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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

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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
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Title

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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
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Title

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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
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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
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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
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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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Tagraxofusp タグラクソフスプ


MGADDVVDSS KSFVMENFSS YHGTKPGYVD SIQKGIQKPK SGTQGNYDDD WKGFYSTDNK
YDAAGYSVDN ENPLSGKAGG VVKVTYPGLT KVLALKVDNA ETIKKELGLS LTEPLMEQVG
TEEFIKRFGD GASRVVLSLP FAEGSSSVEY INNWEQAKAL SVELEINFET RGKRGQDAMY
EYMAQACAGN RVRRSVGSSL SCINLDWDVI RDKTKTKIES LKEHGPIKNK MSESPNKTVS
EEKAKQYLEE FHQTALEHPE LSELKTVTGT NPVFAGANYA AWAVNVAQVI DSETADNLEK
TTAALSILPG IGSVMGIADG AVHHNTEEIV AQSIALSSLM VAQAIPLVGE LVDIGFAAYN
FVESIINLFQ VVHNSYNRPA YSPGHKTRPH MAPMTQTTSL KTSWVNCSNM IDEIITHLKQ
PPLPLLDFNN LNGEDQDILM ENNLRRPNLE AFNRAVKSLQ NASAIESILK NLLPCLPLAT
AAPTRHPIHI KDGDWNEFRR KLTFYLKTLE NAQAQQTTLS LAIF
(disulfide bridge: 187-202, 407-475)

Image result for Tagraxofusp US FDA APPROVAL

methionyl (1)-Corynebacterium diphtheriae toxin fragment (catalytic and transmembrane domains) (2-389, Q388R variant)-His390-Met391-human interleukin 3 (392-524, natural P399S variant) fusion protein, produced in Escherichia coli antineoplastic,https://www.who.int/medicines/publications/druginformation/issues/PL_118.pdf

Tagraxofusp

タグラクソフスプ

CAS: 2055491-00-2
C2553H4026N692O798S16, 57694.4811

FDA 2018/12/21, Elzonris APPROVED

Antineoplastic, Immunotoxin, Peptide

DT-3881L3 / DT388IL3 / Molecule 129 / Molecule-129 / SL-401

UNII8ZHS5657EH

Diphteria toxin fusion protein with peptide and interleukin 3 Treatment of blastic plasmacytoid dendritic cell neoplasm (CD123-directed)

FDA approves first treatment for rare blood disease

>>tagraxofusp<<< MGADDVVDSSKSFVMENFSSYHGTKPGYVDSIQKGIQKPKSGTQGNYDDDWKGFYSTDNK YDAAGYSVDNENPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSLTEPLMEQVG TEEFIKRFGDGASRVVLSLPFAEGSSSVEYINNWEQAKALSVELEINFETRGKRGQDAMY EYMAQACAGNRVRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKMSESPNKTVS EEKAKQYLEEFHQTALEHPELSELKTVTGTNPVFAGANYAAWAVNVAQVIDSETADNLEK TTAALSILPGIGSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGELVDIGFAAYN FVESIINLFQVVHNSYNRPAYSPGHKTRPHMAPMTQTTSLKTSWVNCSNMIDEIITHLKQ PPLPLLDFNNLNGEDQDILMENNLRRPNLEAFNRAVKSLQNASAIESILKNLLPCLPLAT AAPTRHPIHIKDGDWNEFRRKLTFYLKTLENAQAQQTTLSLAIF

December 21, 2018

Release

The U.S. Food and Drug Administration today approved Elzonris (tagraxofusp-erzs) infusion for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients, two years of age and older.

“Prior to today’s approval, there had been no FDA approved therapies for BPDCN. The standard of care has been intensive chemotherapy followed by bone marrow transplantation. Many patients with BPDCN are unable to tolerate this intensive therapy, so there is an urgent need for alternative treatment options,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

BPDCN is an aggressive and rare disease of the bone marrow and blood that can affect multiple organs, including the lymph nodes and the skin. It often presents as leukemia or evolves into acute leukemia. The disease is more common in men than women and in patients 60 years and older.

The efficacy of Elzonris was studied in two cohorts of patients in a single-arm clinical trial. The first trial cohort enrolled 13 patients with untreated BPDCN, and seven patients (54%) achieved complete remission (CR) or CR with a skin abnormality not indicative of active disease (CRc). The second cohort included 15 patients with relapsed or refractory BPDCN. One patient achieved CR and one patient achieved CRc.

Common side effects reported by patients in clinical trials were capillary leak syndrome (fluid and proteins leaking out of tiny blood vessels into surrounding tissues), nausea, fatigue, swelling of legs and hands (peripheral edema), fever (pyrexia), chills and weight increase. Most common laboratory abnormalities were decreases in lymphocytes, albumin, platelets, hemoglobin and calcium, and increases in glucose and liver enzymes (ALT and AST). Health care providers are advised to monitor liver enzyme levels and for signs of intolerance to the infusion. Women who are pregnant or breastfeeding should not take Elzonris because it may cause harm to a developing fetus or newborn baby.

The labeling for Elzonris contains a Boxed Warning to alert health care professionals and patients about the increased risk of capillary leak syndrome which may be life-threatening or fatal to patients in treatment.

The FDA granted this application Breakthrough Therapy and Priority Reviewdesignation. Elzonris also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Elzonris to Stemline Therapeutics.

Tagraxofusp is an IL-3 conjugated truncated diphtheria toxin.[4] It is composed by the catalytic and translocation domains of diphtheria toxin fused via Met-His linker to a full-length human IL-3.[67] Tagraxofusp was developed by Stemline Therapeutics Inc and FDA approved on December 21, 2018, as the first therapy for blastic plasmacytoid dendritic cell neoplasm.[3] This drug achieved approval after being designed with the title of breakthrough therapy, priority review, and orphan drug status.[2] Tagraxofusp has been designed as an orphan drug in EU since November 2015.[7]

Tagraxofusp is indicated for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients over 2 years old. This treatment allows an alternative for the previous intense treatment which consisted of intensive chemotherapy followed by bone marrow transplantation.[2]

BPDCN is a rare hematologic malignancy derived from plasmacytoid dendritic cells. It is characterized by the significantly increased expression of cells expressing CD4/CD56/CD123 and other markers restricted to plasmacytoid dendritic cells and a lack of expression of lymphoid, natural killer or myeloid lineage-associated antigens.[1] A key feature of the malignant cells is the overexpression of CD123, also known as interleukin-3 receptor, and the constant requirement of IL-3 for survival.[6]

Associated Conditions

PharmacodynamicsIn vitro studies showed that BPDCN blasts are ultrasensitive to tagraxofusp by presenting IC50 values in the femtomolar scale.[6] One of the main physiological changes of BPDCN is the presence of elevated interferon alpha and to produce an inflammatory response. In trials with tagraxofusp and following cell depletion, there was observed a significant reduction in the levels of interferon alpha and interleukin 6.[5]

In clinical trials, tagraxofusp reported complete remission and complete remission with a skin abnormality not indicative of active disease in 54% of the treated patients.[2]

Mechanism of actionTagraxofusp binds to cells expressing the IL-3 receptor and delivers in them the diphtheria toxin after binding. This is very useful as the malignant cells in BPDCN present a particularly high expression of IL-3 receptor (CD123+ pDC).[5] To be more specific, tagraxofusp gets internalized to the IL-3 receptor-expressing cell allowing for diphtheria toxin translocation to the cytosol and followed by the binding to ADP-ribosylation elongation factor 2 which is a key factor for protein translation. Once the protein synthesis is inhibited, the cell goes under a process of apoptosis.[4,6]

As the apoptosis induction requires an active state of protein synthesis, tagraxofusp is not able to perform its apoptotic function in dormant cells.[6]

Absorption

The reported Cmax in clinical trials was of around 23 ng/ml.[6] After a 15 min infusion of a dose of 12 mcg/kg the registered AUC and Cmax was 231 mcg.h/L and 162 mcg/L respectively.[Label]

Volume of distributionIn BPDCN patients, the reported volume of distribution is of 5.1 L.[Label]

Protein bindingTagraxofusp is not a substrate of p-glycoprotein and other efflux pump proteins associated with multidrug resistance.[6]

MetabolismFor the metabolism, as tagraxofusp is a fusion protein, it is expected to get processed until small peptides and amino acids by the actions of proteases.

Route of eliminationTagraxofusp is eliminated as small peptides and amino acids. More studies need to be performed to confirm the main elimination route.

Half lifeThe reported half-life of tagraxofusp is of around 51 minutes.[6]

ClearanceThe clearance of tagraxofusp was reported to fit a mono-exponential model.[6] The reported clearance rate is reported to be of 7.1 L/h.[Label]

ToxicityThere haven’t been analysis observing the carcinogenic, mutagenic potential nor the effect on fertility. However, in studies performed in cynomolgus monkeys at an overdose rate of 1.6 times the recommended dose, it was observed severe kidney tubular degeneration. Similar studies at the recommended dose reported the presence of degeneration and necrosis of choroid plexus in the brain were. This effect seems to be progressive even 3 weeks after therapy withdrawal.[Label]

  1. Kharfan-Dabaja MA, Lazarus HM, Nishihori T, Mahfouz RA, Hamadani M: Diagnostic and therapeutic advances in blastic plasmacytoid dendritic cell neoplasm: a focus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013 Jul;19(7):1006-12. doi: 10.1016/j.bbmt.2013.01.027. Epub 2013 Feb 5. [PubMed:23396213]
  2. FDA news [Link]
  3. FDA approvals [Link]
  4. Oncology nursing news [Link]
  5. Stemline therapeutics news [Link]
  6. Blood journal [Link]
  7. NHS reports [Link]

FDA label, Download (455 KB)

/////////Antineoplastic, Immunotoxin, Peptide, Tagraxofusp, Elzonris, タグラクソフスプ  , Stemline Therapeutics, Breakthrough Therapy,  Priority Review designation,  Orphan Drug designation, fda 2018, DT-3881L3 , DT388IL3 ,  Molecule 129 ,  Molecule-129 ,  SL-401, 

K-8986


Figure

YNRQDEGURLSOGN-BTJKTKAUSA-N.png

K-8986

(Z)-but-2-enedioic acid;7-[3-[4-[[1-(2-ethoxyethyl)benzimidazol-2-yl]methyl]piperazin-1-yl]propoxy]-4H-1,4-benzothiazin-3-one

cas 1335112-55-4 mono maleate

cas 1335112-57-6  di maleate

cas 219741-69-2 free form

C27 H35 N5 O3 S . C4 H4 O4
2H-1,4-Benzothiazin-3(4H)-one, 7-[3-[4-[[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]methyl]-1-piperazinyl]propoxy]-, (2Z)-2-butenedioate (1:1)
7-[3-[4-[[1-(2-Ethoxyethyl)benzimidazol-2-yl]methyl]-1-piperazinyl]propoxy]-3,4-dihydro-2H-1,4-benzothiazin-3-one monomaleate
KOWA CO., LTD.
福田 友昭 FUKUDA, Tomoaki; JP
纐纈 章泰 KOKETSU, Akiyasu; JP
金児 佳生 KANEKO, Yoshio; JP
芦川 由香 ASHIKAWA, Yuka; JP

Image result for KOWA CO., LTD.

Mono maleate

1H NMR (396 MHz, DMSO-d6) δ 1.03 (t, J = 7.0 Hz, 3H), 2.04–2.08 (m, 2H), 3.10 (br, 8H), 3.18 (br, 2H), 3.38 (t, J = 7.0 Hz, 2H), 3.42 (s, 2H), 3.71 (t, J = 7.9 Hz, 2H), 3.95 (s, 2H), 4.01 (t, J = 5.9 Hz, 2H), 4.51 (t, J = 5.2 Hz, 2H), 6.06 (s, 2H), 6.79 (dd, J = 9.1, 2.7 Hz, 1H), 6.90–6.92 (m, 2H), 7.17–7.26 (m, 2H), 7.58–7.61 (m, 2H), 10.43 (s, 1H);

13C NMR (100 MHz, DMSO-d6) δ 15.0, 23.8, 29.0, 43.5, 49.7 (×2), 51.3 (×2), 53.2, 53.4, 65.3, 65.7, 68.7, 110.7, 112.8, 113.9, 118.2, 118.8, 120.3, 121.6, 122.2, 131.3, 135.6, 135.8 (×2), 141.8, 150.6, 153.7, 164.7, 167.3 (×2);

HRMS (FD) calcd for C27H36N5O3S [(MH – maleic acid)+] 510.2539, found 510.2558.

Allergic conjunctivitis, which can be classified into seasonal allergic conjunctivitis and perennial allergic conjunctivitis, is a type I hypersensitivity to allergens. Symptoms such as itching, redness, eyelid swelling, and chemosis are common among afflicted patients and are caused by the release of chemical mediators such as histamine from activated mast cells through cross-linking of antigen-specific immunoglobulin E. The binding of histamine to its receptors plays a central role in the induction of allergic symptoms. K-8986 (1), a histamine H1-receptor antagonist, was developed as a potential therapeutic for treatment of allergic conjunctivitis

SYN

Clip

Development of a Synthetic Process for K-8986, an H1-Receptor Antagonist

Tomoaki Fukuda* Takeaki HaraShinji InaTetsuhiro Nemoto , and Takeshi Oshima*

 Tokyo New Drug Research Laboratories, Pharmaceutical DivisionKowa Company, Ltd.2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
 Graduate School of Pharmaceutical SciencesChiba University1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00380
This article is part of the Japanese Society for Process Chemistry special issue.
Abstract Image

This article describes the development of a robust and scalable synthetic process for K-8986 (1). To solve the problems in terms of the physicochemical properties of 6 (a free base unit of 1), we have screened the suitable salt forms of the target. The monomaleate salt was the most suitable form for the API. To overcome challenges regarding the unremovable impurity Imp B caused by the carryover of piperazine in the medicinal chemistry route, we designed and developed a novel synthetic route. This route furnished more opportunities to purify the synthetic intermediates after introduction of the piperazine unit. Both impurities and co-products in each step of the revised synthesis could be easily removed via filtration, leveraging the low solubility of benzothiazine derivatives. The newly established process was applied to the synthesis of 1 (the monomaleate salt of 6) on a practical scale, achieving high purity and reproducibility.

1H NMR (396 MHz, DMSO-d6) δ 1.03 (t, J = 7.0 Hz, 3H), 2.04–2.08 (m, 2H), 3.10 (br, 8H), 3.18 (br, 2H), 3.38 (t, J = 7.0 Hz, 2H), 3.42 (s, 2H), 3.71 (t, J = 7.9 Hz, 2H), 3.95 (s, 2H), 4.01 (t, J = 5.9 Hz, 2H), 4.51 (t, J = 5.2 Hz, 2H), 6.06 (s, 2H), 6.79 (dd, J = 9.1, 2.7 Hz, 1H), 6.90–6.92 (m, 2H), 7.17–7.26 (m, 2H), 7.58–7.61 (m, 2H), 10.43 (s, 1H);

13C NMR (100 MHz, DMSO-d6) δ 15.0, 23.8, 29.0, 43.5, 49.7 (×2), 51.3 (×2), 53.2, 53.4, 65.3, 65.7, 68.7, 110.7, 112.8, 113.9, 118.2, 118.8, 120.3, 121.6, 122.2, 131.3, 135.6, 135.8 (×2), 141.8, 150.6, 153.7, 164.7, 167.3 (×2);

PATENT

WO2011115173

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=CB6FAC725A85FC9DDE6D08A63CD4B038.wapp1nB?docId=WO2011115173&tab=FULLTEXT&queryString=ALL%3A%28%25E7%2582%258E%25E7%2597%2587%25E6%2580%25A7%25E8%2585%25B8%25E7%2596%25BE%25E6%2582%25A3%29&recNum=236&maxRec=6346

Example 1-1 Production of 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- dihydro-2H- 1,4-benzothiazin- Production of On (1a) (Manufacture of Free Body)

[Chemical Formula 5]

 a) 65 g (359 mmol) of 7-hydroxy-3,4-dihydro-2H-1,4-benzothiazin-3-one obtained by the method described in JP-A-60-4176 and JP-A-59-70675, Was suspended in tetrahydrofuran (194 mL) under an argon atmosphere, 104 g (397 mmol) of triphenylphosphine and 32 mL (379 mmol) of 3-chloropropanol were added and the mixture was cooled to 0 ° C. Next, 78 mL (396 mmol) of azodicarboxylic acid diisopropyl ester was added dropwise to the obtained reaction solution at 30 ° C. or less, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the resulting solution under reduced pressure, methanol (390 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and then dried under reduced pressure at 50 ° C. for 5 hours to obtain 59 g (yield 64%) of 7- (3-chloropropoxy) -3,4-dihydro-2H-1,4-benzothiazin- ) As blue-white crystals.
[Chemical Formula 6]
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 2.12 (2H, quint, J = 6.2 Hz), 3.28 (2H, s), 3.76 (2H, t, J = (2H, t, J = 5.8 Hz), 6.78 (1 H, dd, J = 2.8, 8.8 Hz), 6.88 (1 H, d, J = 8.8 Hz ), 6.90 (1 H, d, J = 2.8 Hz), 10.38 (1 H, s)
 57 g (221 mmol) of 7- (3-chloropropoxy) -3,4-dihydro-2H-1,4-benzothiazin-3-one was suspended in dimethylformamide (172 mL), 49 g (355 mmol) of potassium carbonate, 40 g (241 mmol) of potassium iodide and 43 g (231 mmol) of Nt-butoxycarbonylpiperazine were added and the mixture was heated to 100 ° C. and stirred for 4 hours. Water (344 mL) was added to the reaction solution, and the mixture was cooled to 0 ° C. and further stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration and then dried under reduced pressure at 50 ° C. for 5 hours to give 7- [3- (Nt-butoxycarbonylpiperazinyl) propoxy] -3,4-dihydro-2H-1,4-benzothiazine -3-one (89% yield) as bluish-white crystals.
[Chemical Formula 7]
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.39 (9 H, s), 1.83 (2 H, quint, J = 6.8 Hz), 2.31 (4 H, t, J = 4. 3.30 (2H, t, J = 4.6 Hz), 3.41 (2H, s), 3.95 (2H, t, J = 6.4 Hz), 6.78 (1 H, dd, J = 2.8, 8.8 Hz), 6.88 (1 H, d, J = 8.8 Hz), 6.89 (1 H, s) 10.38 (1 H, s)
 c) 87 g (214 mmol) of 7- {3- (Nt-butoxycarbonylpiperazinyl) propoxy} -3,4-dihydro-2H- 1,4-benzothiazin-3-one was suspended in ethanol (174 mL) , 6N hydrochloric acid aqueous solution (174 mL) was added dropwise at 50 ° C., and the mixture was stirred at the same temperature for 1 hour. Ethanol (522 mL) was added to the reaction solution, followed by cooling to 0 ° C. and further stirring at the same temperature for 1 hour. The precipitated crystals were collected by filtration and then dried under reduced pressure at 50 ° C. for 5 hours to give 7- {3- (piperazin-1-yl) propoxy} -3,4-dihydro-2H-1,4-benzothiazin- · Hydrochloride salt 75 g (yield 92%) was obtained as blue-white crystals.
[Chemical Formula 8]
1 H-NMR (400 MHz, D 2 O) [delta]: 2.13 (2H, td, J = 5.9,15.6Hz), 3.34 (2H, s), 3.35 (2H, t, J = 8.0 Hz), 3.44-3.64 (8H, m), 4.02 (2H, t, J = 5.6 Hz), 6.74 (1H, dd, J = 2.4, 6.85 (1 H, d, J = 8.8 Hz), 6.90 (1 H, d, J = 2.4 Hz)
 d) 1- (2-ethoxyethyl) -2-chloromethyl-1H-benzimidazole obtained by the method described in Journal of Heterocyclic Chemistry (1987), 24 (1), 31-37 was dissolved in tetrahydrofuran (293 mL) and Was dissolved in a mixture of water (147 mL), and 7- {3- (Nt-butoxycarbonylpiperazinyl) propoxy} -3,4-dihydro-2H- 73 g (192 mmol) of 1,4-benzothiazin-3-one was added. Then, 117 mL (673 mmol) of diisopropylethylamine and 35 g (211 mmol) of potassium iodide were added, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate (293 mL) and water (147 mL) were added to the reaction solution and extracted, and the organic layer was washed with 20% brine (147 mL). The organic layer was concentrated under reduced pressure to give 115 g (2 steps, quantitative) of the title compound (1a) as a brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.13 (3H, t, J = 7.0 Hz), 1.93 (2H, quint, J = 6.9 Hz), 2.40-2.70 (2H, s), 3.42 (2H, q, J = 6.8 Hz), 3.76 (2H, t, J = 7.2 Hz), 2.51 5. 2 (t, J = 6.0 Hz), 3.88 (2H, s), 3.97 (2H, t, J = 6.2 Hz), 4.51 (2H, t, J = 5.8 Hz), J = 8.8 Hz), 6.85 (1 H, d, J = 2.4 Hz), 7.24 (1 H, d, -7.28 (2H, m), 7.39 (1 H, ddd, J = 1.2, 6, 6.8 Hz), 7.73 (1 H, ddd, J = 1.2, 6.0 , 6.8 Hz) 8.35 (1H, s)
Example 1-2: 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- dihydro-2H-1,4-benzothiazin- Production of On Monomaleate (2a) (Production of Seed Crystal)
[Chemical Formula 9]
 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- dihydro-2H- 1,4-benzothiazin-3-one (1a) 0 g (1.96 mmol) was dissolved in ethanol (8 mL) and warmed to 60 ° C. After adding 211 mg (1.80 mmol) of maleic acid and stirring at 50 ° C. for 1 hour, the mixture was stirred at room temperature for 16 hours and further stirred at 0 ° C. for 3 hours. The precipitated crystals were collected by filtration and then dried under reduced pressure at 50 ° C. for 5 hours to obtain 1.02 g (yield 91%) of the monomaleate (2a) as bluish white crystals (melting point: 148 ° -151 ° C.).
Examples 1-3: 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- dihydro-2H- 1,4-benzothiazin- Preparation of on-monomaleate (2a)
 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- dihydro-2H- 1,4-benzothiazin-3-one (1a). After dissolving 0 g (13.7 mmol) in ethanol (56 mL) and heating to 60 ° C., 1.46 g (12.6 mmol) of maleic acid was added and the mixture was cooled to 50 ° C. to obtain 0.035 g (0.056 mmol) of seed crystals was added. The reaction solution was stirred at 50 ° C. for 1 hour, then stirred at room temperature for 1 hour, and further stirred at 0 ° C. for 3 hours. The precipitated crystals were collected by filtration and then dried under reduced pressure at 50 ° C. for 5 hours to obtain 7.08 g (yield 90%) of monomaleate (2a) as bluish-white crystals.
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.02 (3H, t, J = 7.2 Hz), 2.00-2.07 (2H, m), 2.80-3.61 J = 5.2 Hz), 3.93 (2H, q, J = 6.9 Hz), 3.42 (2H, s), 3.71 (2H, (2H, t, J = 5.2 Hz), 6.03 (2H, s), 6.78 (1 H, dd, J = 2.4, 8.8 Hz), 6.88 (1 H, s), 6.91 (1 H, dd, J = 2.4, 2.4 Hz), 7.18 (1 H, ddd, J = 1 (2H, d, J = 8.4 Hz), 7.24 (1H, ddd, J = 1.4, 7.5, 7.5 Hz), 7.59 10.40 (1 H, s)
 Elementary analysis value of the  monomaleate (2a) obtained in Example 1-3: C 31 H 39 N 5 O 7 S
: theoretical value: C 59.50%; H 6.28%; N 11.19 %
Found: C 59.33%; H 6.29%; N 11.10%
 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- dihydro-2H- 1,4-benzothiazine obtained in Example 1-3 -3-one monomaleate (2a) was subjected to thermal analysis measurement. In the thermal analysis measurement, approximately 5 mg of a sample was accurately weighed in an aluminum pan for thermal analysis, Al 2 O 3 was used as a reference substance , and the temperature was raised at a heating rate of 10 ° C./min in the presence of an atmosphere of N 2 gas (150 mL / min) (DTA) and thermogravimetry (TG) using a Thermo Plus 2 system (manufactured by Rigaku) as a thermal analyzer. The results of the thermal analysis measurement are shown in FIG. The melting point of the monomaleate (2a) was 147-150 ° C. (B – 545, manufactured by BUCHI).
 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- dihydro-2H- 1,4-benzothiazine obtained in Example 1-3 -3-one monomaleate (2a) by infrared spectrophotometer (manufactured by Thermo Nicolet Co., Ltd., AVATAR 370; ATR method) shows the pattern shown in FIG. 2, and it is in the vicinity of 1669 cm -1 , 1492Cm -1 around, 1231Cm -1 around, 1208Cm -1around, 868Cm -1 and around 754Cm -1 had an absorption peak specific to the vicinity.
 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- dihydro-2H- 1,4-benzothiazine obtained in Example 1-3 -3-one monomaleate (2a) was measured by powder X-ray diffraction (Miniflex manufactured by Rigaku Denki Kogyo Co., Ltd.). Measurement of powder X-ray crystal diffraction was carried out by filling the sample in the sample holder part of the silicon non-reflecting sample plate for X-ray diffraction and measuring with a desktop X-ray diffractometer: MiniFlex (Rigaku) a scanning range of diffraction angle 2θ; 3.00 ° to 40.00 °, sampling width: 0.02 °, and scanning speed: 2.00 ° / min. The obtained diffraction pattern is shown in FIG. 3. The monomaleate (2a) had specific diffraction angles and relative intensities shown in Table 1
[table 1]
Examples 1-4: 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- dihydro-2H- 1,4-benzothiazin-3- Preparation of On Monomaleate (2a) (Study of Reproducibility on Large Scale)
 (1a) (115 g) was added to a solution of 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4-benzothiazin- 226 mmol) was dissolved in ethanol (293 mL), activated charcoal 5.5 g was added, and the mixture was stirred at room temperature for 1 hour, then filtered through celite and washed with ethanol (147 mL) and washed. Ethanol (147 mL) was added to the filtrate, and after heating to 60 ° C., 18.9 g (163 mmol) of maleic acid was added and cooled to 50 ° C. 0.58 g (0.93 mmol) of the seed crystals of the monomaleate (2a) obtained in Example 1-3 was added and stirred at 50 ° C. for 1 hour, followed by stirring at room temperature for 15 hours and further at 0 ° C. And the mixture was stirred for 3 hours. The precipitated crystals were collected by filtration and dried under reduced pressure at 50 ° C. for 5 hours to obtain 75.2 g (yield 63%) of monomaleate (2a) as white crystals (melting point: 147 ° -149 ° C.).
 Elementary analysis value of the  monomaleate (2a) obtained in Examples 1-4: C 31 H 39 N 5 O 7 S
: theoretical value: C 59.50%; H 6.28%; N 11.19 %
Found: C 59.41%; H 6.29%; N 11.08%
Comparative Example 1 Synthesis of 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- dihydro-2H- 1,4-benzothiazin- Preparation of dimaleate
 15. 9 g (31 (3-ethoxyethylbenzoimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H-1,4- benzothiazin- . 1 mmol) was dissolved in 70 mL of ethanol, the solution was heated to 60 ° C., 8.0 g (68.9 mmol) of maleic acid was added, and the mixture was stirred at room temperature for 15 hours. The precipitated crystals were collected by filtration and then dried under reduced pressure at 50 ° C. for 5 hours to give 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- 13.3 g of dihydro-2H-1,4-benzothiazin-3-one / dimaleate was obtained. The obtained compound was dissolved in methanol (13 mL), heated to 60 ° C., THF (52 mL) was added, and the mixture was stirred at room temperature for 20 hours. The obtained crystals were collected by filtration and dried under reduced pressure at 50 ° C. for 5 hours to give 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4 -Dihydro-2H-1,4-benzothiazin-3-one · dimaleate was obtained as blueish white crystals.
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.01 (3H, t, J = 7.0 Hz), 2.00-2.07 (2H, m), 3.00 (4H, m) , 3.20 (2H, m), 3.37 (2H, q, J = 6.9 Hz), 3.41-3.47 (4H, m), 3.70 (2H, t, J = 5. (2H, t, J = 5.8 Hz), 4.50 (2H, t, J = 5.0 Hz), 6.14 (4H, s), 3.95 (2H, s) , 6.76 (1 H, dd, J = 2.4, 8.8 Hz), 6.88 (1 H, s), 6.90 (1 H, m), 7.19 – 7.27 (2 H, m) , 7.60 (2H, d, J = 7.6 Hz), 10.40 (1 H, s)
Comparative Example 2 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- dihydro-2H- 1,4-benzothiazin-3-one Production of monofumarate
 6.81 g of 13- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) – 1 – piperazinyl} propoxy] -3,4- dihydro-2H-1,4-benzothiazin- . 3 mmol) was dissolved in a mixed solvent of ethanol (60 mL) and (water 6 mL), and the mixture was heated to 60 ° C. To the mixed solution was added a mixed solution of ethanol (14 mL) containing 1.55 g (13.3 mmol) of fumaric acid and water (1.5 mL), the mixture was stirred at 40 ° C. for 30 minutes, and further stirred at room temperature for 20 hours . The precipitated crystals were collected by filtration and dried under reduced pressure at 40 ° C. for 53.5 hours to give 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] 6.16 g (yield: 74%) of 4-dihydro-2H-1,4-benzothiazin-3-one monofumarate was obtained as slightly yellow crystals.
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.01 (3H, t, J = 7.0 Hz), 1.81 (2H, quint, J = 6.6 Hz), 2.40-2. J = 5.6 Hz), 3.78 (2H, s), 3.93 (2H, m), 3.72 (2H, J = 6.4 Hz), 4.47 (2H, t, J = 5.2 Hz), 6.60 (2H, s), 6.75 (1 H, dd, J = 3.0, 9.0 Hz , 6.87 (1 H, d, J = 8.8 Hz), 6.89 (1 H, s), 7.15 (1 H, t, J = 7.6 Hz), 7.20 (1 H, t, J = 7.4 Hz), 7.54 (2H, t, J = 7.6 Hz), 10.36 (1 H, s)
Comparative Example 3 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- dihydro-2H- 1,4-benzothiazin-3-one Production of disulfate

 8.28 g (16 parts) of 7- [3- {4- (N-ethoxyethylbenzoimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4-dihydro-2H- 1,4-benzothiazin- . 2 mmol) was dissolved in a mixed solvent of ethanol (104 mL) and water (11 mL) and cooled to 0 ° C. A solution of 3.19 g (16.2 mmol) of sulfuric acid in water (11 mL) was added dropwise and the mixture was stirred at 40 ° C. for 30 minutes, and further stirred at room temperature for 20 hours. The precipitated crystals were collected by filtration and dried under reduced pressure at 40 ° C. for 53.5 hours to give 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] (86% yield) of 4-dihydro-2H-1,4-benzothiazin-3-one disulfate as slightly yellow crystals.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.02 (3H, t, J = 6.8 Hz), 2.03 (2H, m), 2.65 (2H, m), 3.00 (4H, m), 3.26 (2H, m), 3.37 (2H, q, J = 6.8 Hz), 3.41-3.47 (4H, m), 3.75 , J = 5.0 Hz), 4.01 (2H, t, J = 5.8 Hz), 4.21 (2H, brs), 4.65 (2H, t, J = 5.0 Hz), 6.78 J = 8.8 Hz), 6.90 (1 H, d, J = 3.2 Hz), 7.50 – (1 H, d, J = 2.8, 9.2 Hz), 6.89 7.55 (2H, m), 7.79 (1H, d, J = 8.4 Hz), 7.91 (1H, d, J = 6.0 Hz), 10.41 (1H, s)

Presence or Absence of Crystallization of Each Product]

 The monomaleate (2a) obtained in Example 1-3 and the comparative compound obtained in Comparative Examples 1 to 3 (the dimaleate of the title compound (1a) , Monofumarate, disulfate) were obtained as crystals as described above. On the other hand, salts of hydrochloric acid, boric acid, phosphoric acid and citric acid were prepared as a comparative example using the title compound (1a) in the same manner as in Comparative Example 2, and crystallization of each compound was attempted. Upon crystallization of each product, methanol or ethanol was used as a crystallization solvent. The results are shown in Table 2.

[Table 2]

 Crystallization studies gave crystalline salts for sulfuric acid, hydrochloric acid, maleic acid and fumaric acid. On the other hand, the borate, phosphate and citrate of the title compound (1a) did not crystallize, the monoborate was an oily substance and the monophosphate and the monocitrate were amorphous. For the maleate, hydrochloride and sulfate of the title compound (1a), a double salt was obtained in addition to the 1-fold salt. The hydrochloride salt of the title compound (1a) showed clear deliquescence for both monohydrochloride salt and dihydrochloride salt.
[Comparison of Purification Efficiency of Monomeric Acid Salt and Dimaleate Salt of
Title Compound (1a) ] Monomaleate and dimaleate of the title compound (1a) were synthesized under the same conditions using the same means to give crystals Was obtained. Means of synthesis of each product is shown below.
(A) Synthesis of
Monomeric Salt of Title Compound (1a) 7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- -1,4-benzothiazin-3-one (1a) (8.26 g, 16.2 mmol) was added to 71.74 g of ethanol and heated to 60 ° C., 1.79 g (15.40 mmol) of maleic acid was added , Cooled to 50 ° C. and 40 mg (0.064 mmol) of seed crystals was added. The reaction solution was stirred at 50 ° C. for 1 hour and then stirred overnight at room temperature. Subsequently, the reaction solution was stirred at 3 ° C. or less for 5 hours. After completion of the stirring, the precipitated crystals were collected by filtration to obtain 6.26 g (yield 62%) of the monomaleic acid salt of the title compound (1a).
(B) Synthesis of Dimaleate of Title Compound (1a)
7- [3- {4- (N-ethoxyethylbenzimidazol-2-ylmethyl) -1-piperazinyl} propoxy] -3,4- dihydro-2H- 8.26 g (16.2 mmol) of 1,4-benzothiazin-3-one (1a) was added to 71.74 g of ethanol and heated to 60 ° C., and 4.7 g (40.48 mmol) of maleic acid was added. After confirming that the maleic acid was completely dissolved in the solution, it was stirred overnight at room temperature. Subsequently, the reaction solution was stirred at 3 ° C. or less for 5 hours. After completion of the stirring, the precipitated crystals were collected by filtration to obtain 8.04 g (yield 67%) of the dimaleic acid salt of the title compound (1a).

[0114]
 Crystals of the monomaleate and dimaleate obtained by means (a) and (b) above were each dissolved in a small amount of solvent and the purity of each substance was measured by high performance liquid chromatography (HPLC). The HPLC conditions are as follows and charts showing the HPLC measurement results are shown in FIGS. 4 and 5. Table 3 summarizes the HPLC measurement results.
 Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 5 cm was
charged
with 3.5 μm of phenylhexylsilylated silica gel for liquid chromatography (HPLC) .
(  B%) 20% → <10 minutes> → 60% (10 minutes) → <10 minutes>
Column temperature: constant temperature around 40 ° C.
Gradient condition (B%) 20% → 85% (10 min)
A solution: 0.01 mol / L phosphate buffer, pH 6.0
B: methanol
flow rate: 1.0 mL / min
area measurement range: 40 minutes
injection volume: 3 [mu] L
sample concentration: 1 mg / mL

PATENT

 JP 2013035773

JP 2013049632

1.(a) Fukuda, T.Koketsu, A.Kaneko, Y.Ashikawa, Y. Monomaleate of Benzothiazine CompoundWO20111151732011.

(b) Fukuda, T.Koketsu, A. Method for Producing Benzothiazine CompoundWO20111151502011.
(b) Fukuda, T.Koketsu, A. Method for Producing Benzothiazine CompoundWO20111151502011.

//////////K-8986, K 8986, 

O=C(O)/C=C\C(=O)O.CCOCCn4c5ccccc5nc4CN1CCN(CC1)CCCOc2ccc3NC(=O)CSc3c2

Ifetroban イフェトロバン


Ifetroban.svg

ChemSpider 2D Image | 3-[2-({(1S,2R,3S)-3-[4-(Pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl}methyl)phenyl]propanoic acid | C25H32N2O5

Ifetroban.png

Ifetroban イフェトロバン

3-[2-({(1S,2R,3S)-3-[4-(Pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl}methyl)phenyl]propanoic acid

  • Molecular FormulaC25H32N2O5
  • Average mass440.532 Da
  • 143443-90-7;
3-[2-({(1S,2R,3S)-3-[4-(Pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl}methyl)phenyl]propanoic acid
Benzenepropanoic acid, 2-[[(1S,2R,3S)-3-[4-[(pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-
3-[2-[[(1S,5S,6R)-5-[4-(pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]heptan-6-yl]methyl]phenyl]propanoic acid
Benzenepropanoic acid, 2-((3-(4-((pentylamino)carbonyl)-2-oxazolyl)-7-oxabicyclo(2.2.1)hept-2-yl)methyl)-, (1S-(exo,exo))-
BMS 180,291
BMS 180291-02
BMS180291
BMS 18029; BMS 180291; BMS 180291A; BMS-180291-02; Boxaban; CPI 211; Hepatoren; Portaban; Vasculan

Ifetroban is a potent and selective thromboxane receptor antagonist.[1]

Ifetroban has been used in trials studying the treatment of Skin Diseases, Autoimmune Diseases, Pathologic Processes, Scleroderma, Limited, and Scleroderma, Diffuse, among others.

This compound belongs to the class of organic compounds known as phenylpropanoic acids. These are compounds with a structure containing a benzene ring conjugated to a propanoic acid.

  • OriginatorBristol-Myers Squibb
  • DeveloperBristol-Myers Squibb; Cumberland Pharmaceuticals; Vanderbilt-Ingram Cancer Center
  • ClassAntiasthmatics; Antihypertensives; Antiplatelets; Heterocyclic bicyclo compounds; Oxazoles; Small molecules
  • Mechanism of ActionThromboxane A2 receptor antagonists
  • Phase IIAsthma; Hepatorenal syndrome; Portal hypertension; Solid tumours; Systemic scleroderma
  • DiscontinuedCoronary thrombosis; Peripheral vascular disorders; Thrombosis
  • 12 Dec 2018Phase-II clinical trials in Solid tumours (Metastatic disease, Late-stage disease, Second-line therapy or greater, Recurrent) in USA (PO) (NCT03694249)
  • 13 Nov 2018Efficacy and adverse events data from a phase II trial in Portal hypertension released by Cumberland Pharmaceuticals
  • 03 Oct 2018Vanderbilt-Ingram Cancer Center and Cumberland Pharmaceuticals plans a phase II trial for Solid tumours (Metastatic disease, Late-stage disease, Second-line therapy or greater, Recurrent) (PO, capsule) (NCT03694249)

ChemSpider 2D Image | Ifetroban sodium | C25H31N2NaO5

Ifetroban sodium

  • Molecular FormulaC25H31N2NaO5
  • Average mass462.514 Da
  • Monoisotopic mass462.213074 Da
156715-37-6 [RN]
Benzenepropanoic acid, 2-[[(1S,2R,3S,4R)-3-[4-[(pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-, sodium salt (1:1)
Ifetroban sodium
Sodium 3-[2-({(1S,2R,3S,4R)-3-[4-(pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl}methyl)phenyl]propanoate

Image result for Aceclofenac DRUG FUTURE

SYN

BMS-180291 sodium salt was prepared from optically active 7-oxabicyclo[2.2.1]heptane lactol (I): The interphenylene side chain was introduced by deprotonation of (I) with ethylmagnesium bromide (0.95 eq.) followed by treatment with excess aryl Grignard (II) to afford crystalline diol (III). The extraneous benzylic hydroxyl group in (III) was removed by reduction with hydrogen in the presence of Pearlman’s catalyst to give alcohol (IV). Transformation of the alpha-side chain silyloxy carbinol of (IV) to a carboxymethyl ester was accomplished by initial protection of the omega-side chain alcohol as the acetate (Ac2O/py) followed by oxidation under Jones conditions and then exposure of the resulting crude acetate-acid to methanolic hydrogen chloride to afford crystalline alcohol-ester (V). Oxidation of (V) under Jones conditions furnished acid-ester (VI). The oxazole side chain was introduced into (VI) via serine-derived amino alcohol (VII). Standard coupling of acid (VI) with (VII) mediated by water-soluble carbodiimide (EDAC) gave amide (VIII). Acyclic side chain intermediate (VIII) was converted into oxazole (X) in three steps by mesylation followed by treatment with triethylamine to furnish cyclized oxazoline (IX). Dehydrogenation of (IX) employing a novel oxidative protocol (1) involving treatment with a mixture of copper (II) bromide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in chloroform/ethyl acetate solvent yielded oxazole (X). Saponification of (X) followed by acidification afforded (BMS-180291) as a white solid which could be purified by recrystallization from acetonitrile. The water-soluble sodium salt (XI) was available as a precipitate from BMS-18091 by treatment with sodium methoxide/methanol in acetone.

SYN

The interphenylene side chain was introduced by deprotonation of (I) with ethylmagnesium bromide (0.95 eq.) followed by treatment with excess aryl Grignard (II) to afford crystalline diol (III). The extraneous benzylic hydroxyl group in (III) was removed by reduction with hydrogen in the presence of Pearlman’s catalyst to give alcohol (IV). Transformation of the alpha-side chain silyloxy carbinol to a carboxy methyl ester was accomplished by initial protection of the omega-side chain alcohol as the acetate (Ac2O/pyr) followed by oxidation under Jones conditions and then exposure of the resulting crude acetate-acid to methanolic hydrogen chloride to afford crystalline alcohol-ester (V). Oxidation of (V) under Jones conditions furnished acid-ester (VI). The oxazole side chain was introduced into (VI) via serine-derived amino alcohol (VII). Standard coupling of acid (VI) with (VII) mediated by water-soluble carbodiimide (EDAC) gave amide (VIII). Acyclic side chain intermediate (VIII) was converted into oxazole (X) in three steps by mesylation followed by treatment with triethylamine to furnish cyclized oxazoline (IX). Dehydrogenation of (IX) employing a novel oxidative protocol involving treatment with a mixture of copper (II) bromide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in chloroform/ethyl acetate solvent yielded oxazole (X). Saponification of (X) followed by acidification afforded (XI) (BMS-180291) as a white solid which could be purified by recrystallization from acetonitrile. The water-soluble sodium salt was available as a precipitate from (XI) by treatment with sodium methoxide/methanol in acetone.

SYN

Org Process Res Dev 1997,1(1),14

The synthesis of [1S-(1alpha,2alpha,3alpha,4alpha)]-2-[2-[2-(methoxycarbonyl)ethyl]benzyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylic acid (VI), a key intermediate in the synthesis of 203961 [see scheme 20396101a] has been presented: This compound has been obtained by two similar ways: 1) The condensation of L-valinol (XII) with anhydride (XXII) catalyzed by oxalic acid gives imide (XIII), which is treated with ethylmagnesium chloride, the Grignard reagent (XIV) and NaBH4 yielding intermediate (XV). This intermediate, without isolation, is treated with HCl in THF to afford the substituted benzaldehyde (XVI), which is condensed with trimethyl phosphonoacetate (XVII) and DBU in acetonitrile giving the propenoic ester (XVIII). Finally, this compound is submitted to a simultaneous reduction and hydrogenolysis with H2 over a Pearlman catalyst in methanol to provide the target of [1S-(1alpha,2alpha,3alpha,4alpha)]-2-[2-[2-(methoxycarbonyl)ethyl]benzyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylic acid (VI). 2) The preceding reaction sequence can also be performed using (S)-2-phenylglycinol (XIX) instead of the L-valinol (XII) yielding the previously reported benzaldehyde (XVI) through the imide (XX) and the nonisolated intermediate (XXI).


References

  1. ^ Dockens, RC; Santone, KS; Mitroka, JG; Morrison, RA; Jemal, M; Greene, DS; Barbhaiya, RH (August 2000). “Disposition of Radiolabeled Ifetroban in Rats, Dogs, Monkeys, and Humans”(PDF)Drug Metabolism and Disposition28 (8): 973–80. PMID 10901709. Retrieved 5 October 2016.
Ifetroban
Ifetroban.svg
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C25H32N2O5
Molar mass 440.53 g/mol
3D model (JSmol)

////////Ifetroban, BMS 18029, BMS 180291, BMS 180291A, BMS-180291-02, Boxaban, CPI 211, Hepatoren, Portaban, Vasculan, イフェトロバン

CCCCCNC(=O)C1=COC(=N1)C2C3CCC(C2CC4=CC=CC=C4CCC(=O)O)O3

Aceclofenac, ацеклофенак , أسيكلوفيناك , 醋氯芬酸 , アセクロフェナク


Aceclofenac.png

Aceclofenac

アセクロフェナク

  • Molecular FormulaC16H13Cl2NO4
  • Average mass354.185 Da
(2-{2-[(2,6-Dichlorophenyl)amino]phenyl}acetoxy)acetic acid [ACD/IUPAC Name]
(2-{2-[(2,6-Dichlorphenyl)amino]phenyl}acetoxy)essigsäure [German] [ACD/IUPAC Name]
5608
89796-99-6 [RN]
Aceclofenac [BAN] [INN] [JAN] [Wiki]
acéclofénac [French] [INN]
Aceclofenaco [Spanish] [INN]
Aceclofenacum [Latin] [INN]
Acide (2-{2-[(2,6-dichlorophényl)amino]phényl}acétoxy)acétique [French] [ACD/IUPAC Name]
Benzeneacetic acid, 2-[(2,6-dichlorophenyl)amino]-, carboxymethyl ester [ACD/Index Name]
RPK779R03H
ацеклофенак[Russian][INN]
أسيكلوفيناك[Arabic][INN]
醋氯芬酸[Chinese][INN]
[({2-[(2,6-dichlorophenyl)amino]phenyl}acetyl)oxy]acetic acid
[2-(2,6-Dichloro-phenylamino)-phenyl]-acetic acid carboxymethyl ester
Aceclofenac
CAS Registry Number: 89796-99-6
CAS Name: 2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid carboxymethyl ester
Additional Names: 2-[(2,6-dichlorophenyl)amino]phenylacetoxyacetic acid; glycolic acid [o-(2,6-dichloroanilino)phenyl]acetate ester
Manufacturers’ Codes: PR-82/3
Trademarks: Airtal (Prodes); Falcol (Bayer); Gerbin (Sanofi Winthrop); Preservex (BMS)
Molecular Formula: C16H13Cl2NO4
Molecular Weight: 354.18
Percent Composition: C 54.26%, H 3.70%, Cl 20.02%, N 3.95%, O 18.07%
Literature References: Prepn: A. V. Casas, ES8404783idem,US4548952 (1984, 1985 both to Prodes). Gastrointestinal tolerance in rats in comparison with diclofenac, q.v.: V. Rimbau et al.,Farmaco Ed. Prat.43, 19 (1988). Clinical trial in comparison with acetaminophen, q.v., in episiotomal pain: A. Yscla, Drugs Exp. Clin. Res.14, 491 (1988). Clinical evaluation in rheumatoid arthritis: R. Ballesteros et al.,Clin. Trials J.27, 12 (1990).
Properties: White crystals from cyclohexane, mp 149-150°. uv max (ethanol): 275 nm (log e 4.14).
Melting point: mp 149-150°
Absorption maximum: uv max (ethanol): 275 nm (log e 4.14)
Therap-Cat: Anti-inflammatory; analgesic.
Keywords: Analgesic (Non-Narcotic); Anti-inflammatory (Nonsteroidal); Arylacetic Acid Derivatives.
UV-Vis spectra of Aceclofenac.
Fig. 9

 Characterization of Aceclofenac by 1H NMR spectroscopy

1H NMR (400 MHz, DMSO-d6δ (ppm) 3.896 (s, 2H, Aliphatic –CH2), 4.634 (s, 2H, Aliphatic –CH2), 6.279 (d J= 8.00HZ, 1H, Aromatic), 6.887 (t, J = 7.2 Hz, 1H), 6.936 (s, 1H, NH), 7.039(t, J = 7.6 Hz, 1H, Aromatic), 7.225 (t J= 8.00 HZ, 1H, Aromatic), 7.260 (d J= 8.00 HZ, 1H, Aromatic), 7.537 (d J= 8.4HZ, 2H, Aromatic), 13.076 (s, 1H, Carboxylic acid) …https://www.sciencedirect.com/science/article/pii/S2214180417301290

str1str2str3str4

 

 

https://www.dea.gov/sites/default/files/pr/microgram-journals/2014/mj11-1_29-41.pdf

Aceclofenac is a nonsteroidal anti-inflammatory drug (NSAID) analog of diclofenac. It is used for the relief of pain and inflammation in rheumatoid arthritisosteoarthritis and ankylosing spondylitis.

Aceclofenac (C16H13Cl2NO4), chemically [(2-{2, 6-dichlorophenyl) amino} phenylacetooxyacetic acid], is a crystalline powder with a molecular weight of 354.19. It is practically insoluble in water with good permeability. It is metabolized in human hepatocytes and human microsomes to form [2-(2′,6′-dichloro-4′-hydroxy- phenylamino) phenyl] acetoxyacetic acid as the major metabolite, which is then further conjugated. According to the Biopharmaceutical Classification System (BCS) drug substances are classified to four classes upon their solubility and permeability. Aceclofenac falls under the BCS Class II, poorly soluble and highly permeable drug.[1]

Aceclofenac works by inhibiting the action of cyclooxygenase (COX) that is involved in the production of prostaglandins (PG) which is accountable for pain, swelling, inflammation and fever. The incidence of gastric ulcerogenicity of aceclofenac has been reported to be significantly lower than that of the other frequently prescribed NSAIDs, for instance, 2-folds lesser than naproxen, 4-folds lesser than diclofenac, and 7-folds lesser than indomethacin.

Aceclofenac should not be given to people with porphyria or breast-feeding mothers, and is not recommended for children. It should be avoided near term in a pregnant woman because of the risk of having a patent ductus arteriosus in the neonate.

Image result for aceclofenac

SYN

Manufacturing Process for Aceclofenac
Stage-1
T Butanol and Chloro Acetyl Chloride react in presence of NN Dimethyl Aniline at low temperature. After reaction
organics mass wash with water and sodium bicarbonate solution to get stage-1

Stage-2
Stage-I react with Diclofenac Sodium in presence of TBAB in Toluene media, further react with formic acid and
reaction mass quenching in water and product is isolated by filtration. Finally Crude Aceclofenac purified in ethyl
acetate and charcoal. Pure product isolated by filtration.

str1 str2 str3

SYN’

EP 0119932; US 4548952

Alkylation of the sodium salt of diclofenac (I) with benzyl bromoacetate (II) in hot DMF yielded the (arylacetoxy)acetate (III). Subsequent hydrogenolysis of the benzyl ester of (III) in the presence of Pd/C gave the title carboxylic acid. Alternatively, the benzyl ester group of (III) was cleaved by means of the combination of chlorotrimethylsilane and sodium iodide. This method of selective ester hydrolysis with in situ generated iodotrimethylsilane was also applied to the corresponding methyl (IV) and tert-butyl (V) esters. In a related procedure, tert-butyl ester (V) was prepared by alkylation of diclofenac (VI) with tert-butyl bromoacetate (VII) in the presence of tertiary amines. Selective cleavage of the tert-butyl ester group of (V) was then performed by treatment with either trifluoroacetic or formic acid.

SYN

ES 2046141

Aceclofenac was prepared by selective hydrolysis of other labile ester precursors. Alkylation of diclofenac sodium (I) with tetrahydropyranyl chloroacetate (IX), prepared by protection of chloroacetic acid (VIII) with dihydropyran, furnished the tetrahydropyranyl ester of aceclofenac (X), which was then deprotected by treatment with HCl. Similarly, the preparation of aceclofenac was reported by acidic hydrolysis of the analogous tetrahydrofuranyl ester (XI).

References

  1. ^ Karmoker, J.R.; Sarkar, S.; Joydhar, P.; Chowdhury, S.F. (2016). “Comparative in vitro equivalence evaluation of some Aceclofenac generic tablets marketed in Bangladesh” (PDF)The Pharma Innovation Journal5: 3–7. Retrieved 2016-09-01.
Sources

References

    • EP 119 932 (Prodes; appl. 19.3.1984; E-prior. 21.3.1983).
    • US 4 548 952 (Prodes; 22.10.1985; appl. 15.3.1984; E-prior. 21.3.1983).
  • Alternative synthesis:

    • ES 2 020 146 (Prodesfarma; appl. 29.5.1990).
    • ATC:M01AB16
  • Use:non-steroidal anti-inflammatory, analgesic, non-selective cyclooxigenase inhibitor
  • Chemical name:2-[(2,6-dichlorophenyl)amino]benzeneacetic acid carboxymethyl ester
  • Formula:C16H13Cl2NO4
  • MW:354.19 g/mol
  • CAS-RN:89796-99-6
  • InChI Key:MNIPYSSQXLZQLJ-UHFFFAOYSA-N
  • InChI:InChI=1S/C16H13Cl2NO4/c17-11-5-3-6-12(18)16(11)19-13-7-2-1-4-10(13)8-15(22)23-9-14(20)21/h1-7,19H,8-9H2,(H,20,21)
  • LD50:121 mg/kg (M, p.o.)
Aceclofenac
Aceclofenac.png
Clinical data
Trade names Hifenac, Cincofen, Zerodol, Nacsiv, Acenac, others
AHFS/Drugs.com International Drug Names
Routes of
administration
oral, topical
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.169.686 Edit this at Wikidata
Chemical and physical data
Formula C16H13Cl2NO4
Molar mass 353.02161 g/mol
3D model (JSmol)

//////////Aceclofenac, ацеклофенак أسيكلوفيناك 醋氯芬酸 , アセクロフェナク

Diclofenac Sodium


Diclofenac sodium.png

Diclofenac Sodium

15307-79-6; Sodium diclofenac; Diclofenac sodium salt; Voltaren; Solaraze

Molecular Formula: C14H10Cl2NNaO2
Molecular Weight: 318.129 g/mol

Diclofenac, sold under the trade names Voltaren among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout.[3] It is taken by mouth or applied to the skin.[3] Improvements in pain typically occur within half an hour and last for as much as eight hours.[3] It is also available in combination with misoprostol in an effort to decrease stomach problems.[4]

Common side effects include abdominal paingastrointestinal bleeding, nausea, dizziness, headache, and swelling.[3] Serious side effects may include heart diseasestrokekidney problems, and stomach ulceration.[4][3] Use is not recommended in the third trimester of pregnancy.[3] It is likely safe during breastfeeding.[4] It is believed to work by decreasing the production of prostaglandin.[5] It blocks both cycloxygenase-1 (COX-1) and cycloxygenase-2 (COX-2).[3]

Diclofenac was patented in 1965 by Ciba-Geigy and came into medical use in the United States in 1988.[3][6] It is available as a generic medication.[3] In the United States the wholesale cost per dose is less than US$0.15 as of 2018.[7] In 2016 it was the 78th most prescribed medication in the United States with more than 9 million prescriptions.[8] It is available as both a sodium and a potassium salt.[4]

Medical uses

Diclofenac is used to treat pain, inflammatory disorders, and dysmenorrhea.[9]

Pain

Inflammatory disorders may include musculoskeletal complaints, especially arthritisrheumatoid arthritispolymyositisdermatomyositisosteoarthritis, dental pain, temporomandibular joint (TMJ) pain, spondylarthritisankylosing spondylitisgout attacks,[10] and pain management in cases of kidney stones and gallstones. An additional indication is the treatment of acute migraines.[11] Diclofenac is used commonly to treat mild to moderate postoperative or post-traumatic pain, in particular when inflammation is also present,[10] and is effective against menstrual pain and endometriosis.

Diclofenac is also available in topical forms and has been found to be useful for osteoarthritis but not other types of long-term musculoskeletal pain.[12]

It may also help with actinic keratosis, and acute pain caused by minor strains, sprains, and contusions (bruises).[13]

In many countries,[14] eye drops are sold to treat acute and chronic nonbacterial inflammation of the anterior part of the eyes (e.g., postoperative states). Diclofenac eye drops have also been used to manage pain for traumatic corneal abrasion.[15]

Diclofenac is often used to treat chronic pain associated with cancer, in particular if inflammation is also present (Step I of the World Health Organization (WHO) scheme for treatment of chronic pain).[16] Diclofenac can be combined with opioids if needed such as a fixed combination of diclofenac and codeine.

Contraindications

Adverse effects

Diclofenac consumption has been associated with significantly increased vascular and coronary risk in a study including coxib, diclofenac, ibuprofen and naproxen.[18] Upper gastrointestinal complications were also reported.[18] Major adverse cardiovascular events (MACE) were increased by about a third by diclofenac, chiefly due to an increase in major coronary events.[18] Compared with placebo, of 1000 patients allocated to diclofenac for a year, three more had major vascular events, one of which was fatal.[18] Vascular death was increased significantly by diclofenac.[18]

Heart

In 2013, a study found major vascular events were increased by about a third by diclofenac, chiefly due to an increase in major coronary events.[18] Compared with placebo, of 1000 people allocated to diclofenac for a year, three more had major vascular events, one of which was fatal.[18] Vascular death was increased by diclofenac (1·65).[18]

Following the identification of increased risks of heart attacks with the selective COX-2 inhibitor rofecoxib in 2004, attention has focused on all the other members of the NSAIDs group, including diclofenac. Research results are mixed, with a meta-analysis of papers and reports up to April 2006 suggesting a relative increased rate of heart disease of 1.63 compared to nonusers.[19] Professor Peter Weissberg, Medical Director of the British Heart Foundation said, “However, the increased risk is small, and many patients with chronic debilitating pain may well feel that this small risk is worth taking to relieve their symptoms”. Only aspirin was found not to increase the risk of heart disease; however, this is known to have a higher rate of gastric ulceration than diclofenac. In Britain the Medicines and Healthcare Products Regulatory Agency (MHRA) said in June 2013 that the drug should not be used by people with serious underlying heart conditions—people who had suffered heart failure, heart disease or a stroke were advised to stop using it completely.[20] As of January 15, 2015 the MHRA announced that diclofenac will be reclassified as a prescription-only medicine (POM) due to the risk of cardiovascular adverse events.[21]

A subsequent large study of 74,838 Danish users of NSAIDs or coxibs found no additional cardiovascular risk from diclofenac use.[22] A very large study of 1,028,437 Danish users of various NSAIDs or coxibs found the “Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death (odds ratio, 1.91; 95% confidence interval, 1.62 to 2.42; and odds ratio, 1.66; 95% confidence interval, 1.06 to 2.59, respectively), with a dose-dependent increase in risk.”[23]

Diclofenac is similar in COX-2 selectivity to celecoxib.[24]

Gastrointestinal

  • Gastrointestinal complaints are most often noted. The development of ulceration and/or bleeding requires immediate termination of treatment with diclofenac. Most patients receive a gastro-protective drug as prophylaxis during long-term treatment (misoprostolranitidine 150 mg at bedtime or omeprazole 20 mg at bedtime).

Liver

  • Liver damage occurs infrequently, and is usually reversible. Hepatitis may occur rarely without any warning symptoms and may be fatal. Patients with osteoarthritis more often develop symptomatic liver disease than patients with rheumatoid arthritis. Liver function should be monitored regularly during long-term treatment. If used for the short-term treatment of pain or fever, diclofenac has not been found more hepatotoxic than other NSAIDs.
  • As of December 2009, Endo, Novartis, and the US FDA notified healthcare professionals to add new warnings and precautions about the potential for elevation in liver function tests during treatment with all products containing diclofenac sodium.[25]
  • Cases of drug-induced hepatotoxicity have been reported in the first month, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.
  • Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 week after initiating treatment with diclofenac.

Kidney

  • NSAIDs “are associated with adverse renal [kidney] effects caused by the reduction in synthesis of renal prostaglandins[26] in sensitive persons or animal species, and potentially during long-term use in nonsensitive persons if resistance to side effects decreases with age. However, this side effect cannot be avoided merely by using a COX-2 selective inhibitor because, “Both isoforms of COX, COX-1 and COX-2, are expressed in the kidney… Consequently, the same precautions regarding renal risk that are followed for nonselective NSAIDs should be used when selective COX-2 inhibitors are administered.”[26] However, diclofenac appears to have a different mechanism of renal toxicity.[citation needed]
  • Studies in Pakistan showed diclofenac caused acute kidney failure in vultures when they ate the carcasses of animals that had recently been treated with it. Drug-sensitive species and individual humans are initially assumed to lack genes expressing specific drug detoxification enzymes.[27]

Mental health

  • Mental health side effects have been reported. These symptoms are rare, but exist in significant enough numbers to include as potential side effects. These include depression, anxiety, irritability, nightmares, and psychotic reactions.[28]

Mechanism of action

The primary mechanism responsible for its anti-inflammatoryantipyretic, and analgesic action is thought to be inhibition of prostaglandin synthesis by inhibition of the transiently expressed prostaglandin-endoperoxide synthase-2 (PGES-2) also known as cycloxygenase-2 (COX-2). It also appears to exhibit bacteriostatic activity by inhibiting bacterial DNA synthesis.[29]

Inhibition of prostaglandin synthesis occurs systemically resulting in undesirable symptoms such as irritation of the gastric epithelium.[citation needed] This is the main side effect of diclofenac. Diclofenac inhibits COX-2 with 20 times greater potency than the constitutively expressed isoenzyme COX-1[30] and has, therefore, a somewhat lower incidence of gastrointestinal complaints than noted with aspirin which inhibits COX-1 to a greater extent.

The action of one single dose is much longer (6 to 8 hr) than the very short 1.2–2 hr half-life of the drug would indicate. This could be partly because it persists for over 11 hours in synovial fluids.[31]

Diclofenac may also be a unique member of the NSAIDs. Some evidence indicates it inhibits the lipoxygenase pathways, thus reducing formation of the leukotrienes(also pro-inflammatory autacoids). It also may inhibit phospholipase A2 as part of its mechanism of action. These additional actions may explain its high potency – it is the most potent NSAID on a broad basis.[32]

Marked differences exist among NSAIDs in their selective inhibition of the two subtypes of cyclooxygenase, COX-1 and COX-2. Much pharmaceutical drug design has attempted to focus on selective COX-2 inhibition as a way to minimize the gastrointestinal side effects of NSAIDs such as aspirin. In practice, use of some COX-2 inhibitors with their adverse effects has led to massive numbers of patient family lawsuits alleging wrongful death by heart attack, yet other significantly COX-selective NSAIDs, such as diclofenac, have been well tolerated by most of the population.\

Besides the COX-inhibition, a number of other molecular targets of diclofenac possibly contributing to its pain-relieving actions have recently been identified. These include:

  • Blockage of voltage-dependent sodium channels (after activation of the channel, diclofenac inhibits its reactivation also known as phase inhibition)[citation needed]
  • Blockage of acid-sensing ion channels (ASICs)[33]
  • Positive allosteric modulation of KCNQ- and BK-potassium channels (diclofenac opens these channels, leading to hyperpolarization of the cell membrane)

Ecological effects

Use of diclofenac for animals is controversial due to toxicity when eaten by scavenging birds that eat dead animals; the drug has been banned for veterinary use in many countries.

Use of diclofenac in animals has been reported to have led to a sharp decline in the vulture population in the Indian subcontinent – a 95% decline by 2003[34] and a 99.9% decline by 2008. The mechanism is presumed to be renal failure;[35] however, toxicity may be due to direct inhibition of uric acid secretion in vultures.[36] Vultures eat the carcasses of livestockthat have been administered veterinary diclofenac, and are poisoned by the accumulated chemical,[37] as vultures do not have a particular enzyme to break down diclofenac. At a meeting of the National Wildlife Board in March 2005, the Government of India announced it intended to phase out the veterinary use of diclofenac.[38] Meloxicam is a safer alternative to replace use of diclofenac.[39] It is more expensive than diclofenac, but the price is coming down as more pharmaceutical companies begin to manufacture it.

Steppe eagles have the same vulnerability to diclofenac as vultures and may also fall victim to it.[40] Diclofenac has been shown also to harm freshwater fish species such as rainbow trout.[41][42][43][44] In contrast, New World vultures, such as the turkey vulture, can tolerate at least 100 times the level of diclofenac that is lethal to Gyps species.[45]

“The loss of tens of millions of vultures over the last decade has had major ecological consequences across the Indian Subcontinent that pose a potential threat to human health. In many places, populations of feral dogs (Canis familiaris) have increased sharply from the disappearance of Gyps vultures as the main scavenger of wild and domestic ungulatecarcasses. Associated with the rise in dog numbers is an increased risk of rabies[39] and casualties of almost 50,000 people.[46] The Government of India cites this as one of the major consequences of a vulture species extinction.[38] A major shift in the transfer of corpse pathogens from vultures to feral dogs and rats could lead to a disease pandemic, causing millions of deaths in a crowded country like India, whereas vultures’ digestive systems safely destroy many species of such pathogens. Vultures are long-lived and slow to breed. They start breeding only at the age of six and only 50% of young survive. Even if the government ban is fully implemented, it will take several years to revive the vulture population.[47]

The loss of vultures has had a social impact on the Indian Zoroastrian Parsi community, who traditionally use vultures to dispose of human corpses in Towers of Silence, but are now compelled to seek alternative methods of disposal.[39]

Despite the vulture crisis, diclofenac remains available in other countries including many in Europe.[48] It was controversially approved for veterinary use in Spain in 2013 and continues to be available, despite Spain being home to around 90% of the European vulture population and an independent simulation showing that the drug could reduce the population of vultures by 1-8% annually. Spain’s medicine agency presented simulations suggesting that the number of deaths would be quite small.[49][50]

Formulations and trade names

The name “diclofenac” derives from its chemical name: 2-(2,6-dichloranilino) phenylacetic acid. Diclofenac was first synthesized by Alfred Sallmann and Rudolf Pfister and introduced as Voltaren by Ciba-Geigy (now Novartis) in 1973, now by Glaxo SmithKline.[51]

In the United Kingdom, United States, India, and Brazil diclofenac may be supplied as either the sodium or potassium salt; in China, it is most often supplied as the sodium salt, while in some other countries it is only available as the potassium salt.

Pennsaid is a minimally systemic prescription topical lotion formulation of 1.5% w/w diclofenac sodium, which is approved in the US, Canada and other countries for osteoarthritis of the knee.

Flector Patch, a minimally systemic topical patch formulation of diclofenac, is indicated for acute pain due to minor sprains, strains, and contusions. The patch has been approved in many other countries outside the US under different brand names.

Voltaren and Voltarol contain the sodium salt of diclofenac. In the United Kingdom, Voltarol can be supplied with either the sodium salt or the potassium salt, while Cataflam, sold in some other countries, is the potassium salt only. However, Voltarol Emulgel contains diclofenac diethylammonium, in which a 1.16% concentration is equivalent to a 1% concentration of the sodium salt. In 2016 Voltarol was one of the biggest selling branded over-the-counter medications sold in Great Britain, with sales of £39.3 million.[52]

Diclofenac is available in stomach acid-resistant formulations (25 and 50 mg), fast-disintegrating oral formulations (25 and 50 mg), powder for oral solution (50 mg), slow- and controlled-release forms (75, 100 or 150 mg), suppositories (50 and 100 mg), and injectable forms (50 and 75 mg).

Diclofenac is also available over-the-counter in some countries: 12.5 mg diclofenac as potassium salt in Switzerland (Voltaren dolo), the Netherlands (Voltaren K), and preparations containing 25 mg diclofenac as the potassium salt in Germany (various trade names), New ZealandAustraliaJapan, (Voltaren Rapid), and Sweden (Voltaren T and Diclofenac T). Diclofenac as potassium salt can be found throughout the Middle East in 25 mg and 50 mg doses (Cataflam).

Solaraze (3% diclofenac sodium gel) is topically applied, twice a day for three months, to manage the skin condition known as actinic or solar keratosis. Parazone-DP is a combination of diclofenac potassium and paracetamol, manufactured and supplied by Ozone Pharmaceuticals and Chemicals, Gujarat, India. It is sold in Uruguay alone or, in combination with orphenadrine to treat muscle spasms/pain due to injuries (Dicloflex Ion).

On 14 January 2015, diclofenac oral preparations were reclassified as prescription-only medicines in the UK. The topical preparations are still available without prescription.[53]

Diclofenac formulations are available worldwide under many different trade names.[1]

Diclofenac
Title: Diclofenac
CAS Registry Number: 15307-86-5
CAS Name: 2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid
Additional Names: [o-(2,6-dichloroanilino)phenyl]acetic acid
Trademarks: Motifene (Sankyo)
Molecular Formula: C14H11Cl2NO2
Molecular Weight: 296.15
Percent Composition: C 56.78%, H 3.74%, Cl 23.94%, N 4.73%, O 10.80%
Literature References: Prepn: NL 6604752; A. Sallmann, R. Pfister, US 3558690 (1966, 1971 both to Geigy). Pharmacology: Renaud, Lecompte, Thromb. Diath. Haemorrh. 24, 577 (1970), C.A. 74, 86215m (1971); Krupp et al., Experientia 29, 450 (1973). HPLC determn in plasma and urine: J. Godbillon et al., J. Chromatogr. 338, 151 (1985). Symposium on pharmacology and clinical experience: Semin. Arthritis Rheum. 15, Suppl. 1, 57-110 (1985); on pharmacology, efficacy and safety: Am. J. Med. 80, Suppl. 4B, 1-87 (1986). Comprehensive description: C. M. Adeyeye, P-K. Li, Anal. Profiles Drug Subs. 19, 123-144 (1990). Review of clinical trials in actinic keratosis: D. C. Peters, R. H. Foster, Drugs Aging 14, 313-319 (1999).
Properties: Crystals from ether-petr ether, mp 156-158°.
Melting point: mp 156-158°
Derivative Type: Diethylammonium salt
CAS Registry Number: 78213-16-8
Trademarks: Voltarol (Novartis)
Molecular Formula: C14H11Cl2NO2.C4H11N
Molecular Weight: 369.29
Percent Composition: C 58.54%, H 6.00%, Cl 19.20%, N 7.59%, O 8.66%
Derivative Type: Sodium salt
CAS Registry Number: 15307-79-6
Manufacturers’ Codes: GP-45840
Trademarks: Allvoran (TAD); Benfofen (Sanofi-Synthelabo); Dealgic (Pharmacia); Deflamat (Sankyo); Delphinac (Riemser); Dicloflex (Dexcel); Diclomax (Provalis); Diclophlogont (Azupharma); Dicloreum (Alfa); Duravolten (Dura); Ecofenac (Ecosol); Effekton (Teofarma); Lexobene (Merckle); Neriodin (Nagase); Novapirina (Novartis); Primofenac (Streuli); Prophenatin (Nipro); Rewodina (AWD); Rhumalgan (Sandoz); Voldal (Novartis); Voltaren (Novartis); Xenid (RPG)
Molecular Formula: C14H10Cl2NNaO2
Molecular Weight: 318.13
Percent Composition: C 52.86%, H 3.17%, Cl 22.29%, N 4.40%, Na 7.23%, O 10.06%
Properties: Crystals from water, mp 283-285°. uv max (methanol) 283 nm (e 1.05 ´ 105); (phosphate buffer, pH 7.2) 276 nm (e1.01 ´ 105). Soly at 25°C (mg/ml): deionized water (pH 5.2) >9; methanol >24; acetone 6; acetonitrile <1; cyclohexane <1; HCl (pH 1.1) <1; phosphate buffer (pH 7.2) 6. pKa 4. Partition coefficient (N-octanol/aq. buffer): 13.4. LD50 in mice, rats (mg/kg): ~390, 150 orally (Krupp).
Melting point: mp 283-285°
pKa: pKa 4
Log P: Partition coefficient (N-octanol/aq. buffer): 13.4
Absorption maximum: uv max (methanol) 283 nm (e 1.05 ´ 105); (phosphate buffer, pH 7.2) 276 nm (e 1.01 ´ 105)
Toxicity data: LD50 in mice, rats (mg/kg): ~390, 150 orally (Krupp)
Derivative Type: Potassium salt
CAS Registry Number: 15307-81-0
Manufacturers’ Codes: CGP-45840B
Trademarks: Cataflam (Novartis)
Molecular Formula: C14H10Cl2KNO2
Molecular Weight: 334.24
Percent Composition: C 50.31%, H 3.02%, Cl 21.21%, K 11.70%, N 4.19%, O 9.57%
Therap-Cat: Anti-inflammatory.
Keywords: Anti-inflammatory (Nonsteroidal); Arylacetic Acid Derivatives.

Synthesis

Image result for diclofenac synthesis

Last step

Proposed mechanism

enter image description here

The mechanism begins with the condensation of hydrazine onto a ketone (details not shown) to give a hydrazone. Under basic conditions, this hydrazone is deprotonated at nitrogen to give an anionic intermediate. In this case, the negative charge can be delocalized onto oxygen, resulting in an enolate structure. Typically, the negative charge is only shared between a nitrogen and carbon, so this substrate gives a particularly stable intermediate. Protonation of the enolate at carbon gives the first C-H bond necessary to form the product. A second deprotonation at nitrogen gives a similar flow of electrons to form another enolate structure, this time with cleavage of the C-N bond and release of nitrogen gas. Another C-protonation gives the lactam precursor to diclofenac. Cleavage of the amide with hydroxide (details not shown) gives the target.

Manufacturing Process
2, 6-Dichlorophenol is reacted with MMCA, Aniline and Chloro Acetyl Chloride and AlCl3 to yield (2, 6 –
Dichlorophenol) Indolinone is hydrolyzed using isopropyl alcohol and sodium hydroxide to give crude Diclofenac
Sodium. This on purification using deminerlised water and isopropyl alcohol gives the pure Diclofenac Sodium

CLIP

Image result for diclofenac nmr

Image result for diclofenac nmr

References

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  36. ^ Naidoo V, Swan GE (August 2008). “Diclofenac toxicity in Gyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction”. Comp. Biochem. Physiol. C Toxicol. Pharmacol149 (3): 269–74. doi:10.1016/j.cbpc.2008.07.014PMID 18727958.
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  40. ^ Phadnis, Mayuri (May 28, 2014). “Eagles fall prey to vulture-killing chemical”Pune Mirror. Retrieved May 28, 2014.
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External links

References

    • US 3 558 690 (Geigy; 26.1.1971; CH-prior. 8.4.1965, 25.2.1966, 30.3.1966, 20.12.1967).
    • DAS 1 543 639 (Ciba-Geigy; appl. 7.4.1966; CH-prior. 8.4.1965).
    • DAS 1 793 592 (Ciba-Geigy; appl. 7.4.1966; CH-prior. 8.4.1965).
    • US 3 652 762 (Ciba-Geigy; 28.3.1972; prior. 9.12.1968, 29.9.1969, 14.4.1970).
    • US 3 778 470 (Geigy; 11.12.1973; appl. 2.10.1970; prior. 4.4.1966).
    • CH 492 679 (Geigy; appl. 30.3.1966).
  • Alternative synthesis:

    • DOS 2 613 838 (Ikeda Mohando; appl. 31.3.1976; J-prior. 31.3.1975).
Diclofenac
Diclofenac.svg
Diclofenac 3D.png
Clinical data
Trade names Cataflam, Voltaren, others[1]
AHFS/Drugs.com Monograph
MedlinePlus a689002
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out) in 1st and 2nd trimester, D in 3rd trimester
Routes of
administration
By mouth, rectal, intramuscularintravenous(renal- and gallstones), topical
ATC code
Legal status
Legal status
  • AU: S2 (Pharmacy only) – S4
  • UK: POM (Prescription only) (P for topical formulation)
  • ℞-only in most preparations/countries, limited OTC in some countries, manufacture and veterinary use is banned in India, Nepal, and Pakistan due to imminent extinction of local vultures
Pharmacokinetic data
Protein binding More than 99%
Metabolism Liver, oxidative, primarily by CYP2C9, also by CYP2C8CYP3A4, as well as conjugative by glucuronidation (UGT2B7) and sulfation;[2] no active metabolites exist
Elimination half-life 1.2–2 hr (35% of the drug enters enterohepatic recirculation)
Excretion 40% biliary 60% urine
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
ECHA InfoCard 100.035.755 Edit this at Wikidata
Chemical and physical data
Formula C14H11Cl2NO2
Molar mass 296.148 g/mol
3D model (JSmol)

Diclofenac

    • ATC:M01AB05; M02AA15; S01BC03
  • Use:anti-inflammatory, antirheumatic
  • Chemical name:2-[(2,6-dichlorophenyl)amino]benzeneacetic acid
  • Formula:C14H11Cl2NO2
  • MW:296.15 g/mol
  • CAS-RN:15307-86-5
  • InChI Key:DCOPUUMXTXDBNB-UHFFFAOYSA-N
  • InChI:InChI=1S/C14H11Cl2NO2/c15-10-5-3-6-11(16)14(10)17-12-7-2-1-4-9(12)8-13(18)19/h1-7,17H,8H2,(H,18,19)
  • EINECS:239-348-5
  • LD50:170 mg/kg (M, p.o.);
    62.5 mg/kg (R, p.o.)

Monosodium salt

  • Formula:C14H10Cl2NNaO2
  • MW:318.14 g/mol
  • CAS-RN:15307-79-6
  • EINECS:239-346-4
  • LD50:116 mg/kg (M, i.v.); 390 mg/kg (M, p.o.);
    117 mg/kg (R, i.v.); 150 mg/kg (R, p.o.)

//////////////Diclofenac Sodium

C1=CC=C(C(=C1)CC(=O)[O-])NC2=C(C=CC=C2Cl)Cl.[Na+]

Diclofenac Sodium

structure depiction
FDA Orange Book Patent
FDA Orange Book Patents: 1 of 21 (FDA Orange Book Patent ID)
Patent 9339551
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 2 of 21 (FDA Orange Book Patent ID)
Patent 9339552
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 3 of 21 (FDA Orange Book Patent ID)
Patent 9415029
Expiration Jul 10, 2029
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 4 of 21 (FDA Orange Book Patent ID)
Patent 9370501
Expiration Jul 10, 2029
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 5 of 21 (FDA Orange Book Patent ID)
Patent 9375412
Expiration Jul 10, 2029
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 6 of 21 (FDA Orange Book Patent ID)
Patent 8946292
Expiration Mar 22, 2027
Applicant JAVELIN PHARMS INC
Drug Application N022396 (Prescription Drug: DYLOJECT. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 7 of 21 (FDA Orange Book Patent ID)
Patent 9168305
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 8 of 21 (FDA Orange Book Patent ID)
Patent 9168304
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 9 of 21 (FDA Orange Book Patent ID)
Patent 9220784
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 10 of 21 (FDA Orange Book Patent ID)
Patent 6407079
Expiration Jun 18, 2019
Applicant JAVELIN PHARMS INC
Drug Application N022396 (Prescription Drug: DYLOJECT. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 11 of 21 (FDA Orange Book Patent ID)
Patent 8252838
Expiration Apr 21, 2028
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 12 of 21 (FDA Orange Book Patent ID)
Patent 8618164
Expiration Jul 10, 2029
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 13 of 21 (FDA Orange Book Patent ID)
Patent 8546450
Expiration Aug 9, 2030
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 14 of 21 (FDA Orange Book Patent ID)
Patent 8217078
Expiration Jul 10, 2029
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 15 of 21 (FDA Orange Book Patent ID)
Patent 8563613
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 16 of 21 (FDA Orange Book Patent ID)
Patent 8871809
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 17 of 21 (FDA Orange Book Patent ID)
Patent 9066913
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 18 of 21 (FDA Orange Book Patent ID)
Patent 8741956
Expiration Jul 10, 2029
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 19 of 21 (FDA Orange Book Patent ID)
Patent 9101591
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
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Patent 9132110
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 21 of 21 (FDA Orange Book Patent ID)
Patent 9539335
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

Clotrimazole


Clotrimazole.svg

Clotrimazole

  • Molecular FormulaC22H17ClN2
  • Average mass344.837 Da
1-((2-Chlorophenyl)diphenylmethyl)-1H-imidazole (9CI)
1-(o-Chloro-a,a-diphenylbenzyl)imidazole
1-[(2-Chlorophenyl)(diphenyl)methyl]-1H-imidazole
1-[(o-Chlorophenyl)diphenylmethyl]imidazole
1-[a-(2-Chlorophenyl)benzhydryl]imidazole
1H-Imidazole, 1-[(2-chlorophenyl)diphenylmethyl]-
1H-Imidazole, 1-[(2-chlorophenyl)-diphenylmethyl]
23593-75-1 [RN]
245-764-8 [EINECS]
2912
Bis-fenil-(2-clorofenil)-1-imidazolil-metano [Italian]
Bisphenyl-(2-chlorphenyl)-1-imidazolyl-methan [German]
Canesten [Trade name]
Canifug [Trade name]
Clotrimazole [BAN] [INN] [JAN] [USAN] [Wiki]
Clotrimazolum [Latin]
Empecid [Trade name]
Fungicip [Trade name]
G07GZ97H65
Gyne-Lotrimin [Trade name]
Imidazole, 1- (o-chloro-α,α-diphenylbenzyl)-
Lotrimin [Trade name]
Mono-baycuten [Trade name]
Mycelex [Trade name]
Mycelex G [Trade name]
Mycosporin [Trade name]
Pedisafe [Trade name]
Rimazole [Trade name]
Tibatin [Trade name]
Trimysten [Trade name]
UNII-G07GZ97H65
Clotrimaderm
Clotrimazole
Title: Clotrimazole
CAS Registry Number: 23593-75-1
CAS Name: 1-[(2-Chlorophenyl)diphenylmethyl]-1H-imidazole
Additional Names: 1-(o-chloro-a,a-diphenylbenzyl)imidazole; 1-[a-(2-chlorophenyl)benzhydryl]imidazole; 1-[(o-chlorophenyl)diphenylmethyl]imidazole; diphenyl-(2-chlorophenyl)-1-imidazolylmethane; 1-(o-chlorotrityl)imidazole
Manufacturers’ Codes: FB-5097; Bay b 5097
Trademarks: Canesten (Bayer); Canifug (Wolff); Empecid (Bayer-Takeda); Gyne-Lotrimin (Schering-Plough); Lotrimin (Schering-Plough); Mono-Baycuten; Mycelex-G (Miles); Mycofug (Hermal); Mycosporin (Bayer); Pedisafe (Sagitta); Rimazole (Cheil Sugar); Tibatin (Dak); Trimysten
Molecular Formula: C22H17ClN2
Molecular Weight: 344.84
Percent Composition: C 76.63%, H 4.97%, Cl 10.28%, N 8.12%
Literature References: Prepn: K. H. Buechel et al., ZA 6805392eidem, US 3705172 (1969, 1972 both to Bayer). Pharmacology: Plempel et al., Antimicrob. Agents Chemother. 1969, 271; eidem, Dtsch. Med. Wochenschr. 94, 1356 (1969). Clinical findings: Oberste-Lehn et al., ibid. 1365. Series of articles on prepn, toxicology, pharmacokinetics, clinical studies: Arzneim.-Forsch. 22,1260-1272, 1276-1299 (1972). Toxicity: D. Tettenborn, ibid. 1276. Comprehensive description: J. G. Hoogerheide, B. E. Wyka, Anal. Profiles Drug Subs. 11, 225-255 (1982).
Properties: Crystals, mp 147-149°. A weak base, slightly sol in water, benzene, toluene; sol in acetone, chloroform, ethyl acetate, DMF. Hydrolyzes rapidly upon heating in aq acids. LD50 in male mice, rats (mg/kg): 923, 708 orally (Tettenborn).
Melting point: mp 147-149°
Toxicity data: LD50 in male mice, rats (mg/kg): 923, 708 orally (Tettenborn)
Derivative Type: Hydrochloride
Molecular Formula: C22H17ClN2.HCl
Molecular Weight: 381.30
Percent Composition: C 69.30%, H 4.76%, Cl 18.60%, N 7.35%
Properties: mp 159°.
Melting point: mp 159°
Therap-Cat: Antifungal.
Therap-Cat-Vet: Antifungal.
Keywords: Antifungal (Synthetic); Imidazoles.

Clotrimazole, sold under the brand name Canesten among others, is an antifungal medication.[1] It is used to treat vaginal yeast infectionsoral thrushdiaper rashpityriasis versicolor, and types of ringworm including athlete’s foot and jock itch.[1] It can be taken by mouth or applied as a cream to the skin or in the vagina.[1]

Common side effects when taken by mouth include nausea and itchiness.[1] When applied to the skin common side effects include redness and burning.[1] In pregnancy, use on the skin or in the vagina is believed to be safe.[1] There is no evidence of harm when used by mouth during pregnancy but this has been less well studied.[1] When used by mouth, greater care should be taken in those with liver problems.[1] It is in the azole class of medications and works by disrupting the cell membrane.[1]

Clotrimazole was discovered in 1969.[2] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[3] It is available as a generic medication.[1] The wholesale cost in the developing world as of 2014 is 0.20–0.86 USD per 20 gram tube of cream.[4] In the United States a course of treatment typically costs less than 25 USD.[5]

Medical uses

It is commonly available without a prescription in various dosage forms, such as a cream, vaginal tablet, or as a prescription troche or throat lozenge (prescription only). Topically, clotrimazole is used for vulvovaginal candidiasis (yeast infection) or yeast infections of the skin. For vulvovaginal candidiasis (yeast infection), clotrimazole tablets and creams are inserted into the vagina. Troche or throat lozenge preparations are used for oropharyngeal candidiasis (oral thrush) or prophylaxis against oral thrush in neutropenic patients.

Clotrimazole is usually used 5 times daily for 14 days for oral thrush, twice daily for 2 to 8 weeks for skin infections, and once daily for 3 or 7 days for vaginal infections.[6]

Clotrimazole may be compounded with a glucocorticoid, such as betamethasone, in a topical cream for the treatment of tinea corporis (ringworm)tinea cruris (jock itch) and tinea pedis (athlete’s foot). Although FDA approved, clotrimazole-betamethasone combination cream is not the preferred treatment for dermatophyte infections due to increased side effects from the topical glucocorticoid. Although temporary relief and partial suppression of symptoms may be observed with the combination therapy, glucocorticoids can elicit an immunosuppressive response and rebound effect that results in more severe infection typically requiring systemic antifungal agents to treat the disease. Combination creams are best avoided in order to improve treatment outcome, reduce the possibility of skin atrophy associated with prolonged topical glucocorticoid use, and to limit the cost of treatment. It can be effective in treating chronic paronychia. The preferred treatment of tinea infections is therefore with clotrimazole monotherapy.[7]

Topical and oral clotrimazole can be used in both adults and children.

Additionally, clotrimazole may be used to treat the sickling of cells (related to sickle cell anemia).[8][9]

Pregnancy

Small amounts of clotrimazole may be absorbed systemically following topical and vaginal administration. However, this may still be used to treat yeast infections in pregnant women.[10]

Side effects

Side effects of the oral formulation include itching, nausea, and vomiting. >10% of patients using the oral formulation may have abnormal liver function tests. Side effects include rash, hives, blisters, burning, itching, peeling, redness, swelling, pain or other signs of skin irritation.[1] For this reason, liver function tests should be monitored periodically when taking the oral clotrimazole (troche). When used to treat vulvovaginal candidiasis (yeast infection), <10% of patient have vulvar or vaginal burning sensation. <1% of patients have the following side effects: Burning or itching of penis of sexual partner; polyuria; vulvar itching, soreness, edema, or discharge [6][11][12]

Clotrimazole creams and suppositories contain oil which may weaken latex condoms and diaphragms.[10]

Drug interactions

There are no known significant drug interactions with topical clotrimazole. However, with oral (troche) clotrimazole, there are multiple interactions as the medication is a CYP450 enzyme inhibitor, primarily CYP3A4. Thus, any medication that is metabolized by the CYP3A4 enzyme will potentially have elevated levels when oral clotrimazole is used. The prescribing physician should be aware of any medication the patient is taking prior to starting oral clotrimazole. Certain medications should not be taken with oral clotrimazole.[11]

Mechanism of action

Clotrimazole works by inhibiting the growth of individual Candida or fungal cells by altering the permeability of the fungal cell wall. It binds to phospholipids in the cell membrane and inhibits the biosynthesis of ergosterol and other sterols required for cell membrane production.[12][11] Clotrimazole may be fungistatic (slow fungal growth) or fungicidal (result in fungal cell death).[1]

Society and culture

Clotrimazole (Canesten) antifungal cream

It is available as a generic medication.[1] The wholesale cost in the developing world as of 2014 is 0.20–0.86 USD per 20gm tube of cream.[4]In the United States a course of treatment typically costs less than 25 USD.[5] In 2016 Canesten was one of the biggest selling branded over-the-counter medications sold in Great Britain, with sales of £39.2 million.[13]

Image result for clotrimazole synthesis

syn

 Image result for clotrimazole synthesis
str3
d (4) as a white crystal (yield 91%). mp 130- 133 0 C; Rf = 0.37; IR (neat) νmax/cm-1 3064, 1489, 1443, 1210, 750; 1 H NMR (300 MHz, CDCl3) δ (ppm): 7.48 (s, 1H), 7.41-7.44 (m 1H), 7.32-7.37 (m, 7H), 7.26-7.29 (m, 1H), 7.19-7.23 (m, 4H), 7.07 (s, 1H), 6.92 (dd, 1H, J = 1.5, 6.3 Hz), 6.76 (s, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm): 151.1, 150.5, 148.9, 144.5, 140.3, 138.0, 137.7, 137.3, 135.5, 135.2, 135.1, 133.8, 127.0, 68.9; m/z calcd for C19H14Cl [M-Imid]+ 277.0784, found 277.0780.
Clip

CLIP

Open Babel bond-line chemical structure with annotated hydrogens.<br>Click to toggle size.

Fig 4. Open Babel bond-line chemical structure with annotated hydrogens.
Click to toggle size.

Spectrum Plot

<sup>1</sup>H NMR spectrum of C<sub>22</sub>H<sub>17</sub>Cl<sub></sub>N<sub>2</sub> in CDCL3 at 400 MHz.<br>Click to toggle size.

Fig 5. 1H NMR spectrum of C22H17ClN2 in CDCL3 at 400 MHz.

Image

Figure 7. 2D 13 C13 C refocused INADEQUATE spectrum of clotrimazole showing intramolecular contacts among 13 C resonances as marked in the molecular structure on the right. The full spectrum is included in the Figure S4. The 2D spectrum was acquired in 17 hr at 106 K on 400 MHz, 384 scans per increment, 2 s recycle delay and 80 t 1 increments of a 27.7 ?s.

2D 13C-13C refocused INADEQUATE spectrum of clotrimazole showing intramolecular contacts among 13C resonances as marked in the molecular structure on the right. The 2D spectrum was acquired in 17 hr at 106 K on 400 MHz.

PATENT

https://patents.google.com/patent/CN105566156A/en

The object of the present invention is to provide a method for synthesizing a pharmaceutical Clotrimazole intermediate o-chlorobenzonitrile, comprising the steps of:

[0004] (i) in a reaction container equipped with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. lmol, aniline (3) 3.6-3 · 9mol, nitromethane burning 310ml, chloro cuprous 1 · 56mol, hook are mixed, controlling the stirring speed 110-160rpm, the solution temperature increased to 110-115 ° C, 3-5h the reaction, the solution temperature increased to 130-135 ° C, the reaction 2-3h, solution temperature increased to 190-195 ° C, the reaction 90-120min, reducing the solution temperature to 15-20 ° C, was added 700 ml of saline solution, sodium bisulfite solution, 130ml, distilled under reduced pressure to collect 130-135 ° C fraction , washed with triethylamine in toluene and recrystallized to give crystals of o-chlorobenzonitrile (1).

[0005] wherein the mass fraction of nitromethane according to step (i) is 60-65%, of the salt solution in step (i) is ammonium nitrate, potassium iodide to any one of the steps of (i) mass fraction of sodium hydrogen sulfite solution was 40-45%, which pressure in the vacuum distillation of step (i) is 1.6-1.7kPa, triethylamine mass fraction of said step (i) is 70-75%, step (i) in toluene of the mass fraction of 90-95%. Throughout the reaction using the following reaction formula:

[0006

[0007 “not as good as Wu Ming 1 point Shi Bian: J Cheng less

Figure CN105566156AD00041

A slave I anti Day “* 1, section A, J array low reaction temperature and reaction time, the reaction yield improved.

Detailed ways

[0008] The following examples with reference to specific embodiments of the present invention is further described:

Clotrimazole synthesis kinds drug intermediates of o-chlorobenzonitrile – [0009]

[0010] Example 1:

[0011] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.6111〇1, mass fraction of 60% nitromethane 3,101,111 chloride cuprous 1.56111 〇1, mixing, stirring speed control lOrpm 1, the solution temperature increased to 110 ° C, the reaction 3h, the solution temperature increased to 130 ° C, the reaction 2h, the solution temperature is raised to 190 ° (:, reaction 9011 ^ 11, reducing the solution temperature to 15 ° (:, 7,001,111 ammonium nitrate solution was added, the mass fraction of 40% sodium bisulfite solution was 130ml, 1.6kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 70 washed% triethylamine, 90% toluene to a mass fraction of recrystallized to give crystals of o-chlorobenzonitrile 308.02g, yield 72%.

[0012] Example 2:

[0013] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.7111〇1, mass fraction of 62% nitromethane 31〇1111, 1.56111〇1 cuprous chloride, mixed, controlling the stirring speed of 130 rpm, the temperature was raised to 112 ° C, the reaction 4h, the solution temperature increased to 132 ° C, the reaction 2h, the solution temperature increased to 192 ° C, the reaction llOmin, reducing the solution temperature to 17 ° C, 700 ml of a solution of potassium iodide was added, the mass fraction of 42% sodium bisulfite solution 130ml, 1.65kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 72% triethylamine washed, recrystallized from toluene to 92% mass fraction, to obtain crystals of o-chlorobenzonitrile 337.96g, yield 79%.

[0014] Example 3:

[0015] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.9111〇1, mass fraction of 65% nitromethane 31〇1111, 1.56111 〇1 cuprous chloride, mixed, controlling stirring speed 160 rpm, temperature was raised to 115 ° C, the reaction 5h, the solution temperature increased to 135 ° C, the reaction 3h, the solution temperature increased to 195 ° C, the reaction 120min, reducing the solution temperature to 20 ° C, was added 700 ml of a solution of ammonium nitrate, 45% mass fraction of sodium bisulfite solution was 130ml, 1.7kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 75% triacetyl amine scrubbing, 95%, recrystallized from toluene to a mass fraction to obtain crystals of o-chlorobenzonitrile 350.80g, yield 82%.

PATENT

https://patents.google.com/patent/US5091540A/en

Clotrimazole, i.e. 1-(o.Cl-α,α-diphenylbenzyl)imidazole, of formula: ##STR1## is a known antimycotic for human use, and a fungicide useful against plant pathogenic fungi.

Methods for its preparation are described in various patents. In particular, U.S. Pat. No. 3,929,820 describes a process starting from chlorophenyldiphenyl methylchloride and imidazole in the presence of a neutralizing agent, such as triethylamine, in a polar organic solvent. The process is strictly limited by the use, as the medium for the reaction in question, of a solvent falling within the given definition, i.e. having a dielectric constant of at least 4.5 and preferably between 15 and 50. In all the examples of the implementation of the process according to the patent in question, acetonitrile (D=37.5) is used as solvent.

EXAMPLE

900 g of benzene and 117.5 g of aluminium chloride are placed in a 2 liter flask fitted with a reflux condenser, stirrer and drying tube.

The mixture is cooled to 0° C. and a solution of 150 g of o.chlorobenzotrichloride in 150 g of benzene is added while maintaining a temperature not exceeding 15° C. The mixture is heated carefully under reflux for 4 hours. HCl is evolved.

The reaction mixture is then cooled to ambient temperature and slowly poured into 300 g of concentrated hydrochloric acid and 800 g of ice, so as not to exceed 25° C. The aqueous layer is then separated and discarded.

The benzene solution is washed with a solution of 230 g of sodium chloride in 800 g of water. The benzene phase is separated and dried over anhydrous sodium sulphate for 1 hour, and then filtered.

45 g of imidazole in 70 g of triethylamine are added to the filtrate and the mixture heated for 3 hours at 45°-50° C. It is then cooled to ambient temperature and 500 g of water are added while stirring. The aqueous layer is separated and discarded, and the benzene phase washed with 200 g of water. The benzene layer is separated and evaporated to dryness under vacuum.

The residue is dissolved in 250 g of ethyl acetate while stirring. 250 g of water are added and the solution titrated to calculate the exact quantity of nitric acid to add.

The solution is cooled to 15° C. and the calculated nitric acid quantity is quickly added. Stirring is halted when precipitation commences, and the system left until precipitation is complete.

The product is centrifuged and washed with 300 g of ethyl acetate and then with 300 g of water.

The moist product is placed into the reaction flask and 300 g of water, 450 g of methylene chloride, 5 g of triethylamine and 110 g of 30% sodium hydroxide are added. The mixture is stirred until a solution forms and the solution then left until the phases separate.

The aqueous phase is washed with 100 g of methylene chloride, and the pooled organic phases are washed twice with 200 g of water each time.

The solution in methylene chloride is treated with YMS decolorizing carbon and filtered, the filter then being washed with methylene chloride which si recovered by distillation. The residue is taken up in 100 g of acetone and redistilled to completely eliminate the methylene chloride.

The residue is taken up in 900 g of acetone and heated to 50° C. to obtain a complete solution. YMS decolorizing carbon and triethylamine are added, the mixture filtered and washed with acetone. Part of the acetone is then removed by distillation, reducing the volume to about 500 c.c. The mixture is cooled to 0° C. and, after five hours, the product is centrifuged and washed with 100 g of acetone. It is dried at 60° C., to obtain 150 g of final product.

References

  1. Jump up to:a b c d e f g h i j k l m American Society of Health-System Pharmacists (8 February 2016). “Clotrimazole Monograph for Professionals”http://www.drugs.comArchived from the original on 28 October 2016. Retrieved 28 October 2016.
  2. ^ Walker, S. R. (2012). Trends and Changes in Drug Research and Development. Springer Science & Business Media. p. 109. ISBN 9789400926592Archived from the original on 2016-09-14.
  3. ^ “WHO Model List of Essential Medicines (19th List)” (PDF)World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
  4. Jump up to:a b “Clotrimazole”International Drug Price Indicator GuideArchived from the original on 10 May 2017. Retrieved 28 October 2016.
  5. Jump up to:a b Tarascon Pharmacopoeia 2016 Professional Desk Reference Edition. Jones & Bartlett Publishers. 2016. p. 176. ISBN 9781284095302Archived from the original on 2016-10-28.
  6. Jump up to:a b “Clotrimazole: MedlinePlus Drug Information”. The American Society of Health-System Pharmacists, Inc. Archived from the original on 18 April 2014. Retrieved 17 April2014.
  7. ^ Moriarty, B; Hay, R; Morris-Jones, R (10 July 2012). “The diagnosis and management of tinea”. BMJ (Clinical research ed.)345: e4380. doi:10.1136/bmj.e4380PMID 22782730.
  8. ^ Marieb & Hoehn, (2010). Human Anatomy and Physiology, p. 643. Toronto: Pearson
  9. ^ Rodgers, Griffin. “Hydroxyurea and other disease-modifying therapies in sickle cell disease”. UpToDate. Archived from the original on 15 April 2014. Retrieved 14 April2014.
  10. Jump up to:a b “Diseases Characterized by Vaginal Discharge”. CDC. Archived from the original on 28 April 2014. Retrieved 17 April 2014.
  11. Jump up to:a b c “Clotrimazole”. DrugBank. Archived from the original on 17 April 2014. Retrieved 17 April 2014.
  12. Jump up to:a b “Clotrimazole (Oral)”. Lexicomp Online. Archived from the original on 23 January 2015. Retrieved 17 April 2014.
  13. ^ “A breakdown of the over-the-counter medicines market in Britain in 2016”. Pharmaceutical Journal. 28 April 2017. Retrieved 29 May 2017.

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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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Omadacycline tosylate


1075240-43-5.pngChemSpider 2D Image | Omadacycline tosylate | C36H48N4O10S

Image result for Omadacycline tosylate

Omadacycline tosylate

728.8521, C29H40N4O7. C7H8O3S

CAS: 1075240-43-5

389139-89-3 FREE FORM

FDA 2018/10/3, Nuzyra

オマダサイクリントシル酸塩;

UNII-5658Y89YCD

(4S,4aS,5aR,12aS)-4,7-Bis(dimethylamino)-9-{[(2,2-dimethylpropyl)amino]methyl}-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-tetracenecarboxamide 4-methylbenzenesulfonate (1:1)
1075240-43-5 [RN]
2-Naphthacenecarboxamide, 4,7-bis(dimethylamino)-9-[[(2,2-dimethylpropyl)amino]methyl]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-, (4S,4aS,5aR,12aS)-, 4-methylbenzenesulfonate (1:1) (salt)
5658Y89YCD
Amadacycline tosylate
PTK 0796 / PTK-0796
Omadacycline.svg
Omadacycline
FREE FORM, 389139-89-3 FREE FORM

Omadacycline has been used in trials studying the treatment of Bacterial Pneumonia, Bacterial Infections, Community-Acquired Infections, and Skin Structures and Soft Tissue Infections. Omadacycline represents a significant advance over the well-known tetracycline family, and has been shown to be highly effective in animal models at treating increasingly problematic, clinically prevalent infections caused by gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), and by gram-negative, atypical and anaerobic bacteria, including those resistant to currently available classes of antibiotics and known to cause diseases such as pneumonias, urinary tract infections, skin diseases and blood-borne infections in both the hospital and community settings.

Omadacycline (formerly known as PTK-0796)[1] is a broad spectrum antibiotic belonging to the aminomethylcycline subclass[2] of tetracycline antibiotics. In the United States, it was approved in October 2018 for the treatment of community-acquired bacterial pneumonia and acute skin and skin structure infections.

In vitro studies

In vitro studies have shown that omadacycline has activity against a broad range of Gram-positive and select Gram-negativepathogens.[3] Omadacycline has potent in vitro activity against Gram-positive aerobic bacteria including methicillin-resistant Staphylococcus aureus (MRSA), pencillin-resistant and multi-drug resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus. Omadacycline also has antimicrobial activity against common Gram-negative aerobes, some anaerobes, and atypical bacteria such as Legionella and Chlamydia.[4] This activity translated to potent efficacy for omadacycline in an in vivo systemic infection model in mice.[5]

Additional in vitro and in vivo studies of omadacycline metabolism, disposition, and drug interactions show that omadacycline is metabolically stable (i.e., it does not undergo significant biotransformation) and neither inhibits nor interacts with metabolizing enzymes or transporters.[6]

Mechanism of action

The mechanism of action of omadacycline is similar to that of other tetracyclines – inhibition of bacterial protein synthesis. Omadacycline has activity against bacterial strains expressing the two main forms of tetracycline resistance (efflux and ribosomal protection).[7]

Clinical trials

phase 2 study was conducted comparing the safety and efficacy of omadacycline to linezolid for the treatment of complicated skin and skin structure infections. Patients were randomized at 11 sites in the US to receive either omadacycline 100 mg intravenously once daily with an option to transition to 200 mg orally once daily or linezolid 600 mg intravenously twice daily with an option to transition to 600 mg orally twice daily. The results indicated that omadacycline is well-tolerated and has the potential to be an effective treatment in patients with complicated skin and skin structure infections.[8]

In June 2013, the US Food and Drug Administration (FDA) designated the intravenous and oral formulations of omadacycline as a qualified infectious disease product in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia.[9]

A 650 patient phase 3 registration study comparing omadacycline to linezolid for the treatment of acute bacterial skin and skin structure infections began in June 2015.[10][11]Omadacycline met the primary efficacy endpoint of early clinical response with statistical non-inferiority (10% margin) compared to linezolid, and was generally safe and well-tolerated. The most common treatment-emergent adverse events were gastrointestinal side effects (18.0% for omadacycline vs. 15.8% for linezolid).[12]

A 750 patient phase 3 study comparing omadacycline to moxifloxacin for the treatment of community-acquired bacterial pneumonia began in November 2015.[13] Omadacycline was statistically non-inferior to moxifloxacin at the early clinical response, 72 to 120 hours after therapy was initiated.[14]

In May 2016, a phase 1b study of omadacycline in urinary tract infection was initiated.[15]

In August 2016, a second phase 3 study of omadacycline was initiated in patients with acute bacterial skin and skin structure infections, comparing the efficacy and safety of once-daily, oral omadacycline to that of twice-daily, oral linezolid.[16] In July 2017, analysis of the data showed that all of the primary and secondary endpoints required for submission to the FDA and EMA were met. This was the third phase 3 registration study of omadacycline with favorable results.[17]

Discovery

Omadacycline was invented at Tufts University School of Medicine by a research team led by Mark L. Nelson with Mohamed Ismail while at Tufts and Kwasi Ohemeng and Laura Honeyman at Paratek Pharmaceuticals, Boston. The team applying their chemistry methods to the tetracycline scaffolds created over 3000 new derivatives, leading to the novel third generation compounds omadacycline and sarecycline18[18]

PAPERS

Tetrahedron Letters (2008), 49(42), 6095-6100

str1

PATENTS

WO 2009120389

WO 2009111064

WO 2017165729

WO 2018026987

WO 2018085216

SYNTHESIS BY PHARMACODIA WEBSITE

Omadacyclinewww.pharmacodia.com

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Image result for Omadacycline tosylate

REF Omadacyclinewww.pharmacodia.com

Route 3

References

  1. Jump up^ Boggs, Jennifer. “Antibiotic Firm Paratek Joins IPO Queue; Aiming for $92M”bioworld.com. Clarivate Analytics. Retrieved October 17, 2017.
  2. Jump up^ Honeyman, Laura; Ismail, Mohamed; Nelson, Mark L.; Bhatia, Beena; Bowser, Todd E.; Chen, Jackson; Mechiche, Rachid; Ohemeng, Kwasi; Verma, Atul K.; Cannon, E. Pat; MacOne, Ann; Tanaka, S. Ken; Levy, Stuart (2015). “Structure-Activity Relationship of the Aminomethylcyclines and the Discovery of Omadacycline”Antimicrobial Agents and Chemotherapy59 (11): 7044–7053. doi:10.1128/AAC.01536-15PMC 4604364PMID 26349824.
  3. Jump up^ Tanaka, S. Ken (20 June 2016). “In Vitro and In Vivo Assessment of Cardiovascular Effects with Omadacycline”Antimicrobial Agents and Chemotherapy60 (9): 5247–53. doi:10.1128/AAC.00320-16PMC 4997885PMID 27324778.
  4. Jump up^ Villano, Stephen (19 August 2016). “Omadacycline: development of a novel aminomethylcycline antibiotic for treating drug-resistant bacterial infections”Future Microbiology11: 1421–1434. doi:10.2217/fmb-2016-0100. Retrieved 24 August 2016.
  5. Jump up^ MacOne, A. B.; Caruso, B. K.; Leahy, R. G.; Donatelli, J.; Weir, S.; Draper, M. P.; Tanaka, S. K.; Levy, S. B. (February 2014). “In Vitro and in Vivo Antibacterial Activities of Omadacycline, a Novel Aminomethylcycline”Antimicrobial Agents and Chemotherapy58 (2): 1127–1135. doi:10.1128/AAC.01242-13PMC 3910882PMID 24295985.
  6. Jump up^ Flarakos, Jimmy (8 August 2016). “Clinical disposition, metabolism and in vitro drug–drug interaction properties of omadacycline”Xenobiotica: 1–15. doi:10.1080/00498254.2016.1213465.
  7. Jump up^ Draper, M. P.; Weir, S.; MacOne, A.; Donatelli, J.; Trieber, C. A.; Tanaka, S. K.; Levy, S. B. (March 2014). “Mechanism of Action of the Novel Aminomethylcycline Antibiotic Omadacycline”Antimicrobial Agents and Chemotherapy58 (3): 1279–1283. doi:10.1128/AAC.01066-13PMC 3957880PMID 24041885.
  8. Jump up^ Noel, G. J.; Draper, M. P.; Hait, H.; Tanaka, S. K.; Arbeit, R. D. (November 2012). “A Randomized, Evaluator-Blind, Phase 2 Study Comparing the Safety and Efficacy of Omadacycline to Those of Linezolid for Treatment of Complicated Skin and Skin Structure Infections”Antimicrobial Agents and Chemotherapy56 (11): 5650–5654. doi:10.1128/AAC.00948-12PMC 3486554PMID 22908151.
  9. Jump up^ “Paratek Pharmaceuticals Announces FDA Grant of Qualified Infectious Disease Product (QIDP) Designation for Its Lead Product Candidate, Omadacycline”prnewsire.com. PR Newswire. January 3, 2013. Retrieved October 17, 2017.
  10. Jump up^ Seiffert, Don (2015). “Paratek presents new trial data for antibiotic as late-stage trials continue”bizjournals.com. American City Business Journals. Retrieved October 17,2017.
  11. Jump up^ “Omadacycline Versus Linezolid for the Treatment of ABSSSI (EudraCT #2013-003644-23)”clinicaltrials.gov. Retrieved 2015-10-13.
  12. Jump up^ “Paratek Announces that Omadacycline Met All Primary and Secondary Efficacy Outcomes Designated by FDA and EMA in a Phase 3 Study in Acute Bacterial Skin Infections; Omadacycline was Generally Safe and Well-Tolerated”finance.yahoo.com. Retrieved 3 July 2016.
  13. Jump up^ “Omadacycline vs Moxifloxacin for the Treatment of CABP (EudraCT #2013-004071-13)”clinicaltrials.gov. Retrieved 2015-10-13.
  14. Jump up^ “Paratek Announces Positive Phase 3 Study of Omadacycline in Community-Acquired Bacterial Pneumonia”http://www.globenewswire.com. April 3, 2017. Retrieved 16 May 2017.
  15. Jump up^ “Paratek Initiates Phase 1b Study of Omadacycline in Urinary Tract Infection”globenewswire.com. May 2, 2016. Retrieved 3 July 2016.
  16. Jump up^ “Paratek Initiates Phase 3 Study of Oral-only Omadacycline in ABSSSI”globenewswire.com. August 15, 2016. Retrieved 15 August 2016.
  17. Jump up^ “Paratek Announces Phase 3 Study of Oral-Only Dosing of Omadacycline Met All Primary and Secondary FDA and EMA Efficacy Endpoints in Acute Bacterial Skin Infections”http://www.globenewswire.com. July 17, 2017. Retrieved 19 July 2017.
  18. Jump up^ Ref: Mark L. Nelson and Kwasi Ohemeng: 4-dedimethylamino tetracycline compounds, United States (US) patent number 7,056,902 (2006)
Omadacycline
Omadacycline.svg
Clinical data
Trade names Nuzyra
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C29H40N4O7
Molar mass 556.66 g·mol−1
3D model (JSmol)

/////////////FDA 2018, Nuzyra, Omadacycline tosylate, Omadacycline, オマダサイクリントシル酸塩 ,PTK-0796, PTK 0796

CC1=CC=C(C=C1)S(O)(=O)=O.[H][C@@]12CC3=C(C=C(CNCC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@]1([H])C2)N(C)C

Golvatinib, ゴルバチニブ


Golvatinib.png

ChemSpider 2D Image | Golvatinib | C33H37F2N7O4

Golvatinib

E-7050, cas 928037-13-2

1-N’-[2-fluoro-4-[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]pyridin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

1,1-Cyclopropanedicarboxamide, N-[2-fluoro-4-[[2-[[[4-(4-methyl-1-piperazinyl)-1-piperidinyl]carbonyl]amino]-4-pyridinyl]oxy]phenyl]-N’-(4-fluorophenyl)- [ACD/Index Name]
516Z3YP58E
928037-13-2 [RN]
9565
E7050, ゴルバチニブ
Molecular Formula: C33H37F2N7O4
Molecular Weight: 633.701 g/mol
  • N’-[2-fluoro-4-[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]pyridin-4-yl]oxyphenyl]-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
    UNII:516Z3YP58E
  • Originator Eisai Co Ltd

  • Class Amides; Antineoplastics; Cyclopropanes; Fluorobenzenes; Piperazines; Piperidines; Pyridines; Small molecules
  • Mechanism of Action Angiogenesis inhibitors; Proto oncogene protein c met inhibitors; Vascular endothelial growth factor receptor-2 antagonists
  • Discontinued Gastric cancer; Glioblastoma; Head and neck cancer; Liver cancer; Malignant melanoma; Solid tumours
  • 15 Nov 2013Eisai completes enrolment in its phase Ib/II trial for Head and neck cancer (second-line combination therapy, late-stage disease) in USA, United Kingdom, South Korea & Ukraine (NCT01332266)
  • 14 Nov 2013Phase-I/II clinical trials in liver cancer (first-line combination therapy, late-stage disease) in Italy & Ukraine (PO)
  • 01 Jul 2013Eisai completes a phase I trial in Solid tumours in Japan (NCT01428141)

Golvatinib is an orally bioavailable dual kinase inhibitor of c-Met (hepatocyte growth factor receptor) and VEGFR-2 (vascular endothelial growth factor receptor-2) tyrosinekinases with potential antineoplastic activity. c-Met/VEGFR kinase inhibitor E7050 binds to and inhibits the activities of both c-Met and VEGFR-2, which may inhibit tumor cell growth and survival of tumor cells that overexpress these receptor tyrosine kinases. c-Met and VEGFR-2 are upregulated in a variety of tumor cell types and play important roles in tumor cell growth, migration and angiogenesis.

Golvatinib has been investigated for the treatment of Platinum-Resistant Squamous Cell Carcinoma of the Head and Neck.
PATENT
WO 2007023768
WO 2008023698
WO 2008102870
PATENT
WO 2012133416

Method for producing a phenoxy pyridine derivative (3)

The present invention, hepatocyte growth factor receptor (Hepatocyte growth factor receptor; hereinafter, abbreviated as “HGFR”) inhibitory action, antitumor action, anti-tumor agents with such angiogenesis inhibitory activity and cancer metastasis inhibitory action, a cancer metastasis suppressing the method for producing a useful phenoxy pyridine derivatives as agents.

Patent Document 1 has a HGFR inhibitory activity, anti-tumor agents, useful phenoxy pyridine derivative as an angiogenesis inhibitor or cancer metastasis inhibitor has been disclosed.

Figure JPOXMLDOC01-appb-C000004


(In the formula, R 1, .R 2 and R 3 means such as 3-10 membered non-aromatic heterocyclic group, .R 4, R 5, R 6 and R 7 which represents a hydrogen atom, same or different, a hydrogen atom, a halogen atom, .R 8 to mean a C 1-6 alkyl group, .R 9 to mean a hydrogen atom or the like is and 3-10 membered non-aromatic heterocyclic group meaning .n is .X to mean 1 to 2 integer, it refers to a group or a nitrogen atom represented by the formula -CH =.)

As a method for producing the phenoxy pyridine derivative, to the Example 48 of Patent Document 1, N, N-dimethylformamide, triethylamine and benzotriazol-1-yloxytris (dimethylamino) or lower in the presence of a phosphonium hexafluorophosphate discloses that perform the reaction.

Figure JPOXMLDOC01-appb-C000005

Patent Document 2, as a manufacturing method suitable for industrial mass synthesis of the phenoxy pyridine derivative in the presence a condensing agent, production method of reacting an aniline derivative with a carboxylic acid derivative.

Figure JPOXMLDOC01-appb-C000006


(In the formula, R 1, is .R 2, R 3, R 4 and R 5, which means such good azetidin-1-yl group which may have a substituent, the same or different and each represents a hydrogen atom or fluorine It refers to an atom .R 6 means a hydrogen atom or a fluorine atom.)

Patent Document 3, another manufacturing method of the phenoxy pyridine derivative, there is disclosed the manufacturing method shown in the following scheme.

Figure JPOXMLDOC01-appb-C000007


(In the formula, R 1 means a 4- (4-methylpiperazin-1-yl) piperidin-1-yl group or a 3-hydroxy-1-yl group .R 2, R 3, R 4 and R 5 are the same or different, represents a hydrogen atom or a fluorine atom. However, among R 2, R 3, R 4 and R 5, 2 or 3 is a hydrogen atom .R 6 is a hydrogen atom or .R 7 to mean a fluorine atom, .Ar which means a protecting group for the amino group means a phenyl group.)

International Publication No. WO 2007/023768 International Publication No. WO 2008/026577 International Publication No. WO 2009/104520

PATENT
WO 2009104520
Example A-5: Preparation of N- (2-fluoro-4 – {[2 – ({[4- (4-methylpiperazin- 1 –yl) piperidin- 1 – yl] carbonyl} amino) pyridin- oxy} phenyl) -N ‘- (4-fluorophenyl) cyclopropane-1,1 dicarboxamide
[Formula
17] 4- (4-methylpiperazin-1-yl) piperidine-1-carboxylic acid [4- ( To a solution of N, N-dimethylformamide (1 ml) of 4-amino-3-fluorophenoxy) pyridin-2-yl] amide (100 mg) and 1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (78 mg) Triethylamine (71 mg) and O- (7-Azabenzotriazol-1-yl) -N, N, N ‘, N’- tetramethyluronium hexafluorophosphate (HATU) (222 mg) were added and stirred at room temperature for 21 hours. A 1 N sodium hydroxide aqueous solution (2 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 ml). After separation, the organic layer was washed with 5% brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a residue. The residue was dissolved in ethyl acetate (3 ml) and extracted with 2 N hydrochloric acid (3 ml × 1, 2 ml × 1). The aqueous layer was rendered alkaline with 5 N aqueous sodium hydroxide solution (5.5 ml). After extraction with ethyl acetate and drying over anhydrous magnesium sulfate, the solvent was distilled off to give the title compound (87 mg).
1 H-NMR Spectrum (DMSO-d 6) .Delta. (Ppm): 1.22-1.33 (2H, m), 1.54-1.63 (4H, m), 1.68-1.78 (2H, m), 2.12 (3H , S), 2.12-2.40 (5H, m), 2.40-2.60 (4H, m), 2.68-2.78 (2H, m), 4.06-4.14 (2H, t, J = 8 Hz), 7.22 (2H, m), 6.60 (1H, dd, J = 2.4 Hz, 5.6 Hz), 7.00 (1 H, dd, J = 2.4 Hz, 11.2 Hz), 7.40 (1 H, s), 7.61 (2 H, dd, J = 5.2 Hz, 8 Hz), 7.93 J = 8.8 Hz), 8.13 (1 H, d, J = 5.6 Hz), 9.21 (1 H, s), 9.90 (1 H, brs), 10.55 (1 H, brs).

PAPER
Journal of Medicinal Chemistry (2017), 60(7), 2973-2982
Patent ID

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///////////////Golvatinib, phase 2, ゴルバチニブ  ,

CN1CCN(CC1)C2CCN(CC2)C(=O)NC3=NC=CC(=C3)OC4=CC(=C(C=C4)NC(=O)C5(CC5)C(=O)NC6=CC=C(C=C6)F)F

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I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP