formaldehyde (XX) in the presence of NaOMe in DMSO gives beta-hydroxyester (XXI). Subsequent dehydration of alcohol (XXI) using MsCl and Et3N in CH2Cl2 provides arylacrylate (XXII), which upon conjugate addition with isopropylamine (XXIII) in the presence of Boc2O in THF yields N-Boc beta-aminoester (XXIV). Basic hydrolysis of ester (XXIV) using KOSiMe3 in THF generates the potassium carboxylate (XXV), which upon condensation with 4(R)-benzyl-2-oxazolidinone (XXVI) via activation with pivaloyl chloride and BuLi in THF at -78 °C affords the N-acyl oxazolidinone (XXVII) (2-6). Finally, removal of the chiral auxiliary group of (XXVII) using LiOH and H2O2 in THF/H2O furnishes the key intermediate (XVII) (1-6,11). Alternative synthesis of intermediate (XXVII): Protection of isopropylamine (XXIII) with Boc2O in toluene affords tert-butyl isopropylcarbamate (XXVIII), which upon N-alkylation with bromomethyl methyl ether (XXIX) in the presence of NaHMDS in 2-MeTHF gives tert-butyl isopropyl(methoxymethyl)carbamate (XXX) (11). Condensation of 4(R)-benzyl-2-oxazolidinone (XXVI) with 2-(4-chlorophenyl)acetyl chloride (XXXIIa) using BuLi in THF at -50 °C (1) or with 2-(4-chlorophenyl)acetic acid (XXXIIb) via activation with pivaloyl chloride and Et3N in refluxing toluene (11) affords N-acyl oxazolidinone(XXXI). After conversion of intermediate (XXXI) to its titanium enolate with TiCl4 and DIEA in CH2Cl2 at -50 °C, diastereoselective Mannich reaction with formaldehyde hemiaminal (XXX) affords adduct (XXVII)

PAPER

Synthesis of Akt inhibitor ipatasertib. Part 2. Total synthesis and first kilogram scale-up
Org Process Res Dev 2014, 18(12): 1652

https://pubs.acs.org/doi/full/10.1021/op500270z

https://pubs.acs.org/doi/suppl/10.1021/op500270z/suppl_file/op500270z_si_001.pdf

Synthesis of Akt Inhibitor Ipatasertib. Part 2. Total Synthesis and First Kilogram Scale-up

 Small Molecule Process Chemistry, Genentech, Inc., a member of the Roche Group, 1 DNA Way, South San Francisco, California 94080-4990, United States
 Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 80301, United States
Org. Process Res. Dev.201418 (12), pp 1652–1666
DOI: 10.1021/op500270z
*E-mail: travisr@gene.com.
Abstract Image

Herein, the first-generation process to manufacture Akt inhibitor Ipatasertib through a late-stage convergent coupling of two challenging chiral components on multikilogram scale is described. The first of the two key components is a trans-substituted cyclopentylpyrimidine compound that contains both a methyl stereocenter, which is ultimately derived from the enzymatic resolution of a simple triester starting material, and an adjacent hydroxyl group, which is installed through an asymmetric reduction of the corresponding cyclopentylpyrimidine ketone substrate. A carbonylative esterification and subsequent Dieckmann cyclization sequence was developed to forge the cyclopentane ring in the target. The second key chiral component, a β2-amino acid, is produced using an asymmetric aminomethylation (Mannich) reaction. The two chiral intermediates are then coupled in a three-stage endgame process to complete the assembly of Ipatasertib, which is isolated as a stable mono-HCl salt.

(S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one, Ipatasertib Mono-HCl

 Ipatasertib mono-HCl (3.23 kg, 80% yield) as an off-white solid. Analytical results: 99.7 A% [0.26% S,R,S-diastereomer observed)]; impurity 23 (M399) was not detected (<0.02 A%) [Method 2.2]; ruthenium content by IPC-AES = 5 ppm; analysis for PF6 anion by CAD-HPLC resulted in not detected [Method 2.3]; residual solvent = 0.4% EtOAc; ion chromatography (IC) = 8.5% chloride (1.14 salt equivalent); DSC = 141 °C; FTIR (neat) 3269 (br OH), 2961–2865 (N–H stretch), 1637 (C═O stretch); 1H NMR (600 MHz, DMSO-d6) 9.39 (s, 1H), 8.64 (s, 1H), 8.49 (s, 1H), 7.49 (q, J = 2.9 Hz, 2H), 7.41 (q, J = 2.9 Hz, 2H), 5.58 (s, 1H), 4.91 (t, J = 6.9 Hz, 1H), 4.78 (dd, J = 8.9, 4.5 Hz, 1H), 3.81 (m, J = 3.3 Hz, 1H), 3.68 (m, J = 3.3 Hz, 1H), 3.67 (m, J = 3.1 Hz, 1H), 3.65 (m, J = 3.2 Hz, 1H), 3.63 (m, J = 3.6 Hz, 1H), 3.59 (m, J = 4.3 Hz, 1H), 3.51 (m, J = 3.5 Hz, 1H), 3.46 (m, J = 3.5 Hz, 1H), 3.36 (m, J = 3.2 Hz, 1H), 3.30 (m, J = 5.7 Hz, 1H), 3.21 (m, J = 3.4 Hz, 1H), 2.98 (m, J = 5.8 Hz, 1H), 1.97 (m, J = 4.8 Hz, 2H), 1.26 (d, J = 6.6 Hz, 3H), 1.25 (d, J = 7.0 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) 170.2, 168.2, 159.4, 155.2, 135.3, 132.5, 129.7 (2C), 129.1 (2C), 120.8, 71.7, 50.4, 47.0, 44.8, 44.5, 44.1, 41.4, 40.8, 34.5, 19.8, 18.4, 18.1; HRMS calcd for C24H32ClN5O2 457.2245; found [M+H]+ 458.2306.

str1

 Ipatasertib freebase (3.9 kg, 98.2 A% containing ~1.2% impurity 23 (M399) and impurity M416 at 0.2 A% [Method 2.2]) as tan solid. By CAD-HPLC (see Figure S1-2), the PF6 anion was present in ~0.86 A% [Method 2.3]; Ion chromatography (IC) = 4.0% chloride (0.56 salt equivalent); 1 H NMR (600 MHz, DMSO-d6) 8.44 (s, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 5.48 (br s, 1H), 4.86 (t, J = 6.9 Hz, 1H), 4.58 (dd, J = 7.3, 4.6 Hz, 1H), 3.74 (m, 1H), 3.40 (m, 1H), 3.63 (m, 2H), 3.61 (m, 1H), 3.42 (m, 1H), 3.57 (m, 1H), 3.18 (m, 1H), 3.50 (m, J = 2.9 Hz, 1H), 3.09 (m, J = 3.1 Hz, 1H), 3.42 (m, 1H), 2.87 (m, J = 4.7 Hz, 1H), 2.00 (m, 1H), 1.92 (m, J = 3.1 Hz, 1H), 1.15 (d, J = 6.4 Hz, 6H), 1.03 (d, J = 6.9 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) 172.0, 169.0, 159.6, 156.3, 136.3, 132.1, 129.7 (2C), 128.9 (2C), 120.9, 72.0, 49.4, 48.7, 45.4, 44.9, 44.8, 44.6, 41.4, 40.9, 34.3, 20.1, 19.9, 19.7; HRMS calcd for C24H32ClN5O2 [M+H]+ 458.2317; found 458.2312. See supporting information (S2) for the NMR spectra (DMSO-d6) of Ipatasertib freebase: ( 1 H) S2, Figure S2-5.12 and ( 13C) Figure S2-5.13.

https://pubs.acs.org/doi/suppl/10.1021/op500270z/suppl_file/op500270z_si_002.pdf

Table S2-1 1 H NMR Assignments of Ipatasertib mono-HCl. S2-52 Figure S2-5.10. 13C NMR (DMSO-d6) spectrum of Ipatasertib mono-HCl. S2-53 Table S2-2 13C NMR Assignments of Ipatasertib mono-HCl. S2-54 Table S2-3 Characteristic Ipatasertib mono-HCl Infrared Signals. S2-55 Figure S2-5.11. FTIR Spectrum of Ipatasertib mono-HCl. S2-56 Figure S2-5.12. XRPD Pattern of Ipatasertib mono-HCl. S2-57

PAPER

https://pubs.acs.org/doi/abs/10.1021/op500271w

https://pubs.acs.org/doi/suppl/10.1021/op500271w/suppl_file/op500271w_si_001.pdf

Synthesis of Akt Inhibitor Ipatasertib. Part 1. Route Scouting and Early Process Development of a Challenging Cyclopentylpyrimidine Intermediate

 Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 80301, United States
 Genentech Inc., a member of the Roche Group, 1 DNA Way, South San Francisco, California 94080-4990, United States
Org. Process Res. Dev.201418 (12), pp 1641–1651
DOI: 10.1021/op500271w
Abstract Image

Herein, the route scouting and early process development of a key cyclopentylpyrimidine ketone intermediate toward the synthesis of Akt inhibitor Ipatasertib are described. Initial supplies of the intermediate were prepared through a method that commenced with the natural product (R)-(+)-pulegone and relied on the early construction of a methyl-substituted cyclopentyl ring system. The first process chemistry route, detailed herein, enabled the synthesis of the ketone on a hundred-gram scale, but it was not feasible for the requisite production of multikilogram quantities of this compound and necessitated the exploration of alternative strategies. Several new synthetic approaches were investigated towards the preparation of the cyclopentylpyrimidine ketone, in either racemic or chiral form, which resulted in the discovery of a more practical route that hinged on the initial preparation of a highly substituted dihydroxypyrimidine compound. The cyclopentane ring in the target was then constructed through a key carbonylative esterification and subsequent tandem Dieckmann cyclization–decarboxylation sequence that was demonstrated in a racemic synthesis. This proof-of-concept was later developed into an asymmetric synthesis of the cyclopentylpyrimidine ketone, which will be described in a subsequent paper, along with the synthesis of Ipatasertib.

PAPER

Discovery and preclinical pharmacology of a selective ATP-Competitive akt inhibitor (GDC-0068) for the treatment of human tumors
J Med Chem 2012, 55(18): 8110

PAPER

Asymmetric synthesis of akt kinase inhibitor ipatasertib
Org Lett 2017, 19(18): 4806

PATENT

WO 2008006040

PATENT

WO 2012135753

PATENT

WO 2012135759

PATENT

WO 2012135781

PATENT

WO 2013173784

PATENT

WO 2015073739

PATENT

WO 2012135779

PATENT

WO 2013173768

References

  1. Jump up^ https://www.clinicaltrials.gov/ct2/show/NCT02301988
  2. Jump up^ Lin K, Friedman L, Gloor S, Gross S, Liederer BM, Mitchell I, et al. Preclinical characterization of GDC-0068, a novel selective ATP competitive inhibitor of Akt. 22nd-EORTC-NCI-AACR-2010 2010; abstr. 79
Ipatasertib
Ipatasertib.svg
Clinical data
Routes of
administration
PO
ATC code
  • None
Identifiers
ChemSpider
KEGG
Chemical and physical data
Formula C24H32ClN5O2
Molar mass 458.00 g·mol−1
3D model (JSmol)

////////////// ipatasertib, orphan drug designation, GDC-0068 , RG7440, PHASE 3

CC(C)NC[C@@H](C(=O)N1CCN(CC1)c2ncnc3[C@H](O)C[C@@H](C)c23)c4ccc(Cl)cc4

It has been found that ipatasertib exhibits a very high solubility (>1 g/g water; >2 g/g water/ethanol 1:1) and a very high hygroscopicity (˜6% at 50% RH, >35% at 95% RH). Whereas poor solubility is often a limiting factor in the development of galenical formulations of other API’s (active pharmaceutical ingredient), a high solubility can equally be problematic for the process performance. Due to this very high intrinsic hygroscopicity of the API, ipatasertib drug substance tends to auto-dissolve to a honey-like viscous liquid at increased humidity. Such high solubility and hygroscopicity may pose serious problems for processing as well as for stability and shelf-life of the final product. Therefore, conventional pharmaceutical compositions comprising ipatasertib and processes for the manufacture of pharmaceutical compositions comprising wetting (e.g. wet granulation) are difficult due to the high solubility and high hygroscopicity of the API.

ABL 001, Asciminib


img

Image result for ABL001 / Asciminib

ABL001 / Asciminib

Cas 1492952-76-7
Chemical Formula: C20H18ClF2N5O3
Molecular Weight: 449.8428
Elemental Analysis: C, 53.40; H, 4.03; Cl, 7.88; F, 8.45; N, 15.57; O, 10.67

N-[4-[Chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

3-Pyridinecarboxamide, N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-(1H-pyrazol-3-yl)-

PHASE 3, Chronic Myeloid Leukemia, NOVARTIS

Asciminib is an orally bioavailable, allosteric Bcr-Abl tyrosine kinase inhibitor with potential antineoplastic activity. Designed to overcome resistance, ABL001 binds to the Abl portion of the Bcr-Abl fusion protein at a location that is distinct from the ATP-binding domain. This binding results in the inhibition of Bcr-Abl-mediated proliferation and enhanced apoptosis of Philadelphia chromosome-positive (Ph+) hematological malignancies. The Bcr-Abl fusion protein tyrosine kinase is an abnormal enzyme produced by leukemia cells that contain the Philadelphia chromosome.

ABL001 has been used in trials studying the health services research of Chronic Myelogenous Leukemia and Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia.
  • Originator Novartis
  • Developer Novartis; Novartis Oncology
  • Class Antineoplastics; Pyrazoles; Pyrrolidines; Small molecules
  • Mechanism of Action Bcr-abl tyrosine kinase inhibitors

Highest Development Phases

  • Phase III Chronic myeloid leukaemia
  • No development reported Precursor cell lymphoblastic leukaemia-lymphoma

Most Recent Events

  • 04 Nov 2017 No recent reports of development identified for phase-I development in Acute-lymphoblastic-leukaemia(Second-line therapy or greater) in Australia (PO)
  • 04 Nov 2017 No recent reports of development identified for phase-I development in Acute-lymphoblastic-leukaemia(Second-line therapy or greater) in France (PO)
  • 04 Nov 2017 No recent reports of development identified for phase-I development in Acute-lymphoblastic-leukaemia(Second-line therapy or greater) in Germany (PO)
  • The tyrosine kinase activity of the ABLl protein is normally tightly regulated, with the N-terminal cap region of the SH3 domain playing an important role. One regulatory mechanism involves the N-terminal cap glycine-2 residue being myristoylated and then interacting with a myristate binding site within the SHI catalytic domain. A hallmark of chronic myeloid leukemia (CML) is the Philadelphia chromosome (Ph), formed by the t(9,22) reciprocal chromosome translocation in a haematopoietic stem cell. This chromosome carries the BCR-ABL1 oncogene which encodes the chimeric BCR-ABL1 protein, that lacks the N-terminal cap and has a constitutively active tyrosine kinase domain.Although drugs that inhibit the tyrosine kinase activity of BCR-ABL1 via an ATP-competitive mechanism, such as Gleevec® / Glivec® (imatinib), Tasigna® (nilotinib) and Sprycel® (dasatinib), are effective in the treatment of CML, some patients relapse due to the emergence of drug-resistant clones, in which mutations in the SHI domain compromise inhibitor binding. Although Tasigna® and Sprycel® maintain efficacy towards many Gleevec-resistant mutant forms of BCR-ABLl, the mutation in which the threonine-315 residue is replaced by an isoleucine (T315I) remains insensitive to all three drugs and can result in CML patients developing resistance to therapy. Therefore, inhibiting BCR-ABLl mutations, such as T315I, remains an unmet medical need. In addition to CML, BCR-ABLl fusion proteins are causative in a percentage of acute lymphocytic leukemias, and drugs targeting ABL kinase activity also have utility in this indication.Agents targeting the myristoyl binding site (so-called allosteric inhibitors) have potential for the treatment of BCR-ABLl disorders (J. Zhang, F. J. Adrian, W. Jahnke, S. W. Cowan- Jacob, A. G. Li, R. E. Iacob4, T. Sim, J. Powers, C. Dierks, F. Sun, G.-R. Guo, Q. Ding, B. Okram, Y. Choi, A. Wojciechowski, X. Deng, G. Liu, G. Fendrich, A. Strauss, N. Vajpai, S. Grzesiek, T. Tuntland, Y. Liu, B. Bursulaya, M. Azam, P. W. Manley, J. R. Engen, G. Q. Daley, M. Warmuth., N. S. Gray. Targeting BCR-ABL by combining allosteric with ATP -binding-site inhibitors. Nature 2010;463:501-6). To prevent the emergence of drug resistance from ATP inhibitor and/or allosteric inhibitor use, a combination treatment using both types of inhibitor can be developed for the treatment of BCR-ABLl related disorders. In particular, the need exists for small molecules, or combinations thereof, that inhibit the activity of BCR-ABLl and BCR-ABLl mutations via the ATP binding site, the myristoyl binding site or a combination of both sites.Further, inhibitors of ABL 1 kinase activity have the potential to be used as therapies for the treatment of metastatic invasive carcinomas and viral infections such as pox and Ebola viruses.The compounds from the present invention also have the potential to treat or prevent diseases or disorders associated with abnormally activated kinase activity of wild-type ABL1, including non-malignant diseases or disorders, such as CNS diseases in particular neurodegenerative diseases (for example Alzheimer’s, Parkinson’s diseases), motoneuroneuron diseases (amyotophic lateral sclerosis), muscular dystrophies, autoimmune and inflammatory diseases (diabetes and pulmonary fibrosis), viral infections, prion diseases.

Asciminib is an allosteric inhibitor of BCR-ABL kinase in phase III clinical development at Novartis for the treatment of patients with chronic myelogenous leukemia (CML) in chronic phase who have been previously treated with ATP-binding site tyrosine kinase inhibitors. Early clinical trials are also under way in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and as first-line threapy of CML.

PATENT

WO2013171639

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013171639&recNum=141&docAn=IB2013053768&queryString=EN_ALL:nmr%20AND%20PA:novartis&maxRec=3644

To illustrate tautomerism with the following specific examples, (R)-N-(4- (chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-l-yl)-5-(lH-pyrazol-5-yl)nicotinamide

(right structure, below) is a tautomer of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-l-yl)-5-(lH-pyrazol-3-yl)nicotinamide (left structure, below) and vice versa:

[0045] Where the plural form (e.g. compounds, salts) is used, this includes the singular

Example 9

(R)-N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hvdroxypyrrolidin-l-yl)-5-(lH-pyrazol-5- vDnicotinamide

[00365] A mixture of (R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-l-yl)nicotinamide (Stage 9.2, 100 mg, 0.216 mmol) and 5-(4 ,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- IH-pyrazole (215 mg, 0.663 mmol), Pd(PPh3)2Cl2 (17 mg, 0.024 mmol), Na2C03 (115 mg, 1.081 mmol), DME (917 μί), water (262 μΕ) and EtOH (131 μί) in a MW vial was sealed, evacuated / purged 3 times with argon and subjected to MW irradiation at 125°C for 20 min. The RM was diluted with 2 mL

of DME, stirred with Si-Thiol (Silicycle 1.44 mmol/g, 90 mg, 0.130 mmol) for 3 h. The mixture was centrifuged and the supernatant was filtered through a 0.45 μηι PTFE filter and the solvent was evaporated off under reduced pressure. The crude product was purified by flash

chromatography (RediSep® Silica gel column, 12 g, cyclohexane / EtOAc from 40% to 100% EtOAc) to afford the protected intermediate as a colorless oil. Ethylene diamine (96 μί, 1.428 mmol) and TBAF 1 M in THF (1.428 mL, 1.428 mmol) were then added and the RM was stirred at 80-85°C for 5 days. The solvent was evaporated off under reduced pressure and the residue was dissolved in EtOAc (40 mL), washed 3 times with sat. aq. NaHCC and brine, dried over Na2S04 and The solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column DEAP, from 25% to 30% in 6 min) to yield the title compound as a white solid.

[00366] Alternatively, Example 9 was prepared by adding TFA (168 mL, 2182 mmol) to a solution of N-(4-(chlorodifluoromethoxy)phenyl)-6-((R)-3-hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl)nicotinamide (Stage 9.1, 31.3 g, 54.6 mmol) in DCM (600 mL). The mixture was stirred at RT for 2.5 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in EtOAc (1.5 L),washed with a sat. solution of NaHC03 (3 x 500 mL) and brine (500 mL), dried over Na2S04 and the solvent was evaporated off under reduced pressure to give a residue which was suspended in DCM (300 mL), stirred at RT for 15 min, filtered, washed with DCM (200 mL), dried and purified by chromatography (Silica gel, 1 kg, DCM / MeOH 95:5). The residue was dissolved in MeOH (500 mL) and treated with Si-Thiol (Biotage, 5.0 g , 6.5 mmol) for 16 h at 25°C. The resin was filtered off, the solvent was evaporated off under reduced pressure and the residue was crystallized from MeCN to afford the title compound as a white crystalline solid.

[00367] Alternatively, Example 9 was prepared by the dropwise addition of aqueous HC1

(7.7 mL of 6M) to a solution of N-(4-(chlorodifluoromethoxy)phenyl)-6-((R)-3-hydroxypyrrolidin- 1 -yl)-5-( 1 -(tetrahydro-2H-pyran-2-yl)- 1 H-pyrazol-5-yl)nicotinamide (Stage 9.1, 3.8 g, 7.12 mmol) in MeOH (20 mL) and THF (10 mL) with cooling (below 35°C). The mixture was stirred at 22°C for 2 h and then added to cooled (10°C) 1.2 M NaOH (22 mL).

Throughout the addition the temperature was kept below 30°C and pH was kept in the range of 9-10. The RM was then stirred for 30 min at 30°C. The solvent was evaporated off under reduced pressure, until the desired compound precipitated. The precipitate was filtered and dried to give the title compound as a yellow solid.

[00368] Analytical data for Example 9: HPLC (Condition 5) tR = 5.54 min, HPLC Chiral

(CHIRALCEL® OD-H, 250 x 4.6 mm, eluent : n-heptane/EtOH/MeOH (85: 10:5), 1 mL/min, UV 210 nm) tR = 10.17 min, UPLC-MS (condition 3) tR = 0.93 min, m/z = 450.3 [M+H]+, m/z = 494.1 [M+formic acid-H]XH-NMR (400 MHz, DMSO-d6) δ ppm 1.65 – 1.76 (m, 1 H) 1.76 – 1.87 (m, 1 H) 2.93 (d, J=l 1.73 Hz, 1 H) 3.19 – 3.29 (m, 2 H) 3.35 – 3.51 (m, 1 H) 4.10 – 4.25 (m, 1 H) 4.89 (br. s, 1 H) 6.41 (br. s, 1 H) 7.33 (d, J=8.50 Hz, 2 H) 7.57/7.83 (br. s, 1 H) 7.90 (d, J=8.50 Hz, 2 H) 8.07 (br. s, 1 H) 8.77 (br. s, 1 H) 10.23 (s, 1 H) 12.97/13.15 (br. s, 1 H).

[00369] Stage 9.1 : N-(4-(Chlorodifluoromethoxy)phenyl)-6-((R)-3-hydroxypyrrolidin- 1 -yl)-5-( 1 -(tetrahydro-2H-pyran-2- l)- 1 H-pyrazol-5-yl)nicotinamide

[00370] l-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (29.6 g, 102 mmol), K3P04 (51.6 g, 236 mmol) and Pd(PPh3)4 (4.55 g, 3.93 mmol) were added to a suspension of (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-l-yl)nicotinamide (Stage 9.2, 36.4 g, 79 mmol) in toluene (360 mL) under an argon atmosphere and the mixture was stirred at 110°C for 4 h. The RM was poured into brine (500 mL) and extracted with EtOAc (2 x 1 L). The combined extracts were washed with brine (500 mL), dried over Na2S04, and the solvent was evaporated off under reduced pressure to give a residue which was purified by chromatography (Silica gel column, 1.5 kg, DCM / MeOH 95:5) to afford a dark yellow foam, that was dissolved in MeOH / DCM (1 L of 3: l) and treated with Si-Thiol (Biotage, 35 g , 45.5 mmol) for 17 h at 30°C. The resin was filtered off, and solvent was evaporated off under reduced pressure, until the desired compound crystallized. The product was filtered washed with MeOH and dried to afford the title compound.

[00371] Alternatively, Stage 9.1 was prepared by adding 4-(chlorodifluoromethoxy)aniline

(16.6 g, 84.9 mmol), NMM (21.7 g, 212.1 mmol), hydroxybenzotriazole hydrate (HOBt H20, 11.9 g, 77.77 mmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCIHCl, 20.9 g, 109.0 mmol) to a solution of 6-((R)-3-hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl)nicotinic acid (Stage 9.4, 29.83 g, 70.7 mmol) in THF (271 mL). The mixture was stirred for 1.5 h at 25°C and then at 65°C for 16 h. After cooling the RM to 35 °C, further EDCIHCl (13.3 g, 69.4 mmol) was added and the RM was stirred for 1.5 h at 35°C then again at 65°C for 16 h. After cooling the RM to 35°C, water (150 mL) was added, the THF was removed under reduced pressure, EtOAc (180 mL) was added and the mixture was stirred for at 35 °C fori h. The two layers were separated and the aq. phase was then extracted with EtOAc (60 mL). The combined organic layers were washed with water (90 mL), brine (90 mL). The solvent was evaporated off under reduced pressure to give a brown solid which was purified by column chromatography (Silica gel, DCM / MeOH 40: 1 to 20: 1) to afford the title compound as a yellow solid.

[00372] Analytical data for Stage 9.1: HPLC (Condition 5) tR = 6.12 min, UPLC-MS

(Condition 3) tR = 1.06 min, m/z = 533.2 [M+H]+XH-NMR (400 MHz, DMSO-d6) δ ppm 1.36 -2.02 (m, 7 H) 2.23 – 2.38 (m, 1 H) 3.08 – 3.29 (m, 2 H) 3.32 – 3.52 (m, 2 H) 3.73 – 3.93 (m, 1 H) 4.13 – 4.25 (m, 1 H) 4.80 – 4.90 (m, 1 H) 4.95 – 5.17 (m, 1 H) 6.33 – 6.50 (m, 1 H) 7.33 (d, J=8.99 Hz, 2 H) 7.61 (d, J=1.56 Hz, 1 H) 7.86 (d, J=8.99 Hz, 2 H) 7.97 – 8.11 (m, 1 H) 8.82 (s, 1 H) 10.13 – 10.25 (m, 1 H).

[00373] Stage 9.2: (R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin- 1 -yl)nicotinamide

[00374] (R)-Pyrrolidin-3-ol (9.55 g, 109.6 mmol) and DIPEA (35.1 ml, 201.3 mmol) were added to a suspension of 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 9.3, 37.7 g, 91.5 mmol) in iPrOH (65 mL) and stirred at 140°C for 1 h. EtOAc (700 mL) was added and the solution was washed IN HC1 (2 x 200 mL), sat. NaHCC (200 mL) and brine (2 x 200 mL), dried over Na2S04, and the solution was concentrated under reduced pressure until crystallization commenced. n-Heptane (1 L) were added and the mixture was stirred at RT for 30 min, filtered and washed with ΪΡΓ20 (500 mL) to afford the title compound as a white crystalline solid. HPLC (Condition 5) tR = 6.68 min, UPLC-MS (Condition 3) tR = 1.10 min, m/z =

462.2/464.2 [M+H]+XH-NMR (400 MHz, DMSO-d6) δ ppm 1.78 – 2.01 (m, 2 H) 3.55 (d, J=l 1.34 Hz, 1 H) 3.66 – 3.75 (m, 1 H) 3.79 – 3.93 (m, 2 H) 4.34 (br. s, 1 H) 4.98 (d, =3.13 Hz, 1 H) 7.32 (d, J=8.99 Hz, 2 H) 7.84 (d, J=8.99 Hz, 2 H) 8.33 (d, J=1.96 Hz, 1 H) 8.66 (d, J=1.96 Hz, 1 H) 10.21 (s, 1 H).

[00375] Stage 9.3: 5-Bromo-6-chloro-N- 4-(chlorodifluoromethoxy)phenyl)nicotinamide

[00376] DMF (2.55 mL, 33.0 mmol) and SOCl2 (24.08 ml, 330 mmol) were added to a suspension of 5-bromo-6-chloro-nicotinic acid (26 g, 110 mmol) in toluene (220 mL) and the RM was stirred at 80°C for 1 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in THF (220 mL) and cooled to -16°C. DIPEA (38.4 mL, 220 mmol) was added, followed by dropwise addition of a solution of 4-(chlorodifluoromethoxy)aniline (22.35 g, 115 mmol) in THF (220 mL) over 15 min. The suspension was stirred for 1 h at RT. The solvent was evaporated off under reduced pressure and the residue was dissolved in TBME (700 mL), washed with IN HC1 (2 x 200 mL), sat. NaHC03 (200 mL) and brine (2 x 200 mL), dried over Na2S04, and the solvent was evaporated off under reduced pressure to give the product which was crystallized from EtOAc – n-heptane to afford the title compound as a white crystalline solid. HPLC (Condition 5) tR = 7.77 min, UPLC-MS (Condition 3) tR = 1.24 min, m/z =

409.1/411.1/413.1 [M+H]+XH-NMR (400 MHz, DMSO-d6) δ ppm 7.38 (d, =8.99 Hz, 2 H) 7.85 (d, =8.99 Hz, 2 H) 8.72 (br. s, 1 H) 8.92 (br. s, 1 H) 10.68 (s, 1 H).

[00377] Stage 9.4: 6-((R)-3-Hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl)nicotinic acid

[00378] Aq. NaOH (180 niL of 2.6 M) was added to a solution of methyl 6-((R)-3-hydroxypyrrolidin- 1 -yl)-5-(l -(tetrahydro-2H-pyran-2-yl)- 1 H-pyrazol-5-yl)nicotinate (Stage 9.5, 11 lg, 299 mmol) in MeOH (270 mL) and the RM was stirred at RT for 14 h. The MeOH was evaporated off under reduced pressure and the aq. residue was treated with brine (90 mL), extracted with MeTHF twice (540 mL + 360 mL) and the combined organic layers were washed with water (90 mL). MeTHF was added to the combined aq. layers, the biphasic mixture was cooled to 0 °C and acidified (pH = 4-4.5) with aq. HC1 solution (18%) and extracted with

MeTHF. The combined organic extracts were washed with brine and the solvent was evaporated off under reduced pressure to give a residue which was recrystallized from a EtOAc / TBME (1 : 1) to afford the title compound as a white solid. HPLC (Condition 7) tR = 4.74 min, LC-MS

(Condition 8) tR = 3.37 min, m/z = 359.0 [M+H]+XH-NMR (400 MHz, DMSO-d6) δ ppm 1.44 (br. s, 2 H), 1.51 (d, J=11.54 Hz, 2 H), 1.64 – 1.86 (m, 4 H), 1.90 (br. s, 1 H), 2.31 (d, J=9.29 Hz, 1 H), 2.77 (br. s, 1 H), 3.10 (br. s, 1 H), 3.21 (d, J=8.78 Hz, 2 H), 3.27 – 3.51 (m, 4 H), 3.87 (d, J=11.54 Hz, 1 H), 4.16 (br. s, 1 H), 4.75 – 4.93 (m, 1 H), 5.04 (br. s, 1 H), 6.35 (d, J=17.32 Hz, 1 H), 7.51 – 7.64 (m, 1 H), 7.64 – 7.82 (m, 1 H), 8.67 (d, J=2.26 Hz, 1 H), 12.58 (br. s, 1 H).

[00379] Stage 9.5: Methyl 6-((R)-3-hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro-2H-pyran-2-yl)- 1 H-pyrazol-5-yl)nicotinate

[00380] A mixture of (R)-methyl 5-bromo-6-(3-hydroxypyrrolidin-l-yl)nicotinate (Stage

9.6, 90 g, 299 mmol), l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-5-boronic acid pinacol ester (103.9 g, 373.6 mmol), K3P04 (126.9 g, 597.7 mmol), Pd(PPh3)2Cl2 (6.29 g, 8.97 mmol) in toluene (900 mL) was stirred at 92°C and for 16 h. After cooling the mixture to RT, the solution was washed with water (450 mL), 5% NaHCC solution (430 mL) and the solvent was evaporated off under reduced pressure to give a residue which was used without further purifications in the next step. HPLC (Condition 7) tR = 6.929 min, LC-MS (Condition 8) tR = 4.30 min, m/z = 373.0 [M+H ; XH-NMR (400 MHz, DMSO-d6) δ ppm 1.19 – 1.28 (m, 1 H), 1.35 – 1.63 (m, 4 H), 1.63 -1.86 (m, 3 H), 1.89 (br. s, 1 H), 2.12 – 2.39 (m, 1 H), 3.11 (br. s, 1 H), 3.18 – 3.48 (m, 4 H), 3.78 (s, 4 H), 3.88 (d, J=11.54 Hz, 1 H), 4.08 – 4.24 (m, 1 H), 4.86 (dd, J=18.20, 2.89 Hz, 1 H), 5.02 (d, J=8.28 Hz, 1 H), 6.39 (br. s, 1 H), 7.58 (d, J=1.25 Hz, 1 H), 7.78 (br. s, 1 H), 8.69 (t, J=2.01 Hz, 1 H).

[00381] Stage 9.6: (R)-methyl 5-bromo-6-(3-hydroxypyrrolidin-l-yl)nicotinate

[00382] DIPEA (105.3 g, 142.2 mL, 814.4 mmol) was added to a solution of methyl-5-bromo-6-chroronicotinate (85 g, 339.5 mmol) and (R)-pyrrolidin-3-ol (54.2 g, 441.2 mmol) in isopropyl acetate and the RM was stirred at 70°C for 14 h . The solvent was evaporated off under reduced pressure to give a the residue which was dissolved in toluene (850 mL), washed with water (127 mL) and brine (127 mL)and concentrated under reduced pressure until precipitation commenced. n-Heptane (340 mL) was slowly added to the stirred mixture at 22 °C, which was then cooled to 0 °C and the product was filtered, washed with a toluene / n-heptane mixture

(1 : 1.5) and dried to give the title compound as a yellow solid. HPLC (Condition 7) tR = 8.54 min, LC-MS (Condition 8) tR = 4.62 min, m/z = 300.9/302.9 [M+H]+XH-NMR (400 MHz, DMSO-d6) δ ρριη 1.77 – 1.99 (m, 2 H), 3.57 (d, J=11.54 Hz, 1 H), 3.72 (ddd, J=l 1.11, 7.97, 3.26 Hz, 1 H), 3.78 (s, 3 H), 3.81 -3.90 (m, 2 H), 4.26 – 4.39 (m, 1 H), 4.99 (br. s, 1 H), 8.11 (d, J=2.01 Hz, 1 H), 8.56 (d, J=1.76 Hz, 1 H).

PAPER

  • By Wylie, Andrew A.; Schoepfer, Joseph; Jahnke, Wolfgang; Cowan-Jacob, Sandra W.; Loo, Alice; Furet, Pascal; Marzinzik, Andreas L.; Pelle, Xavier; Donovan, Jerry; Zhu, Wenjing; et al
  • From Nature (London, United Kingdom) (2017), 543(7647), 733-737.

By Wylie, Andrew A. et alFrom Nature (London, United Kingdom), 543(7647), 733-737; 2017

PAPER

  • By Molica, Matteo; Massaro, Fulvio; Breccia, Massimo
  • From Expert Opinion on Pharmacotherapy (2017), 18(1), 57-65.

PATENT

US 20170216289

PAPER

  • By El Rashedy, Ahmed A.; Olotu, Fisayo A.; Soliman, Mahmoud E. S.
  • From Chemistry & Biodiversity (2018), 15(3), n/a.
Patent ID

Patent Title

Submitted Date

Granted Date

US2016108123 ANTIBODY MOLECULES TO PD-L1 AND USES THEREOF
2015-10-13
2016-04-21
US2014343086 COMPOUNDS AND COMPOSITIONS FOR INHIBITING THE ACTIVITY OF ABL1, ABL2 AND BCR-ABL1
2014-07-31
2014-11-20
US8829195 Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
2013-05-13
2014-09-09

////////////////ABL001, Asciminib, ABL 001, ABL-001, PHASE 3, Chronic Myeloid Leukemia,  NOVARTIS

 O=C(NC1=CC=C(OC(F)(Cl)F)C=C1)C2=CN=C(N3C[C@H](O)CC3)C(C4=CC=NN4)=C2

Glasdegib, PF-04449913


Glasdegib.svgChemSpider 2D Image | Glasdegib | C21H22N6OGlasdegib.png

str1

Glasdegib (PF-04449913)

1-[(2R,4R)-2-(1H-Benzimidazol-2-yl)-1-methyl-4-piperidinyl]-3-(4-cyanophenyl)urea [ACD/IUPAC Name]
1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea
CAS 1095173-27-5 [RN]Orphan Drug Status

Glasdegib

  • Molecular FormulaC21H22N6O
  • Average mass374.439 Da
  • Urea, N-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methyl-4-piperidinyl]-N’-(4-cyanophenyl)- [ACD/Index Name]
    гласдегиб [Russian] [INN]
    غلاسديغيب [Arabic] [INN]
    格拉德吉 [Chinese] [INN]

FACT SHEET   https://www.pfizer.com/files/news/asco/Glasdegib-Fact-Sheet-6JUNE2018.pdf

Glasdegib (PF-04449913) is an experimental cancer drug developed by Pfizer. It is a small molecule inhibitor of the Sonic hedgehog pathway, which is overexpressed in many types of cancer. It inhibits smoothened receptor, as do most drug in its class.[1]

Four phase II clinical trials are in progress. One is evaluating the efficacy of glasdegib in treating myelofibrosis in patients who were unable to control the disease with ruxolitinib.[2] Another is a combination trial of glasdenib with ARA-Cdecitabinedaunorubicin, or cytarabine for the treatment of acute myeloid leukemia.[3] The third is for the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia.[4] The fourth administers glasdegib to patients at high risk for relapse after stem cell transplants in acute lymphoblastic or myelogenous leukemia.[5]

  • OriginatorPfizer
  • DeveloperGrupo Espanol de Trasplante Hematopoyetico y Terapia Celular; H. Lee Moffitt Cancer Center and Research Institute; Netherlands Cancer Institute; Pfizer
  • ClassAntineoplastics; Benzimidazoles; Phenylurea compounds; Piperidines; Small molecules
  • Mechanism of ActionHedgehog cell-signalling pathway inhibitors; SMO protein inhibitors
  • Orphan Drug StatusYes – Acute myeloid leukaemia; Myelodysplastic syndromes
  • New Molecular EntityYes

Highest Development Phases

  • Phase IIIAcute myeloid leukaemia
  • Phase IIChronic myeloid leukaemia; Colorectal cancer; Myelodysplastic syndromes; Myelofibrosis; Non-small cell lung cancer
  • Phase I/IIChronic myelomonocytic leukaemia; Glioblastoma; Graft-versus-host disease
  • Phase ICancer; Haematological malignancies
  • No development reportedSolid tumours

Most Recent Events

  • 20 Apr 2018Phase-III clinical trials in Acute myeloid leukaemia (Combination therapy, First-line therapy) in Japan (PO) (NCT03416179)
  • 02 Apr 2018Pfizer terminates a phase II trial in Myelofibrosis (Second-line therapy or greater) in USA, Japan, Austria, France, Spain and United Kingdom (PO) (NCT02226172) (EudraCT2014-001048-40)
  • 06 Feb 2018Phase-I/II clinical trials in Glioblastoma (Newly diagnosed) in Spain (PO) (EudraCT2017-002410-31)

Glasdegib is an orally bioavailable small-molecule inhibitor of the Hedgehog (Hh) signaling pathway with potential antineoplastic activity. Glasdegib appears to inhibit Hh pathway signaling. The Hh signaling pathway plays an important role in cellular growth, differentiation and repair. Constitutive activation of Hh pathway signaling has been observed in various types of malignancies.

Glasdegib is under investigation for the treatment of Acute Myeloid Leukemia.

SYNTHESIS

Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened

https://pubs.acs.org/doi/abs/10.1021/ml2002423

 Michael J. Munchhof LLC, 266 West Road, Salem, Connecticut 06420, United States
 Pfizer Global Research and Development, Groton, Connecticut 06340, United States
§ 24 Queen Eleanor Drive, Gales Ferry, Connecticut 06335, United States
 INC Research, Old Lyme, Connecticut 06371, United States
 Reiter.MedChem, 32 West Mystic Avenue, Mystic, Connecticut 06355, United States
# Bristol-Meyers Squibb, Princeton, New Jersey 08540, United States
ACS Med. Chem. Lett.20123 (2), pp 106–111
DOI: 10.1021/ml2002423
Publication Date (Web): December 21, 2011
Copyright © 2011 American Chemical Society
*Tel: 860-287-5924. E-mail: mikemunchhof@yahoo.com.
Abstract Image

Inhibitors of the Hedgehog signaling pathway have generated a great deal of interest in the oncology area due to the mounting evidence of their potential to provide promising therapeutic options for patients. Herein, we describe the discovery strategy to overcome the issues inherent in lead structure 1 that resulted in the identification of Smoothened inhibitor 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea (PF-04449913, 26), which has been advanced to human clinical studies

1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea (26)

https://pubs.acs.org/doi/suppl/10.1021/ml2002423/suppl_file/ml2002423_si_001.pdf

str1

Product was purified by Companion (ReadySep 40g, silica gel packed) with CH3OH/CH2Cl2 from 1-5% to give the title compound as an off-white solid 915mg (73%). LC-MS 375.3.

1H NMR(acetone-D6): δ 1.81 (m, 2H), 1.9- 2.05 (m, 2H), 2.10 (m, 1H), 2.17 (s, 3H), 2.52 (m, 1H), 2.94 (m, 1H), 3.86 (m, 1H), 4.2 (m, 1H), 6.4 (d, 1H), 7.16 (m, 2H), 7.52 (m, 2H), 7.60 (m, 2H), 7.62 (m, 2H), 8.46 (s, 1H).

The dihydrochloride salt was prepared by adding 4M HCl in dioxane (1.22mL, 4.86 mmol) to a solution of 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4- cyanophenyl)urea (910 mg’s, 2.43mmol) in methanol (10mL). The mixture was stirred at at 230C for 10 minutes. The solution was concentrated to give a white solid, 1082 mg’s as the 2 .HCl monohydrate salt. M.P. > 125 0C with dehydration above 130 0C. Analytical calculated for free base C21H22N6O: C 67.38%, H 5.88%, N 22.46%; Found: C 67.16%, H 5.54%, N 22.18%. Purity of the dihydrochloride monohydrate salt was determined to be > 99.9% by analytical HPLC using a Xbridge C18; 3.5µm column and eluting with 95:5 0.1% Perchloric Acid (HClO4) solution in water and acetonitrile, over a gradient of 25 minutes, with and ending solvent ratio of 5:95. Enantiomeric purity of the dihydrochloride monohydrate salt was > 99.9% by chiral HPLC using a Chiralcel OJ column and eluting with 96:4 Heptane:Ethanol(with 0.1% diethylamine).

Syn 2

Development of a Concise, Asymmetric Synthesis of a Smoothened Receptor (SMO) Inhibitor: Enzymatic Transamination of a 4-Piperidinone with Dynamic Kinetic Resolution

https://pubs.acs.org/doi/10.1021/ol403630g

Chemical Research & Development, Analytical Research & Development, Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, United States
Org. Lett.201416 (3), pp 860–863
DOI: 10.1021/ol403630g
Publication Date (Web): January 22, 2014
Copyright © 2014 American Chemical Society
Abstract Image

A concise, asymmetric synthesis of a smoothened receptor inhibitor (1) is described. The synthesis features an enzymatic transamination with concurrent dynamic kinetic resolution (DKR) of a 4-piperidone (4) to establish the two stereogenic centers required in a single step. This efficient reaction affords the desired anti amine (3) in >10:1 dr and >99% ee. The title compound is prepared in only five steps with 40% overall yield.

https://pubs.acs.org/doi/suppl/10.1021/ol403630g/suppl_file/ol403630g_si_001.pdf

1-((2R,4R)-2-(1H-Benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea (1)

1 as white solids3 (27.1 g, 99.5 wt%, 90.0% corrected yield, > 99.0 UPLC area% purity): m.p. 223–224 °C; UPLC tR 2.11 min; 1 H NMR (DMSO-d6) δ 12.39 (s, 1H), 8.94 (s, 1H), 7.69 (m, 2 H), 7.57 (m, 3 H), 7.43 (m, 1 H), 7.13 (m, 2H), 6.75 (d, J = 7.2 Hz, 1H), 4.08 (m, 1H), 3.63 (dd, J = 10.3, 3.5 Hz, 1H), 2.89 (dt, J = 12.0, 4.0 Hz, 1H), 2.40 (td, J = 11.9, 3.1 Hz, 1H), 2.06 (s, 3H), 1.98–2.10 (m, 1H), 1.83–1.95 (m, 2H), 1.72 (m, 1H); 13C NMR (DMSO-d6) δ 155.7, 153.9, 144.8, 142.7, 134.3, 133.2, 121.8, 120.9, 119.4, 118.5, 117.3, 111.2, 102.4, 58.6, 49.9, 43.7, 42.4, 36.0, 29.8. HRMS (EI) calcd. for C21H23N6O [M+H]+ : 375.1928; Found 375.1932.

To the crude solution of 3 in DMSO-H2O (UPLC assay ~55.0 mg/mL, 104 mL, ~5.74 g of 3, 24.9 mmol) from the enzymatic transamination reaction (vide supra) was added THF (57.0 mL) followed by 17 (mixture with imidazole, 9.31 gm, 74.0 wt%, 31.2 mmol). The mixture was then stirred at rt for three hours. Once the reaction was complete (<1 % of 3 remaining by UPLC), methanol (10.1 mL, 249 mmol) was added followed by 2-MeTHF (57.0 mL). The layers were separated and the aqueous was extracted with 2-MeTHF (57.0 mL). The combined organic layers were then washed with 2 × 50.0 mL water and 2 × 50.0 mL of 10% aqueous NaCl solution. The organic solution was then concentrated under vacuum and the solvent was switched to acetonitrile to give a slurry with a final volume of ~90.0 mL. The slurry was stirred at rt for three hours and filtered, and the solids were washed with 2 × 10.0 mL of acetonitrile and dried in oven at 60 °C for two hours. The solids (~7.90 gm) were then slurried in 70.0 mL of acetonitrile. The slurry was heated to 60 °C for two hours, cooled to rt, filtered, and the solids were dried in oven under vacuum at 60 °C for 12 hours to give 1 as white solids (7.64 g, 98.0 wt%, 80.0% corrected yield, > 98 UPLC area% purity). The analytical data were identical to that obtained with method A.

References

1. Lin TL, Matsui W. Hedgehog pathway as a drug target: smoothened inhibitors in development. Onco Targets Ther. 2012;5:47-58.

2. Munchhof MJ, Li Q, Shavnya A, et al. Discovery of PF-04449913, a potent and orally bioavailable inhibitor of smoothened. ACS Med Chem Lett. 2012;3(2):106-111.

3. Clement V, Sanchez P, de Tribolet N, et al. Hedgehog-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol. 2007;17(2):165-172.

4. Deschler, B. and Lübbert, M. (2006), Acute myeloid leukemia: Epidemiology and etiology. Cancer, 107: 2099–2107. doi: 10.1002/cncr.22233.

5. American Cancer Society. Key statistics for acute myeloid leukemia. Available at https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html. Accessed January 25, 2018.

6. SEER Cancer Stat Facts: Acute Myeloid Leukemia. National Cancer Institute. Bethesda, MD, April 2017. Available at: http://seer.cancer.gov/statfacts/html/amyl.html. Accessed January 25, 2018.

7. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood 2006; 107(9): 3481-5.

8. Estey E. Acute myeloid leukemia and myelodysplastic syndromes in older patients. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2007; 25(14): 1908-15.

9. Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2012; 30(21): 2670-7.

10. Ornstein MC, Mukherjee S, Sekeres MA. More is better: combination therapies for myelodysplastic syndromes. Best Pract Res Clin Haematol. 2015;28(1):22-31.

11. American Cancer Society. What are the key statistics about myelodysplastic syndromes? Available at: http://www.cancer.org/cancer/myelodysplasticsyndrome/detailedguide/myelo-dysplastic-syndromes-key-statistics. Accessed January 25, 2018. 12. Ma X, Does M, Raza A, et al. Myelodysplastic syndromes: incidence and survival in the United States. Cancer. 2007;109(8):1536-1542

Glasdegib
Glasdegib.svg
Clinical data
Synonyms PF-04449913
Identifiers
CAS Number
ChemSpider
KEGG
Chemical and physical data
Formula C21H22N6O
Molar mass 374.45 g·mol−1
3D model (JSmol)
 to 3 of 3
Patent ID

Patent Title

Submitted Date

Granted Date

US8431597 Benzimidazole derivatives
2012-02-24
2013-04-30
US8148401 BENZIMIDAZOLE DERIVATIVES
2009-01-01
2012-04-03
US9611330 COMPOSITIONS AND METHODS FOR CANCER AND CANCER STEM CELL DETECTION AND ELIMINATION
2012-09-07
2014-10-09

////////////Glasdegib, PF-04449913, гласдегиб غلاسديغيب 格拉德吉 , PF04449913, PF 04449913, phase 3, aml, Orphan Drug Status

CN1CCC(CC1C2=NC3=CC=CC=C3N2)NC(=O)NC4=CC=C(C=C4)C#N

Talazoparib, MDV3800


Talazoparib.svg

Talazoparib, BMN-673, MDV-3800

(2S,3S)-methyl-7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

(8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one

CAS 1207456-01-6
Chemical Formula: C19H14F2N6O
Exact Mass: 380.11972

BMN673, BMN673, BMN-673, LT673, LT 673, LT-673,  Talazoparib

BioMarin Pharmaceutical Inc

phase 3

Poly ADP ribose polymerase 2 inhibitor; Poly ADP ribose polymerase 1 inhibitor

cancer

(85,9R)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one toluenesulfonate salt

CAS 1373431-65-2(Talazoparib Tosylate)

1H NMR DMSOD6

str1

13C NMR DMSOD6

str1

HMBC NMR

str1

HSQC NMR

str1

Talazoparib (BMN-673) is an investigational drug that acts as a PARP inhibitor. It is in clinical trials for various cancers.

Talazoparib.png

Medivation, under license from BioMarin Pharmaceuticals, following its acquisition of LEAD Therapeutics, is developing a PARP-1/2 inhibitor, talazoparib, for treating cancer, particularly BRCA-mutated breast cancer. In February 2016, talazoparib was reported to be in phase 3 clinical development

Talazoparib, also known as BMN-673, is an orally bioavailable inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential antineoplastic activity (PARP1 IC50 = 0.57 nmol/L). BMN-673 selectively binds to PARP and prevents PARP-mediated DNA repair of single strand DNA breaks via the base-excision repair pathway. This enhances the accumulation of DNA strand breaks, promotes genomic instability and eventually leads to apoptosis. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins that signal and recruit other proteins to repair damaged DNA and is activated by single-strand DNA breaks. BMN-673 has been proven to be highly active in mouse models of human cancer and also appears to be more selectively cytotoxic with a longer half-life and better bioavailability as compared to other compounds in development. Check for active clinical trials or closed clinical trials using this agent.

Talazoparib is C19H14F2N6O.

Talazoparib tosylate is C26H22F2N6O4S.[1]

Approvals and indications

None yet.

Mechanism of action

Main article: PARP inhibitor

Clinical trials

After trials for advanced hematological malignancies and for advanced or recurrent solid tumors.[2] it is now in phase 3 for metastatic germline BRCA mutated breast cancer.[3] Trial estimated to complete in June 2016.[4]

As of January 2016 it in 14 active clinical trials.[5]

WO2010017055,  WO2015069851, WO 2012054698, WO 2011130661, WO 2013028495, US 2014323725, WO 2011097602

PAPER

Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent

BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, California 94949, United States
J. Med. Chem.201659 (1), pp 335–357
DOI: 10.1021/acs.jmedchem.5b01498
Publication Date (Web): December 10, 2015
Copyright © 2015 American Chemical Society
*Phone: 1-415-506-3319. E-mail: bwang@bmrn.com.

Abstract

Abstract Image

We discovered and developed a novel series of tetrahydropyridophthlazinones as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. Lead optimization led to the identification of (8S,9R)-47 (talazoparib; BMN 673; (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one). The novel stereospecific dual chiral-center-embedded structure of this compound has enabled extensive and unique binding interactions with PARP1/2 proteins. (8S,9R)-47 demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with Ki = 1.2 and 0.87 nM, respectively. It inhibits PARP-mediated PARylation in a whole-cell assay with an EC50 of 2.51 nM and prevents proliferation of cancer cells carrying mutant BRCA1/2, with EC50 = 0.3 nM (MX-1) and 5 nM (Capan-1), respectively. (8S,9R)-47 is orally available, displaying favorable pharmacokinetic (PK) properties and remarkable antitumor efficacy in the BRCA1 mutant MX-1 breast cancer xenograft model following oral administration as a single-agent or in combination with chemotherapy agents such as temozolomide and cisplatin. (8S,9R)-47 has completed phase 1 clinical trial and is currently being studied in phase 2 and 3 clinical trials for the treatment of locally advanced and/or metastatic breast cancer with germline BRCA1/2 deleterious mutations.

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01498

http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01498/suppl_file/jm5b01498_si_001.pdf

Preparation of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one Tosylate Salt ((8S,9R)-47 Tosylate Salt)

A suspension of (8S,9R)-47 (BMN 673) (400 mg, 1.05 mmol) in a mixture of acetone (27 mL) and THF (13 mL) was heated to reflux until the suspension became clear. TsOH (220 mg, 1.16 mmol) was then added to the solution. White solids started to precipitate out from the solution shortly after the addition of TsOH. After stirring at 25 °C for 30 min, the mixture was filtered to collect the white crystal solids, which were washed with a mixture of acetone (10 mL) and 1,4-dioxane (4 mL) and then dried under vacuum at 45 °C for 3 days. This afforded the product as a white crystalline solid (540 mg, yield 93%). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 2.29 (s, 3H), 3.67 (s, 3H), 4.97–5.06 (m, 2H), 6.91–6.94 (dd, J1 = 2.0 Hz, J2 = 10.8 Hz, 1H), 7.06–7.19 (m, 5H), 7.19–7.51 (m, 4H), 7.74 (s, 1H), 7.87 (s, 1H), 10.32 (brs, 1H), 12.36 (s, 1H). LC-MS (ESI)m/z: 381 (M + H)+. Anal. Calcd for C19H14F2N6O·toluene sulfonic acid: C, 56.52; H, 4.01; N, 15.21. Found: C, 56.49; H, 3.94; N, 15.39.

(8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (8S,9R)-47 or BMN 673 and (8R,9S)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (8R,9S)-47

Compound 47 was dissolved in DMF, and chiral resolution was performed using supercritical-fluid chromatography (SFC) with a CHIRALPAK IA chiral column and methanol (20% with 0.1% DEA) and CO2 (80%) as the eluents. Yield 90%. For (8S,9R)-47 (BMN 673): retention time 8.8 min and ee 99.3%. For (8R,9S)-47: retention time 10.2 min and ee 99.2%.
Alternatively, compound (8S,9R)-47 could also be made using (2S,3R)-60a as a starting material and employing the same procedure described for the conversion of 60a to 47.
The optical rotation for both (8S,9R)-47 and (8R,9S)-47 was measured using a RUDOLPH (AUTOPOL V) automatic polarimeter at a concentration of 6.67 mg/mL in MeOH/MeCN/DMF = 0.5:0.5:1 at 20 °C. The specific rotation for (8S,9R)-47 was +92.2°, whereas it was −93.4° for (8R,9S)-47.

PATENT

WO-2016019125

WO2016019125

The compound (85,9R)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one toluenesulfonate salt (Compound (A))

Compound (A)

is an inhibitor of poly(ADP-ribose)polymerase (PARP). Methods of making it are described in WO2010017055, WO2011097602, and WO2012054698. However, the disclosed synthetic routes require chiral chromatography of one of the synthetic intermediates in the route to make Compound (A), methyl 7-fluoro-2-(4-fluorophenyl)-3-(l -methyl- lH-1, 2,4-triazol-5-yl)-4-oxo- 1 ,2,3,4-tetrahydroquinoline-5-carboxylate (Intermediate (A)),

Intermediate (A)

to yield the chirally pure (2S,35)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH- 1,2,4-triazol-5-yl)-4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (Compound (1))

Compound (1).

Using conventional chiral chromatography is often solvent and time intensive.

Use of more efficient chromatography methods, such as simulated moving bed (SMB) chromatography still requires the use of expensive chiral chromatography resins, and is not practical on a large scale to purify pharmaceutical compounds. Also, maintaining

Compound (1) in solution for an extended time period during chromatography can lead to epimerization at the 9-position and cleavage of the methyl ester group in Compound (1). Replacing the chromatography step with crystallization step(s) to purify Compound (1) is desirable and overcomes these issues. Therefore, it is desirable to find an alternative to the use of chiral chromatography separations to obtain enantiomeric Compound (1).

Scheme 1 below describes use of Ac49 as a coformer acid for the preparation of Compound (la) and for the chiral resolution of Compound (1).

Scheme 1

Compound (1 )

Example 2 – Preparation of Compound (1) Using Scheme 1

Step la

Intermediate (A) (5 g, 12.5 mmol) was dissolved in 9: 1 v/v MIBK/ethanol (70 mL, 14 vol.) at 50 °C with stirring and dissolution was observed in less than about 5 minutes. [(lS)-en<io]-(+)-3-bromo-10-camphor sulfonic acid monohydrate (4.1 g, 12.5 mmol) was added and dissolution was observed in about 10-20 minutes. Seeding was then performed with Compound (la) (95% e.e., 5 mg, 0.1% w.) and the system was allowed to equilibrate for about 1 hour at 50 °C, was cooled to about 20 °C at 0.15 °C/min, and then equilibrated at 20 °C for 2 hours. The solid phase was isolated by filtration, washed with ethanol, and dried at about 50 °C and 3 mbar for about 2 to 3 hours to yield Compound (la) as a 0.6 molar equiv. EtOH solvate and 0.6 molar equiv. hydrate (93.4% e.e.).

Step lb

Compound (la) was then suspended in MIBK/ethanol 95/5% by volume (38 mL, 10 vol.) at 50 °C with stirring. After about 2 hours at 50 °C, the suspension was cooled to about 5 °C for 10 to 15 hours. The solid phase was recovered by filtration and dried at about 50 °C and 3 mbar for about 3 hours. Compound (la) (97.4% e.e.) was recovered. Step 2

000138] Compound (1) was released by suspending Compound (la) (3.9 g, 5.5 mmoi), without performing the optional reslurrying in Step 1, in 20 mL of water at room temperature and treating with 5M sodium hydroxide in water (1.3 mL, 1.2 mol). The mixture was kept at room temperature for about 15 hours and the solid was isolated by filtration and dried at 50 °C and 3 mbar for about 3 hours. Compound (1) was recovered (94.4% e.e.).

Example 3 – Large Scale Preparation of Compound (1) Using Scheme 1

The procedure of Example 1 was followed using 3.3 kg of Intermediate (A) and the respective solvent ratios to provide 95.7% e.e. in Step la; 99.2% e.e. in Step lb; and 99.2% e.e. in Step 2.

Example 4 – Alternative Preparation of Compound (1) Using Scheme 1

Step la

Intermediate (A) (751 mg, 1.86 mmol)) was dissolved in 9: 1 v/v

MIBK/ethanol (7.5 mL, 10 vol.) at 50 °C with stirring. [(15)-eni o]-(+)-3-bromo-10-camphor sulfonic acid monohydrate (620 mg, 1.88 mmol, 1 equiv.) was added. Formation of a precipitate was observed at about 1 hour at 50 °C. The system was then cooled to about 5 °C at 0.1 °C/min, and then equilibrated at 5 °C for about 60 hours. The solid phase was isolated by filtration and dried at about 50 °C and 3 mbar for about 2 hours to yield

Compound (la)(92% e.e.). See Figures 1-4 for XRPD (Figure 1), chiral HPLC (Figure 2), Ή NMR (Figure 3), and TGA/DSC analyses (Figure 4). The XRPD pattern from the material in Example 3 is similar to that in Example 1 with some slight shifts in the positions of specific diffraction peaks (highlighted by black arrows in Figure l). The ‘H NIVIR was consistent with a mono-salt of Compound (la) containing 0.5 molar equivalent of EtOH and 0.6% by weight residual MIBK. The TGA analysis showed a stepwise mass loss of 3.5% between 25 and 90 °C (potentially representing loss of the 0.5 molar equivalent of EtOH) and a gradual mass loss of 1.2% between 90 and 160 °C (potentially representing the loss of adsorbed water). The DSC analysis had a broad endotherm between 25 and 90 °C

representing desolvation and an endotherm at 135 °C representing melt/degradation.

Step lb

Compound (la) (100.3 mg, 0.141 mmol) was re-suspended in 95:5 v/v MIBK EtOH (1 mL, 10 vol.) at 50 °C and stirred for 1 hour before cooling to 5 °C at

0.1 °C/min. The solid (99.4% e.e.) was recovered by filtration after 1 night at 5 °C. Shifts in the XRPD diffraction peaks were no longer detected (Figure 5; compare Figure 1). Figure 6 shows the chiral HPLC for Compound (la).

Step 2

Compound (la) (100.2 mg, 0.141 mmol) from Step la was suspended in water (2 mL, 20 vol.) at 50 °C and 5 M NaOH in water (34 μL·, 1.2 molar equiv) was added. The resulting suspension was kept at 50 °C for one night, cooled to room temperature

(uncontrolled cooling) and filtered to yield Compound (1) (92% e.e.). The chiral purity was not impacted by this step and no [(15)-enJo]-(+)-3-bromo-10-camphor sulfonic acid was detected by NMR. Figure 7 compares the XRPD of Compound (1) in Step 2 with

Intermediate (A), the starting material of Step 1. Figure 8 shows the NMR of Compound (1) in Step 2 with Intermediate (A), the starting material of Step 1.

Example 5 – Alternative Preparation of Compound (1) Using Scheme 1 Step la

000144] Intermediate (A) (1 equiv.) was added with stirring to a solution of MIBK (12-13 vol), ethanol (1-1.5 vol), and water (0.05-0.10 vol) and the reaction was heated within 15 minutes to an internal temperature of about 48 °C to about 52 °C . [(lS)-endo]-(+)-3-bromo- 10-camphor sulfonic acid (1 equiv) was added and the reaction was stirred for about 5-10 mins at an internal temperature of about 48 °C to about 52 °C until dissolution occurred. Seed crystals of Compound (la) were added and the reaction was allowed to proceed for 1 hour at an internal temperature of about 48 °C to about 52 °C. The reaction was cooled at a rate of 0.15 °C /min to about 19-21 °C. The suspension was stirred for 2 hours at an internal temperature of about 19 °C to 21 °C and then was collected by filtration and washed twice with ethanol. The product was characterized by 1H NMR and 13C NMR (Figures 13a and 13b), IR Spectrum (Figure 14), DSC (Figure 15), and chiral HPLC (Figure 16).

Step 2a

To Compound (la) (1 equiv.) was added acetone (1.1 vol), IPA (0.55 vol), and methanol (0.55 vol) and the reaction was heated to an internal temperature of about 38 °C to 42 °C. Aqueous ammonia (25%) (1.3 equiv) was added and the reaction was stirred for about 10 minutes. The pH of the reaction was confirmed and the next step performed if > 7. Water was added (0.55 vol), the reaction was cooled to an internal temperature of about 35 °C, seed crystals of Compound (1) were added, and the reaction was stirred for about 10 mins. Water was added (3.3 vol) dropwise within about 30 minutes, the suspension was cooled within 30 minutes to an internal temperature of about 0 °C to 5 °C, and the reaction was stirred for 15 minutes. The solid was collected by filtration and washed three times with water.

Step 2b

To the product of Step 2a) was added acetone (4 vol), ΓΡΑ (1 vol), and methanol (1 vol) and the reaction was heated to an internal temperature of about 38 °C to 42 °C resulting in a clear solution. Water (2 vol) and seed crystals of Compound (1) were added and the system was stirred for about 15 minutes at an internal temperature of about 35 °C. Water (342 mL) was added dropwise in about 30 minutes. The suspension was then cooled in 30 min to an internal temperature of about 0 °C to 5 °C and was stirred for an additional 15 minutes. The solid was collected by filtration, washed twice with water, and chiral purity was determined. If > 99% e.e., then the solid was dried at an internal temperature of about 60 °C under reduced pressure to yield Compound (1). The product was characterized by Ή NMR (Figure 19), 13C NMR (Figure 20), IR (Figure 21), DSC (Figure 22), chiral HPLC (Figure 23).

Scheme 2 below describes use of Acl 10 as a coformer acid for the preparation of Compound (lb) and the chiral resolution of Compound (1).

Intermediate (A)

Compound (1 b)

Intermediate (A)

Compound (1 b)

Compound (1 )

Example 6 – Preparation of Compound (1) Using Scheme 2

Step la

Intermediate (A) (102 mg, 0.256 mmol) was dissolved in MIBK (1 mL, 10 vol.) at 65 °C with stirring. (lS)-phenylethanesulfonic acid, prepared using procedures known to one of skill in the art, in MIBK (3.8 M, 80 μί, 1 molar equiv.) was added and a suspension was observed after 30 minutes at 65 °C. The system was kept at 65 °C for another 30 minutes before cooling to 5 °C at 0.1 C/min. After one night at 5 °C, the solid was filtered, dried at 50 °C, 3 mbar pressure for about 2 hours to yield Compound (lb). See Figures 9-12 for XRPD (Figure 9), chiral HPLC (Figure 10), Ή NMR (Figure 11), and TGA/DSC analyses (Figures 12a and 12b). The XRPD diffraction pattern of the solid obtained in Example 5 differed from the XRPD pattern obtained with the solid from in the salt screen of Example 1 and was consistent with the production of different solids in Examples 1 and 5. The Ή NMR was consistent with the mono-salt with a 0.3% by weight residue of dioxane. In Figure 12a, the thermal behavior was consistent with a non-solvated form exhibiting a melt/degradation at 201 °C. Figure 12b compares the melt pattern of Compound (lb) in Example 5 with Compound (lb) in Example 1.

Steps lb and 2 can be carried out using procedures similar to those used in Examples 2-5.

Example 7 – Polymorphism of Compound (la)

Compound (1) (92% e.e., 10 mg, mmol) was placed in 1.5 mL vials and the solvents (1 mL or less) of Table 3 were added at 50 °C until dissolution was achieved. [(1S)-eni o]-(+)-3-bromo-10-camphorsulfonic acid was added as a solid at 50 °C. The samples were kept at 50 °C for about 1 hour prior to being cooled to room temperature overnight

(uncontrolled cooling rate). Clear solutions were successively cooled to 4 °C, -20 °C and evaporated at room temperature. Any gum obtained after evaporation was re-suspended in diethyl ether. The solid phases generated were characterized by XRPD and if relevant, by Ή NMR and TGA/DSC.

Table 3. Compound (la) Polymorphism Conditions

C.S. means clear solution and Susp. means suspension. “A” means the XRPD diffraction pattern was new but similar to that for Ac49 in

Example 1. “B” means the XRPD diffraction pattern was the same as that for Ac49 in Example 1. “M.E.” means molar equiv.

Page 38 of 64

NAI- 1500460480V I

Each of the seven solvents in which solvates were observed (heterosolvates not included) were mixed with MIBK (90% vol). Solutions of Intermediate (A) were prepared in the solvent mixtures (10 vol) at 50 C and [(15)-en<io]-(+)-3-bromo-10-camphor sulfonic acid (1 molar equivalent) was added. The resulting clear solutions were cooled to 5 °C at 0.2 C/min. Surprisingly, no crystallization was reported in any sample. Seeding was performed with a few crystals of each solvate at about 25 °C. The solid phases were analyzed by XRPD and the liquid phases were analyzed by chiral HPLC. See Table 4 for a summary of the results (where “Dias 2” is the (2R, 3R) diastereomer of Compound (la)) .

Table 4. Compound (la) Solvate Analysis

As seen in Table 4 above, the ethanol/MIBK system yielded 93% pure Compound (la) which demonstrates that Compound (la) does crystallize in a very pure form as an ethanolate solvate.

Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following description. It should be understood, however, that the description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the present description will become apparent from this detailed description.

All publications including patents, patent applications and published patent applications cited herein are hereby incorporated by reference for all purposes.

PATENT

US 2011196153

http://www.google.co.ve/patents/US20110237581

STR1.jpg

Patent

US 2011237581

PATENTSTR1.jpg

PATENT

http://www.google.com/patents/WO2015069851A1?cl=en

SYNTHETIC EXAMPLES

Example 1

\ , 

(1 a) (2) (3) (la) (5)

To a flask was added N-methyl-l,2,4-triazole (la)(249.3 g, 3.0 mol, 1 equiv.),

2-methyl-THF (1020 mL, about 1 :4 m/v), and DMF (2)(230.2 g, 3.15 mol, 1.05 equiv.), in any order. The solution was cooled to an internal temperature of about -5 to 0 °C. To the flask was added LiHMDS (3) as a 20% solution in 2-methyl-THF (3012 g, 3.6 mol, 1.2 equiv.) dropwise within about 60 minutes. During the addition of the LiHMDS (3), the desired Compound (la) was precipitated as the 2-methyl-THF solvate, and the flask was cooled to about -30 °C. The reaction was stirred for about 30 minutes at an internal temperature of about -5 to 0 °C.

The precipitated crystals were removed from the reaction mixture by filtration and washed with 2-methyl-THF. The product, Compound (la) as the 2-methyl-THF solvate, was dried under vacuum at an internal temperature of about 60 °C (about 72.5% as measured by NMR) to yield Compound (la).

Example 2

As shown in Example 2, the Compounds of Formula I are useful in the synthesis of more complex compounds. See General Scheme 1 for a description of how the first step can be accomplished. Compounds of Formula I can be reacted with compound (6) to yield Compounds of Formula II. In Example 2, Compound (la) can be reacted with

Compound (6) to yield Compound (7). The remaining steps are accomplished using procedures known to one of ordinary skill in the art, for example, as disclosed in

WO2010017055 and WO2011097602 to yield Compound (12).

PATENT

US 2014323725/http://www.google.com/patents/WO2011097602A1

5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9- dihydro-2H-pyrido[4,3,2-Je]phthalazin-3(7H)-one, as shown in formula (1), and its enantiomer compounds, as shown in formulas (la) and (lb):

Figure imgf000003_0001

Example 1

(Z)-6-Fluoro-3-(( 1 -methyl- IH- 1 ,2,4-triazol-5 -yl)methylene)-4-nitroisobenzofuran- 1 (3H)-one (3)

Figure imgf000013_0001

[0053] To a 80 L jacketed glass reactor equipped with a chiller, mechanical stirrer, thermocouple, and nitrogen inlet/outlet, at 15 – 25 °C, anhydrous 2-methyl-tetrahydrofuran (22.7 kg), 6-fluoro-4- nitroisobenzofuran-l(3H)-one (2) (2.4 kg, 12.2 mol, 1.00 eq.), and 2-methyl-2H-l,2,4-triazole-3- carbaldehyde (49.6 – 52.6 % concentration in dichloromethane by GC, 3.59 – 3.38 kg, 16.0 mol, 1.31 eq.) were charged consecutively. Triethylamine (1.50 kg, 14.8 mol, 1.21 eq.) was then charged into the above reaction mixture. The reaction mixture was stirred for another 10 minutes. Acetic anhydride (9.09 – 9.10 kg, 89.0 – 89.1 mol, 7.30 eq.) was charged into the above reaction mixture at room temperature for 20 – 30 minutes. The reaction mixture was heated from ambient to reflux temperatures (85 – 95 °C) for 80 – 90 minutes, and the mixture was refluxed for another 70 – 90 minutes. The reaction mixture was monitored by HPLC, indicating compound (2) was reduced to < 5 %. The resulting slurry was cooled down to 5 – 15 °C for 150 – 250 minutes. The slurry was aged at 5 – 15 °C for another 80 – 90 minutes. The slurry was filtered, and the wet cake was washed with ethyl acetate (2L x 3). The wet cake was dried under vacuum at 40 – 50 °C for 8 hours to give 2.65 – 2.76 kg of (Z)-6-fluoro-3-((l -methyl-lH-l ,2,4-triazol-3- yl)methylene)-4-nitroisobenzofuran-l(3H)-one (3) as a yellow solid (2.66 kg, yield: 75.3 %, purity: 98.6 – 98.8 % by HPLC). LC-MS (ESI) m/z: 291 (M+l)+. Ή-ΝΜΡ (400 MHz, DMSO-d6) δ (ppm): 3.94 (s, 3H), 7.15 (s, 1H), 8.10 (s, 1H), 8.40-8.42 (dd, Jx = 6.4 Hz, J2 = 2.4 Hz, 1H), 8.58-8.61 (dd, Jx = 8.8 Hz, J2 = 2.4 Hz, 1H).

Example 2

Methyl 5- enzoate (4)

Figure imgf000014_0001

Example 2A

[0054] (¾-6-Fluoro-3-((l-methyl-lH-l,2,4-taazol-3-yl)m (3) (177 g, 0.6 mol, 1.0 eq.), and HC1 (2 N in methanol, 3 L, 6 mol, 10 eq.) were charged into a 5 L 3-neck flask equipped with mechanical stirrer, thermometer, and nitrogen inlet/outlet. The reaction mixture was stirred at room temperature for 25 hours. The reaction mixture was monitored by HPLC, indicating 0.8 % compound (3) remained. The reaction mixture was concentrated under vacuum at 40 °C to dryness, and methyl 5-fluoro-2-(2-(l -methyl- lH-l,2,4-triazole-3-yl)acetyl)-3-nitrobenzoate hydrochloride (4) was obtained as a yellow solid (201 g, yield: 93.4 %). It was used for the next step without further purification. LC-MS (ESI) m/z: 323 (M+l)+ ¾-NMR (400 MHz, DMSO-J6) δ (ppm): 3.89 (s, 3H), 3.92 (s, 3H), 4.60 (s, 2H), 7.85 (s, 1H), 8.25-8.28 (dd, Jx = 8.4 Hz, J2 = 2.8 Hz, 2H), 8.52-8.54 (dd, Jx = 8.4 Hz, J2 = 2.8 Hz, 2H).

Example 2B

An alternative workup procedure to that illustrated in Example 2A follows. Instead of evaporating the reaction mixture to dryness, it was condensed to 2 volumes, followed by solvent exchange with 12 volumes of THF, and then 12 volumes of heptane. The slurry mixture was concentrated to 2 volumes and filtered to give the product. As such, 1.8 kilograms of (Z)-6-fluoro-3-((l-methyl-lH-l,2,4-triazol-3- yl)methylene)-4-nitroisobenzofuran-l(3H)-one (3) gave 2.15 kilograms (yield 96.4 %) of the product methyl 5-fluoro-2-(2-(l -methyl- lH-l,2,4-triazole-3-yl)acetyl)-3-nitrobenzoate hydrochloride (4).

Example 3

Methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4- tetrahydroquinoline-5 -carboxylate (5)

Figure imgf000015_0001

Example 3A

To a suspension of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3-nitrobenzoate (4) (5 g, 15.5 mmol, leq.) and 4-fluorobenzaldehyde (3.6 g, 29 mmol, 1.87 eq.) in a mixture of solvents tetrahydrofuran (30 mL) and MeOH (5 mL) was added titanium(III) chloride (20 % w/w solution in 2N Hydrochloric acid) (80 mL, 6 eq.) dropwise with stirring at room temperature. The reaction mixture was allowed to stir at 30~50°C for 2 hours. The mixture was then diluted with water (160 mL), and the resulting solution was extracted with ethyl acetate (100 mL x 4). The combined organic layers were washed with saturated NaHC03 (50 mL x 3) and aqueous NaHS03 (100 mL x 3), dried by Na2S04, and concentrated to dryness. This afforded a crude solid, which was washed with petroleum ether (120 mL) to obtain the title compound as a yellow solid (5.9 g, yield: 95 %, purity: 97 %). LC-MS (ESI) m/z: 399 (M+l)+. ^-NMR (400 MHz, CDCla) δ (ppm): 3.58 (s, 3H), 3.87 (s, 3H), 4.16-4.19 (d, J2=13.2 Hz, 1H), 4.88 (s, 1H), 5.37-5.40 (d, J2=13.2 Hz, 1H), 6.47-6.53 (m, 2H) , 6.97-7.01 (m, 2H), 7.37-7.41 (m, 2H), 7.80 (s, 1H).

Example 3B

An alternative workup procedure to that illustrated in Example 3A follows. After the completion of the reaction, the mixture was extracted with isopropyl acetate (20 volumes x 4) without water dilution. The product was isolated by solvent exchange of isopropyl acetate with heptanes followed by re-slurry with MTBE and filtration. As such, 3 kilograms of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5- yl)acetyl)-3-nitrobenzoate (4) afforded 2.822 kilograms of the title compound (5) (yield 81 %).

Example 3C

To a stirred solution of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3- nitrobenzoate (4) (580 mg, 2 mmol) and 4-fluorobenzaldehyde (488 mg, 4 mmol) in methanol (0.75 mL) and tetrahydrofuran (4.5 mL) was added concentrated HC1 solution (w/w 37 %, 6 mL), then reductive powdered Fe (672 mg, 12 mmol) was added slowly to the reaction system. After the addition was complete, the resulting mixture was heated to 60 °C and kept at this temperature for 3 hours. After the disappearance of the starting material (4) as monitored by LC-MS, the reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL) and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried with Na2S04, concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether = 1 : 1) to give the title compound (5) as a pale yellow solid (300 mg, yield 40 %). LC-MS (ESI) m/z: 399 (M+l)+LH-NMR (400 MHz, CDC13) δ (ppm): 3.58 (s, 3H), 3.87 (s, 3H), 4.17 (d, 1H), 4.87 (s, 1H), 5.38 (d, 1H), 6.50 (dd, 2H), 6.99 (dd, 2H), 7.38 (dd, 2H), 7.80 (s, 1H).

Example 3D

To a stirred solution of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3- nitrobenzoate (4) (580 mg, 2 mmol) and 4-fluorobenzaldehyde (488 mg, 4 mmol) in methanol (0.75 mL) and tetrahydrofuran (4.5 mL) was added SnCl2 (2.28 g, 12 mmol) and concentrated HC1 (w/w 37 %, 6 mL), the resulting mixture was reacted at 45 °C for 3 hours, until LC-MS indicating the disappearance of the starting material (4) and about 50 % formation of the product. The mixture was then partitioned between ethyl acetate (30 mL) and water (30 mL) and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried with Na2S04, concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether = 1 : 1) to give the title compound (5) as a pale yellow solid (10 mg, yield 1.3 %). LC-MS (ESI) m/z: 399 (M+l)+LH-NMR (400 MHz, CDC13) δ (ppm): 3.58 (s, 3H), 3.87 (s, 3H), 4.17 (d, 1H), 4.87 (s, 1H), 5.38 (d, 1H), 6.50 (dd, 2H), 6.99 (dd, 2H), 7.38 (dd, 2H), 7.80 (s, 1H).

Example 3E

A solution of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3-nitrobenzoate (4) (580 mg, 2 mmol) and 4-fluorobenzaldehyde (488 mg, 4 mmol) in methanol (20 mL) and acetic acid (1 mL) was stirred at room temperature for 24 hours under hydrogen (1 barr) in the presence of a catalytic amount of 10 % Pd/C (212 mg, 0.2 mmol). After the reaction was complete, the catalyst was removed by filtration through a pad of Celite, the solvent was removed in vacuo, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1 : 1) to give the title compound (5) as a pale yellow solid (63 mg, yield 8 %). LC-MS (ESI) m/z: 399 (M+l)+ . 1HNMR (400 MHz, DMSO-d6) δ (ppm): 3.56 (s, 3H), 3.86 (s, 3H), 7.02 (dd, 2H), 7.21 (dd, 2H), 7.90 (s, 1H), 8.08 (s, 1H), 8.26 (dd, 1H), 8.56 (dd, 1H).

Example 4

5-Fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-

Figure imgf000016_0001

 Methyl 7-fluoro-2-(4-fluorophenyl)-3-(l -methyl-lH-l ,2,4-triazol-5-yl)-4-oxo-l,2,3,4- tetrahydroquinoline-5-carboxylate (5) (150 g, 0.38 mol, 1.0 eq.) and methanol (1.7 L) were charged into a 3 L 3-neck flask equipped with a mechanical stirrer, thermometer, and nitrogen inlet/outlet. The resulted suspension was stirred at room temperature for 15 minutes. Hydrazine hydrate (85 % of purity, 78.1 g, 1.33 mol, 3.5 eq.) was charged dropwise into the above reaction mixture within 30 minutes at ambient temperature. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by HPLC, showing about 2 % of compound (5) left. The obtained slurry was filtered. The wet cake was suspended in methanol (2 L) and stirred at room temperature for 3 hours. The above slurry was filtered, and the wet cake was washed with methanol (0.5 L). The wet cake was then dried in vacuum at 45 – 55 °C for 12 hours. This afforded the title compound as a pale yellow solid (112 g, yield: 78.1 %, purity: 95.98 % by HPLC). LC-MS (ESI) m/z: 381 (M+l)+. ^-NMR (400 MHz, DMSO-J6) δ (ppm): 3.66 (s, 3H), 4.97-5.04 (m, 2H), 6.91-6.94 (dd, Jx = 2.4, J2 = 11.2 Hz, 1H), 7.06-7.09 (dd, Jx = 2.4, J2 = 8.8 Hz, 1H), 7.14-7.18 (m, 3H), 7.47-7.51 (m, 2H), 7.72 (s, 1H), 7.80 (s, 1H), 12.35 (s, 1H).

Example 5

5 -Amino-7-flu in- 1 (2H)-one

Figure imgf000017_0001

To a solution of 6-fluoro-3-((l-methyl-lH-l,2,4-triazol-3-yl)methylene)-4-nitroiso-benzofuran- l(3H)-one (3) (4.0 g, 135 mmol) in THF (100 mL) was added hydrazine monohydrate (85 %) (6 mL) at room temperature under nitrogen atmosphere. The mixture was stirred for 2 hours, then acetic acid (6 mL) was added and the mixture was heated to and kept at 60 °C for 18 hours. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was dried over anhydrous Na2S04 and evaporated to dryness to afford the title compound as a yellow solid (1.6 g, yield 42 %). LC-MS (ESI) m/z: 275(M+1)+.

Example 6

(£’)-7-fluoro-5-(4-fluorobenzylideneamino)-4-((l -methyl- IH- 1 ,2,4-triazol-5-yl)methyl)phthalazin- 1 (2H)- one

Figure imgf000018_0001

(7)

To a suspended of 5-amino-7-fluoro-4-((l-methyl-lH-l,2,4-triazol-3-yl)methyl) phthalazin- l(2H)-one (7) (1.6 g, 5.8 mmol) in acetonitrile (50 mL) was added 4-fluorobenzaldehyde (2.2 g, 17.5 mmol). The mixture was stirred under reflux under nitrogen for 48 hours. The precipitate was filtered and washed with a mixture of solvents (ethyl acetate/hexane, 1 :1, 10 mL). After drying in vacuum, it afforded the title compound as a yellow solid (1.2 g, yield 52 %). LC-MS (ESI) m/z: 381(M+1)+.

Example 7

5-Fluoro-8 4-fluorophenyl)-9 l-methyl H-l,2,4-triazol-5-yl)-8,9-dihydro-2H^yrido[4,3,2-

Figure imgf000018_0002

(8) (1 )

To a suspension of (£’)-7-fluoro-5-(4-fluorobenzylideneamino)-4-((l-methyl-lH-l,2,4-triazol-5- yl)methyl)phthalazin-l(2H)-one (8) (2.0 g, 5.3 mmol) in THF (80 mL) was added cesium carbonate (3.4 g, 10.6 mmol). The reaction mixture was stirred at 55 °C for 4 hours and cooled down to room temperature. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and evaporated to dryness to afford the title compound as a white solid (1.6 g, yield 80 %). LC-MS (ESI) m/z: 381(M+1)+. ^-NMR (400 MHz, DMSO- ) δ (ppm): 3.66 (s, 3H), 4.97-5.04 (m, 2H), 6.91-6.94 (dd, Jx = 2.4, J2 = 11.2 Hz, 1H), 7.06-7.09 (dd, Ji = 2.4, J2 = 8.8 Hz, 1H), 7.14-7.18 (m, 3H), 7.47-7.51 (m, 2H), 7.72 (s, 1H), 7.80 (s, 1H), 12.35 (s, 1H).

Example 8

(£)-Methyl 5-fluoro-2-(3-(4-fluorophenyl)-2-(l-methyl-lH-l,2,4-triazol-5-yl)acryloyl)-3-nitrobenzoate

(9)

Figure imgf000019_0001

To a stirred solution of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3- nitrobenzoate (4) (580mg, 2 mmol) and 4-fluorobenzaldehyde (488 mg, 4 mmol) in dimethylsulfoxide (2 mL) was added L-proline (230 mg, 2 mmol). The resulting mixture was kept with stirring at 45 °C for 48 hours. The reaction system was then partitioned between ethyl acetate (50 mL) and water (30 mL), and the organic phase was washed with water (20 mL x 3), dried with Na2S04, concentrated in vacuo, and purified by column chromatography (ethyl acetate: petroleum ether = 1 :3) to give the title compound (9) as a pale yellow foam (340 mg, yield 40 %). LC-MS (ESI) m/z: 429 (M+l)+. ^-NMR (400 MHz, DMSO-dg); δ (ppm): 3.56 (s, 3H), 3.86 (s, 3H), 7.02 (dd, 2H), 7.21 (dd, 2H), 7.90 (s, IH), 8.08 (s, IH), 8.26 (dd, IH), 8.56 (dd, IH).

Example 9

Methyl 7-fluoro-2-(4-fluorophenyl)- 1 -hydroxy-3-( 1 -methyl- IH- 1 ,2,4-triazol-5-yl)-4-oxo- 1 ,2,3,4- tetrahydroquinoline-5 -carboxylate (10)

Figure imgf000019_0002

To a solution of (£)-Methyl 5-fluoro-2-(3-(4-fluorophenyl)-2-(l-methyl-lH-l,2,4-triazol-5- yl)acryloyl)-3-nitrobenzoate (9) (200 mg, 0.467 mmol) in methanol (20 mL) was added 10 % Pd/C (24 mg). After the addition, the mixture was stirred under H2 (1 atm) at room temperature for 0.5 h. The reaction system was then filtered and evaporated under reduced pressure. The residue was purified by chromatography (ethyl acetate: petroleum ether = 1 :1) to give the title compound (10) (110 mg, yield 57 %) as an off-white foam. LC-MS (ESI) m/z: 415 (M+H)+. ¾-NMR (400 MHz, DMSO-d6) δ (ppm): 3.53 (s, 3H), 3.73 (s, 3H), 5.08 (d, 2H), 5.27 (d, 2H), 6.95 (dd, IH), 7.08 (dd, 2H), 7.15 (dd, IH), 7.42 (dd, 2H), 7.77 (s, IH), 9.92 (s, IH). Example 10

Methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4-

Figure imgf000020_0001

(10) (5)

To a stirred solution of methyl 7-fluoro-2-(4-fluorophenyl)-l-hydroxy-3-(l-methyl-lH-l,2,4- triazol-5-yl)-4-oxo-l, 2,3, 4-tetrahydroquinoline-5 -carboxylate (10) (41.4 mg, 0.1 mmol) in methanol (5 mL) was added concentrated HCl solution (w/w 37 %, 1 mL) and reductive powdered Fe (56 mg, 1 mmol). The reaction mixture was refluxed for 3 hours. After the disappearance of compound (10) as monitored by LC-MS, the reaction system was partitioned between ethyl acetate (20 mL) and water (20 mL) and then the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried with Na2S04, concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether = 1 :1) to give the title compound (5) as a pale yellow solid (12 mg, yield 30 %). LC-MS (ESI) m/z: 399 (M+l)+. ¾-NMR (400 MHz, CDC13) δ (ppm): 3.58 (s, 3H), 3.87 (s, 3H), 4.17 (d, 1H), 4.87 (s, 1H), 5.38 (d, 1H), 6.50 (dd, 2H), 6.99 (dd, 2H), 7.38 (dd, 2H), 7.80 (s, 1H).

Example 11

Methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4-

Figure imgf000020_0002

To a solution of (£)-Methyl 5-fluoro-2-(3-(4-fluorophenyl)-2-(l-methyl-lH-l,2,4-triazol-5- yl)acryloyl)-3-nitrobenzoate (9) (214 mg, 0.5 mmol) in methanol (5 mL) was added concentrated HCl solution (w/w 37 %, 1 mL), then reductive Fe powder (140 mg, 2.5 mmol) was added slowly to the reaction system. After the addition was complete the resulting mixture was refluxed for 24 hours. The reaction mixture was then filtered, concentrated, neutralized with saturated NaHC03 (20 mL), and extracted with ethyl acetate (10 mL x 3). The residue was purified by chromatography (ethyl acetate: petroleum ether = 1 : 1) to give the title compound (5) (30 mg, yield 15 %) as an off-white foam. LC-MS (ESI) m/z: 399 (M+H)+. ^-NMR (400 MHz, DMSO-d6) δ (ppm): 3.56 (s, 3H), 3.86 (s, 3H), 7.02 (dd, 2H), 7.21 (dd, 2H), 7.90 (s, 1H), 8.08 (s, 1H), 8.26 (dd, 1H), 8.56 (dd, 1H).

Example 12

(8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(l-me

Je]phthalazin-3(7H)-one (la) and (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-

Figure imgf000021_0001

(1) (la) (lb)

A chiral resolution of 5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9- dihydro-2H-pyrido[4,3,2-Je]phthalazin-3(7H)-one (1) (52.5 g) was carried out on a super-fluid chromatography (SFC) unit using a CHIRALPAK IA column and C02/methanol/diethylamine

(80/30/0.1) as a mobile phase. This afforded two enantiomers with retention times of 7.9 minute (23.6 g, recovery 90 %, > 98 % ee) and 9.5 minute (20.4 g, recovery 78 %, > 98 % ee) as analyzed with a CHIRALPAK IA 0.46 cm x 15 cm column and C02/methanol/diethylamine (80/30/0.1) as a mobile phase at a flow rate of 2 g/minute.

Example 13

(2R,3R)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4- tetrahydroquinoline-5-carboxylate (6a) and (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-

Figure imgf000021_0002

(5) (6a) (6b)

Example 13A

The chiral resolution of compound (5) was carried out on a SFC unit with a CHIRALPAK®IC 3 cm (I.D.) x 25 cm, 5 μηι column, using C02/MeOH (80/20) as a mobile phase at a flow rate of 65 g/ minute while maintaining the column temperature at 35 °C and with a detection UV wavelength of 254 nm. As such, a racemate of compound (5) (5 g) in methanol solution was resolved, which resulted in two enantiomers with a retention times of 2.35 minute (2.2 g, 88 % recovery, >98 % ee) and 4.25 minute (2.3 g, 92 % recovery, >98 % ee), respectively when analyzed using CHIRALPAK®IC 0.46 cm x 15 cm column and CO2/MeOH(80/20) as a mobile phase at a flow rate of 2 mL/ minute.

Example 13B

The chiral resolution of compound (5) was carried out on a SFC unit with a CHIRALPAK®IC 5cm (I.D.) x 25 cm, 5 μηι column, using C02/MeOH (75/25) as a mobile phase at a flow rate of 200 mL/ minute while maintaining the column temperature at 40 °C and with a detection UV wavelength of 255 nm. As such, a racemate of compound (5) (1.25 kg) in methanol solution was resolved, which resulted in two enantiomers in about 83 % yield and 97.4 % purity.

Example 13C

Alternatively, the separation can also be achieved on a Simulated Moving Bed (SMB) unit with a CHIRALPAK®IC column and acetonitrile as a mobile phase. The retention times for the two enantiomers are 3.3 and 4.1 minutes, respectively. In certain embodiments, the productivity can be greater than 6 kg Feed/day/kg CSP.

Example 14

(8R,9S)-5-fluoro-8 4-fluorophenyl)-9<l-me

Je]phthalazin-3(7H)-one (la) and (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5- (lb)

Figure imgf000022_0001

Example 14A

To a solution of (2R,3R)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)- 4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (6a) or (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l- methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (6b) (400 mg, 1.0 mmol) in ethanol (8.0 mL) was added hydrazine monohydrate (85 %, 2.0 mL), and the solution stirred at room temperature for 2 hours. The resulting solution was then concentrated to a volume of 2 mL and filtered, and the resultant cake washed with ethanol (1 mL). After drying in vacuum at 50°C, this afforded the title compound as a white solid (209 mg, yield 55 %). LC-MS (ESI) m/z: 381(M+1)+. ^-NMR (400 MHz, DMSO-dg): δ (ppm): 3.681 (s, 3H), 4.99-5.06 (m, 2H), 6.92-6.96 (m, 1H), 7.08-7.11 (m, 1H), 7.16-7.21 (t, J= 8.8 Hz, 2H), 7.49-7.53 (m, 2H), 7.75 (s, 1H), 7.83 (s, 1H), 12.35 (s, 1H).

Example 14B

To a solution of (2R,3R)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)- 4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (6a) or (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l- methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (6b) (446 g) in acetonitrile (10 volume) was added hydrazine monohydrate (2.9 eq.), and the solution stirred at room temperature for 2 hours. The resulting solution was then concentrated to a volume of 2 mL and filtered. The crude product was re-slurried with water (3~5 volumes) at 15-16 °C. After drying in vacuum at 50 °C, this affords the title compound as a white solid (329 g, yield 77%, 99.93% purity). LC-MS (ESI) m/z:

381(M+1)+; ¾-NMR (400 MHz, DMSO-d6) δ (ppm): 3.681 (s, 3H), 4.99-5.06 (m, 2H), 6.92-6.96 (m, 1H), 7.08-7.11 (m, 1H), 7.16-7.21 (t, J= 8.8 Hz, 2H), 7.49-7.53 (m, 2H), 7.75 (s, 1H), 7.83 (s, 1H), 12.35 (s, 1H).

Talazoparib (BMN-673) is an orally available poly ADP ribose polymerase (PARP) inhibitor currently in development by Pfizer for the treatment of advanced breast cancer patients with germline BRCA mutations.[1] Talazoparib is similar to the first in class PARP inhibitor, olaparib.[2][3] However, talazoparib is thought to be more potent than olaparib.[3]

Mechanism of action

Talazoparib acts as an inhibitor of poly ADP ribose polymerase(PARP) which aids in single strand DNA repair. Cells that have BRCA1/2mutations are susceptible to the cytotoxic effects of PARP inhibitors because of an accumulation of DNA damage.[1] Talazoparib is theorized to have a higher potency than olaparib due to the additional mechanism of action called PARP trapping. PARP trapping is the mechanism of action where the PARP molecule is trapped on the DNA, which interferes with the cells ability to replicate. Talazoparib is found to be ~100 fold more efficient in PARP trapping than olaparib.[4] However, this increased potency may not translate directly to clinical effectiveness as many other factors must be considered.[3][4]

Commercialization

Talazoparib was originally developed by BioMarin Pharmaceutical Inc. However, Medivation Inc. acquired all worldwide rights to talazoparib in August 2015 to expand their global oncology franchise.[5] Medivation acquired talazoparib for $410 million with additional payments of up to $160 million in royalties and milestones. Under this agreement, Medivation assumed all financial responsibilities for the continued development, regulatory, and commercialization of talazoparib.[5][6]

Clinical trials

As of January 2016, talazoparib is in 14 active clinical trials [7] including a new arm of I-SPY 2.[8] These trials cover a variety of cancers types and combination therapies. The most notable clinical trials are the ABRAZO and EMBRACA studies.

ABRAZO

ABRAZO is a phase II study for the safety and efficacy of treatment of BRCA breast cancer patients with Talazoparib monotherapy. This study is for patients who have failed at least two prior chemotherapy treatments for metastatic breast cancer or been previously treated with a platinum regimen.[6][9][10] The original target enrollment for the study was 70 patients but Biomarin expanded the trial to 140 patients.[9][10] The estimated completion date is December 2016.[10]

EMBRACA

EMBRACA is a phase III study for the treatment of BRCA breast cancer patients with Talazoparib.[11][12][13] This trial is an open-label, randomized, parallel, 2-arm, multi-center comparison of talazaporib against physician’s preference for the treatment of patients with locally advanced or metastatic breast cancer. Patients must also have received prior chemotherapy regimens for metastatic breast cancer.[12][13] Patients participating in this study are randomly selected for either talazoparib or physician’s choice of chemotherapy at a 2:1 ratio to talazoparib.[6] The target enrollment for the study was 430 patients [12][13] and the estimated completion date is June 2017.[13]

References

  1. Jump up to:a b Medivation Inc. “Talazoparib”.
  2. Jump up^ FDA (19 December 2014). “FDA approves Lynparza to treat advanced ovarian cancer”FDA News Release.
  3. Jump up to:a b c Jessica Brown, Stan Kaye, Timothy Yap (29 March 2016). “PARP inhibitors: the race is on”British Journal of Cancer114: 713–5. doi:10.1038/bjc.2016.67PMC 4984871Freely accessiblePMID 27022824.
  4. Jump up to:a b Yuqiao Shen, Mika Aoyagi-Scharber, Bing Wang (June 2015). “Trapping Poly(ADP-Ribose) Polymerase”Journal of Pharmacology and Experimental Therapeutics.
  5. Jump up to:a b Biomarin (24 August 2015). “Medivation to Expand Global Oncology Franchise With the Acquisition of All Worldwide Rights to Talazoparib (BMN 673), a Potent PARP Inhibitor, From BioMarin”.
  6. Jump up to:a b c Silus Inman (25 August 2015). “Medivation Acquires BioMarin’s PARP Inhibitor Talazoparib”.
  7. Jump up^ BMN 673 trials registered
  8. Jump up^ I-SPY 2 TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2)
  9. Jump up to:a b “BioMarin Provides Program Update for Talazoparib in Metastatic Breast Cancer”. 20 July 2015.
  10. Jump up to:a b c “A Phase 2, 2-Stage, 2-Cohort Study of Talazoparib (BMN 673), in Locally Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (ABRAZO Study)”ClinicalTrials.gov.
  11. Jump up^ “EMBRACA CLINICAL STUDY IS NOW ENROLLING”.
  12. Jump up to:a b c “A Study Evaluating Talazoparib (BMN 673), a PARP Inhibitor, in Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (EMBRACA Study)”ClinicalTrials.gov.
  13. Jump up to:a b c d “BioMarin Initiates Phase 3 BMN 673 Trial for Metastatic gBRCA Breast Cancer”Benzinga.

External links

nmr……http://www.medkoo.com/uploads/product/Talazoparib__BMN-673_/qc/BMN673-QC-BBC20130523-Web.pdf

Patent                       Submitted                        Granted

PROCESSES OF SYNTHESIZING DIHYDROPYRIDOPHTHALAZINONE DERIVATIVES [US2014323725]2014-06-022014-10-30

CRYSTALLINE (8S,9R)-5-FLUORO-8-(4-FLUOROPHENYL)-9-(1-METHYL-1H-1,2,4-TRIAZOL-5-YL)-8,9-DIHYDRO-2H-PYRIDO[4,3,2-DE]PHTHALAZIN-3(7H)-ONE TOSYLATE SALT [US2014228369]2014-04-142014-08-14

Crystalline (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt [US8735392]2011-10-202014-05-27

DIHYDROPYRIDOPHTHALAZINONE INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP) [US8012976]2010-02-112011-09-06

DIHYDROPYRIDOPHTHALAZINONE INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP) FOR USE IN TREATMENT OF DISEASES ASSOCIATED WITH A PTEN DEFICIENCY [US2014066429]2013-08-212014-03-06

METHODS AND COMPOSITIONS FOR TREATMENT OF CANCER AND AUTOIMMUNE DISEASE [US2013184342]2013-03-132013-07-18

WO2012054698A1 Oct 20, 2011 Apr 26, 2012 Biomarin Pharmaceutical Inc. Crystalline (8s,9r)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1h-1,2,4-triazol-5-yl)-8,9-dihydro-2h-pyrido[4,3,2-de]phthalazin-3(7h)-one tosylate salt
WO2015069851A1 Nov 6, 2014 May 14, 2015 Biomarin Pharmaceutical Inc. Triazole intermediates useful in the synthesis of protected n-alkyltriazolecarbaldehydes
US8420650 Mar 31, 2011 Apr 16, 2013 Biomarin Pharmaceutical Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
US8541403 Feb 3, 2011 Sep 24, 2013 Biomarin Pharmaceutical Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) for use in treatment of diseases associated with a PTEN deficiency
US8735392 Oct 20, 2011 May 27, 2014 Biomarin Pharmaceutical Inc. Crystalline (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt
US8765945 Feb 8, 2011 Jul 1, 2014 Biomarin Pharmaceutical Inc. Processes of synthesizing dihydropyridophthalazinone derivatives
US8999987 Mar 6, 2013 Apr 7, 2015 Biomarin Pharmaceutical Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
US9018201 Aug 21, 2013 Apr 28, 2015 Biomarin Pharmaceuticial Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) for use in treatment of diseases associated with a PTEN deficiency

SEE………..http://orgspectroscopyint.blogspot.in/2016/02/talazoparib.html

http://apisynthesisint.blogspot.in/2016/02/talazoparib.html

Talazoparib
Talazoparib.svg
Systematic (IUPAC) name
(8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one
Clinical data
Legal status
  • Investigational
Chemical data
Formula C19H14F2N6O
Molar mass 380.35 g/mol
Talazoparib
Talazoparib.svg
Legal status
Legal status
  • Investigational
Identifiers
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C19H14F2N6O
Molar mass 380.35 g/mol
3D model (JSmol)

/////////////BMN 673, talazoparib, phase 3, BMN673, BMN673, BMN-673, LT673, LT 673, LT-673, Poly ADP ribose polymerase 2 inhibitor, Poly ADP ribose polymerase 1 inhibitor, cancer, MDV-3800 , MDV 3800

Cn1c(ncn1)[C@H]2c3c4c(cc(cc4N[C@@H]2c5ccc(cc5)F)F)c(=O)[nH]n3

O=C1NN=C2C3=C1C=C(F)C=C3N[C@H](C4=CC=C(F)C=C4)[C@H]2C5=NC=NN5C

Talazoparib tosylate タラゾパリブトシル酸塩;

str1

1373431-65-2.png

Talzenna

fda 2018/10/16

CAS: 1373431-65-2
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