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VOXELOTOR

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VOXELOTOR

GBT 440; GTx-011, Treatment of Sickle Cell Disease

RN: 1446321-46-5
UNII: 3ZO554A4Q8

Molecular Formula, C19-H19-N3-O3, Molecular Weight, 337.3771

Benzaldehyde, 2-hydroxy-6-((2-(1-(1-methylethyl)-1H-pyrazol-5-yl)-3-pyridinyl)methoxy)-

2-hydroxy-6-((2-(1-(propan-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde

NMR http://file.selleckchem.com/downloads/nmr/S854001-GBT440-CDCl3-hnmr-selleck.pdf

Originator Global Blood Therapeutics
Class Antianaemics; Small molecules
Mechanism of Action Abnormal haemoglobin modulators; Sickle haemoglobin modulators

Orphan Drug Status Yes – Sickle cell anaemia
New Molecular Entity Yes

Highest Development Phases

Phase III Sickle cell anaemia
Phase I Hypoxia; Liver disorders
Discontinued Idiopathic pulmonary fibrosis

Most Recent Events

01 Nov 2017 Chemical structure information added
28 Oct 2017 Efficacy and adverse event data from a case study under the compassionate use programme in Sickle cell anaemia released by Global Blood Therapeutics
27 Oct 2017 Discontinued – Phase-II for Idiopathic pulmonary fibrosis in USA (PO)

Voxelotor, also known as GBT-440, is a hemoglobin S allosteric modulator. GBT440 Inhibits Sickling of Sickle Cell Trait Blood Under In Vitro Conditions Mimicking Strenuous Exercise. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease.

Treatment Of Sickle Cell Disease In Adults And Adolescents With Episodes Of Vaso-Occlusive Crisis

FDA gave breakthrough therapy designation to this product

Innovator – Global Blood Therapeutics

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PATENT

WO 2013102142

Inventors	Brian Metcalf, Chihyuan Chuang, Jeffrey Warrington, Kumar PAULVANNAN, Matthew P. Jacobson, Lan HUA, Bradley Morgan
Applicant	Global Blood Therapeutics, Inc., Cytokinetics, Inc., The Regents Of The University Of California

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013102142

Hemoglobin (Hb) is a tetrameric protein in red blood cells that transports up to four oxygen molecules from the lungs to various tissues and organs throughout the body.

Hemoglobin binds and releases oxygen through conformational changes, and is in the tense (T) state when it is unbound to oxygen and in the relaxed (R) state when it is bound to oxygen. The equilibrium between the two conformational states is under allosteric regulation. Natural compounds such as 2,3-bisphosphoglycerate (2,3-BPG), protons, and carbon dioxide stabilize hemoglobin in its de-oxygenated T state, while oxygen stabilizes hemoglobin in its oxygenated R state. Other relaxed R states have also been found, however their role in allosteric regulation has not been fully elucidated.

Sickle cell disease is a prevalent disease particularly among those of African and Mediterranean descent. Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, allowing the T state to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape. The sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels. Certain synthetic aldehydes have been found to shift the equilibrium from the polymer forming T state to the non-polymer forming R state (Nnamani et al. Chemistry & Biodiversity Vol. 5, 2008 pp. 1762-1769) by acting as allosteric modulators to stabilize the R state through formation of a Schiff base with an amino group on hemoglobin.

US 7, 160,910 discloses 2-furfuraldehydes and related compounds that are also allosteric modulators of hemoglobin. One particular compound 5-hydroxymethyl-2-furfuraldehyde (5HMF) was found to be a potent hemoglobin modulator both in vitro and in vivo. Transgenic mice producing human HbS that were treated with 5HMF were found to have significantly improved survival times when exposed to extreme hypoxia (5% oxygen). Under these hypoxic conditions, the 5HMF treated mice were also found to have reduced amounts of hypoxia-induced sickled red blood cells as compared to the non-treated mice.

A need exists for therapeutics that can shift the equilibrium between the deoxygenated and oxygenated states of Hb to treat disorders that are mediated by Hb or by abnormal Hb such as HbS. A need also exists for therapeutics to treat disorders that would benefit from having Hb in the R state with an increased affinity for oxygen. Such therapeutics would have applications ranging, for example, from sensitizing hypoxic tumor cells that are resistant to standard radiotherapy or chemotherapy due to the low levels of oxygen in the cell, to treating pulmonary and hypertensive disorders, and to promoting wound healing

Example 18. Preparation of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (Compound 43).

A mixture of 2,6-dihydroxybenzaldehyde (1.58 g, 11.47 mmol, 2 eq.) and K₂CO₃ (2.4 g, 17.22 mmol, 3 eq.) in DMF (150 mL) was stirred at rt for 10 min. To this mixture was added 3-(chloromethyl)-2-(1-isopropyI-1H-pyrazol-5-yl)pyridine hydrochloride (1.56 g, 5.74 mmol, leq.) at rt. The mixture was heated at 50 °C for 2 h, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (1.71 g, 88%) as a pale yellow solid.

PAPER

ACS Medicinal Chemistry Letters (2017), 8(3), 321-326.

http://pubs.acs.org/doi/full/10.1021/acsmedchemlett.6b00491

Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin

Brian Metcalf^†, Chihyuan Chuang^‡, Kobina Dufu^†, Mira P. Patel^†, Abel Silva-Garcia^†, Carl Johnson^†, Qing Lu^‡, James R. Partridge^†, Larysa Patskovska^∥, Yury Patskovsky^∥, Steven C. Almo^∥, Matthew P. Jacobson^¶

, Lan Hua^¶, Qing Xu^†, Stephen L. Gwaltney II^†, Calvin Yee^†, Jason Harris^†, Bradley P. Morgan^‡, Joyce James^‡, Donghong Xu^‡, Athiwat Hutchaleelaha^†, Kumar Paulvannan^§, Donna Oksenberg^†, and Zhe Li ^*^†

^† Global Blood Therapeutics, Inc., South San Francisco, California 94080, United States

^‡ Cytokinetics, Inc., South San Francisco, California 94080, United States

^∥ Albert Einstein College of Medicine, Bronx, New York 10461, United States

^¶ Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, United States

^§ Tandem Sciences, Inc., Menlo Park, California 94025, United States

ACS Med. Chem. Lett., 2017, 8 (3), pp 321–326

DOI: 10.1021/acsmedchemlett.6b00491

*E-mail: zli@globalbloodtx.com.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1:1 stoichiometry. Compound 36 is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ∼150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 (36) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).

Scheme 1. Synthesis of 36^a

^aReagents and conditions: (a) MOMCl, DIEPA, DCM, 0 °C to rt 2 h, 90%; (b) nBuLi, DMF, THF, −78 to 0 °C, 94%; (c) 12 N HCl, THF, rt, 1.5 h, 81%; (d) Pd(dppf)Cl₂, NaHCO₃, H₂O/dioxane, 100 °C, 12 h, 40%; (e) SOCl₂, DCM, rt, 100%; (f) Na₂CO₃, DMF, 65 °C, 1.5 h, 81%; (g) 12 N HCl, THF, rt, 3 h, 96%.

GBT440 (36) (15.3 g).

HRMS calcd for C19H20N3O3 (M+H + ) 338.1499, found 338.1497; MS (ESI) m/z 338.4 [M+H]+ ;

1H NMR (400 MHz, Chloroform-d) δ 11.94 (s, 1H), 10.37 (d, J = 0.6 Hz, 1H), 8.75 (dd, J = 4.8, 1.7 Hz, 1H), 7.97 (dd, J = 7.8, 1.6 Hz, 1H), 7.63 – 7.57 (m, 1H), 7.46 – 7.33 (m, 2H), 6.57 (dt, J = 8.6, 0.7 Hz, 1H), 6.34 (d, J = 1.9 Hz, 1H), 6.27 (dt, J = 8.3, 1.0 Hz, 1H), 5.07 (s, 2H), 4.65 (hept, J = 6.6 Hz, 1H), 1.47 (d, J = 6.6 Hz, 7H);

13C NMR (101 MHz, DMSO-d6) δ 194.0, 162.9, 161.1, 149.6, 149.1, 139.1, 138.2, 138.2, 138.0, 131.6, 124.0, 111.1, 110.2, 107.4, 103.5, 67.8, 50.5, 23.1.

http://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00491/suppl_file/ml6b00491_si_001.pdf

PATENT

WO 2015031285

https://www.google.co.in/patents/WO2015031285A1?cl=en

2-Hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde is a compound having the formula:

Sickle cell disease is a disorder of the red blood cells, found particularly among those of African and Mediterranean descent. The basis for sickle cell disease is found in sickle hemoglobin (HbS), which contains a point mutation relative to the prevalent peptide sequence of hemoglobin (Hb).

[ Hemoglobin (Hb) transports oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through

conformational changes. Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, allowing HbS to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape. The sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels. A need exists for therapeutics that can treat disorders that are mediated by Hb or by abnormal Hb such as HbS, such as 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde hydrochloride.

When used for treating humans, it is important that a crystalline form of a therapeutic agent, like 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, or a salt thereof, retains its polymorphic and chemical stability, solubility, and other physicochemical properties over time and among various manufactured batches of the agent. If the physicochemical properties vary with time and among batches, the administration of a therapeutically effective dose becomes problematic and may lead to toxic side effects or to ineffective therapy, particularly if a given polymorph decomposes prior to use, to a less active, inactive, or toxic compound. Therefore, it is important to choose a form of the crystalline agent that is stable, is manufactured reproducibly, and has physicochemical properties favorable for its use as a therapeutic agent.

Figure imgf000016_0001

Example ί : Synthesis of Compound 15

OH DIPEA OMOM

(8063J To s solution of 2 >ronao enzsae-i -diol (5 g, 26.45 m ol) m. DCM (50 ml) at 0 *C was added DIPEA (11.54 mL, 66.13 aan l) and MOMCi (4.42 mL. 58.19 ratnoi). The mixture was stirred at 0 °C for 1.5 h, and then warmed to room temperature. The so ntioa was dilated with DCM, washed with sat. NaH€<¾, brum dried and concentrated to give crude product, which was purified by coinran ihexane&/EtOAc^~4;l) to give desired product 15.58 g (90%).

14C

Example 2: Synthesis of Compound 13 from 15

Figure imgf000018_0001

[0064] To a solution of 2-bromo-l ,3-bis(methoxymethoxy)benzene (15) (19.9g, 71.8 mmol) in THF (150 mL) at -78 °C was added BuLi (2.5 M, 31.6 mL, 79.0 mmol) dropwise. The solution was stirred at -78 °C for 25 min (resulting white cloudy mixture), then it was warmed to 0 °C and stirred for 25 min. The reaction mixture slowly turns homogenous. To the solution was added DMF at 0 °C. After 25 min, HPLC showed reaction completed. The mixture was quenched with sat. NH4C1 (150 mL), diluted with ether (300 mL). The organic layer was separated, aq layer was further extracted with ether (2X200 mL), and organic layer was combined, washed with brine, dried and concentrated to give crude product, which was triturated to give 14.6 g desired product. The filtrate was then concentrated and purified by column to give additional 0.7 g, total mass is 15.3 g.

Example 3: Synthesis of Compound 13 from resorcinol 11

1.1 R:TMEDA R:BuLi S:THF 2 h -10°C

Figure imgf000018_0002

Journal of Organic Chemistry, 74(1 1), 431 1-4317; 2009

[0065] A three-necked round-bottom flask equipped with mechanical stirrer was charged with 0.22 mol of NaH (50 % suspension in mineral oil) under nitrogen atmosphere. NaH was washed with 2 portions (100 mL) of n-hexane and then with 300 mL of dry diethyl ether; then 80 mL of anhydrous DMF was added. Then 0.09 mol of resorcinol 11, dissolved in 100 mL of diethyl ether was added dropwise and the mixture was left under stirring at rt for 30 min. Then 0.18 mol of MOMCI was slowly added. After 1 h under stirring at rt, 250 mL of water was added and the organic layer was extracted with diethyl ether. The extracts were

15A

washed with brine, dried (Na₂S0₄), then concentrated to give the crude product that was purified by silica gel chromatography to give compound 12 (93 % yield).

15B

[0066] A three-necked round-bottom flask was charged with 110 mL of n-hexane, 0.79 mol of BuLi and 9.4 mL of tetramethylethylendiamine (TMEDA) under nitrogen atmosphere. The mixture was cooled at -10 °C and 0.079 mol of bis-phenyl ether 12 was slowly added. The resulting mixture was left under magnetic stirring at -10 °C for 2 h. Then the temperature was raised to 0 °C and 0.067 mol of DMF was added dropwise. After 1 h, aqueous HC1 was added until the pH was acidic; the mixture was then extracted with ethyl ether. The combined extracts were washed with brine, dried (Na₂S0₄), and concentrated to give aldehyde 13

(84%).

[0067] 2,6-bis(methoxymethoxy)benzaldehyde (13): mp 58-59 °C (n-hexane) ; IR (KBr) n: 1685 (C=0) cm^“1; 1H-NMR (400 MHz, CDC1₃) δ 3.51 (s, 6H, 2 OCH₃), 5.28 (s, 4H, 2 OCH₂0), 6.84 (d, 2H, J = 8.40 Hz, H-3, H-5), 7.41 (t, 1H, J = 8.40 Hz, H-4), 10.55 (s, 1H, CHO); MS, m/e (relative intensity) 226 (M+, 3), 180 (4), 164 (14), 122 (2), 92 (2), 45 (100); Anal. Calc’d. for CnHi₄0₅: C,58.40; H, 6.24. Found: C, 57.98; H, 6.20.

Example 4: The Synthesis of Compound 16

Figure imgf000020_0001

13 16

81 %

[0068] To a solution of 2,6-bis(methoxymethoxy)benzaldehyde (13) (15.3 g, 67.6 mmol) in THF (105 mL) (solvent was purged with N₂) was added cone. HC1 (12N, 7 mL) under N₂, then it was further stirred under N₂ for 1.5 h. To the solution was added brine (100 mL) and ether (150 ml). The organic layer was separated and the aqueous layer was further extracted with ether (2×200 mL). The organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (300g,

hexanes/EtOAc=85: 15) to give desired product 16 (9.9 g) as yellow liquid.

Example 5: Synthesis of Compound 17

Figure imgf000020_0002

[0069] To a solution of 2-hydroxy-6-(methoxymethoxy)benzaldehyde (16) (10.88 g, 59.72 mmol) in DMF (120 mL) (DMF solution was purged with N₂ for 10 min) was added K₂C0₃ (32.05 g, 231.92 mmol) and 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine hydrochloride (10) (15.78 g, 57.98 mmol). The mixture was heated at 65 °C for 1.5 h, cooled to rt, poured into ice water (800 mL). The precipitated solids were isolated by filtration, dried and concentrated to give desired product (17, 18 g).

Example 6: Synthesis of Compound (I)

Figure imgf000021_0001

[0070] To a solution of 2-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-(methoxymethoxy)benzaldehyde (17) (18 g, 47.19 mmol) in THF (135 mL, solution was purged with N₂) was added cone. HCI (12N, 20 mL). The solution was stirred at rt for 3 h when HPLC showed the reaction complete. The mixture was added to a solution of NaHC0₃ (15 g) in water (1.2 L), and the resulting precipitate was collected by filtration, dried to give crude solid, which was further purified by column (DCM/EtOAc=60:40) to give pure product

(15.3 g).

Example 7: Synthesis of Compound I (free base) and its HCI salt form

[0071] Compound (I) free base (40g) was obtained from the coupling of the alcohol intermediate 7 and 2,6-dihydroxybenzaldedhye 9 under Mitsunobu conditions. A procedure is also provided below:

Figure imgf000021_0002

Example 8: Synthesis of Compound (I) by Mitsunobu coupling

[0072] Into a 2000-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of [2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-yl]methanol (7) (70 g, 322.18 mmol, 1.00 equiv) in tetrahydrofuran (1000 mL). 2,6-Dihydroxybenzaldehyde (9) (49.2 g, 356.21 mmol, 1.10 equiv) and PPh₃ (101 g, 385.07 mmol, 1.20 equiv) were added to the reaction mixture. This was followed by the addition of a solution of DIAD (78.1 g, 386.23 mmol, 1.20 equiv) in tetrahydrofuran (200 ml) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 500 ml of H₂0. The resulting solution was extracted with 3×500 ml of dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EA:PE (1 :50-l :3) as eluent to yield the crude product. The crude product was re-crystallized from i-propanol/H₂0 in the ratio of 1/1.5. This resulted in 40 g (37%) of 2-hydroxy-6-([2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-yl]methoxy)benzaldehyde as a light yellow solid. The compound exhibited a melting point of 80-82 °C. MS (ES, m/z): 338.1 [M+l]. 1H NMR (300 MHz, DMSO-d6) δ 11.72(s, 1H), 10.21(s, 1H), 8.76(d, J=3.6Hz, 1H), 8.24(d, J=2.7Hz, lH),7.55(m, 3H), 6.55(m,3H) ,5.21 (s, 2H), 4.65 (m, 1H), 1.37 (d, J=5.1Hz, 6H). 1H NMR (400 MHz, CDC1₃) δ 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J= 4.8, 1.5 Hz, 1H), 8.00 (d, J= 7.8 Hz, 1H), 7.63 (d, J= 1.8 Hz, 1H), 7.49 – 7.34 (m, 2H), 6.59 (d, J= 8.5 Hz, 1H), 6.37 (d, J= 1.8 Hz, 1H), 6.29 (d, J= 8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J= 6.7 Hz, 1H), 1.50 (d, J= 6.6 Hz, 6H).

[0073] In another approach, multiple batches of Compound (I) free base are prepared in multi gram quantities (20g). The advantage of this route is the use of mono-protected 2,6-dihydroxybenzaldehyde (16), which effectively eliminates the possibility of bis-alkylation side product. The mono-MOM ether of 2,6-dihydroxybenzaldehyde (16) can be obtained from two starting points, bromoresorcinol (14) or resorcinol (11) [procedures described in the Journal of Organic Chemistry, 74(11), 4311-4317; 2009 ]. All steps and procedures are provided below. Due to the presence of phenolic aldehyde group, precautions (i.e., carry out all reactions under inert gas such as nitrogen) should be taken to avoid oxidation of the phenol and/or aldehyde group.

Preparation of compound I HC1 salt: A solution of compound I (55.79 g, 165.55 mmol) in acetonitrile (275 mL) was flushed with nitrogen for 10 min, then to this solution was added 3N aqueous HC1 (62 mL) at room temperature. The mixture was stirred for additional 10 min after the addition, most of the acetonitrile (about 200 mL) was then removed by evaporation on a rota

PATENT

WO2017096230

PATENT

WO-2017197083

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017197083

Processes for the preparation of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (also referred to as voxelotor or Compound (I)) and its intermediates is claimed. Compound (I) binds to hemoglobin and increases it oxygen affinity and hence can be useful for the treatment of diseases such as sickle cell disease.

Disclosed herein are processes for synthesizing 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (Compound (I)) and intermediates used in such processes. Compound (I) binds to hemoglobin and increases it oxygen affinity and hence can be useful for the treatment of diseases such as sickle cell disease.

BACKGROUND

Compound (I) is disclosed in Example 17 of the International Publication No.

WO2013/102142. Compound (I) binds to hemoglobin and increases it oxygen affinity and hence can be useful for the treatment of diseases such as sickle cell disease.

In general, for a compound to be suitable as a therapeutic agent or part of a therapeutic agent, the compound synthesis must be amendable to large scale manufacturing and isolation. The large scale manufacturing and isolation should not impact the physical properties and purity of the compound nor should it negatively impact cost or efficacy of a formulated active ingredient. Accordingly, scale up of manufacturing and isolation may require significant efforts to meet these goals.

ompound (I) has been synthesized by certain methods starting with 2,6-dihydroxbenzaldehyde (compound 1) where each hydroxyl moiety is protected with an unbranched, straight-chain alkyl or alkoxyalkyl such as, for example, methyl or methoxymethyl. Following installation of the aldehyde group, various methods of deprotection of the hydroxyl group were employed to synthesize compound (1) used in the synthesis and production of Compound (I). However, the deprotection processes used lead to unwanted polymerization and decomposition reactions of compound (1) – attributed, in part, to the conditions used for

deprotection of the hydroxy groups. The undesired byproducts yield complex mixtures, lower yields of Compound (I), and require significant effort to purify Compound (I) to a degree acceptable for use as a part of a therapeutic agent, thus rendering the above processes impractical for commercial scale synthesis of Compound (I).

Provided herein are processes for the synthesis of Compound (I):

Examples

Example 1

Synthesis of 2,6-dihydroxybenzaldehyde (Compound (1))

Step 1:

Tetrahydrofuran (700 mL) was added to resorcinol (170g, 1.54 mol, leq.) under inert gas protection, followed by addition of pyridinium tosylate (3.9 g, 15.4 mmol, O.Oleq.), THF 65 mL) and the reaction mixture was cooled down to 0 – 5 °C. Within 1 – 1.5 h ethylvinyl ether (444 mL, 4.63 mol, 3.0 eq.) was added while maintaining a temperature <5°C. After the addition was complete the reaction mixture was allowed to reach room temperature within 1.5 h. The reaction was stirred overnight, cooled down to 10-15 °C, and 510 mL of ½ sat. NaHC0₃ was added while maintaining the reaction solution below 20 °C. The phases were separated. The organic phase was washed once with 425 mL of water and once with 425 mL 12.5% NaCl solution and evaporated and azeotroped with THF to give bis-EOE-protected resorcinol (401.2 g, 1.55 mol, 102% uncorrected) as a clear colorless to yellowish oil.

Step 2:

Bis-EOE-protected resorcinol (390 g of, actual: 398.6g = 1.53 mol, 1 eq., corrected to 100%) conversion) was added under inert gas protection to a 6 L glass vessel and THF (1170 mL) was added. The reaction mixture was cooled down to -10°C to -5°C and n-BuLi (625 mL, 2.7 M in heptane, 1.687 mol, 1.1 eq.) was added. The reaction mixture was agitated at -5°C- 0°C for 30-40 min and then DMF (153.4 mL, 1.99 mmol, 1.3 eq.) was added starting at -10°C to -5°C. The reaction mixture was stirred until complete and then quenched with lNHCl/EtOAc. It was also discovered, inter alia, that protection with the EOE groups not only resulted in less byproducts but appeared to increase the speed of the formylation reaction to provide 2,6-bis(l-ethoxyethoxy)benzaldehyde (compound (2)).

The mixture was worked up, phase separated and the aqueous washed with MTBE. After aqueous wash to remove salts the organic phase was concentrated to the neat oil to obtain the compound (2) as yellow oil (almost quantitative).

A batch preparation was performed using solvent swap and was completed faster than other known methods for synthesizing Compound (I) with better purity and yield. The deprotection sequence allowed in-situ use of compound (2).

Step 3:

To the reaction solution of Step 2 was added IN HC1 (1755 mL) while maintaining the temperature < 20°C. The pH was of the solution was adjusted to pH = 0.7 – 0.8 with 6 M HC1.

The reaction mixture was stirred for 16 h. After the reaction was complete the organic phase was separated and 1560 mL of methyl tert butyl ether was added. The organic phase was washed once with 1170 mL of IN HC1, once with 780 mL of ½ sat. NaCl solution and once with 780 mL of water and then concentrated to a volume of – 280mL. To the solution was added 780 mL of methyl tert butyl ether and concentrate again to 280 mL [temperature <45°C, vacuo]. To the slurry was added 780 mL of acetonitrile and the solution was concentrated in vacuo at T < 45°C to a final volume of – 280 mL. The slurry was heated to re-dissolve the solids. The solution was cooled slowly to RT and seeded at 60-65 °C to initiate crystallization of the product. The slurry was cooled down to -20°C to -15°C and agitated at this temperature for 1-2 h. The product was isolated by filtration and washed with DCM (pre-cooled to -20°C to -15°C) and dried under a stream of nitrogen to give 2,6-dihydroxybenzaldehyde as a yellow solid. Yield: 138.9 g (1.00 mol, 65.6%).

Example 1A

Alternate Synthesis of 2,6-dihydroxybenzaldehyde compound (1)

Step 1:

In a suitable reactor under nitrogen, tetrahydrofuran (207 L) was added to resorcinol (46 kg, 0.42 kmol, leq.) followed by addition of pyridinium tosylate (1.05 kg, 4.2 mol, O.Oleq.), and the reaction mixture was cooled down to 0 – 5 °C. Within 1 – 1.5 h ethylvinyl ether (90.4 kg, 120.5 L, 125 kmol, 3.0 eq.) was added while maintaining a temperature <5°C. After the addition was complete the reaction mixture was allowed to reach room temperature within 1.5 h. The reaction was stirred overnight, cooled down to 10-15 °C, and 138 L of aqueous 4% NaHC0₃ was added while maintaining the reaction solution below 20 °C. The phases were separated. The organic phase was washed once with 115 L of water and once with 125.2 kg of a 12.5% NaCl solution. The organic layer was dried by azeotropic distillation with THF to a water content value < 0.05%) (by weight) to yield bis-EOE-protected resorcinol (106.2 kg, 0.42 kmol) as a solution in THF. An advantage over previously reported protection procedures is that the bis-EOE-protected resorcinol product does not need to be isolated as a neat product. The

product-containing THF solution can be used directly in the next reaction step thus increasing throughput and reducing impurity formation.

Step 2:

Bis-EOE-protected resorcinol solution (assumption is 100% conversion) was added under inert gas protection to suitable reactor. The reaction mixture was cooled down to -10°C to -5°C and n-BuLi (117.8 kg, 25% in heptane, 1.1 eq.) was added. The reaction mixture was agitated at -5°C- 0°C for 30-40 min and then DMF (39.7 kg, 0.54 kmol, 1.3 eq.) was added at -10°C to -5°C. The reaction mixture was stirred until complete and then quenched with aqueous HC1 (1M, 488.8 kg) to give 2,6-bis(l-ethoxyethoxy)benzaldehyde. An advantage over previously reported procedures of using EOE protecting group is that the HC1 quenched solution can be used directly in the deprotection step, and 2,6-bis(l-ethoxyethoxy)benzaldehyde does not need to be isolated as a neat oil.

Step 3:

The pH of the quenched solution was adjusted to < 1 with aqueous HC1 (6M, ca 95.9 kg) and the reaction mixture stirred at ambient temperature for 16 h. After the reaction was complete the organic phase was separated and 279.7 kg of methyl tert butyl ether was added. The organic phase was washed once with aqueous IN HC1 (299 kg), once with aqueous 12.5% NaCl (205.8 kg) and once with 189 kg of water and then concentrated to a volume of ca. 69 L. To the slurry was added 164 kg of acetonitrile and the solution was concentrated in vacuo at T < 45°C to a final volume of ca. 69 L. The slurry was heated to re-dissolve the solids. The solution was seeded at 60-65 °C to initiate crystallization of the product and cooled slowly to RT over 8 hrs. The slurry was cooled down to -20 °C to -15°C and agitated at this temperature for l-2h. The product was isolated by filtration and washed with DCM (50.3 kg, pre-cooled to -20 °C to -15 °C) and dried under a stream of nitrogen to yield 2,6-dihydroxybenzaldehyde as a yellow solid. Yield: 37.8 kg (0.27 kmol, 65.4% Yield). The described telescoped approach from deprotection to crystallization increases the throughput and integrity of the product.

Example 2

Synthesis of 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine

dihydrochloride salt

Step 1:

An appropriately sized flask was purged with nitrogen and charged with (2-chloropyridin-3-yl)methanol (1.0 equiv), sodium bicarbonate (3.0 equiv), [1, l ‘-bis(diphenyl-phosphino)-ferrocene]dichloropalladium (5 mol %), l-isopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.2 equiv), and a mixture of 2-MeTHF (17.4 vol) and deionized water (5.2 vol). The resulting solution was heated to 70°C to 75°C and conversion monitored by HPLC. Once the reaction was complete, the reaction mixture was cooled to room temperature, diluted with deionized water, and the phases were separated. The organic layer was extracted with 2 N HC1 (10 vol) and the phases were separated. The aqueous phase was washed with MTBE. The pH of the aqueous phase was adjusted to 8-9 with 6 N NaOH. The product was extracted into EtOAc, treated with Darco G-60 for 30 to 60 min, dried over MgS0₄, filtered through Celite®, and concentrated to give (2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol as a brown oil.

Step 2:

A suitably equipped reactor was charged with (2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol hydrochloride salt (1 equivalent) and purified water. An aqueous sodium

bicarbonate solution (8% NaHC0₃) was added slowly to maintain the solution temperature between 17 °C to 25 °C. After addition was complete, the reaction mixture was stirred at 17 °C to 25 °C and dichloromethane was added and the organic layer was separated. DCM solution was then distilled under atmospheric conditions at approximately 40°C and the volume was reduced. DCM was added the reactor and the contents of the reactor are stirred at 20°C to 30°C until a clear solution is formed. The contents of the reactor were cooled to 0°C to 5°C and thionyl chloride was charged to the reactor slowly to maintain a temperature of < 5 °C. The reaction solution was stirred at 17 °C to 25 °C. When the reaction was complete, a solution of HC1 (g) in 1,4-dioxane (ca. 4 N, 0.8 equiv.) was charged to the reactor slowly to maintain the solution temperature between 17 °C and 25 °C. The product 3-(chloromethyl)-2-(l-isopropyl- lH-pyrazol-5-yl)pyridine dihydrochloride salt was filtered washed with dichloromethane and dried.

Example 3

Synthesis of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde

Form I

(I)

tably equipped reactor was charged with 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine dihydrochloride salt (1 equivalent), sodium iodide (0.05 equivalent), sodium bicarbonate (4 equivalent), l-methyl-2-pyrrolidinone (NMP), and 2,6-dihydroxy-benzaldehyde (1 to 1.05 equiv.). The reaction mixture was heated slowly to 40 °C to 50 °C and stirred until the reaction was complete. Water was then added and the reaction mixture was cooled and maintained at 17 °C to 25 °C. When the water addition was complete, the reaction mixture was stirred at 17 °C to 25 °C and slowly cooled to 0°C to 5°C and the resulting solids were collected by filtration. The solids were washed with a 0 °C to 5 °C 2: 1 water/NMP solution, followed by 0 °C to 5 °C water. The solids were filtered and dried to give 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde as Form I or a mixture of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde as Form I Form I and NMP solvates.

Alternative Synthesis:

A suitably equipped reactor was charged with 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine bishydrochloride salt (1 equivalent), sodium iodide (0.05 equivalent), sodium bicarbonate (3 to 4 equivalent), l-methyl-2-pyrrolidinone (7 equivalent, NMP), and 2,6-dihydoxybenzaldehyde (1.05 equivalent). The reaction mixture was heated to 40 °C to 50° C and stirred until the reaction was complete. Water (5 equivalent) was then added while maintaining the contents of the reactor at 40 °C to 46⁰ C and the resulting clear solution seeded with 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde Form I. Additional water (5 equivalent) was added while maintaining the contents of the reactor at 40 °C to 50⁰ C, the reactor contents cooled to 15 °C to 25 ⁰ C, and the reactor contents stirred for at least 1 hour at 15 °C to 25 ⁰ C. The solids were collected, washed twice with 1 :2 NMP: water and twice with water, and dried to yield 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde Form I devoid of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde as NMP solvates.

Example 4

Preparation of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)- benzaldehyde Form II

Step 1:

A suitably equipped reactor with an inert atmosphere was charged with crude 2-hydroxy- 6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (from Example 3 above) and MTBE and the contents stirred at 17°C to 25°C until dissolution was achieved. The reaction solution was passed through a 0.45 micron filter and MTBE solvent volume reduced using vacuum distillation at approximately 50 °C. The concentrated solution was heated to 55°C to 60°C to dissolve any crystallized product. When a clear solution was obtained, the solution was cooled to 50 °C to 55 °C and n-heptane was added. 2-Hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (e.g., Form II) seeds in a slurry of n-heptane were charged and the solution was stirred at 50°C to 55°C. The solution was cooled to 45 °C to 50 °C and n-heptane was added to the reactor slowly while maintaining a reaction solution temperature of 45°C to 50°C. The reaction solution are stirred at 45°C to 50°C and then slowly cooled to 17°C to 25°C. A sample was taken for FTIR analysis and the crystallization was considered complete when FTIR analysis confirmed 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)-benzaldehyde (Form II). The contents of the reactor were then cooled to 0°C to 5°C and the solids were isolated and washed with cold n-heptane and dried.

POLYMORPHS

US9447071

US2016207904

US2016346263

PATENT

https://patents.google.com/patent/US20160207904

PATENT

https://patents.google.com/patent/US20160346263A1/en

2-Hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde is a compound having the formula:
[0000]
[0003]

Sickle cell disease is a disorder of the red blood cells, found particularly among those of African and Mediterranean descent. The basis for sickle cell disease is found in sickle hemoglobin (HbS), which contains a point mutation relative to the prevalent peptide sequence of hemoglobin (Hb).
[0004]

Hemoglobin (Hb) transports oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through conformational changes. Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, allowing HbS to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape. The sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels. A need exists for therapeutics that can treat disorders that are mediated by Hb or by abnormal Hb such as HbS, such as 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde.
[0005]

When used for treating humans, it is important that a crystalline form of a therapeutic agent, like 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, or a salt thereof, retains its polymorphic and chemical stability, solubility, and other physicochemical properties over time and among various manufactured batches of the agent. If the physicochemical properties vary with time and among batches, the administration of a therapeutically effective dose becomes problematic and may lead to toxic side effects or to ineffective therapy, particularly if a given polymorph decomposes prior to use, to a less active, inactive, or toxic compound. Therefore, it is important to choose a form of the crystalline agent that is stable, is manufactured reproducibly, and has physicochemical properties favorable for its use as a therapeutic agent.
[0006]

However, the art remains unable to predict which crystalline form of an agent will have a combination of the desired properties and will be suitable for human administration, and how to make the agent in such a crystalline form.

PATENT

https://patents.google.com/patent/US9447071B2/en

It has now been discovered that 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-y1)methoxy)benzaldehyde (or Compound 1) i.e., the free base of Compound 1, can be obtained as one or more crystalline ansolvate forms, several of which are referred to here as crystalline Form I, Form II and Material N. In preferred embodiments, the free base of Compound 1 is a crystalline ansolvate, such as a crystalline anhydrous form. The free base of Compound 1, can be obtained from its corresponding salt form, such as the HCl salt of Compound 1.

Three anhydrous crystalline forms of the free base were identified, termed Free Base Forms I, II, and Material N. It has been discovered that nucleation of Free Base Form I generally occurs first from a slurry. Extending the slurry time can induce the transformation of Free Base Form I to Free Base Form II, a thermodynamically more stable phase relative to Form I. It has further been discovered that Free Base Material N can be stable relative to Forms I and II, at room temperature.

Synthetic Routes for Preparing Compound 1

The compound of formula (I) was synthesized as schematically described below and elaborated thereafter.

Example 1 Synthesis of Compound 15

To a solution of 2-bromobenzene-1,3-diol (5 g, 26.45 mmol) in DCM (50 ml) at 0° C. was added DIPEA (11.54 mL, 66.13 mmol) and MOMCl (4.42 mL, 58.19 mmol). The mixture was stirred at 0° C. for 1.5 h, and then warmed to room temperature. The solution was diluted with DCM, washed with sat. NaHCO₃, brine, dried and concentrated to give crude product, which was purified by column (hexanes/EtOAc=4:1) to give desired product 15.58 g (90%).

Example 2 Synthesis of Compound 13 from 15

To a solution of 2-bromo-1,3-bis(methoxymethoxy)benzene (15) (19.9 g, 71.8 mmol) in THF (150 mL) at −78° C. was added BuLi (2.5 M, 31.6 mL, 79.0 mmol) dropwise. The solution was stirred at −78° C. for 25 min (resulting white cloudy mixture), then it was warmed to 0° C. and stirred for 25 min. The reaction mixture slowly turns homogenous. To the solution was added DMF at 0° C. After 25 min, HPLC showed reaction completed. The mixture was quenched with sat. NH4Cl (150 mL), diluted with ether (300 mL). The organic layer was separated, aq layer was further extracted with ether (2×200 mL), and organic layer was combined, washed with brine, dried and concentrated to give crude product, which was triturated to give 14.6 g desired product. The filtrate was then concentrated and purified by column to give additional 0.7 g, total mass is 15.3 g.

Example 3 Synthesis of Compound 13 from resorcinol 11

A three-necked round-bottom flask equipped with mechanical stirrer was charged with 0.22 mol of NaH (50% suspension in mineral oil) under nitrogen atmosphere. NaH was washed with 2 portions (100 mL) of n-hexane and then with 300 mL of dry diethyl ether; then 80 mL of anhydrous DMF was added. Then 0.09 mol of resorcinol 11, dissolved in 100 mL of diethyl ether was added dropwise and the mixture was left under stirring at rt for 30 min. Then 0.18 mol of MOMCl was slowly added. After 1 h under stirring at rt, 250 mL of water was added and the organic layer was extracted with diethyl ether. The extracts were washed with brine, dried (Na₂SO₄), then concentrated to give the crude product that was purified by silica gel chromatography to give compound 12 (93% yield).

A three-necked round-bottom flask was charged with 110 mL of n-hexane, 0.79 mol of BuLi and 9.4 mL of tetramethylethylendiamine (TMEDA) under nitrogen atmosphere. The mixture was cooled at −10° C. and 0.079 mol of bis-phenyl ether 12 was slowly added. The resulting mixture was left under magnetic stirring at −10° C. for 2 h. Then the temperature was raised to 0° C. and 0.067 mol of DMF was added dropwise. After 1 h, aqueous HCl was added until the pH was acidic; the mixture was then extracted with ethyl ether. The combined extracts were washed with brine, dried (Na₂SO₄), and concentrated to give aldehyde 13 (84%).

2,6-bis(methoxymethoxy)benzaldehyde (13): mp 58-59° C. (n-hexane); IR (KBr) n: 1685 (C═O) cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ 3.51 (s, 6H, 2 OCH₃), 5.28 (s, 4H, 2 OCH₂O), 6.84 (d, 2H, J=8.40 Hz, H-3, H-5), 7.41 (t, 1H, J=8.40 Hz, H-4), 10.55 (s, 1H, CHO); MS, m/e (relative intensity) 226 (M+, 3), 180 (4), 164 (14), 122 (2), 92 (2), 45 (100); Anal. Calc’d. for C₁₁H₁₄O₅: C, 58.40; H, 6.24. Found: C, 57.98; H, 6.20.

Example 4 The Synthesis of Compound 16

To a solution of 2,6-bis(methoxymethoxy)benzaldehyde (13) (15.3 g, 67.6 mmol) in THF (105 mL) (solvent was purged with N₂) was added conc. HCl (12N, 7 mL) under N₂, then it was further stirred under N₂for 1.5 h. To the solution was added brine (100 mL) and ether (150 ml). The organic layer was separated and the aqueous layer was further extracted with ether (2×200 mL). The organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (300 g, hexanes/EtOAc=85:15) to give desired product 16 (9.9 g) as yellow liquid.

Example 5 Synthesis of Compound 17

To a solution of 2-hydroxy-6-(methoxymethoxy)benzaldehyde (16) (10.88 g, 59.72 mmol) in DMF (120 mL) (DMF solution was purged with N₂for 10 min) was added K₂CO₃(32.05 g, 231.92 mmol) and 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (10) (15.78 g, 57.98 mmol). The mixture was heated at 65° C. for 1.5 h, cooled to rt, poured into ice water (800 mL). The precipitated solids were isolated by filtration, dried and concentrated to give desired product (17, 18 g).

Example 6 Synthesis of Compound (I)

To a solution of 2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-(methoxymethoxy)benzaldehyde (17) (18 g, 47.19 mmol) in THF (135 mL, solution was purged with N₂) was added conc. HCl (12N, 20 mL). The solution was stirred at rt for 3 h when HPLC showed the reaction complete. The mixture was added to a solution of NaHCO₃(15 g) in water (1.2 L), and the resulting precipitate was collected by filtration, dried to give crude solid, which was further purified by column (DCM/EtOAc=60:40) to give pure product (15.3 g).

Example 7 Synthesis of Compound I (Free Base) and its HCl Salt Form

Compound (I) free base (40 g) was obtained from the coupling of the alcohol intermediate 7 and 2,6-dihydroxybenzaldedhye 9 under Mitsunobu conditions. A procedure is also provided below:

Example 8 Synthesis of Compound (I) by Mitsunobu Coupling

Into a 2000-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (7) (70 g, 322.18 mmol, 1.00 equiv) in tetrahydrofuran (1000 mL). 2,6-Dihydroxybenzaldehyde (9) (49.2 g, 356.21 mmol, 1.10 equiv) and PPh₃(101 g, 385.07 mmol, 1.20 equiv) were added to the reaction mixture. This was followed by the addition of a solution of DIAD (78.1 g, 386.23 mmol, 1.20 equiv) in tetrahydrofuran (200 ml) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 500 ml of H₂O. The resulting solution was extracted with 3×500 ml of dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EA:PE (1:50-1:3) as eluent to yield the crude product. The crude product was re-crystallized from i-propanol/H₂O in the ratio of 1/1.5. This resulted in 40 g (37%) of 2-hydroxy-6-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)benzaldehyde as a light yellow solid. The compound exhibited a melting point of 80-82° C. MS (ES, m/z): 338.1 [M+1]. ¹H NMR (300 MHz, DMSO-d6) δ 11.72 (s, 1H), 10.21 (s, 1H), 8.76 (d, J=3.6 Hz, 1H), 8.24 (d, J=2.7 Hz, 1H), 7.55 (m, 3H), 6.55 (m, 3H), 5.21 (s, 2H), 4.65 (m, 1H), 1.37 (d, J=5.1 Hz, 6H). ¹H NMR (400 MHz, CDCl₃) δ 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J=4.8, 1.5 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.49-7.34 (m, 2H), 6.59 (d, J=8.5 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H), 6.29 (d, J=8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J=6.7 Hz, 1H), 1.50 (d, J=6.6 Hz, 6H).

In another approach, multiple batches of Compound (I) free base are prepared in multi gram quantities (20 g). The advantage of this route is the use of mono-protected 2,6-dihydroxybenzaldehyde (16), which effectively eliminates the possibility of bis-alkylation side product. The mono-MOM ether of 2,6-dihydroxybenzaldehyde (16) can be obtained from two starting points, bromoresorcinol (14) or resorcinol (11) [procedures described in the Journal of Organic Chemistry, 74(11), 4311-4317; 2009]. All steps and procedures are provided below. Due to the presence of phenolic aldehyde group, precautions (i.e., carry out all reactions under inert gas such as nitrogen) should be taken to avoid oxidation of the phenol and/or aldehyde group. Preparation of compound I HCl salt: A solution of compound I (55.79 g, 165.55 mmol) in acetonitrile (275 mL) was flushed with nitrogen for 10 min, then to this solution was added 3N aqueous HCl (62 mL) at room temperature. The mixture was stirred for additional 10 min after the addition, most of the acetonitrile (about 200 mL) was then removed by evaporation on a rotary evaporator at around 32° C., the remaining solution was frozen by cooling in an acetone-dry ice bath and lyophilized to afford compound I HCl salt (59.4 g).

Biological Activity

Description	Voxelotor(GBT440, GTx011) is a novel small molecule hemoglobin modifier which increases hemoglobin oxygen affinity.
In vitro	GBT440 is a new potent allosteric effector of sickle cell hemoglobin that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. GBT440 inhibits these isozymes(CYP 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4) with IC50 ranging from 7.9 to 148 μM. It is not a substrate for either P-gp or BCRP transporters^[1]. It binds to the N-terminal a chain of Hb^[2].
In vivo	GBT440 has favorable oral bioavailability of 60, 37, and 36% in rats, dogs, and monkeys, respectively, with similar blood and plasma half-lives of approximately 20 h each. T1/2 value of GBT440 in all animal species is significantly shorter than the T1/2 of red blood cells (∼20 days), which supports that binding of GBT440 to hemoglobin is a reversible process. GBT440 is currently in Phase 3 clinical trials (NCT03036813) in SCD patients^[1]. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. In a murine model of SCD, GBT440 extends the half-life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. GBT440 shows dose proportional PK, a terminal half-life of 1.5-3 d^[2].

GBT Receives FDA Breakthrough Therapy Designation for Voxelotor for Treatment of Sickle Cell Disease (SCD)

Voxelotor is First Investigational Treatment for SCD to Receive Breakthrough Therapy Designation

SOUTH SAN FRANCISCO, Calif., Jan. 09, 2018 (GLOBE NEWSWIRE) — Global Blood Therapeutics, Inc. (GBT) (NASDAQ:GBT) today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) to voxelotor (previously called GBT440) for the treatment of sickle cell disease (SCD). Voxelotor is being developed as a disease-modifying therapy for SCD and previously received European Medicines Agency (EMA) Priority Medicines (PRIME) designation for the treatment of SCD.

“The FDA’s decision to grant voxelotor the first Breakthrough Therapy designation for the treatment of sickle cell disease reflects a recognition of the promising efficacy and safety data we have collected to date for this investigational drug, as well as an acknowledgement of the overwhelming need for major advances over available therapies in the treatment of SCD patients,” said Ted W. Love, president and chief executive officer of GBT. “This designation is another significant milestone for GBT as we work to expedite the development of voxelotor.”

The FDA selectively grants BTD to expedite the development and review of drugs that have demonstrated preliminary clinical evidence indicating the potential for substantial improvement over available therapy. The BTD decision for voxelotor was based on clinical data submitted from the following studies:

Preliminary efficacy and safety data from Part A of the Phase 3 HOPE Study (GBT440-031)
Phase 1/2 study and open-label extension in adults (GBT440-001/024)
Ongoing Phase 2 HOPE-KIDS 1 study in children age 6 to 17 (GBT440-007)
Compassionate Access experience in adults with severe SCD (not eligible for the HOPE Study)

About Sickle Cell Disease (SCD)
SCD is a lifelong inherited blood disorder caused by a genetic mutation in the beta-chain of hemoglobin, which leads to the formation of abnormal hemoglobin known as sickle hemoglobin (HbS). In its deoxygenated state, HbS has a propensity to polymerize, or bind together, forming long, rigid rods within a red blood cell (RBC). The polymer rods deform RBCs to assume a sickled shape and to become inflexible, which can cause blockage in capillaries and small blood vessels. Beginning in childhood, SCD patients suffer unpredictable and recurrent episodes or crises of severe pain due to blocked blood flow to organs, which often lead to psychosocial and physical disabilities. This blocked blood flow, combined with hemolytic anemia (the destruction of RBCs), can eventually lead to multi-organ damage and early death.

About Voxelotor in Sickle Cell Disease
Voxelotor (previously called GBT440) is being developed as an oral, once-daily therapy for patients with SCD. Voxelotor works by increasing hemoglobin’s affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, GBT believes voxelotor blocks polymerization and the resultant sickling of red blood cells. With the potential to restore normal hemoglobin function and improve oxygen delivery, GBT believes that voxelotor may potentially modify the course of SCD. In recognition of the critical need for new SCD treatments, the U.S. Food and Drug Administration (FDA) has granted voxelotor Fast Track, Orphan Drug and Rare Pediatric Disease designations for the treatment of patients with SCD. The European Medicines Agency (EMA) has included voxelotor in its Priority Medicines (PRIME) program, and the European Commission (EC) has designated voxelotor as an orphan medicinal product for the treatment of patients with SCD.

GBT is currently evaluating voxelotor in the HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS PolymErization) Study, a Phase 3 clinical study in patients age 12 and older with SCD. Additionally, voxelotor is being studied in the ongoing Phase 2a HOPE-KIDS 1 Study, an open-label, single- and multiple-dose study in pediatric patients (age 6 to 17) with SCD. HOPE-KIDS 1 is assessing the safety, tolerability, pharmacokinetics and exploratory treatment effect of voxelotor.

About GBT
GBT is a clinical-stage biopharmaceutical company determined to discover, develop and deliver innovative treatments that provide hope to underserved patient communities. GBT is developing its lead product candidate, voxelotor, as an oral, once-daily therapy for sickle cell disease. To learn more, please visit www.gbt.com and follow the company on Twitter @GBT_news.

REFERENCES

1: Oksenberg D, Dufu K, Patel MP, Chuang C, Li Z, Xu Q, Silva-Garcia A, Zhou C, Hutchaleelaha A, Patskovska L, Patskovsky Y, Almo SC, Sinha U, Metcalf BW, Archer DR. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br J Haematol. 2016 Oct;175(1):141-53. doi: 10.1111/bjh.14214. PubMed PMID: 27378309.

2: Dufu K, Lehrer-Graiwer J, Ramos E, Oksenberg D. GBT440 Inhibits Sickling of Sickle Cell Trait Blood Under In Vitro Conditions Mimicking Strenuous Exercise. Hematol Rep. 2016 Sep 28;8(3):6637. PubMed PMID: 27757216; PubMed Central PMCID: PMC5062624.

3: Ferrone FA. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br J Haematol. 2016 Aug;174(4):499-500. doi: 10.1111/bjh.14212. PubMed PMID: 27410726.

4: Oder E, Safo MK, Abdulmalik O, Kato GJ. New developments in anti-sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo? Br J Haematol. 2016 Oct;175(1):24-30. doi: 10.1111/bjh.14264. Review. PubMed PMID: 27605087; PubMed Central PMCID: PMC5035193.

Patent ID	Patent Title	Submitted Date	Granted Date
US2016346263	CRYSTALLINE POLYMORPHS OF THE FREE BASE OF 2-HYDROXY-6-((2-(1-ISOPROPYL-1H-PYRAZOL-5-YL)PYRIDIN-3-YL)METHOXY)BENZALDEHYDE	2016-08-12
US2014271591	Compositions and methods for the modulation of hemoglobin (s)	2013-03-15	2014-09-18
US2016303099	METHODS OF TREATMENT	2016-03-29
US2016206614	SUBSTITUTED BENZALDEHYDE COMPOUNDS AND METHODS FOR THEIR USE IN INCREASING TISSUE OXYGENATION	2016-03-25	2016-07-21
US9248199	1:1 ADDUCTS OF SICKLE HEMOGLOBIN	2014-01-29	2015-07-30

Patent ID	Patent Title	Submitted Date	Granted Date
US2015057251	COMPOUNDS AND USES THEREOF FOR THE MODULATION OF HEMOGLOBIN	2013-08-26	2015-02-26
US9422279	Compounds and uses thereof for the modulation of hemoglobin	2013-03-15	2014-09-18
US9018210	SUBSTITUTED BENZALDEHYDE COMPOUNDS AND METHODS FOR THEIR USE IN INCREASING TISSUE OXYGENATION	2012-12-28	2013-07-25
US2017157101	DOSING REGIMENS FOR 2-HYDROXY-6-((2-(1-ISOPROPYL-1H-PYRAZOL-5-YL)PYRIDIN-3-YL)METHOXY)BENZALDEHYDE	2016-12-02
US2016206604	FORMULATIONS COMPRISING WETTING AGENTS AND COMPOUNDS FOR THE MODULATION OF HEMOGLOBIN (S)	2014-08-25	2016-07-21

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US2016024127	COMPOUNDS AND USES THEREOF FOR THE MODULATION OF HEMOGLOBIN	2014-03-10	2016-01-28
US2016046613	COMPOUNDS AND USES THEREOF FOR THE MODULATION OF HEMOGLOBIN	2014-03-10	2016-02-18

////////////VOXELOTOR, GBT 440, GTx-011, Treatment of Sickle Cell Disease, phase 3, gbt, 1446321-46-5, orphan drug, breakthrough therapy designation

CC(C)n1nccc1c2ncccc2COc3cccc(O)c3C=O

DISCLAIMER

“NEW DRUG APPROVALS ” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

TAFAMIDIS

November 16, 2017 9:23 am / 1 Comment on TAFAMIDIS

ChemSpider 2D Image | Tafamidis | C14H7Cl2NO3

Tafamidis

Molecular Formula C₁₄H₇Cl₂NO₃
Average mass 308.116 Da

TAFAMIDIS, Fx-1006A
PF-06291826

2-(3,5-Dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid

594839-88-0 [RN]

6-Benzoxazolecarboxylic acid, 2-(3,5-dichlorophenyl)-

Vyndaqel

Tafamidis meglumine

Familial amyloid polyneuropathy LAUNCHED PFIZER 2011 EU

ApprovedJapanese Pharmaceuticals and Medical Devices Agency in September 2013

PHASE 3, at FDA, Amyloidosis, PFIZER

Image result for Vyndaqel tafamidis meglumine

Molecular Formula:	C₂₁H₂₄Cl₂N₂O₈
Molecular Weight:	503.329 g/mol

CAS 951395-08-7

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002294/WC500117838.pdf

D-Glucitol, 1-deoxy-1-(methylamino)-, 2-(3,5-dichlorophenyl)-6-benzoxazolecarboxylate

Tafamidis (INN, or Fx-1006A,^[1] trade name Vyndaqel) is a drug for the amelioration of transthyretin-related hereditary amyloidosis(also familial amyloid polyneuropathy, or FAP), a rare but deadly neurodegenerative disease.^[2]^[3] The drug was approved by the European Medicines Agency in November 2011 and by the Japanese Pharmaceuticals and Medical Devices Agency in September 2013.^[4]

In 2011 and 2012, orphan drug designation was assigned in Japan and the U.S., respectively, for the treatment of transthyretin amyloid polyneuropathy. This designation was assigned in the E.U. in 2012 for the treatment of senile systemic amyloidosis. In 2017, fast drug designation was assigned in the U.S. for the treatment of transthyretin cardiomyopathy.

Tafamidis is a novel specific transthyretin (TTR) stabilizer or dissociation inhibitor. TTR is a tetramer that is responsible in transporting the retinol-binding protein-vitamin A complex and minimally transporting thyroxine in the blood. In TTR-related disorders such as transthyretin familial amyloid polyneuropathy (TTR-FAP), tetramer dissociation is accelerated that results in unregulated amyloidogenesis and amyloid fibril formation. Eventually the failure of autonomic and peripheral nervous system is induced. Tafamidiswas approved by the European Medicines Agency (EMA) in 2011 under the market name Vyndaqel for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adult patients with early-stage symptomatic polyneuropathy to delay peripheral neurologic impairment. Tafamidis is an investigational drug under the FDA and in June 2017, Pfizer received FDA Fast Track Designation for tafamidis

Image result for TAFAMIDIS

The marketed drug, a meglumine salt, has completed an 18 month placebo controlled phase II/III clinical trial,^[5]^[6] and an 12 month extension study^[7] which provides evidence that tafamidis slows progression of Familial amyloid polyneuropathy.^[8] Tafamidis (20 mg once daily) is used in adult patients with an early stage (stage 1) of familial amyloidotic polyneuropathy.^[9]^[10]

Tafamidis was discovered in the Jeffery W. Kelly Laboratory at The Scripps Research Institute^[11] using a structure-based drug design strategy^[12] and was developed at FoldRx pharmaceuticals, a biotechnology company Kelly co-founded with Susan Lindquist. FoldRx was led by Richard Labaudiniere when it was acquired by Pfizer in 2010.

Tafamidis functions by kinetic stabilization of the correctly folded tetrameric form of the transthyretin (TTR) protein.^[13] In patients with FAP, this protein dissociates in a process that is rate limiting for aggregation including amyloid fibril formation, causing failure of the autonomic nervous system and/or the peripheral nervous system (neurodegeneration) initially and later failure of the heart. Kinetic Stabilization of tetrameric transthyretin in familial amyloid polyneuropathy patients provides the first pharmacologic evidence that the process of amyloid fibril formation causes this disease, as treatment with tafamidis dramatically slows the process of amyloid fibril formation and the degeneration of post-mitotic tissue. Sixty % of the patients enrolled in the initial clinical trial have the same or an improved neurologic impairment score after six years of taking tafamidis, whereas 30% of the patients progress at a rate ≤ 1/5 of that predicted by the natural history. Importantly, all of the V30M FAP patients remain stage 1 patients after 6 years on tafamidis out of four stages of disease progression. [Data presented orally by Professor Coelho in Brazil in 2013]^[7]

The process of wild type transthyretin amyloidogenesis also appears to cause wild-type transthyretin amyloidosis (WTTA), also known as senile systemic amyloidosis (SSA), leading to cardiomyopathy as the prominent phenotype.^[14] Some mutants of transthyretin — including V122I, which is primarily found in individuals of African descent — are destabilizing, enabling heterotetramer dissociation, monomer misfolding, and subsequent misassembly of transthyretin into a variety of aggregate structures ^[15] including amyloid fibrils^[16]leading to familial amyloid cardiomyopathy.^[17] While there is clinical evidence from a small number of patients that tafamidis slows the progression of the transthyretin cardiomyopathies,^[18] this has yet to be demonstrated in a placebo-controlled clinical trial. Pfizer has enrolled a placebo-controlled clinical trial to evaluate the ability of tafamidis to slow the progression of both familial amyloid cardiomyopathy and senile systemic amyloidosis (ClinicalTrials.gov identifier: NCT01994889).

Regulatory Process

Tafamidis was approved for use in the European Union by the European Medicines Agency in November 2011, specifically for the treatment of early stage transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP (all mutations). In September 2013 Tafamidis was approved for use in Japan by the Pharmaceuticals and Medical Devices Agency, specifically for the treatment of transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP (all mutations). Tafamidis is also approved for use in Brazil, Argentina, Mexico and Israel by the relevant authorities.^[19] It is currently being considered for approval by the United States Food and Drug Administration (FDA) for the treatment of early stage transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP.

In June 2012, the FDA Peripheral and Central Nervous System Drugs Advisory Committee voted “yes” (13-4 favorable vote) when asked if the findings of the pivotal clinical study with tafamidis were “sufficiently robust to provide substantial evidence of efficacy for a surrogate endpoint that is reasonably likely to predict a clinical benefit”. The Advisory Committee voted “no” 4-13 to reject the drug–in spite of the fact that both primary endpoints were met in the efficacy evaluable population (n=87) and were just missed in the intent to treat population (n=125), apparently because more patients than expected in the intent to treat population were selected for liver transplantation during the course of the trial, not owing to treatment failure, but because their name rose to the top of the transplant list. However, these patients were classified as treatment failures in the conservative analysis used.

Pfizer (following its acquisition of FoldRx ), under license from Scripps Research Institute , has developed and launched tafamidis, a small-molecule transthyretin stabilizer, useful for treating familial amyloid polyneuropathy.

SYN

European Journal of Medicinal Chemistry, 121, 823-840; 2016

SYN 2

INNOVATORS

THE SCRIPPS RESEARCH INSTITUTE [US/US]; 10550 N Torrey Pines Road, La Jolla, CA 92037 (US)

KELLY, Jeffrey, W.; (US).
SEKIJIMA, Yoshiki; (US)

Dr. Jeffery W. Kelly

Lita Annenberg Hazen Professor of Chemistry

Co-Chairman, Department of Molecular Medicine

Click here to download a concise version of Dr. Jeffery Kelly’s curriculum vitae.

Image result for The Scripps Research Institute

PATENT

WO2004056315

Example 5: Benzoxazoles as Transthyretin Amyloid Fibril Inhibitors
Transthyretin’s two thyroxine binding sites are created by its quaternary structural interface. The tetramer can be stabilized by small molecule binding to these sites, potentially providing a means to treat TTR amyloid disease with small molecule drugs. Many families of compounds have been discovered whose binding stabilizes the tetrameric ground state to a degree proportional to the small molecule dissociation constants Km and Ka₂. This also effectively increases the dissociative activation barrier and inhibits amyloidosis by kinetic stabilization. Such inhibitors are typically composed of two aromatic rings, with one ring bearing halogen substituents and the other bearing hydrophilic substituents. Benzoxazoles substituted with a carboxylic acid at C(4)-C(7) and a halogenated phenyl ring at C(2) also appeared to complement the TTR thyroxine binding site. A small library of these compounds was therefore prepared by dehydrocyclization of N-acyl amino-hydroxybenzoic acids as illustrated in Scheme 1.

Scheme 1: General Synthesis of Benzoxazoles
Reagents: (a) ArCOCl, THF, pyridine (Ar = Phenyl, 3,5-Difluorophenyl, 2,6-Difluorophenyl, 3,5-Dichlorophenyl, 2,6-Dichlorophenyl, 2-(Trifluoromethyl)phenyl, and 3-(Trifluoromethyl)phenyl); (b) TsOH*H₂O, refluxing xylenes; (c) TMSCHN₂, benzene, MeOH; (d) LiOH, THF, MeOH, H₂O (8-27% yield over 4 steps).

The benzoxazoles were evaluated using a series of analyses of increasing stringency. WT TTR (3.6 μM) was incubated for 30 min (pH 7, 37 °C) with a test compound (7.2 μM). Since at least one molecule ofthe test compound must bind to each molecule of TTR tetramer to be able to stabilize it, a test compound concentration of 7.2 μM is only twice the minimum effective concentration. The pH was then adjusted to 4.4, the optimal pH for fibrilization. The amount of amyloid formed after 72 h (37 °C) in the presence ofthe test compound was determined by turbidity at 400 nm and is expressed as % fibril formation (ff), 100%) being the amount formed by TTR alone. Ofthe 28 compounds tested, 11 reduced fibril formation to negligible levels (jf< 10%; FIG. 7).
The 11 most active compounds were then evaluated for their ability to bind selectively to TTR over, all other proteins in blood. Human blood plasma (TTR cone. 3.6 -5.4 μM) was incubated for 24 h with the test compound (10.8 μM) at 37 °C. The TTR and any bound inhibitor were immunoprecipitated using a sepharose-bound polyclonal TTR antibody. The TTR with or without inhibitor bound was liberated from the resin at high pH, and the inhibitor: TTR stoichiometry was ascertained by HPLC analysis (FIG. 8). Benzoxazoles with carboxylic acids in the 5- or 6-position, and 2,6-dichlorophenyl (13, 20) or 2-trifluoromethylphenyl (11, 18) substituents at the 2-position displayed the highest binding stoichiometries. In particular, 20 exhibited excellent inhibitory activity and binding selectivity. Hence, its mechanism of action was characterized further.
To confirm that 20 inhibits TTR fibril formation by binding strongly to the tetramer, isothermal titration calorimetry (ITC) and sedimentation velocity experiments were conducted with wt TTR. ITC showed that two equivalents of 20 bind with average dissociation constants of K_di = Kd₂ = 55 (± 10) nM under physiological conditions. These are comparable to the dissociation constants of many other highly efficacious TTR
amyloidogenesis inhibitors. For the sedimentation velocity experiments, TTR (3.6 μM) was incubated with 20 (3.6 μM, 7.2 μM, 36 μM) under optimal fibrilization conditions (72 h, pH 4.4, 37 °C). The tetramer (55 kDa) was the only detectable species in solution with 20 at 7.2 or 36 μM. Some large aggregates formed with 20 at 3.6 μM, but the TTR remaining in solution was tetrameric.
T119M subunit inclusion and small molecule binding both prevent TTR amyloid formation by raising the activation barrier for tetramer dissociation. An inhibitor’s ability to do this is most rigorously tested by measuring its efficacy at slowing tetramer dissociation in 6 M urea, a severe denaturation stress. Thus, the rates of TTR tetramer dissociation in 6 M urea in the presence and absence of 20, 21 or 27 were compared (FIG. 9). TTR (1.8 μM) was completely denatured after 168 h in 6 M urea. In contrast, 20 at 3.6 μM prevented tetramer dissociation for at least 168 h (> 3 the half-life of TTR in human plasma). With an equimolar amount of 20, only 27% of TTR denatured in 168 h. Compound 27 (3.6 μM) was much less able to prevent tetramer dissociation (90% unfolding after 168 h), even though it was active in the fibril formation assay. Compound 21 did not hinder the dissociation of TTR at all. These results show that inhibitor binding to TTR is necessary but not sufficient to kinetically stabilize the TTR tetramer under strongly denaturing conditions; it is also important that the dissociation constants be very low (or that the off rates be very slow). Also, the display of functional groups on 20 is apparently optimal for stabilizing the TTR tetramer; moving the carboxylic acid from C(6) to C(7), as in 27, or removing the chlorines, as in 21, severely diminishes its activity.

The role ofthe substituents in 20 is evident from its co-crystal stracture with TTR (FIG. 10). Compound 20 orients its two chlorine atoms near halogen binding pockets 2 and 2′ (so-called because they are occupied by iodines when thyroxine binds to TTR). The 2,6 substitution pattern on the phenyl ring forces the benzoxazole and phenyl rings out of planarity, optimally positioning the carboxylic acid on the benzoxazole to hydrogen bond to the ε-NH₃⁺ groups of Lys 15/15′. Hydrophobic interactions between the aromatic rings of 20 and the side chains of Leu 17, Leu 110, Ser 117, and Val 121 contribute additional binding energy.

PAPER

ChemMedChem (2013), 8(10), 1617-1619.

Nature Reviews Drug Discovery (2012), 11(3), 185-186

PAPER

Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV
J Med Chem 2011, 54(2): 510

PATENT

WO-2017190682

Novel crystalline forms of tafamidis methylglucamine (designated as Form E), processes for their preparation and compositions comprising them are claimed. Also claimed is their use for treating familial amyloid neuropathy. Represents first PCT filing from Crystal Pharmatech and the inventors on this API.

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=2C2DC88BD4DC90B179C38EC5283D0941.wapp2nA?docId=WO2017190682&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

CLIP

http://pubs.rsc.org/en/content/articlelanding/2016/ob/c5ob02496j/unauth#!divAbstract

Image result for TAFAMIDIS

2-(3, 5-Dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis)

m.p. = 200.4–202.7 °C; Rf = 0.37 (petroleum ether/ethyl acetate/acetic acid = 6:1:0.01).

IR (cm-1 , KBr): 3383, 1685, 1608, 1224, 769;

1H NMR (DMSO-d6, 400 MHz) (ppm) 8.27 (s, 1H), 8.18 (d, J = 6.8 Hz, 1H), 8.04–8.02 (m, 1H), 7.94 (s, 1H), 7.88 (d, J = 1.6 Hz, 1H), 7.67 (dd, J = 6.8 Hz, 5.2 Hz, 1H);

13C NMR (DMSOd6, 100 MHz) (ppm) 167.2, 162.1, 150.1, 145.0, 137.8, 133.7, 131.4, 128.6, 126.8, 124.3, 120.5, 112.6.

Data was consistent with that reported in the literature. [27]Yamamoto, T.; Muto, K.; Komiyama, M.; Canivet, J.; Yamaguchi, J.; Itami, K. Chem. Eur. J. 2011, 17, 10113.

Clip

http://synth.chem.nagoya-u.ac.jp/wordpress/publication/nicatalystscopemechanism?lang=en

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CLIP

Proc Natl Acad Sci U S A. 2012 Jun 12; 109(24): 9629–9634.

Published online 2012 May 29. doi: 10.1073/pnas.1121005109

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386102/

The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport of thyroxine and the vitamin A–retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation. One such compound, tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of Transthyretin Type Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (K_ds ∼2 nM and ∼200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis.

4-Amino-3-hydroxybenzoic acid (AHBA) is reacted with HCl (3 to 6 M equivalents) in methanol (8 to 9 L/kg). Methyl t-butyl ether (TBME) (9 to 11 L/kg) is then added to the reaction mixture. The product, methyl 4-amino-3-hydroxybenzoate hydrochloride salt, is isolated by filtration and then reacted with 3,5-dichlorobenzoyl chloride (0.95 to 1.05 M equivalents) in the presence of pyridine (2.0 to 2.5 M equivalents) in dichloromethane (DCM), (8 to 9 L/kg) as a solvent. After the distillation of DCM, acetone and water are added to the reaction mixture, producing methyl 4-(3,5-dichlorobenzoylamino)-3- hydroxy-benzoate. This is recovered by filtration and reacted with p-toluenesulfonic acid monohydrate (0.149 to 0.151 M equivalents) in toluene (12 to 18 L/kg) at reflux with water trap. Treatment with charcoal is then performed. After the distillation of toluene, acetone (4-6 L/kg) is added. The product, methyl 2-(3,5-dichlorophenyl)-benzoxazole-6- carboxylate, is isolated by filtration and then reacted with LiOH (1.25 to 1.29 M equivalents) in the presence of tetrahydrofuran (THF) (7.8 to 8.2 L/kg) and water (7.8 to 8.2 L/kg) at between 40 and 45 °C. The pH of the reaction mixture is adjusted with aqueous HCl to yield 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid, the free acid of tafamidis. This is converted to the meglumine salt by reacting with N-methyl-Dglucamine (0.95 to 1.05 M equivalents) in a mixture of water (4.95 to 5.05 L/kg)/isopropyl alcohol (19.75 to 20.25 L/kg) at 65-70 °C. Tafamidis meglumine (dglucitol, 1-deoxy-1-(methylamino)-,2-(3,5-dichlorophenyl)-6-benzoxazole carboxylate) is then isolated by filtration.

2 The following fragments were identified from electrospray ionization mass spectra acquired in positive-ion mode: meglumine M+ (C7H18NO5+, m/z = 196.13), M (carboxylate form) +2H (C14H6Cl2NO3, m/z = 308.13), M (salt) + H (C21H24Cl2N2O8, m/z = 504.26). 1 H-nuclear magnetic resonance spectra were acquired on a 700 MHz Bruker AVANCE II spectrometer in acetone:D2O (~8:2). Data were reported as chemical shift in ppm (δ), multiplicity (s = singlet, dd = double of doublets, m = multiplet), coupling constant (J Hz), relative integral and assignment: δ = 8.14 (m, JH2-H5 = 0.6 and JH2-H6 = 1.5, 1H, H2), 8.02 (dd, JH9-H11 = 1.9 and JH13-H11 = 1.9, 2H, H9 and H13), 7.97 (dd, JH6-H5 = 8.25, 1H, H6), 7.67 (dd, JH5-H2 = 0.6 and JH5-H6 = 8.25, 1H, H5), 7.58 (m, JH11-H9 = 1.9 and JH11-H13 = 1.9, 1H, H11), 4.08 (m, JH16-H17 = 4.9, 1H, H16), 3.79 (dd, JH17-H18 = 2.2, 1H, H17), 3.73 (dd, JH19-H20 = 3.2, 1H, H20), 3.69 (m, JH19-H20 = 3.2, 1H, H19), 3.61 (m, JH18-H19 = 12.25, 1H, H18), 3.58 (m, JH19-H20′ = 5.8 and JH20-H20′ = 11.7, 1H, H20′ ), 3.19 (m, JH15-H15′ = 12.9 and JH15′-H16 = 9.25 and JH15-H16 = 3.5, 2H, H15).

CLIP

http://onlinelibrary.wiley.com/store/10.1002/chem.201101091/asset/supinfo/chem_201101091_sm_miscellaneous_information.pdf?v=1&s=7badb204a12057710743c1711a744253eccd636a

Concise Synthesis of Tafamidis (Scheme 8)

4-(6-Benzoxazoyl)morpholine (8)

A mixture of 4-amino-3-hydroxybenzoic acid (1.53 g, 10 mmol) and trimethyl orthofomate (3 mL) was heated at 100 ºC for 5 h. After cooling to room temperature, trimethyl orthofomate was removed under reduced pressure. To a solution of benzoxazole 6-carboxylic acid in CH2Cl2 (10 mL) were added DMF (0.1 mL) and oxalyl chloride (1.8 mL, 20 mmol) and the resultant mixture was stirred at room temperature for 12 h. After cooling to room temperature, DMF and oxalyl chloride were removed under reduced pressure to yield the corresponding acid chloride as a solid. Thus-generated acid chloride and morpholine (2.2 mL) were stirred at room temperature for 3 h. After removing solvents under reduced pressure, the mixture was treated with saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate (20 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with brine (20 mL), dried with anhydrous magnesium sulfate, and the solvent removed under reduced pressure. Purification of the resulting oil by flash column chromatography on silica (5% methanol in CHCl3 as eluent) afforded heteroarene 8 (1.30 g, 56%) as a white solid. Rf = 0.47 (MeOH/CHCl3 = 1:20). 1 H NMR (600 MHz, CDCl3) δ 8.23 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.71 (s, 1H) 7.44 (d, J = 7.6 Hz, 1H), 4.00–3.25 (br, 8H). 13C NMR (150 MHz, CDCl3) δ 169.52, 153.87, 149.67, 141.24, 132.90, 123.79, 120.76, 110.48, 66.81. HRMS (DART) m/z calcd for C12H13N2O3 [MH]+ : 233.0926, found 233.0926.

4-(3,5-Dichlorophenyl 6-benzoxazoyl)morpholine

To a 20-mL glass vessel equipped with J. Young® O-ring tap containing a magnetic stirring bar were added Ni(cod)2 (13.9 mg, 0.05 mmol), 2,2’-bipyridyl (7.8 mg, 0.05 mmol), LiOt-Bu (60 mg, 0.75 mmol), 8 (174.2 mg, 0.5 mmol), 3,5-dichloroiodobenzene (9: 203.9 mg, 0.75 mmol), followed by dry 1,2-dimethoxyethane (2.0 mL). The vessel was sealed with an O-ring tap and then heated at 100 °C in an 8-well reaction block with stirring for 24 h. After cooling the reaction mixture to room temperature, the mixture was passed through a short silica gel pad (EtOAc). The filtrate was concentrated and the residue was subjected to preparative thin-layer chromatography (5% methanol in CHCl3 as eluent) to afford SI-2 (139.6 mg, 74 %) as a white foam. Rf = 0.70 (MeOH/CHCl3 = 1:20). 1 H NMR (600 MHz, CDCl3) δ 8.16 (d, J = 2.0 Hz, 2H), 7.82 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 4.00–3.25 (br, 8H). 13C NMR (150 MHz, CDCl3) δ 169.38, 161.78, 150.40, 142.90, 135.82, 132.95, 131.61, 129.26, 125.91, 124.23, 120.41, 110.26, 66.77. HRMS (DART) m/z calcd for C18H15Cl2N2O3 [MH]+ : 377.0460 found 377.0465.

Tafamidis[19 ] Razavi, H.; Palaninathan, S. K.; Powers, E. T.; Wiseman, R. L.; Purkey, H. E.; Mohamedmohaideen, N. N.; Deechongkit, S.; Chiang, K. P.; Dendle, M. T. A.; Sacchettini, J. C.; Kelly, J. W. Angew. Chem. Int. Ed. 2003, 42, 2758.]

HF·pyridine (0.5 mL) was added to a stirred solution of SI-2 (32 mg, 0.09 mmol) in THF (0.5 mL) at 70 ºC for 12 h. After cooling the reaction mixture to room temperature, the mixuture was diluted with EtOAc and washed sequentially with sat.NaHCO3, 2N HCl and brine. The organic layer was concentrated and the residue was subjected to preparative thin-layer chromatography (1% acetic acid, 5% methanol in CHCl3 as eluent) to afford tafamidis (24.7 mg, 94%) as a white foam.

1 H NMR (600 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.08 (d, J = 1.4 Hz, 2H), 8.00 (d, J = 8.3 Hz, 1H), 7.88 (m, 2H).

13C NMR (150 MHz, DMSO-d6) δ 166.6, 162.0, 150.0, 144.6, 135.1, 131.7, 129.1, 128.7, 126.5, 125.8, 120.0, 112.2.

HRMS (DART) m/z calcd for C14H8Cl2NO3 [MH]+ : 307.9881, found 307.9881.

References

Jump up^ Bulawa, C.E.; Connelly, S.; DeVit, M.; Wang, L. Weigel, C.;Fleming, J. Packman, J.; Powers, E.T.; Wiseman, R.L.; Foss, T.R.; Wilson, I.A.; Kelly, J.W.; Labaudiniere, R. “Tafamidis, A Potent and Selective Transthyretin Kinetic Stabilizer That Inhibits the Amyloid Cascade”. Proc. Natl. Acad. Sci., 2012 109, 9629-9634.
Jump up^ Ando, Y., and Suhr, O.B. (1998). Autonomic dysfunction in familial amyloidotic polyneuropathy (FAP). Amyloid, 5, 288-300.
Jump up^ Benson, M.D. (1989). “Familial Amyloidotic polyneuropathy”. Trends in Neurosciences, 12.3, 88-92, PMID 2469222, doi:10.1016/0166-2236(89)90162-8.
Jump up^ http://www.businesswire.com/news/home/20111117005505/en/Pfizer%E2%80%99s-Vyndaqel%C2%AE-tafamidis-Therapy-Approved-European-Union
Jump up^ Clinical trial number NCT00409175 for “Safety and Efficacy Study of Fx-1006A in Patients With Familial Amyloidosis” at ClinicalTrials.gov
Jump up^ Coelho, T.; Maia, L.F.; Martins da Silva, A.; Cruz, M.W.; Planté-Bordeneuve, V.; Lozeron, P.; Suhr, O.B.; Campistol, J.M.; Conceiçao, I.; Schmidt, H.; Trigo, P. Kelly, J.W.; Labaudiniere, R.; Chan, J., Packman, J.; Wilson, A.; Grogan, D.R. “Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial”. Neurology, 2012, 79, 785-792.
^ Jump up to:^a ^b Coelho, T.; Maia, L.F.; Martins da Silva, A.; Cruz, M.W.; Planté-Bordeneuve, V.; Suhr, O.B.; Conceiçao, I.; Schmidt, H. H. J.; Trigo, P. Kelly, J.W.; Labaudiniere, R.; Chan, J., Packman, J.; Grogan, D.R. “Long-term Effects of Tafamidis for the Treatment of Transthyretin Familial Amyloid Polyneuropathy”. J. Neurology, 2013 260, 2802-2814.
Jump up^ Ando, Y.; Sekijima, Y.; Obayashi, K.; Yamashita, T.; Ueda, M.; Misumi, Y.; Morita, H.; Machii, K; Ohta, M.; Takata, A; Ikeda, S-I. “Effects of tafamidis treatment on transthyretin (TTR) stabilization, efficacy, and safety in Japanese patients with familial amyloid polyneuropathy (TTR-FAP) with Val30Met and non-Varl30Met: A phase III, open-label study”. J. Neur. Sci., 2016 362, 266-271, doi:10.1016/j.jns.2016.01.046.
Jump up^ Andrade, C. (1952). “A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves”. Brain: a Journal of Neurology, 75, 408-427.
Jump up^ Coelho, T. (1996). “Familial amyloid polyneuropathy: new developments in genetics and treatment”. Current Opinion in Neurology, 9, 355-359.
Jump up^ Razavi, H.; Palaninathan, S.K. Powers, E.T.; Wiseman, R.L.; Purkey, H.E.; Mohamadmohaideen, N.N.; Deechongkit, S.; Chiang, K.P.; Dendle, M.T.A.; Sacchettini, J.C.; Kelly, J.W. “Benzoxazoles as Transthyretin Amyloid Fibril Inhibitors: Synthesis, Evaluation and Mechanism of Action”. Angew. Chem. Int. Ed., 2003, 42, 2758-2761.
Jump up^ Connelly, S., Choi, S., Johnson, S.M., Kelly, J.W., and Wilson, I.A. (2010). “Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses”. Current Opinion in Structural Biology, 20, 54-62.
Jump up^ Hammarstrom, P.; Wiseman, R. L.; Powers, E.T.; Kelly, J.W. “Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics”. Science, 2003, 299, 713-716
Jump up^ Westermark, P., Sletten, K., Johansson, B., and Cornwell, G.G., 3rd (1990). “Fibril in senile systemic amyloidosis is derived from normal transthyretin”. Proc Natl Acad Sci U S A, 87, 2843-2845.
Jump up^ Sousa, M.M., Cardoso, I., Fernandes, R., Guimaraes, A., and Saraiva, M.J. (2001). “Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy: evidence for toxicity of nonfibrillar aggregates”. The American Journal of Pathology, 159, 1993-2000.
Jump up^ Colon, W., and Kelly, J.W. (1992). “Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro”. Biochemistry 31, 8654-8660.
Jump up^ Jacobson, D.R., Pastore, R.D., Yaghoubian, R., Kane, I., Gallo, G., Buck, F.S., and Buxbaum, J.N. (1997). “Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans”. The New England Journal of Medicine, 336, 466-473.
Jump up^ Maurer, M.S.; Grogan, D.R.; Judge, D.P.; Mundayat, R.; Lombardo, I.; Quyyumi, A.A.; Aarts, J.; Falk, R.H. “Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes.” Circ. Heart. Fail. 2015 8, 519-526.
Jump up^http://www.pfizer.com/sites/default/files/news/Brazil%20Approval%20Press%20Statement%2011-7-16_0.pdf

Patent ID	Patent Title	Submitted Date	Granted Date
US2016185739	Solid Forms Of A Transthyretin Dissociation Inhibitor	2015-12-22	2016-06-30
US2017196985	SULFUR(VI) FLUORIDE COMPOUNDS AND METHODS FOR THE PREPARATION THEREOF	2015-06-05
US9770441	Crystalline solid forms of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole	2015-08-31	2017-09-26

Patent ID	Patent Title	Submitted Date	Granted Date
US9771321	Small Molecules That Covalently Modify Transthyretin	2014-04-14	2014-11-13
US9610270	NEW THERAPY FOR TRANSTHYRETIN-ASSOCIATED AMYLOIDOSIS	2012-10-23	2014-10-02
US2015057320	TRANSTHYRETIN LIGANDS CAPABLE OF INHIBITING RETINOL-DEPENDENT RBP4-TTR INTERACTION FOR TREATMENT OF AGE-RELATED MACULAR DEGENERATION, STARGARDT DISEASE, AND OTHER RETINAL DISEASE CHARACTERIZED BY EXCESSIVE LIPOFUSCIN ACCUMULATION	2014-10-31	2015-02-26
US9249112	SOLID FORMS OF A TRANSTHYRETIN DISSOCIATION INHIBITOR	2012-09-12	2015-01-29
US9499527	COMPOSITIONS AND METHODS FOR THE TREATMENT OF FAMILIAL AMYLOID POLYNEUROPATHY	2013-02-27	2015-05-07

Patent ID	Patent Title	Submitted Date	Granted Date
US9150489	1-(2-FLUOROBIPHENYL-4-YL)-ALKYL CARBOXYLIC ACID DERIVATIVES FOR THE THERAPY OF TRANSTHYRETIN AMYLOIDOSIS	2011-10-27
US2014134753	METHODS FOR TREATING TRANSTHYRETIN AMYLOID DISEASES	2014-01-15	2014-05-15
US8703815	Small molecules that covalently modify transthyretin	2010-10-14	2014-04-22
US8653119	Methods for treating transthyretin amyloid diseases	2011-11-22	2014-02-18
US2008131907	ASSAYS FOR DETECTING NATIVE-STATE PROTEINS AND IDENTIFYING COMPOUNDS THAT MODULATE THE STABILITY OF NATIVE-STATE PROTEINS	2007-09-14	2008-06-05

Patent ID	Patent Title	Submitted Date	Granted Date
US7214695	Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding	2004-08-05	2007-05-08
US7214696	Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding	2006-03-16	2007-05-08
US7560488	Methods for treating transthyretin amyloid diseases	2007-04-05	2009-07-14
US8168663	Pharmaceutically acceptable salt of 6-carboxy-2-(3, 5 dichlorophenyl)-benzoxazole, and a pharmaceutical composition comprising the salt thereof	2010-05-13	2012-05-01
US8236984	COMPOUND AND USE THEREOF IN THE TREATMENT OF AMYLOIDOSIS	2010-09-30	2012-08-07

Tafamidis
Clinical data

Trade names	Vyndaqel
License data	EU EMA: by INN
Routes of administration	Oral
ATC code	N07XX08 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Identifiers
IUPAC name [show]
CAS Number	594839-88-0
PubChem CID	11001318
ChemSpider	9176510
UNII	8FG9H9D31J
KEGG	D09673
ChEBI	CHEBI:78538
Chemical and physical data
Formula	C₁₄H₇Cl₂NO₃
Molar mass	308.116 g/mol
3D model (JSmol)	Interactive image

//////////////TTAFAMIDIS, Fx-1006A, PF-06291826, Orphan Drug, SCRIPP, PFIZER

C1=CC2=C(C=C1C(=O)O)OC(=N2)C3=CC(=CC(=C3)Cl)Cl

CNC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.c1cc2c(cc1C(=O)O)oc(n2)c3cc(cc(c3)Cl)Cl

“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

BMS-986020

October 30, 2017 10:25 am / Leave a comment

Image result for BMS-986020

BMS-986020

AM-152; BMS-986020; BMS-986202

cas 1257213-50-5
Chemical Formula: C29H26N2O5
Molecular Weight: 482.536

(R)-1-(4′-(3-methyl-4-(((1-phenylethoxy)carbonyl)amino)isoxazol-5-yl)-[1,1′-biphenyl]-4-yl)cyclopropane-1-carboxylic acid

Cyclopropanecarboxylic acid, 1-(4′-(3-methyl-4-((((1R)-1-phenylethoxy)carbonyl)amino)-5-isoxazolyl)(1,1′-biphenyl)-4-yl)-

1-(4′-(3-Methyl-4-(((((R)-1-phenylethyl)oxy)carbonyl)amino)isoxazol-5-yl)biphenyl-4-yl)cyclopropanecarboxylic acid

UNII: 38CTP01B4L

For treatment for pulmonary fibrosis, phase 2, The lysophosphatidic acid receptor, LPA₁, has been implicated as a therapeutic target for fibrotic disorders

Lysophospholipids (LPs), including lysophosphatidic acid (LPA), sphingosine 1-phospate (S1P), lysophosphatidylinositol (LPI), and lysophosphatidylserine (LysoPS), are bioactive lipids that transduce signals through their specific cell-surface G protein-coupled receptors, LPA1-6, S1P1-5, LPI1, and LysoPS1-3, respectively. These LPs and their receptors have been implicated in both physiological and pathophysiological processes such as autoimmune diseases, neurodegenerative diseases, fibrosis, pain, cancer, inflammation, metabolic syndrome, bone formation, fertility, organismal development, and other effects on most organ systems.

Image result for Amira Pharmaceuticals

Originator Amira Pharmaceuticals
DeveloperB ristol-Myers Squibb; Duke University
Class Antifibrotics; Azabicyclo compounds; Carboxylic acids; Small molecules; Tetrazoles
Mechanism of Action Lysophosphatidic acid receptor antagonists

Orphan Drug Status Yes – Fibrosis

Phase II Idiopathic pulmonary fibrosis
Phase IPsoriasis

Most Recent Events

05 May 2016 Bristol-Myers Squibb plans a phase I trial for Psoriasis in Australia (PO, Capsule, Liquid) (NCT02763969)
01 May 2016 Preclinical trials in Psoriasis in USA (PO) before May 2016
14 Mar 2016 Bristol-Myers Squibb withdraws a phase II trial for Systemic scleroderma in USA, Canada, Poland and United Kingdom (PO) (NCT02588625)

BMS-986020, also known as AM152 and AP-3152 free acid, is a potent and selective LPA1 antagonist. BMS-986020 is in Phase 2 clinical development for treating idiopathic pulmonary fibrosis. BMS-986020 selectively inhibits the LPA receptor, which is involved in binding of the signaling molecule lysophosphatidic acid, which in turn is involved in a host of diverse biological functions like cell proliferation, platelet aggregation, smooth muscle contraction, chemotaxis, and tumor cell invasion, among others

Image result for BMS-986020

PRODUCT PATENT

GB 2470833, US 20100311799, WO 2010141761

Hutchinson, John Howard; Seiders, Thomas Jon; Wang, Bowei; Arruda, Jeannie M.; Roppe, Jeffrey Roger; Parr, Timothy

Assignee: Amira Pharmaceuticals Inc, USA

Image result for Hutchinson, John Howard AMIRA

John Hutchinson

PATENTS

WO 2011159632

WO 2011159635

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013025733&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

WO 2013025733

Synthesis of Compound 74

Synthetic Route (Scheme XLV)

Compound 74 Compound 74a

[0562] Compound XLV-1 was prepared by the same method as described in the synthesis of compound 1-4 (Scheme 1-A).

[0563] To a solution of compound XLV-1 (8 g, 28.08 mmol) in dry toluene (150 mL) was added compound XLV-2 (1.58 g, 10.1 mmol), triethylamine (8.0 mL) and DPPA (9.2 g, 33.6 mmol). The reaction mixture was heated to 80 °C for 3 hours. The mixture was diluted with EtOAc (50 mL), washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was purified by column chromatography (PE/EA = 10 IX) to give compound XLV-3 (9.4 g, yield: 83 %). MS (ESI) m/z (M+H)⁺402.0.

[0564] Compound 74 was prepared analogously to the procedure described in the synthesis of Compound 28 and was carried through without further characterization.

[0565] Compound 74a was prepared analogously to the procedure described in the synthesis of Compound 44a. Compound 74a: 1HNMR (DMSO-d₆ 400MHz) δ 7.81 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.29-7.32 (m, 7 H), 5.78 (q, 1 H), 2.15 (s, 3 H), 1.52 (d, J = 6.0 Hz, 3H), 1.28 (br, 2 H), 0.74 (br, 2 H). MS (ESI) m/z (M+H)⁺ 483.1.

Paper

Development of a Concise Multikilogram Synthesis of LPA-1 Antagonist BMS-986020 via a Tandem Borylation–Suzuki Procedure

Michael J. Smith ^*

, Michael J. Lawler, Nathaniel Kopp, Douglas D. Mcleod, Akin H. Davulcu, Dong Lin, Kishta Katipally

, and Chris Sfouggatakis

Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00301

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00301

*E-mail: michael.smith2@bms.com.

Abstract Image

The process development for the synthesis of BMS-986020 (1) via a palladium catalyzed tandem borylation/Suzuki reaction is described. Evaluation of conditions culminated in an efficient borylation procedure using tetrahydroxydiboron followed by a tandem Suzuki reaction employing the same commercially available palladium catalyst for both steps. This methodology addressed shortcomings of early synthetic routes and was ultimately used for the multikilogram scale synthesis of the active pharmaceutical ingredient 1. Further evaluation of the borylation reaction showed useful reactivity with a range of substituted aryl bromides and iodides as coupling partners. These findings represent a practical, efficient, mild, and scalable method for borylation.

¹H NMR (500 MHz, DMSO-d₆) δ 1.19 (dd, J = 6.8, 3.8 Hz, 2H), 1.50 (dd, J = 6.8, 3.8 Hz, 2H), 1.56 (br s, 3H), 2.14 (br s, 3H), 5.78 (br s, 1H), 6.9–7.45 (br, 5H), 7.45 (br d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.79 (br d, 2H), 7.82 (br d, 2H), 8.87 (br s, 0.8H), 9.29 (s, 0.2H), 12.39 (br s, 1H). ¹³C NMR (126 MHz, DMSO-d₆) δ 9.2, 15.8, 22.4, 28.3, 72.8, 113.8, 125.4, 125.6, 126.2, 126.3, 127.1, 127.7, 128.4, 130.9, 137.4, 140.0, 141.5, 142.2, 154.4, 159.6, 160.8, 175.2. HRMS (ESI+) Calculated M + H 483.19145, found 483.19095.

REFERENCES

1: Kihara Y, Mizuno H, Chun J. Lysophospholipid receptors in drug discovery. Exp
Cell Res. 2015 May 1;333(2):171-7. doi: 10.1016/j.yexcr.2014.11.020. Epub 2014
Dec 8. Review. PubMed PMID: 25499971; PubMed Central PMCID: PMC4408218.

//////////////BMS-986020, AM 152, BMS 986020, BMS 986202, Orphan Drug, BMS, Amira Pharmaceuticals, Bristol-Myers Squibb, Duke University, Antifibrotics, PHASE 2, pulmonary fibrosis

O=C(C1(C2=CC=C(C3=CC=C(C4=C(NC(O[C@H](C)C5=CC=CC=C5)=O)C(C)=NO4)C=C3)C=C2)CC1)O

FDA approves Mylotarg (gemtuzumab ozogamicin) for treatment of acute myeloid leukemia

September 2, 2017 1:48 am / Leave a comment

FDA approves Mylotarg for treatment of acute myeloid leukemia

09/01/2017

The U.S. Food and Drug Administration today approved Mylotarg (gemtuzumab ozogamicin) for the treatment of adults with newly diagnosed acute myeloid leukemia whose tumors express the CD33 antigen (CD33-positive AML). The FDA also approved Mylotarg for the treatment of patients aged 2 years and older with CD33-positive AML who have experienced a relapse or who have not responded to initial treatment (refractory).

Mylotarg originally received accelerated approval in May 2000 as a stand-alone treatment for older patients with CD33-positive AML who had experienced a relapse. Mylotarg was voluntarily withdrawn from the market after subsequent confirmatory trials failed to verify clinical benefit and demonstrated safety concerns, including a high number of early deaths. Today’s approval includes a lower recommended dose, a different schedule in combination with chemotherapy or on its own, and a new patient population.

“We are approving Mylotarg after a careful review of the new dosing regimen, which has shown that the benefits of this treatment outweigh the risk,” 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. “Mylotarg’s history underscores the importance of examining alternative dosing, scheduling, and administration of therapies for patients with cancer, especially in those who may be most vulnerable to the side effects of treatment.”

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of white blood cells in the bloodstream. The National Cancer Institute of the National Institutes of Health estimates that approximately 21,380 people will be diagnosed with AML this year and that 10,590 patients with AML will die of the disease.

Mylotarg is a targeted therapy that consists of an antibody connected to an anti-tumor agent that is toxic to cells. It is thought to work by taking the anti-tumor agent to the AML cells that express the CD33 antigen, blocking the growth of cancerous cells and causing cell death.

The safety and efficacy of Mylotarg in combination with chemotherapy for adults were studied in a trial of 271 patients with newly diagnosed CD33-positive AML who were randomized to receive Mylotarg in combination with daunorubicin and cytarabine or to receive daunorubicin and cytarabine without Mylotarg. The trial measured “event-free survival,” or how long patients went without certain complications, including failure to respond to treatment, disease relapse or death, from the date they started the trial. Patients who received Mylotarg in combination with chemotherapy went longer without complications than those who received chemotherapy alone (median, event-free survival 17.3 months vs. 9.5 months).

The safety and efficacy of Mylotarg as a stand-alone treatment were studied in two, separate trials. The first trial included 237 patients with newly diagnosed AML who could not tolerate or chose not to receive intensive chemotherapy. Patients were randomized to receive treatment with Mylotarg or best supportive care. The trial measured “overall survival,” or how long patients survived from the date they started the trial. Patients who received Mylotarg survived longer than those who received only best supportive care (median overall survival 4.9 months vs. 3.6 months). The second trial was a single-arm study that included 57 patients with CD33-positive AML who had experienced one relapse of disease. Patients received a single course of Mylotarg. The trial measured how many patients achieved a complete remission. Following treatment with Mylotarg, 26 percent of patients achieved a complete remission that lasted a median 11.6 months.

Common side effects of Mylotarg include fever (pyrexia), nausea, infection, vomiting, bleeding, low levels of platelets in the blood (thrombocytopenia), swelling and sores in the mouth (stomatitis), constipation, rash, headache, elevated liver function tests, and low levels of certain white blood cells (neutropenia). Severe side effects of Mylotarg include low blood counts, infections, liver damage, blockage of the veins in the liver (hepatic veno-occlusive disease), infusion-related reactions, and severe bleeding (hemorrhage). Women who are pregnant or breastfeeding should not take Mylotarg, because it may cause harm to a developing fetus or a newborn baby. Patients with hypersensitivity to Mylotarg or any component of its formulation should not use Mylotarg.

The prescribing information for Mylotarg includes a boxed warning that severe or fatal liver damage (hepatotoxicity), including blockage of veins in the liver (veno-occlusive disease or sinusoidal obstruction syndrome), occurred in some patients who took Mylotarg.

Mylotarg received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Mylotarg to Pfizer Inc.

Image result for gemtuzumab ozogamicin

Gemtuzumab ozogamicin
Monoclonal antibody
Type	Whole antibody
Source	Humanized (from mouse)
Target	CD33
Clinical data
Trade names	Mylotarg
AHFS/Drugs.com	Monograph
MedlinePlus	a607075
Pregnancy category	D
Routes of administration	Intravenous
ATC code	L01XC05 (WHO)
Legal status
Legal status	US: ℞-only
Identifiers
CAS Number	220578-59-6
DrugBank	DB00056
ChemSpider	none
KEGG	D03259
ChEMBL	CHEMBL1201506
Chemical and physical data
Molar mass	151–153 g/mol

Gemtuzumab ozogamicin (marketed by Wyeth as Mylotarg) is a drug-linked monoclonal antibody (an antibody-drug conjugate) that was used to treat acute myelogenous leukemia from 2000 to 2010. It was withdrawn from market in June 2010 when a clinical trial showed the drug increased patient death and added no benefit over conventional cancer therapies.

Mechanism and side effects

Gemtuzumab is a monoclonal antibody to CD33 linked to a cytotoxic agent from the class of calicheamicins. CD33 is expressed in most leukemic blast cells but also in normal hematopoietic cells, the intensity diminishing with maturation of stem cells.

Common side effects of administration included shivering, fever, nausea and vomiting. Serious side effects included severe myelosuppression (suppressed activity of bone marrow, which is involved in formation of various blood cells [found in 98% of patients]), disorder of the respiratory system, tumor lysis syndrome, Type III hypersensitivity, venous occlusion, and death.

History

Gemtuzumab ozogamicin was created in a collaboration between Celltech and Wyeth that began in 1991.^[1]^[2] The same collaboration later produced inotuzumab ozogamicin.^[3] Celltech was acquired by UCB in 2004^[4] and Wyeth was acquired by Pfizer in 2009.^[5]

In the United States, it was approved under an accelerated-approval process by the FDA in 2000 for use in patients over the age of 60 with relapsed acute myelogenous leukemia (AML); or those who are not considered candidates for standard chemotherapy.^[6] The accelerated approval was based on the surrogate endpoint of response rate.^[7] It was the first antibody-drug conjugate to be approved.^[8]

Within the first year after approval, the FDA required a black box warning be added to Gemtuzumab packaging. The drug was noted to increase the risk of veno-occlusive disease in the absence of bone marrow transplantation.^[9] Later the onset of VOD was shown to occur at increased frequency in Gemtuzumab patients even following bone marrow transplantation.^[10] The drug was discussed in a 2008 JAMA article, which criticized the inadequacy of postmarketing surveillance of biologic agents.^[11]

A randomized phase 3 comparative controlled trial (SWOG S0106) was initiated in 2004 by Wyeth in accordance with the FDA accelerated-approval process. The study was stopped^[when?] prior to completion due to worrisome outcomes. Among the patients evaluated for early toxicity, fatal toxicity rate was significantly higher in the gemtuzumab combination therapy group vs the standard therapy group. Mortality was 5.7% with gemtuzumab and 1.4% without the agent (16/283 = 5.7% vs 4/281 = 1.4%; P = .01).^[7]

In June 2010, Pfizer withdrew Mylotarg from the market at the request of the US FDA.^[12]^[13] However, some other regulatory authorities did not agree with the FDA decision, with Japan’s Pharmaceuticals and Medical Devices Agency stating in 2011 that the “risk-benefit balance of gemtuzumab ozogamicin has not changed from its state at the time of approval”.^[14]

In early 2017 Pfizer reapplied for US and EU approval, based on a meta-analysis of prior trials and results of the ALFA-0701 clinical trial, an open-label Phase III trial in 280 older people with AML. ^[8]

References

Jump up^ “Mylotarg”. Informa Biomedtracker. Retrieved 19 August 2017.
Jump up^ Niculescu-Duvaz, I (December 2000). “Technology evaluation: gemtuzumab ozogamicin, Celltech Group.”. Current opinion in molecular therapeutics. 2 (6): 691–6. PMID 11249747.
Jump up^ Damle, NK; Frost, P (August 2003). “Antibody-targeted chemotherapy with immunoconjugates of calicheamicin.”. Current opinion in pharmacology. 3 (4): 386–90. PMID 12901947. doi:10.1016/S1471-4892(03)00083-3.
Jump up^ “Celltech sold to Belgian firm in £1.5bn deal”. The Guardian. 18 May 2004.
Jump up^ Sorkin, Andrew Ross; Wilson, Duff (25 January 2009). “Pfizer Agrees to Pay $68 Billion for Rival Drug Maker Wyeth”. The New York Times.
Jump up^ Bross PF, Beitz J, Chewn G, Chen XH, Duffy E, Kieffer L, Roy S, Sridhara R, Rahman A, Williams G, Pazdur R (2001). “Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia.”. Clin Cancer Res. 7 (6): 1490–6. PMID 11410481.
^ Jump up to:^a ^b Gemtuzumab Voluntarily Withdrawn From US Market. June 2010
^ Jump up to:^a ^b Stanton, Dan (February 1, 2017). “Pfizer resubmits US and EU application for withdrawn ADC Mylotarg”. BioPharma Reporter.
Jump up^ Giles FJ, Kantarjian HM, Kornblau SM, Thomas DA, Garcia-Manero G, Waddelow TA, David CL, Phan AT, Colburn DE, Rashid A, Estey EH (2001). “Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation.”. Cancer. 92 (2): 406–13. PMID 11466696. doi:10.1002/1097-0142(20010715)92:2<406::AID-CNCR1336>3.0.CO;2-U.
Jump up^ Wadleigh M, Richardson PG, Zahrieh D, Lee SJ, Cutler C, Ho V, Alyea EP, Antin JH, Stone RM, Soiffer RJ, DeAngelo DJ (2003). “Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation.”. Blood. 102 (5): 1578–82. PMID 12738663. doi:10.1182/blood-2003-01-0255.
Jump up^ The Research on Adverse Drug Events and Reports (RADAR) Project, JAMA
Jump up^ Mylotarg (gemtuzumab ozogamicin): Market Withdrawal, US FDA
Jump up^ Pfizer pulls leukemia drug from U.S. market, Reuters
Jump up^ Pharmaceuticals and Medical Devices Safety Information, No. 277, February 2011 (PDF) (Technical report). Pharmaceuticals and Medical Devices Agency of Japan. 2011.

////////////gemtuzumab ozogamicin, Mylotarg, treatment of acute myeloid leukemia, FDA 2017, ORPHAN DRUG, PFIZER

FDA approves first subcutaneous C1 Esterase Inhibitor to treat rare genetic disease

June 23, 2017 1:01 am / Leave a comment

FDA approves first subcutaneous C1 Esterase Inhibitor to treat rare genetic disease

06/22/2017

The U.S. Food and Drug Administration today approved Haegarda, the first C1 Esterase Inhibitor (Human) for subcutaneous (under the skin) administration to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients. The subcutaneous route of administration allows for easier at-home self-injection by the patient or caregiver, once proper training is received.

HAE, which is caused by having insufficient amounts of a plasma protein called C1-esterase inhibitor (or C1-INH), affects approximately 6,000 to 10,000 people in the U.S. People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract or airway. These attacks of swelling can occur spontaneously, or can be triggered by stress, surgery or infection.

“The approval of Haegarda provides a new treatment option for adolescents and adults with Hereditary Angioedema,” said Peter Marks, M.D., Ph.D., director of FDA’s Center for Biologics Evaluation and Research. “The subcutaneous formulation allows patients to administer the product at home to help prevent attacks.”

Haegarda is a human plasma-derived, purified, pasteurized, lyophilized (freeze-dried) concentrate prepared from large pools of human plasma from U.S. donors. Haegarda is indicated for routine prophylaxis to prevent HAE attacks, but is not indicated for treatment of acute HAE attacks.

The efficacy of Haegarda was demonstrated in a multicenter controlled clinical trial. The study included 90 subjects ranging in age from 12 to 72 years old with symptomatic HAE. Subjects were randomized to receive twice per week subcutaneous doses of either 40 IU/kg or 60 IU/kg, and the treatment effect was compared to a placebo treatment period. During the 16 week treatment period, patients in both treatment groups experienced a significantly reduced number of HAE attacks compared to their placebo treatment period.

The most common side effects included injection site reactions, hypersensitivity (allergic) reactions, nasopharyngitis (swelling of the nasal passages and throat) and dizziness. Haegarda should not be used in individuals who have experienced life-threatening hypersensitivity reactions, including anaphylaxis, to a C1-INH preparation or its inactive ingredients.

Haegarda received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs to treat rare diseases or conditions.

The FDA granted approval of Haegarda to CSL Behring LLC.

///////////Haegarda, C1 Esterase inhibitor, CSL Behring LLC, fda 2017, orphan drug

TRIENTINE HYDROCHLORIDE, 塩酸トリエンチン , 曲恩汀

March 27, 2017 10:39 am / 1 Comment on TRIENTINE HYDROCHLORIDE, 塩酸トリエンチン , 曲恩汀

TRIENTINE

Molecular Formula C₆H₁₈N₄
Average mass 146.234 Da

112-24-3 CAS

曲恩汀, KD-034, MK-0681, MK-681, TECZA, TETA, TJA-250

1,2-Ethanediamine, N¹,N²-bis(2-aminoethyl)-

1,8-diamino-3,6-diazaoctane

TRIENTINE HYDROCHLORIDE

Molecular Formula C₆H₁₉ClN₄
Average mass 182.695 Da

38260-01-4 CAS

Launched – 1986 VALEANT, WILSONS DISEASE

Image result for MSD

Image result for VALEANT

塩酸トリエンチン
Trientine Hydrochloride

C₆H₁₈N₄2HCl : 219.16
[38260-01-4]

UPDATE CDSCO INDIA Trientine 08.06.2021 APPROVED

Trientine Tetrahydrochloride bulk and
Trientine Tetrahydrochloride capsules 333 mg
(Each capsule contains Trientine
tetrahydrochloride 333mg equivalent to
Trientine 167mg base)

For the treatment of Wilson’s disease
(hepatolenticular degeneration) in patients
intolerant to Penicillamine. It should be
used when continued treatment with
Penicillamine is no longer possible because
of intolerable or life endangering side
effects.

Aton Pharma, a subsidiary of Valeant Pharmaceuticals, has developed and launched Syprine, a capsule formulation of trientine hydrochloride, for treating Wilson disease.

Image result for TRIENTINE

Triethylenetetramine, abbreviated TETA and trien and also called trientine (INN), is an organic compound with the formula [CH₂NHCH₂CH₂NH₂]₂. This oily liquid is colorless but, like many amines, assumes a yellowish color due to impurities resulting from air-oxidation. It is soluble in polar solvents. The branched isomer tris(2-aminoethyl)amine and piperazine derivatives may also be present in commercial samples of TETA.^[1]

Trientine hydrochloride is a metal antagonist that was first launched by Merck, Sharp & Dohme in the U.S. in 1986 under the brand name Syprine for the oral treatment of Wilson’s disease.

Orphan drug designation has also been assigned in the U.S. for the treatment of patients with Wilson’s disease who are intolerant or inadequately responsive to penicillamine and in the E.U. by Univar for the treatment of Wilson’s disease

Trientine hydrochloride pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=90373

By condensation of ethylenediamine (I) with 1,2-dichloroethane (II)

Trientine hydrochloride is N,N’-bis (2-aminoethyl)-1,2-ethanediamine dihydrochloride. It is a white to pale yellow crystalline hygroscopic powder. It is freely soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform and ether.

The empirical formula is C6H18N4·2HCI with a molecular weight of 219.2. The structural formula is:

NH₂(CH₂)₂NH(CH₂)₂NH(CH₂)₂NH₂•2HCI

Trientine hydrochloride is a chelating compound for removal of excess copper from the body. SYPRINE (Trientine Hydrochloride) is available as 250 mg capsules for oral administration. Capsules SYPRINE contain gelatin, iron oxides, stearic acid, and titanium dioxide as inactive ingredients.

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Production

TETA is prepared by heating ethylenediamine or ethanolamine/ammonia mixtures over an oxide catalyst. This process gives a variety of amines, which are separated by distillation and sublimation.^[2]

Uses

The reactivity and uses of TETA are similar to those for the related polyamines ethylenediamine and diethylenetriamine. It was primarily used as a crosslinker (“hardener”) in epoxy curing.^[2]

The hydrochloride salt of TETA, referred to as trientine hydrochloride, is a chelating agent that is used to bind and remove copper in the body to treat Wilson’s disease, particularly in those who are intolerant to penicillamine. Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive.^[3]

Coordination chemistry

TETA is a tetradentate ligand in coordination chemistry, where it is referred to as trien.^[4] Octahedral complexes of the type M(trien)Cl₃ can adopt several diastereomeric structures, most of which are chiral.^[5]

Trientine, chemically known as triethylenetetramine or N,N’-bis(2-aminoethyl)-l,2-ethanediamine belongs to the class of polyethylene polyamines. Trientine dihydrochloride is a chelating agent which is used to bind and remove copper in the body in the treatment of Wilson’s disease.

Image result for TRIENTINE

Trientine dihydrochloride (1)

Trientine dihydrochloride formulation, developed by Aton with the proprietary name SYPRINE, was approved by USFDA on November 8, 1985 for the treatment of patients with Wilson’s disease, who are intolerant to penicillamine. Trientine dihydrochloride, due to its activity on copper homeostasis, is being studied for various potential applications in the treatment of internal organs damage in diabetics, Alzheimer’s disease and cancer.

Various synthetic methods for preparation of triethylenetetramine (TETA) and the corresponding dihydrochloride salt have been disclosed in the prior art.

U.S. 4,806,517 discloses the synthesis of triethylenetetramine from ethylenediamine and monoethanolamine using Titania supported phosphorous catalyst while U.S. 4,550,209 and U.S. 5,225,599 disclose catalytic condensation of ethylenediamine and ethylene glycol for the synthesis of linear triethylenetetramine using catalysts like zirconium trimethylene diphosphonate, or metatungstate composites of titanium dioxide and zirconium dioxide.

U.S. 4,503,253 discloses the preparation of triethylenetetramine by reaction of an alkanolamine compound with ammonia and an alkyleneamine having two primary amino groups in the presence of a catalyst, such as supported phosphoric acid wherein the support is comprised of silica, alumina or carbon.

The methods described above for preparation of triethylenetetramine require high temperatures and pressure. Further, due to the various possible side reactions and consequent associated impurities, it is difficult to control the purity of the desired amine.

CN 102924289 discloses a process for trientine dihydrochloride comprising reduction of Ν,Ν’-dibenzyl-,N,N’-bis[2-(l,3-dioxo-2H-isoindolyl)ethyl]ethanediamine using hydrazine hydrate to give N,N’-dibenzyl-,N,N’-bis(2-aminoethyl)ethanediamine, which, upon condensation with benzyl chloroformate gave N,N’-dibenzyl-,N,N’-bis[2-(Cbz-amino)ethyl]ethanediamine, and further reductive deprotection to give the desired compound.

CS 197,093 discloses a process comprising reaction of triethylenetetramine with concentrated hydrochloric acid to obtain the crystalline tetrahydrochlonde salt. Further reaction of the salt with sodium ethoxide in solvent ethanol, filtration of the solid sodium chloride which is generated in the process, followed by slow cooling and crystallization of the filtrate provided the dihydrochloride salt. Optionally, aqueous solution of the tetrahydrochloride salt was passed through a column of an anion exchanger and the eluate containing free base was treated with a calculated amount of the tetrahydrochloride, evaporated, and the residue was crystallized from aqueous ethanol to yield the dihydrochloride salt.

The process is quite circuitous and cumbersome, requiring use of strong bases, filtration of sodium chloride and results in yields as low as 60%.

US 8,394,992 discloses a method for preparation of triethylenetetramine dihydrochloride wherein tertiary butoxycarbonyl (boc) protected triethylenetetramine is first converted to its tetrahydrochloride salt using large excess of hydrochloric acid in solvent isopropanol, followed by treatment of the resulting tetrahydrochloride salt with a strong base like sodium alkoxide to produce the amine free base (TETA) and sodium chloride salt in anhydrous conditions. The free amine is extracted with tertiary butyl methyl ether (TBME), followed by removal of sodium chloride salt and finally the amine free base TETA is treated with hydrochloric acid in solvent ethanol to give trientine hydrochloride salt.

PATENT

WO-2017046695

EXAMPLES

Example 1: Preparation of 2-([2-[cyanomethyl]-t-butyloxycarbonylamino]ethyl- 1-butyloxy carbonylamino)acetonitrile (5)

Potassium carbonate (481.9 g) was added to a stirred mixture of ethylenediamine (100.0 g) in acetonitrile (800 ml) and cooled to around 10°C. Chloroacetonitrile (263.8 g) was gradually added at same temperature and stirred at 25-30°C, till completion of the reaction, as monitored by HPLC. The mixture was cooled to 5-15°C and Boc-anhydride (762. lg) was added to it, followed by stirring at the same temperature. The temperature was raised to 25-30°C and the mass was stirred till completion of the reaction, as monitored by HPLC.

The reaction mass was filtered and the filtrate was concentrated. Toluene was added to the residue, and the mixture was heated to around 70°C followed by cooling and filtration to give 2-([2-[cyanomethyl)-t-butyloxycarbonylamino]ethyl-t-butyloxycarbonylamino) acetonitrile (5).

Yield: 506.8 g

% Yield: 89.9 %

Example 2: Preparation of t-butyl( N-2-aminoethyl)N-([2-[(2-aminoethyl)t-butyloxy)carbonylamino] ethyl) carbamate (6)

Raney nickel (120.0 g) in isopropanol (100 ml) was charged into an autoclave, followed by a mixture of Compound 5 (200 g) in isopropanol (400 ml). Cooled ammonia solution prepared by purging ammonia gas in 1400 ml isopropanol, equivalent to 125 g ammonia was gradually charged to the autoclave and the reaction was carried out around 15-25°C under hydrogen pressure of 2-5 Kg/cm².

After completion of the reaction, as monitored by HPLC, the mass was filtered, concentrated, and methyl tertiary butyl ether was added to the residue. The mixture was heated to around 50°C, followed by cooling of the mass, stirring, optional seeding with compound 6 and filtration to give tertiary butyl-(N-2-aminoethyl)N-([2-[(2-aminoethyl)-(tert-butyloxy) carbonylamino] ethyl) carbamate.

Yield: 174 g

%Yield: 85 %

Example 3: Preparation of triethylenetetramine dihydrochloride (1)

Concentrated hydrochloric acid (121.5 g) was gradually added to a stirred mixture of tertiary-butyl-N-(2-aminoethyl)-N-2-[(2-aminoethyl)-(tert-butoxy) carbonyl] amino] ethyl} carbamate (Compound 6, 200.0 g) and water (1400 ml) at 20-30°C. The reaction mixture was heated in the temperature range of 100-105°C till completion of the reaction, as monitored by HPLC, with optionally distilling out water, if so required.

The reaction mass was concentrated and ethanol (600 ml) was added to the residue, followed by heating till a clear solution was obtained. The reaction mixture was gradually cooled with stirring, filtered and dried to provide triethylenetetramine dihydrochloride (1).

Yield: 88.9 g, (70 %)

Purity : > 99%

Patent

https://www.google.com/patents/US8394992

Trientine was said to be used in the synthesis of benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine in French Patent No. FR2810035 to Guilard et al. Cetinkaya, E., et al., “Synthesis and characterization of unusual tetraminoalkenes,” J. Chem. Soc. 5:561-7 (1992), is said to be directed to synthesis of benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine from trientine, as is Araki T., et al., “Site-selective derivatization of oligoethyleneimines using five-membered-ring protection method,” Macromol., 21:1995-2001 (1988). Triethylenetetramine may reportedly also be used in the synthesis of N-methylated triethylenetetramine, as reported in U.S. Pat. No. 2,390,766, to Zellhoefer et al.

Synthesis of polyethylenepolyamines, including triethylenetetramines, from ethylenediamine and monoethanolamine using pelleted group IVb metal oxide-phosphate type catalysts was reported by Vanderpool et al. in U.S. Pat. No. 4,806,517. Synthesis of triethylenetetramine from ethylenediamine and ethanolamine was also proposed in U.S. Pat. No. 4,550,209, to Unvert et al. U.S. Pat. No. 5,225,599, to King et al. is said to be directed to the synthesis of linear triethylene tetramine by condensation of ethylenediamine and ethylene glycol in the presence of a catalyst. Joint production of triethylenetetramine and 1-(2-aminoethyl)-aminoethyl-piperazine was proposed by Borisenko et al. in U.S.S.R. Patent No. SU1541204. U.S. Pat. No. 4,766,247 and European Patent No. EP262562, both to Ford et al., reported the preparation of triethylenetetramine by reaction of an alkanolamine compound, an alkaline amine and optionally either a primary or secondary amine in the presence of a phosphorous containing catalyst, for example phosphoric acid on silica-alumina or Group IIIB metal acid phosphate, at a temperature from about 175° C. to 400° C. under pressure. These patents indicate that the synthetic method used therein was as set forth in U.S. Pat. No. 4,463,193, to Johnson. The Ford et al. ‘247 patent is also said to be directed to color reduction of polyamines by reaction at elevated temperature and pressure in the presence of a hydrogenation catalyst and a hydrogen atmosphere. European Patent No. EP450709 to King et al. is said to be directed to a process for the preparation of triethylenetetramine and N-(2-aminoethyl)ethanolamine by condensation of an alkylenamine and an alkylene glycol in the presence of a condensation catalyst and a catalyst promoter at a temperature in excess of 260° C.

Russian Patent No. RU2186761, to Zagidullin, proposed synthesis of diethylenetriamine by reaction of dichloroethane with ethylenediamine. Ethylenediamine has previously been said to have been used in the synthesis of N-carboxylic acid esters as reported in U.S. Pat. No. 1,527,868, to Hartmann et al.

Japanese Patent No. 06065161 to Hara et al. is said to be directed to the synthesis of polyethylenepolyamines by reacting ethylenediamine with ethanolamine in the presence of silica-treated Nb205 supported on a carrier. Japanese Patent No. JP03047154 to Watanabe et al., is said to be directed to production of noncyclic polyethylenepolyamines by reaction of ammonia with monoethanolamine and ethylenediamine. Production of non-cyclic polyethylenepolyamines by reaction of ethylenediamine and monoethanolamine in the presence of hydrogen or a phosphorous-containing substance was said to be reported in Japanese Patent No. JP03048644. Regenerative preparation of linear polyethylenepolyamines using a phosphorous-bonded catalyst was proposed in European Patent No. EP115,138, to Larkin et al.

A process for preparation of alkyleneamines in the presence of a niobium catalyst was said to be provided in European Patent No. 256,516, to Tsutsumi et al. U.S. Pat. No. 4,584,405, to Vanderpool, reported the continuous synthesis of essentially noncyclic polyethylenepolyamines by reaction of monoethanolamine with ethylenediamine in the presence of an activated carbon catalyst under a pressure between about 500 to about 3000 psig., and at a temperature of between about 200° C. to about 400° C. Templeton, et al., reported on the preparation of linear polyethylenepolyamides asserted to result from reactions employing silica-alumina catalysts in European Patent No. EP150,558.

Production of triethylenetetramine dihydrochloride was said to have been reported in Kuhr et al., Czech Patent No. 197,093, via conversion of triethylenetetramine to crystalline tetrahydrochloride and subsequently to triethylenetetramine dihydrochloride. “A study of efficient preparation of triethylenetetramine dihydrochloride for the treatment of Wilson’s disease and hygroscopicity of its capsule,” Fujito, et al., Yakuzaigaku, 50:402-8 (1990), is also said to be directed to production of triethylenetetramine.

Preparation of triethylenetetramine salts used for the treatment of Wilson’s disease was said to be reported in “Treatment of Wilson’s Disease with Triethylene Tetramine Hydrochloride (Trientine),” Dubois, et al., J. Pediatric Gastro. & Nutrition, 10:77-81 (1990); “Preparation of Triethylenetetramine Dihydrochloride for the Treatment of Wilson’s Disease,” Dixon, et al., Lancet, 1(1775):853 (1972); “Determination of Triethylenetetramine in Plasma of Patients by High-Performance Liquid Chromatography,” Miyazaki, et al., Chem. Pharm. Bull., 38(4):1035-1038 (1990); “Preparation of and Clinical Experiences with Trien for the Treatment of Wilson’s Disease in Absolute Intolerance of D-penicillamine,” Harders, et al., Proc. Roy. Soc. Med., 70:10-12 (1977); “Tetramine cupruretic agents: A comparison in dogs,” Allen, et al., Am. J. Vet. Res., 48(1):28-30 (1987); and “Potentiometric and Spectroscopic Study of the Equilibria in the Aqueous Copper(II)-3,6-Diazaoctane-1,8-diamine System,” Laurie, et al., J.C.S. Dalton, 1882 (1976).

Preparation of Triethylenetetramine Salts by Reaction of Alcohol Solutions of Amines and acids was said to be reported in Polish Patent No. 105793, to Witek. Preparation of triethylenetetramine salts was also asserted in “Polycondensation of polyethylene polyamines with aliphatic dicarboxylic acids,” Witek, et al., Polimery, 20(3):118-119 (1975).

Baganz, H., and Peissker, H., Chem. Ber., 1957; 90:2944-2949; Haydock, D. B., and Mulholland, T. P. C., J. Chem. Soc., 1971; 2389-2395; and Rehse, K., et al., Arch. Pharm., 1994; 393-398, report on Strecker syntheses. Use of Boc and other protecting groups has been described. See, for example, Spicer, J. A. et al., Bioorganic & Medicinal Chemistry, 2002; 10: 19-29; Klenke, B. and Gilbert, I. H., J. Org. Chem., 2001; 66: 2480-2483.

FIG. 6 shows an ¹H-NMR spectrum of a triethylenetetramine hydrochloride salt in D₂O, as synthesized in Example 3. NMR values include a frequency of 400.13 Mhz, a 1H nucleus, number of transients is 16, points count of 32768, pulse sequence of zg30, and sweep width of 8278.15 H

Image result for TRIENTINE

CLIP

Click to access JP17e_1.pdf

Method of purification: Dissolve Trientine Hydrochloride in water while warming, and recrystallize by addition of ethanol (99.5). Or dissolve Trientine Hydrochloride in water while warming, allow to stand after addition of activated charcoal in a cool and dark place for one night, and filter. To the filtrate add ethanol (99.5), allow to stand in a cool and dark place, and recrystallize. Dry the crystals under reduced pressure not exceeding 0.67 kPa at 409C until ethanol odor disappears.

References

“Ethyleneamines” (PDF). Huntsman. 2007.
^ Jump up to:^a ^b Eller, K.; Henkes, E.; Rossbacher, R.; Höke, H. (2005). “Amines, Aliphatic”. Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a02_001.
Jump up^ Roberts, E. A.; Schilsky, M. L. (2003). “A practice guideline on Wilson disease” (pdf). Hepatology. 37 (6): 1475–1492. doi:10.1053/jhep.2003.50252. PMID 12774027.
Jump up^ von Zelewsky, A. (1995). Stereochemistry of Coordination Compounds. Chichester: John Wiley. ISBN 047195599X.
Utsuno, S.; Sakai, Y.; Yoshikawa, Y.; Yamatera, H. (1985). “Three Isomers of the Trans-Diammine-[N,N′-bis(2-Aminoethyl)-1,2-Ethanediamine]-Cobalt(III) Complex Cation”. Inorganic Syntheses. 23: 79–82. doi:10.1002/9780470132548.ch16.

Triethylenetetramine
Names



Other names N,N’-Bis(2-aminoethyl)ethane-1,2-diamine; TETA; Trien; Trientine (INN); Syprine (brand name)
Identifiers
CAS Number	112-24-3
3D model (Jmol)	Interactive image
Beilstein Reference	605448
ChEBI	CHEBI:39501
ChemSpider	21106175
ECHA InfoCard	100.003.591
EC Number	203-950-6
Gmelin Reference	27008
KEGG	C07166
MeSH	Trientine
PubChem CID	5565
RTECS number	YE6650000
UNII	SJ76Y07H5F
UN number	2259
InChI [show]
SMILES [show]
Properties
Chemical formula	C₆H₁₈N₄
Molar mass	146.24 g·mol⁻¹
Appearance	Colorless liquid
Odor	Fishy, ammoniacal
Density	982 mg mL⁻¹
Melting point	−34.6 °C; −30.4 °F; 238.5 K
Boiling point	266.6 °C; 511.8 °F; 539.7 K
Solubility in water	Miscible
log P	1.985
Vapor pressure	<1 Pa (at 20 °C)
Refractive index (n_D)	1.496
Thermochemistry
Specific heat capacity (C)	376 J K⁻¹ mol⁻¹ (at 60 °C)
Pharmacology
ATC code	A16AX12 (WHO)
Hazards
GHS pictograms
GHS signal word	DANGER
GHS hazard statements	H312, H314, H317, H412
GHS precautionary statements	P273, P280, P305+351+338, P310
EU classification (DSD)	C
R-phrases	R21, R34, R43, R52/53
S-phrases	(S1/2), S26, S36/37/39, S45
Flash point	129 °C (264 °F; 402 K)
Lethal dose or concentration (LD, LC):
LD₅₀ (median dose)	550 mg kg⁻¹ (dermal, rabbit) 2.5 g kg⁻¹ (oral, rat)
Related compounds
Related amines	Ethylenediamine Diethylenetriamine Cyclam
Related compounds	Ethylenediaminetetraacetic acid
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////////////TRIENTINE, 112-24-3, 曲恩汀 , KD-034 , MK-0681, MK-681, TECZA, TETA, TJA-250, Orphan drug

NCCNCCNCCN

Lorlatinib, лорлатиниб , لورلاتينيب , 洛拉替尼 , PF-6463922

February 13, 2017 10:43 am / Leave a comment

ChemSpider 2D Image | lorlatinib | C21H19FN6O2

Lorlatinib, PF-6463922

For Cancer; Non-small-cell lung cancer

Molecular Formula C₂₁H₁₉FN₆O₂
Average mass 406.413 Da

Phase 2

WO 2013132376

Andrew James Jensen, Suman Luthra, Paul Francis RICHARDSON
Applicant	Pfizer Inc.

(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8- methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile

(16R)-19-Amino-13-fluoro-4,8,16-trimethyl-9-oxo-17-oxa-4,5,8,20-tetraazatetracyclo[16.3.1.0^2,6.0^10,15]docosa-1(22),2,5,10,12,14,18,20-octaene-3-carbonitrile

(10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile

CAS 1454846-35-5 [RN]

UNII:OSP71S83EU

лорлатиниб [Russian]

لورلاتينيب [Arabic]

洛拉替尼 [Chinese]

Ros1 tyrosine kinase receptor inhibitor; Anaplastic lymphoma kinase receptor inhibitor

useful for treating cancer mediated by anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 (ROS1) receptor tyrosine kinase, particularly NSCLC. an ATP-competitive inhibitor of ROS1/ALK, for treating NSCLC. In February 2017, lorlatinib was reported to be in phase 2 clinical development.

Originator Pfizer
Developer Pfizer; The Childrens Hospital of Philadelphia; Yale University
Class Antineoplastics; Aza compounds; Benzoxazines; Pyrazoles; Pyrazolones; Small molecules
Mechanism of Action Anaplastic lymphoma kinase inhibitors; ROS1-protein-inhibitors

Orphan Drug Status Yes – Non-small cell lung cancer

Lorlatinib (PF-6463922) is an experimental anti-neoplastic drug in development by Pfizer. It is a orally-administered small molecule inhibitor of ROS1 and ALK.

In 2015, FDA granted Pfizer orphan drug status for lorlatinib for the treatment of non-small cell lung cancer.^[1]

05 Oct 2016 Massachusetts General Hospital plans a phase II trial for Non-small cell lung cancer (Late-stage disease, Metastatic disease) in USA (PO, unspecified formulation) (NCT02927340)
01 Oct 2016 Pfizer completes a phase I trial in pharmacokinetic trial in Healthy volunteers in USA (NCT02804399)
01 Aug 2016 Pfizer initiates a phase I drug-drug interaction trial in Healthy volunteers in Belgium (PO, unspecified formulation) (NCT02838264)

Structures of ALK inhibitors marketed or currently in the clinic

Synthesis

NEED COLOUR

Clinical studies

Several clinical trials are ongoing. A phase II trial comparing avelumab alone and in combination with lorlatinib or crizotinib for non-small cell lung cancer is expected to be complete in late 2017. A phase II trial comparing lorlatinib with crizotinib is expected to be complete in mid-2018.^[2] A phase II trial for treatment of ALK-positive or ROS1-positive non-small cell lung cancer with CNA metastases is not expected to be complete until 2023.^[3] Preclinical studies are investigating lorlatinib for treatment of neuroblastoma.

Lorlatinib is an investigational medicine that inhibits the anaplastic lymphoma kinase (ALK) and ROS1 proto-oncogene. Due to tumor complexity and development of resistance to treatment, disease progression is a challenge in patients with ALK-positive metastatic non-small cell lung cancer (NSCLC). A common site for progression in metastatic NSCLC is the brain. Lorlatinib was specifically designed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood brain barrier.

ABOUT LORLATINIB

ALK in NSCLC ROS1 in NSCLC PRECLINICAL DATA CLINICAL STUDIES Originally discovered as an oncogenic driver in a type of lymphoma, ALK gene alterations were also found to be among key drivers of tumor development in cancers, such as NSCLC.1 In ALK-positive lung cancer, a normally inactive gene called ALK is fused with another gene. This genetic alteration creates the ALK fusion gene and ultimately, the production of an ALK fusion protein, which is responsible for tumor growth.1,2 This genetic alteration is present in 3-5% of NSCLC patients.3,4,5 Another gene that can fuse with other genes is called ROS1. Sometimes a ROS1 fusion protein can contribute to cancer-cell growth and tumor survival. This genetic alteration is present in approximately 1% of NSCLC patients.5 Preclinical data showed lorlatinib is capable of overcoming resistance to existing ALK inhibitors and penetrated the blood brain barrier in ALK-driven tumor models.2 Specifically, in these preclinical models, lorlatinib had activity against all tested clinical resistance mutations in ALK.

A Phase 1/2 clinical trial of lorlatinib in patients with ALK-positive or ROS1-positive advanced NSCLC is currently ongoing. • The primary objective of the Phase 1 portion was to assess safety and tolerability of single-agent lorlatinib at increasing dose levels in patients with ALK-positive or ROS1-positive advanced NSCLC.6 • Data from the Phase 1 study showed that lorlatinib had promising clinical activity in patients with ALK-positive or ROS1- positive advanced NSCLC. Most of these patients had developed CNS metastases and had received ≥1 prior tyrosine kinase inhibitor.7 o The most common treatment-related adverse events (AEs) were hypercholesterolemia (69%) and peripheral edema (37%). Hypercholesterolemia was the most common (11%) grade 3 or higher treatment-related AE and the most frequent reason for dose delay or reduction. No patients discontinued due to treatment-related AEs. At the recommended Phase 2 dose, 4 out of 17 patients (24%) experienced a treatment-related AE of any grade that led to a dose delay or hold.

PATENT

WO2014207606

This invention relates to crystalline forms of the macrocyclic kinase inhibitor, (10R)-7-amino-12-fluoro-2, 10,16-trimethyl-15-OXO-10,15, 16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4, 3-?][2,5,1 1 ]benzoxadiazacyclotetradecine-3-carbonitrile, including crystalline solvates thereof, that may be useful in the treatment of abnormal cell growth, such as cancer, in mammals. The invention also relates to compositions including such crystalline forms, and to methods of using such compositions in the treatment of abnormal cell growth in mammals, especially humans.

Background of the Invention

The compound (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2/-/-8,4-(metheno)pyrazolo[4,3- ?][2,5,1 1 ]benzoxadiazacyclotetradecine-3-carbonitrile, represented by the formula (I):

(I)

is a potent, macrocyclic inhibitor of both wild type and resistance mutant forms of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) receptor tyrosine kinase. Preparation of the free base compound of formula (I) as an amorphous solid is disclosed in International Patent Publication No. WO 2013/132376 and in United States Patent Publication No. 2013/0252961 , the contents of which are incorporated herein by reference in their entirety.

Human cancers comprise a diverse array of diseases that collectively are one of the leading causes of death in developed countries throughout the world (American Cancer Society, Cancer Facts and Figures 2005. Atlanta: American Cancer Society; 2005). The progression of cancers is caused by a complex series of multiple genetic and molecular events including gene mutations, chromosomal translocations, and karyotypic abnormalities (Hanahan & Weinberg, The hallmarks of cancer. Cell 2000; 100: 57-70). Although the underlying genetic causes of

cancer are both diverse and complex, each cancer type has been observed to exhibit common traits and acquired capabilities that facilitate its progression. These acquired capabilities include dysregulated cell growth, sustained ability to recruit blood vessels (i.e., angiogenesis), and ability of tumor cells to spread locally as well as metastasize to secondary organ sites (Hanahan & Weinberg 2000). Therefore, the ability to identify novel therapeutic agents that inhibit molecular targets that are altered during cancer progression or target multiple processes that are common to cancer progression in a variety of tumors presents a significant unmet need.

Receptor tyrosine kinases (RTKs) play fundamental roles in cellular processes, including cell proliferation, migration, metabolism, differentiation, and survival. RTK activity is tightly controlled in normal cells. The constitutively enhanced RTK activities from point mutation, amplification, and rearrangement of the corresponding genes have been implicated in the development and progression of many types of cancer. (Gschwind et al., The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat. Rev. Cancer 2004; 4, 361-370; Krause & Van Etten, Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med. 2005; 353: 172-187.)

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, grouped together with leukocyte tyrosine kinase (LTK) to a subfamily within the insulin receptor (IR) superfamily. ALK was first discovered as a fusion protein with nucleophosmin (NPM) in anaplastic large cell lymphoma (ALCL) cell lines in 1994. (Morris et al., Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994; 263:1281-1284.) NPM-ALK, which results from a chromosomal translocation, is implicated in the pathogenesis of human anaplastic large cell lymphoma (ALCL) (Pulford et al., Anaplastic lymphoma kinase proteins in growth control and cancer. J. Cell Physiol., 2004; 199: 330-58). The roles of aberrant expression of constitutively active ALK chimeric proteins in the pathogenesis of ALCL have been defined (Wan et. al., Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large cell lymphoma cells. Blood, 2006; 107:1617-1623). Other chromosomal rearrangements resulting in ALK fusions have been subsequently detected in ALCL (50-60%), inflammatory myofibroblastic tumors (27%), and non-small-cell lung cancer (NSCLC) (2-7%). (Palmer et al., Anaplastic lymphoma kinase: signaling in development and disease. Biochem. J. 2009; 420:345-361 .)

The EML4-ALK fusion gene, comprising portions of the echinoderm microtubule associated protein-like 4 (EML4) gene and the ALK gene, was first discovered in NSCLC archived clinical specimens and cell lines. (Soda et al., Identification of the transforming EML4-ALK fusion gene in non-small cell lung cancer. Nature 2007; 448:561-566; Rikova et al., Cell 2007; 131 :1 190-1203.) EML4-ALK fusion variants were demonstrated to transform NIH-3T3 fibroblasts and cause lung adenocarcinoma when expressed in transgenic mice, confirming the

potent oncogenic activity of the EML4-ALK fusion kinase. (Soda et al., A mouse model for EML4-ALK-positive lung cancer. Proc. Natl. Acad. Sci. U.S.A. 2008; 105:19893-19897.) Oncogenic mutations of ALK in both familial and sporadic cases of neuroblastoma have also been reported. (Caren et al., High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumors. Biochem. J. 2008; 416:153-159.)

ROS1 is a proto-oncogene receptor tyrosine kinase that belongs to the insulin receptor subfamily, and is involved in cell proliferation and differentiation processes. (Nagarajan et al. Proc Natl Acad Sci 1986; 83:6568-6572). ROS is expressed, in humans, in epithelial cells of a variety of different tissues. Defects in ROS expression and/or activation have been found in glioblastoma, as well as tumors of the central nervous system (Charest et al., Genes Chromos. Can. 2003; 37(1): 58-71). Genetic alterations involving ROS that result in aberrant fusion proteins of ROS kinase have been described, including the FIG-ROS deletion translocation in glioblastoma (Charest et al. (2003); Birchmeier et al. Proc Natl Acad Sci 1987; 84:9270-9274; and NSCLC (Rimkunas et al., Analysis of Receptor Tyrosine Kinase ROS1 -Positive Tumors in Non-Small Cell Lung Cancer: Identification of FIG-ROS1 Fusion, Clin Cancer Res 2012; 18:4449-4457), the SLC34A2-ROS translocation in NSCLC (Rikova et al. Cell 2007;131 :1 190-1203), the CD74-ROS translocation in NSCLC (Rikova et al. (2007)) and cholangiocarcinoma (Gu et al. PLoS ONE 201 1 ; 6(1 ): e15640), and a truncated, active form of ROS known to drive tumor growth in mice (Birchmeier et al. Mol. Cell. Bio. 1986; 6(9):3109-31 15). Additional fusions, including TPM3-ROS1 , SDC4-ROS1 , EZR-ROS1 and LRIG3-ROS1 , have been reported in lung cancer patient tumor samples (Takeuchi et al., RET, ROS1 and ALK fusions in lung cancer, Nature Medicine 2012; 18(3):378-381).

The dual ALK/c-MET inhibitor crizotinib was approved in 201 1 for the treatment of patients with locally advanced or metastatic NSCLC that is ALK-positive as detected by an FDA-approved test. Crizotinib has also shown efficacy in treatment of NSCLC with ROS1 translocations. (Shaw et al. Clinical activity of crizotinib in advanced rson-smali cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. Presented at the Annual Meeting of the American Society of Clinical Oncology, Chicago, June 1-5, 2012.) As observed clinically for other tyrosine kinase inhibitors, mutations in ALK and ROS1 that confer resistance to ALK inhibitors have been described (Choi et ai., EML4-ALK Mutations in Lung Cancer than Confer Resistance to ALK Inhibitors, N Engl J Med 2010; 363:1734-1739; Awad et ai., Acquired Resistance to Crizotinib from a Mutation in CD74-ROS1, Engl J Med 2013; 368:2395-2401 ).

Thus, ALK and ROS1 are attractive molecular targets for cancer therapeutic intervention. There remains a need to identify compounds having novel activity profiles against wild-type and mutant forms of ALK and ROS1 .

The present invention provides crystalline forms of the free base of (10R)-7-amino-12-fluoro-2, 10,16-trimethyl-15-OXO-10,15, 16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3- ?][2, 5,1 1 ]-benzoxadiazacyclotetradecine-3-carbonitrile having improved properties, such as improved crystallinity, dissolution properties, decreased hygroscopicity, improved mechanical properties, improved purity, and/or improved stability, while maintaining chemical and enantiomeric stability.

Comparative Example 1A

Preparation of (10f?)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3- ?l[2,5,1 Hbenzoxadiazacyclo-tetradecine-3-carbonitrile (amorphous)

Example 1A

Step 1 :

Palladium (II) acetate (53 mg, 0.24 mmol) and cataCXium^® A (180 mg, 0.5 mmol) were mixed together in toluene (1 .5 mL, de-gassed) and the resulting solution was added via pipette to a stirred solution of compound 7 (0.9 g, 2.4 mmol), compound 15 (1 .0 g, 3.0 mmol) bis-pinacolato diboron (0.9 g, 3.6 mmol) and CsF (1 .9 g, 12.6 mmol) in MeOH/H₂0 (9:1 , 12 mL, degassed) at 60 °C. The resulting mixture was then stirred at reflux for 3 hrs. A further portion of Palladium (II) acetate (26 mg, 0.12 mmol) and cataCXium^® A (90 mg, 0.25 mmol) in toluene (1 .5 mL, de-gassed) was added, and the yellow reaction mixture stirred at 60 °C overnight. After cooling to room temperature, the mixture was diluted with EtOAc (150 mL) and filtered through CELITE®. The filtrate was washed with water (100 mL), then brine (100 mL), dried (Na₂S0₄) and evaporated. The residue was purified by flash chromatography over silica gel, which was eluted with 1 :1 EtOAc/cyclohexane, to give compound 22 as a yellow oil (570 mg, 43% yield). TLC (Rf = 0.40, 1 :1 EtOAc/cyclohexane). ¹H NMR (400 MHz, CDCI₃) δ 8.03 (m, 1 H), 7.65 (s, 1 H), 7.27 (dd,1 H, J = 9.9, 2.7 Hz), 7.01 (m, 1 H), 6.68 (m, 1 H), 6.40 (m, 1 H), 4.90 (br s, 2 H), 4.20 – 4.30 (m, 2 H), 3.96 (s, 3 H), 3.94 (s, 3 H), 2.55 – 2.85 (m, 3 H), 1 .68 (d, 3 H, J = 6.6 Hz), 1 .24 (s, 9 H). LCMS ES m/z 539 [M+H]⁺.

Step 2:

To a solution of compound 22 (69% purity, 0.95 g, assumed 1 .05 mmol) in MeOH (20 mL) was added a solution NaOH (1 .0 g, 25 mmol) in water (2 mL). The mixture was stirred at 40 °C for 3.5 hours. The reaction was diluted with water (80 mL), concentrated by 20 mL to remove MeOH on the rotary evaporator, and washed with MTBE (100 mL). The aqueous layer was then acidified carefully with 1 M aq HCI to approx. pH 2 (pH paper). Sodium chloride (15 g) was added to the mixture and the mixture was extracted with EtOAc (100 mL). The organic layer was separated, dried (Na₂S0₄) and evaporated to give compound 23 as a pale yellow solid (480 mg, 87% yield). ¹H NMR (400 MHz, CD₃OD) δ 8.05 (m, 1 H), 7.45 (s, 1 H), 7.37 (dd,1 H, J = 10.4, 2.8 Hz), 7.10 (dt, 1 H, J = 8.5, 2.4 Hz), 6.50 – 6.60 (m, 2 H), 4.05 – 4.30 (m, 2 H), 3.99 (s, 3 H), 2.60 – 2.80 (m, 3 H), 1 .72 (d, 3 H, J = 6.5 Hz). LCMS ES m/z 525 [M+H]⁺.

Step 3:

A solution of HCI in dioxane (4 M, 6.0 mL) was added to a solution of compound 23

(480 mg, 0.91 mmol) in MeOH (methanol) (6 mL) and the reaction was stirred at 40 °C for 2.5 hours. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was taken-up in MeOH (50 mL) and acetonitrile (100 mL) was added and the mixture was then again evaporated to dryness, to give compound 24 as an off white solid (400 mg, 87% yield). ¹H NMR (400 MHz, CD₃OD) δ 8.07 (dd, 1 H, J = 8.9. 5.9 Hz), 7.51 (d, 1 H, J = 1 .7 Hz), 7.42 (dd, 1 H, J = 9.8, 2.6 Hz), 7.23 (d, 1 H, J = 1 .6 Hz), 7.16 (dt, 1 H, J = 8.5, 2.7 Hz), 6.73 (dd, 1 H, J = 1 1 .9, 6.9 Hz), 4.22 (d, 1 H, J = 14.7 Hz), 4.14 (d, 1 H, J = 14.7 Hz), 4.07 (s, 3 H), 2.75 (s, 3 H), 1 .75 (d, 3 H, J = 5.5 Hz). LCMS ES m/z 425 [M+H]⁺.

Step 4:

A solution of compound 24 (400 mg, assumed 0.91 mmol) as the HCI salt and DIPEA

(diisopropylethylamine) (1 .17 g, 9.1 mmol) in DMF (dimethylformamide) (5.0 mL) and THF (0.5 mL) was added drop-wise to a solution of HATU (2-(1 H-7-azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyl uronium hexafluorophosphate methanaminium) (482 mg, 1 .27 mmol) in DMF (10.0 mL) at 0 °C over 30 minutes. After complete addition, the mixture was stirred at 0 °C for a further 30 mins. Water (70 mL) was added and the mixture was extracted into EtOAc (2 x 60 mL). The combined organics were washed with saturated aqueous NaHC0₃ (2 x 100 mL), brine (100 mL), dried over Na₂S0₄, and evaporated. The residue was purified by column chromatography over silica gel, which was eluted with 70% EtOAc/cyclohexane giving 205 mg of a pale yellow residue (semi-solid). The solids were dissolved in MTBE (7 mL) and cyclohexane (20 mL) was added slowly with good stirring to precipitate the product. After stirring for 30 minutes, the mixture was filtered, and Example 1A was collected as an

amorphous white solid (1 10 mg, 29% yield). TLC (Rf = 0.40, 70% EtOAc in cyclohexane). ¹H NMR (400 MHz, CDCI₃) δ 7.83 (d, 1 H, J = 2.0 Hz), 7.30 (dd, 1 H, J = 9.6, 2.4 Hz), 7.21 (dd, 1 H, J = 8.4, 5.6 Hz), 6.99 (dt, 1 H, J = 8.0, 2.8 Hz), 6.86 (d, 1 H, J = 1 .2 Hz), 5.75 – 5.71 (m, 1 H), 4.84 (s, 2 H), 4.45 (d, 1 H, J = 14.4 Hz), 4.35 (d ,1 H, J = 14.4 Hz), 4.07 (s, 3 H), 3.13 (s, 3 H), 1 .79 (d, 3 H, J = 6.4Hz). LCMS ES m/z 407 [M+H]⁺.

Example 1

Preparation of crystalline hydrate of (10 ?)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo- 10,15,16,17-tetrahvdro-2/-/-8,4-(metheno)pyrazolo[4,3- ?l[2,5,1 Hbenzoxa-diazacyclo-tetradecine-3-carbonitrile (Form 1)

Example 1A Example 1

(amorphous) _{(Form 1 }}

Amorphous (10f?)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3- ?][2,5,11 ]benzoxa-diazacyclo-tetradecine-3-carbonitrile free base, prepared as described in Example 1A (and Example 2 of United States Patent Publication No. 2013/0252961), was dissolved in 1 .0 : 1 .1 (v:v) H₂0:MeOH at a concentration of 22 mg/mL at 50°C, then allowed to cool to room temperature . This slurry was granulated for approximately 72 hours. The solids were isolated by filtration and vacuum dried overnight at 60°C to produce crystalline hydrate Form 1 of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-/?][2,5,1 1 ]benzoxadiazacyclotetradecine-3-carbonitrile.

Example 4

Alternative preparation of crystalline acetic acid solvate of (10 ?)-7-amino-12-fluoro-2, 10,16-trimethyl-15-OXO-10,15, 16,17-tetrahvdro-2H-8,4-(metheno)pyrazolo[4,3- ?U2,5, 1 1 lbenzoxa-diazacyclotetradecine-3-carbonitrile (Form 3)

Step 1 :

To a reaction vessel under N₂ were charged compound 9 (9.97 kg, 17.95 mol), compound 21 (3.52 kg, 18.85 mol) and 2-methyltetrahydrofuran (97 L). Triethylamine (7.45 kg, 73.6 mol) was added while keeping the internal temperature below 35°C. The reaction mixture was held for 30 min and n-propylphosphonic anhydride (T3P), 50% solution in ethyl acetate (22.85 kg, 35.9 mol) was charged slowly, maintaining the internal temperature below 25°C. The reaction mixture was held at 20°C for at least 2 h until reaction was deemed complete. Ethyl acetate (35 L) and water (66 L) were added followed by 0.5N Hydrochloric acid solution (80 L). The aqueous layer was removed and the organic layer was washed with brine solution (80 L). The organic layer was concentrated and solvent exchanged with 2-methyl-2-butanol (80 L) give compound 25 (23 wt/wt%) solution in 2-methyl-2-butanol . This solution was carried forward to the next step directly in three batches, assuming 12.00 kg (100% yield) from this step.

Step 2:

2-Methyl-2-butanol (100 L) was combined with potassium acetate (1 .8 kg, 18.34 mol), palladium(ll) acetate (0.10 kg, 0.46 mol) and water (0.10 kg, 5.73 mol). The resulting mixture was purged with nitrogen. Di(1 -adamantyl)n-butylphosphine (0.23 kg, 0.43 mol) was added. An amount of 20% of compound 25 (3.97 kg active or 17.3 L of step 1 solution in 2-methyl-2-butanol) was added, and the resulting reaction mixture was heated at reflux for 2 h. The remaining solution of compound 25 in 2-methyl-2-butanol was subsequently added to the reaction over a period of 5 h. The resulting mixture was heated until the reaction was deemed complete (typically 16 – 20 h). This reaction step was processed in three batches, and the isolation was done in one single batch. Thus, the combined three batches were filtered through CELITE® to remove insoluble materials. The filtrate was concentrated to a low volume (approximately 20 L). Acetonitrile (60 L) was added. The resulting mixture was heated to reflux for 2 – 4 h, then cooled to RT for granulation. The resulting slurry was filtered to give compound 26 as a crude product. The crude product was combined with ethyl acetate (80 L) and Silicycle thiol (5 kg). The resulting mixture was heated for 2 h, cooled to RT and filtered. The filtrate was concentrated to approx. 20 L, and the resulting slurry was granulated and filtered. The filter cake was rinsed with ethyl acetate (4 L) and dried in a vacuum oven to give compound 26 as a pure product (4.74 kg, 43.5% overall last two steps). ¹H NMR (CDCI₃) δ 8.25 – 8.23 (m, 1 H), 7.28 (1 H, dd, 2.76 and 9.79 Hz), 7.22 (1 H, dd, 5.52 and 8.53 Hz), 7.18 (1 H, d, J = 1 .76 Hz), 7.01 (1 H, dt, J = 2.50 and 8.03 Hz), 5.78 – 5.70 (m, 1 H), 4.76 (1 H, d, J = 14.3 Hz), 4.13 (s, 3H), 3.16 (s, 3H), 1 .78 (d, 3H, J = 6.02 Hz), 1 .45 (s, 18H); 13C NMR (CDCI₃) δ 167.0, 162.9, 160.4, 148.7, 146.3, 143.0, 140.7, 139.9, 135.5, 129.9, 129.8, 126.1 , 123.8, 123.5, 1 19.7, 1 13.8, 1 13.5, 1 1 1 .6, 108.1 , 81 .1 , 70.1 , 45.5, 37.0, 29.7, 26.0, 20.7; LCMS (M+1)⁺ 607.3, 507.1 , 451 .2.

Step 3:

To a reactor under N₂ was added compound 26 (4.74 kg, 7.82 mol) and ethyl acetate (54 L). Hydrochloric acid 37% (5.19 L, 63.2 mol) was charged slowly while keeping the internal temperature below 25°C. The reaction mixture was stirred for 24 – 48 h until the reaction was complete. Ethyl acetate (54L) and water (54 L) were added. The reaction mixture was then treated with triethylamine until pH 8 – 9 was reached. The aqueous layer was removed and then the organic layer was washed water (2 x 54 L). The organic layer was concentrated under reduced pressure to approx. 54 L to give compound 27 (unisolated).

Step 4:

Acetic acid (1 .0 kg, 16.6 mol) was added to the organic layer containing compound 27. The reaction mixture was concentrated and then held for at least 3 h with stirring at RT. The resulted slurry was filtered. The filter cake was washed with ethyl acetate (2 L) and dried under vacuum to give 3.20 kg (87.8% yield) of Example 4 acetic acid solvate (Form 3). The spectroscopic data of this material was identical to that of an authentic sample of the crystalline acetic acid Form 3 of (10R)-7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2/-/-8,4-(metheno)pyrazolo[4,3- ?][2,5,1 1 ]-benzoxadiazacyclo-tetradecine-3-carbonitrile prepared according to Example 3.

Preparation of Synthetic Intermediates

7 6 5

Step 1 :

A solution of (-)-DIPCI ((-)-B-chlorodiisopinocampheylborane) (57.1 g, 178 mmol) in THF

(tetrahydrofuran) (100 ml) was cooled to -20 to -30 °C. A solution of compound 1 (31 .3 g, 1 19 mmol) in THF (100 ml) was then added dropwise, via addition funnel (30 min addition). The reaction was left to warm up to room temperature (RT). After 2 h, the reaction was cooled to -30 °C and another portion of (-)-DIPCI (38.0 g, 1 19 mmol) was added. After 30 min, the reaction was allowed to warm to RT and after 1 h, the solvents were removed in vacuo and the residue re-dissolved in MTBE (methyl tertiary-butyl ether) (200 ml). A solution of diethanolamine (31 g, 296 mmol) in ethanol/THF (15 ml/30 ml) was added via addition funnel, to the reaction mixture under an ice bath. The formation of a white precipitate was observed. The suspension was heated at reflux for 2 hours then cooled to room temperature, filtered and the mother liquids concentrated in vacuo. The residue was suspended in heptane/EtOAc (7:3, 200 ml) and again

filtered. This procedure was repeated until no more solids could be observed after the liquids were concentrated. The final yellow oil was purified by column chromatography (eluent: cyclohexane/EtOAc 99:1 to 96:4). The resulting colorless oil was further purified by recrystallization from heptanes, to give alcohol compound 2 (25 g, 80% yield, 99% purity and 96% ee) as white crystals. ¹H NMR (400 MHz, CDCI₃) δ 7.73 (dd, 1 H), 7.32 (dd, 1 H), 6.74 (ddd, 1 H), 4.99 – 5.04 (m, 1 H), 2.01 (d, 1 H), 1 .44 (d, 3 H). LCMS-ES: No ionization, Purity 99%. Chiral GC (column CP-Chirasil-DexnCB): 96% ee; Rt (minor) 17.7 minutes and Rt (major) 19.4 minutes.

Step 2:

A solution of compound 2 (22 g, 83 mmol) in MTBE (350 mL) was cooled under an ice bath and triethylamine (23 mL, 166 mmol) followed by mesyl chloride (9.6 mL, 124 mmol) were added drop-wise. The reaction was then warmed to RT and stirred for 3 h. The reaction mixture was filtered and the solids washed with EtOAc. The mother liquids were concentrated in vacuo to give compound 3 (35 g, 80% yield) as a pale yellow oil. This material was taken into the following step without further purification. ¹H NMR (400 MHz, CDCI₃) δ 7.78 (dd, 1 H), 7.24 (dd, 1 H), 6.82 (ddd, 1 H), 2.92 (s, 3 H), 1 .64 (d, 3 H). LCMS-ES no ionization.

Step 3:

A suspension of Cs₂C0₃ (65 g, 201 mmol) and compound 4 (13.3 g, 121 mmol) in 2-CH₃-THF (2-methyitetrahydrofuran) (600 mL) and acetone (300 mL) was stirred at RT for 30 minutes then heated at 40 °C before drop-wise addition of a solution of compound 3 (34.4 g, 80 mmol) in 2-CH₃-THF (300 mL) via addition funnel. The resulting mixture was left stirring at 75 -80 °C for 24 h. The reaction was then filtered through CELITE® with MTBE, the solvents removed in vacuo and the residue purified by column chromatography over silica gel which was eluted with cyclohexane/EtOAc (9:1 to 1 :1) to give compound 5 (14.3 g, 39 % yield, 90% ee) as a white solid. The solids were then re crystallized from heptane/EtOAc to give compound 5 (10.8 g, 37% yield, 95% ee). ¹H NMR (400 MHz, CDCI₃) 5 7.38 (dd, 1 H), 7.62 (dd, 1 H), 7.10 (dd, 1 H), 6.75 (ddd, 1 H), 6.44 – 6.51 (m, 2 H), 5.34 – 5.39 (m, 1 H), 4.73 (br s, 2 H), 1 .61 (d, 3 H). LCMS-ES m/z 359 [M+H]⁺. HPLC (Chiralpak IC 4.6 x 250 mm): 95% ee; Rt (minor) 10.4 minutes; Rt (major) 14.7 minutes; eluent: Heptane 80%/IPA 20% with 0.2% DEA, 0.7 mL/min. Step 4:

Compound 5 (20 g, 57 mmol) was dissolved in methanol (300 mL), and sequentially treated with triethylamine (TEA) (15.4 mL, 1 13 mmol) and PdCI₂(dppf) (1 ,1 -bis(diphenylphosphino)ferrocene]dichloropalladium(ll) ) (4.1 g, 5.7 mmol). This mixture was heated at 100 °C for 16 hours, under a 100 psi carbon monoxide atmosphere. LCMS indicated consumption of starting material. The reaction mixture was filtered through a pad of CELITE®, and the filtrate evaporated to a brown oil. The crude product was purified by flash

chromatography over silica gel which was eluted with 50% to 75% ethyl acetate in cyclohexane, affording the pure product 6 as a brick-red solid (13.0 g, 79% yield). ¹H NMR (400 MHz, CDCI₃) δ 1 .65 (d, 3 H), 3.94 (s, 3 H), 4.75 (br s, 2 H), 6.32 (q, 1 H), 6.42 (dd, 1 H), 6.61 (dd, 1 H), 7.00 (ddd, 1 H), 7.28 (dd, 1 H), 7.60 (dd, 1 H), 8.03 (dd, 1 H). LCMS ES m/z 291 for [M+H]⁺.

Step 5:

Compound 6 (13.0 g, 45 mmol) was dissolved in acetonitrile (195 mL), and cooled to <10 °C in an ice water bath. NBS (N-bromosuccinimide) (7.9 g, 45 mmol) was added drop-wise to the cooled reaction mixture as a solution in acetonitrile (195 mL), monitoring the internal temperature to ensure it did not rise above 10 °C. After addition was complete, the mixture was stirred for 15 minutes. Thin layer chromatography (TLC) (1 :1 cyclohexane/ethyl acetate) showed consumption of starting material. The reaction mixture was evaporated, and the residue redissolved in ethyl acetate (400 mL), and washed with 2M aqueous NaOH (2 x 300 mL), and 10% aqueous sodium thiosulfate solution (300 mL). The organic extracts were dried over MgS0₄, and evaporated to a red oil (17.6 g). The crude product was purified over silica gel, which was eluted with 10% to 50% ethyl acetate in cyclohexane, which gave compound 7 (12.0 g, 73% yield). ¹H NMR (400 MHz, CDCI₃) δ 1 .65 (d, 3 H), 3.96 (s, 3 H), 4.74 – 4.81 (br s, 2 H), 6.33 (q, 1 H), 6.75 (d, 1 H), 7.03 (ddd, 1 H), 7.25 (dd, 1 H), 7.66 (d, 1 H), 8.06 (dd, 1 H). LCMS ES m/z 369/371 [M+H]⁺. A Chiralpak AD-H (4.6 x 100 mm, 5 micron) column was eluted with 10% MeOH (0.1 % DEA) in C0₂ at 120 bar. A flow rate of 5.0 mL/min gave the minor isomer Rt 0.6 minutes and the major isomer Rt 0.8 minutes (99% ee). Optical rotation: [ ]_d²⁰ = -92.4 deg (c=1 .5, MeOH).

Preparation of (/?)-methyl 2-(1 -((N,N-di-Boc-2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorobenzoic acid (9)

Step 1 :

To a solution of compound 7 (2000 g, 5.4 mol) in dry DCM (dichloromethane) (32000 mL) was added DIPEA (N.N-dsisopropyleibylamine) (2100 g, 16.28 mol) and DMAP (4-dimethylaminopyridine) (132 g, 1 .08 mol). Then Boc₂0 (di-tert-butyl-dicarbonate) (3552 g, 16.28 mol) was added to the mixture in portions. The reaction was stirred at RT for overnight. TLC (petroleum ether/EtOAc =5:1) show the reaction was complete, the mixture was washed with sat. NH₄CI (15 L) two times, then dried over Na₂S0₄and concentrated to give a crude product which was purified by column (silica gel, petroleum ether/EtOAc from 20:1 to 10:1) to give compound 8 (2300 g, 75%) as a white solid.

Step 2:

Compound 8 (50 g, 87.81 mmol, 100 mass%) was charged to a round bottom flask (RBF) containing tetrahydrofuran (12.25 mol/L) in Water (5 mL/g, 3060 mmol, 12.25 mol/L) and sodium hydroxide (1 mol/L) in Water (1 .5 equiv., 131 .7 mmol, 1 mol/L). The biphasic mixture was stirred at RT for 14 hours. 1 N HCI was added to adjust pH to < 2. THF was then removed by vacuum distillation. The product precipitated out was collected by filtration. The filter cake was rinsed with water, pulled dried then dried in vacuum oven to constant weight (48 h, 55°C, 25 mbar). 48.3g isolated, 99% yield. ¹H NMR (CDCI₃, 400MHz) δ 8.24 (1 H, dd, 1 H, J = 5.76 and 3.0 Hz), 8.16 (1 H, d, J = 2.0 Hz), 7.37 (1 H, dd, J = 2.5 and 9.8 Hz), 7.19 (1 H, d, J = 2 Hz), 7.14 – 7.06 (1 H, m), 6.50 (1 H, q, J = 6.3 Hz), 1 .67 (3H, d, J = 8.4 Hz), 1 .48 (18H, s). ¹³C NMR (CDCI₃, 100 MHz), δ 170.1 , 169.2, 167.6, 165.1 , 150.6, 149.2, 148.6, 141 .4, 140.7, 135.2, 135.1 , 124.2, 122.2,122.1 , 1 19.9, 1 15.4, 1 15.1 , 1 13.4, 1 13.2, 100.0, 83.4, 73.3, 27.9, 23.9. LCMS (M⁺ +1) 557.2, 555.3, 457.1 , 455.1 , 401 , 0, 399.0.

Step 1 :

Ethyl 1 ,3-dimethylpyrazole-5-carboxylate (5.0 g, 30 mmol) was dissolved in 1 ,2-dichloroethane (200 mL), followed by addition of NBS (5.3 g, 30 mmol) and dibenzoyi peroxide (727 mg, 3.0 mmol), in small portions and stirred at 85 °C for 2 hours. The mixture was allowed to cool, diluted to 400 mL with dichloromethane, and washed with water (2 x 200 mL). The organic layer was dried over MgS0₄, and evaporated to give compound 10 (4.1 g, 42% yield). TLC (EtOAc/Cyclohexane; 1 :10; KMn0₄): Rf~0.3. ¹H NMR (400 MHz, CDCI₃) δ 4.47 (s, 2 H), 4.41 (q, 2 H), 4.15 (s, 3 H), 1 .42 (t, 3 H). LCMS ES m/z 324/326/328 [M+H]⁺.

Step 2:

Compound 10 (3.0 g, 9.2 mmol) was dissolved in methylamine solution (33% solution in ethanol, 70 mL), and stirred at RT for 16 hours. The mixture was evaporated to give compound 11 (1 .8 g, 71 % yield). ¹H NMR (400 MHz, CDCI₃) δ 4.39 (q, 2 H), 4.14 (s, 3 H), 4.05 (s, 2 H), 2.62 (d, 3 H), 1 .41 (t, 3 H). LCMS ES m/z 276/278 [M+H]⁺.

Step 3:

Compound 11 (1 .8 g, 6.5 mmol) was dissolved in dichloromethane (20 mL), and the mixture cooled to 0 °C. A solution of di(fe/?-butyl) dicarbonate (1 .75 g, 8 mmol) in dichloromethane (17.5 mL) was added dropwise. The ice bath was removed and the mixture stirred for 18 hours at room temperature. The mixture was diluted to 100 mL with dichloromethane, and washed with water (2 x 50 mL). Organic extracts were dried over magnesium sulfate, and evaporated to give compound 12 (1 .8 g, 72% yield). ¹H NMR (400 MHz, CDCI₃) δ 4.48 – 4.44 (m, 2 H), 4.41 (q, 2 H), 4.12 (s, 3 H), 2.82 – 2.79 (m, 3 H), 1 .47 (s, 9 H), 1 .41 (t, 3 H). LCMS ES m/z 376/378 [M+H]⁺ and 276/278 [M-BOC]⁺.

Step 4:

Compound 12 (4 g, 1 1 mmol) was dissolved in dioxane (43 mL). Sodium amide (1 g, 27 mmol) was added in one portion. The reaction mixture was stirred at 100 °C for 24 h. After this time, the solvent was removed under reduced pressure to give a white solid. The material was suspended in EtOAc (100 mL) and washed with 5% citric acid solution (100 mL). The organic phase was separated and washed with water (100 mL), dried over MgS0₄, filtered and the solvent removed in vacuo to give compound 13 as a yellow gum (3.1 g, 84% yield). ¹H NMR (400 MHz, DMSO-c/₆) δ 4.27 (s, 2 H), 3.92 (s, 3 H), 2.70 (s, 3 H), 1 .40 (s, 9 H). LCMS ES m/z 348/350 [M+H]⁺ and 248/250 [M-BOC]+.

Step 5:

Compound 13 (3 g, 8.6 mmol) was dissolved in DMF (43 mL, 0.2 M). HOBt (1 .2 g, 8.6 mmol) was added, followed by ammonium chloride (0.9 g, 17.2 mmol). EDCI (2.5 g, 13 mmol) was then added, followed by TEA (2.4 mL, 17 mmol). The reaction mixture was stirred at room temperature. After 18h, the solvent was removed under reduced pressure to give a yellow oil

(8.0 g). The residue was dissolved in EtOAc (75ml_). The organic phase was washed with NaHC0₃ (sat. solution, 70 ml_) and then brine (100 ml_). The combined organic layers were dried over MgS0₄ and the solvent removed in vacuo to give compound 14 as a dark yellow oil (2.7 g, 91 % yield). This material was used directly in the next step without further purification. ¹H NMR (400 MHz, CDCI₃) δ 6.74 (br s, 1 H), 5.95 (br s, 1 H), 4.49 (br s, 2 H), 4.16 (s, 3 H), 2.81 (br s, 3 H), 1 .47 (s, 9 H). LCMS ES m/z 347/349 [M+H]⁺ and 247/249 [M-BOC]⁺.

Step 6:

Compound 14 (2.7 g, 7.9 mmol) was dissolved in DCM (80 ml_, 0.1 M). TEA (3.3 ml_, 23.8 mmol) was then added and the reaction mixture cooled down to -5 °C. Trifluoroacetic anhydride (2.2 ml_, 15.8 mmol) in DCM (15 ml_) was added dropwise over 30 min. After addition, the reaction mixture was stirred at 0 °C for 1 h. After this time, the solvents were removed under reduced pressure to give a dark yellow oil. This residue was diluted in DCM (100 ml_), washed with 5% citric acid, sat. NaHC0₃and brine, dried over MgS0₄, filtered and the solvents removed in vacuo to give a dark yellow oil (2.6 g). The crude product was purified by reverse phase chromatography to give compound 15 as a yellow oil (2.3 g, 87% yield). ¹H NMR (400 MHz, CDCI₃) δ 4.46 (br s, 2 H), 4.01 (s, 3 H), 2.83 (br s, 3 H), 1 .47 (s, 9 H). LCMS ES m/z 331 /329 [M+H]⁺ and 229/231 [M-BOC]⁺ as the base ion.

Preparation o/^: 1 -methyl-3-((methylamino)methyl)-1 H-pyrazole-5-carbonitrile (21)

Step 1 :

To /V-benzylmethylamine (2.40 kg, 19.8 mol) and ethyldiisopropylamine (2.61 kg, 20.2 mol) in acetonitrile (6 L) at 16°C was added chloroacetone (1 .96 kg, 21 .2 mol) over 60 mins [exothermic, temp kept <30°C]. The mixture was stirred at 22°C for 18 hours then concentrated to an oily solid. The residue was triturated with MTBE (5 L), and then filtered through a pad of CELITE® (600 g, top) and silica (1 .5 kg, bottom), washing with MTBE (8 L). The filtrate was evaporated to afford compound 16 (3.35 kg, 18.9 mol, 95%) as a brown oil.

Step 2:

Compound 16 (1 .68 kg, 9.45 mol), Boc-anhydride (2.1 kg, 9.6 mol) and 20wt% Pd/C (50% H₂0, 56 g) in ethanol (5 L) were hydrogenated in an 1 1 -L autoclave at 50 psi [exotherm to 40°C with 20°C jacket]. The atmosphere became saturated with carbon dioxide during the reaction and so needed to be vented and de-gassed twice to ensure sufficient hydrogen uptake and completion of the reaction. The total reaction time was ~1 .5 hours. Two runs (for a total of 18.9 mol) were combined and filtered through a pad of SOLKA-FLOC®, washing with methanol. The filtrate was treated with DMAP (45 g, 0.37 mol) and stirred at room temperature overnight to destroy the excess Boc-anhydride. The mixture was then concentrated to dryness, dissolved in MTBE (6 L) and filtered through a pad of magnesol (1 kg), washing with MTBE (4 L). The filtrate was evaporated to afford compound 17 (3.68 kg, ~95 wt%, 18.7 mol, 99%) as an orange-brown oil.

Step 3:

To compound 17 (3.25 kg, -95 wt%, 16.5 mol) and diethyl oxalate (4.71 kg, 32.2 mol) in methanol (12 L) at 15°C was added 25 wt% sodium methoxide in methanol (6.94 kg, 32.1 mol) over 25 mins [temp kept <25°C]. The mixture was stirred at 20°C for 16 hours then cooled to -37°C and 37% hydrochloric acid (3.1 kg, 31 mol) was added over 5 mins [temp kept <-10°C]. The mixture was cooled to -40°C and methylhydrazine (1 .42 kg, 30.8 mol) was added over 7 mins [temp kept <-17°C]. The mixture was warmed to 5°C over 90 minutes, then re-cooled to 0°C and quenched by addition of 2.4M KHS0₄ (6.75 L, 16.2 mol) in one portion [exotherm to 27°C]. The mixture was diluted with water (25 L) and MTBE (15 L), and the layers separated. The organic layer was washed with brine (7 L) and the aqueous layers then sequentially re-extracted with MTBE (8 L). The combined organics were evaporated and azeotroped with toluene (2 L) to afford crude compound 18. Chromatography (20 kg silica, 10-40% EtOAc in hexane) afforded compound 18 (3.4 kg, ~95 wt%, 11 .4 mol, 69%) as an orange oil.

Step 4:

Ammonia (3 kg, 167 mol) was bubbled in to cooled methanol (24 L) [temp kept <18°C]. A solution of compound 18 (4.8 kg, ~95 wt%, 16.1 mol) in methanol (1 .5 L) was added over 30 minutes and the mixture stirred at 25°C for 68 hours and then at 30°C for 24 hours. Two runs (from a total of 9.68 kg of ~95 wt% Step 3) were combined and concentrated to ~13 L volume. Water (30 L) was slowly added over 80 minutes, keeping the temperature 30 to 40°C. The resulting slurry was cooled to 20°C, filtered, washed with water (12 L) and pulled dry on the filter overnight. The solids were triturated in MTBE (8 L) and hexane (8 L) at 45°C then re-cooled to 15°C, filtered, washed with hexane (4 L) and dried under vacuum to afford compound 19 (7.95 kg, 29.6 mol, 90%) as an off-white solid.

Step 5:

To compound 19 (7.0 kg, 26.1 mol) in DCM (30 L) at 0°C was added triethylamine (5.85 kg, 57.8 mol). The mixture was further cooled to -6°C then trifluoroacetic anhydride (5.85 kg, 27.8 mol) added over 90 minutes [temp kept 0 to 5°C]. TLC assay showed the reaction was incomplete. Additional triethylamine (4.1 kg, 40.5 mol) and trifluoroacetic acid (4.1 kg, 19.5 mol) were added over 2 hours until TLC showed complete reaction. The reaction mixture was quenched in to water (40 L) [temp to 23°C]. The layers were separated and the aqueous re-extracted with DCM (8 L). The organic layers were sequentially washed with brine (7 L), filtered through a pad of silica (3 kg) and eluted with DCM (10 L). The filtrate was evaporated and chromatographed (9 kg silica, eluent 10-30% EtOAc in hexane). Product fractions were evaporated and azeotroped with IPA to afford compound 20 (6.86 kg, -94 wt%, 25.8 mol, 99%) as an orange oil.

Step 6:

To compound 20 (6.86 kg, -94 wt%, 25.8 mol) in IPA (35 L) at 17°C was added 37% hydrochloric acid (6.4 L, 77.4 mol). The mixture was heated to 35°C overnight then concentrated to a moist solid and residual water azeotroped with additional IPA (8 L). The resulting moist solid was triturated with MTBE (12 L) at 45°C for 30 minutes then cooled to 20°C and filtered, washing with MTBE (5 L). The solids were dried under vacuum at 45°C to afford compound 21 (4.52 kg, 24.2 mol, 94%) as a white solid. ¹H-NMR was consistent with desired product; mp 203-205°C; HPLC 99.3%. ¹H NMR (CD₃OD, 400 MHz) δ 7.12 (1 H, s), 4.28 (2H, s), 4.09 (3H, s), 2.77 (3H, s). ¹³C NMR (CD₃OD, 100 MHz) δ 144.5, 177.8, 1 14.9, 110.9, 45.9, 39.0, 33.2. LCMS (M⁺+1) 151 .1 , 138.0, 120.0.

PATENT

WO2013132376

PATENT

WO 2016089208

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017021823&redirectedID=true

Preparation of the free base of lorlatinib as an amorphous solid is disclosed in

International Patent Publication No. WO 2013/132376 and in United States Patent No. 8,680,1 1 1 . Solvated forms of lorlatinib free base are disclosed in International Patent Publication No. WO 2014/207606.

Example 1

Lab Scale Preparation of Form 7 of (10 ?^‘)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2/-/-8,4-(metheno)pyrazolo[4,3- ?l[2,5,1 l lbenzoxadiazacyclotetra-decine- -carbonitrile (lorlatinib) Free Base

[AcOH solvate]

Form 7 of lorlatinib free base was prepared by de-solvation of the acetic acid solvate of lorlatinib (Form 3), prepared as described in International Patent Publication No. WO 2014/207606, via an intermediate methanol solvate hydrate form of lorlatinib (Form 2).

The acetic acid solvate of lorlatinib (Form 3) (5 g, 10.72 mmol) was slurried in methanol

(10 mL/g, 1235.9 mmol) at room temperature in an Easymax flask with magnetic stirring to which triethylamine (1 .2 equiv., 12.86 mmol) was added over 10 minutes. The resulting solution was heated to 60°C and water (12.5 mL/g, 3469.3 mmol) was added over 10 minutes, while maintaining a temperature of 60°C. Crystallization was initiated by scratching the inside of the glass vessel to form a rapidly precipitating suspension which was triturated to make the system mobile. The suspension was then cooled to 25°C over 1 hour, then cooled to 5°C and granulated for 4 hours. The white slurry was filtered and washed with 1 mL/g chilled

water/methanol (1 :1) then dried under vacuum at 50°C overnight to provide the methanol solvate hydrate Form 2 of lorlatinib.

Form 7 was then prepared via a re-slurry of the methanol solvate hydrate Form 2 of lorlatinib in heptane. 100 mg of lorlatinib Form 2 was weighed into a 4-dram vial and 3 mL of heptane was added. The mixture was slurried at room temperature on a roller mixer for 2 hours. Form conversion was confirmed by PXRD revealing complete form change to Form 7 of lorlatinib free base.

Paper

http://pubs.acs.org/doi/abs/10.1021/jm500261q

*E-mail: ted.w.johnson@pfizer.com. Phone: (858) 526-4683., *E-mail: paul.f.richardson@pfizer.com. Phone: (858) 526-4290.

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations

La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States

J. Med. Chem., 2014, 57 (11), pp 4720–4744

DOI: 10.1021/jm500261q

(10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (8k)

white solid:

TLC R_f = 0.40 (70% EtOAc in cyclohexane);

LC–MS (ESI), m/z 407.1 [M + H]⁺;

¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 2.0 Hz, 1 H), 7.30 (dd, J = 9.6, 2.4 Hz, 1 H), 7.21 (dd, J = 8.4, 5.6 Hz, 1 H), 6.99 (dt, J = 8.0, 2.8 Hz, 1 H), 6.86 (d, J = 1.2 Hz, 1 H), 5.75–5.71 (m, 1 H), 4.84 (s, 2 H), 4.45 (d, J = 14.4 Hz, 1 H), 4.35 (d, J = 14.4 Hz, 1 H), 4.07 (s, 3 H), 3.13 (s, 3 H), 1.79 (d, J = 6.4 Hz, 3 H).

References

1H NMR PREDICT

13C NMR PREDICT

Lorlatinib
Clinical data

Routes of administration	PO
Legal status
Legal status	experimental
Identifiers
IUPAC name [show]
CAS Number	1454846-35-5
ChemSpider	32813339
Chemical and physical data
Formula	C₂₂H₂₀FN₅O₂
Molar mass	405.43 g·mol⁻¹
3D model (Jmol)	Interactive image
SMILES [hide] C[C@@H]1c2cc(ccc2C(=O)N(Cc3c(c(n(n3)C)C#N)-c4cc(c(nc4)N)O1)C)F

///////////////////Lorlatinib, PF-6463922, anti-neoplastic, Pfizer, ROS1, ALK, phase 2, UNII:OSP71S83EU, лорлатиниб , لورلاتينيب , 洛拉替尼 , Orphan Drug, PF 6463922

Fc2ccc3C(=O)N(C)Cc1nn(C)c(C#N)c1c4cc(O[C@H](C)c3c2)c(N)nc4

Brigatinib, Бригатиниб, بريغاتينيب , 布格替尼 ,

January 20, 2017 11:10 am / 1 Comment on Brigatinib, Бригатиниб, بريغاتينيب , 布格替尼 ,

ChemSpider 2D Image | Brigatinib | C29H39ClN7O2P Image result for Brigatinib Figure imgf000127_0001

Brigatinib, AP26113

Molecular Formula:	C₂₉H₃₉ClN₇O₂P
Molecular Weight:	584.102 g/mol

CAS 1197953-54-0

2,4-Pyrimidinediamine, 5-chloro-N⁴-[2-(dimethylphosphinyl)phenyl]-N²-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-

Бригатиниб[Russian][INN]

بريغاتينيب[Arabic][INN]

布格替尼[Chinese][INN]

5-chloro-N4-[2-(dimethylphosphinyl)phenyl]-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-2,4-pyrimidinediamine

AP-26113

MFCD29472221

UNII:HYW8DB273J

In 2016, orphan drug designation was assigned to the compound in the U.S. for the treatment of ALK, ROS1 or EGFR-positive non-small cell lung cancer (NSCLC).

fda 2017 approved

BRIGATINIB

Figure imgf000127_0001

TAKEDA

Image result for BRIGATINIB

Alunbrig		FDA 4/28/2017	To treat patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib Drug Trials Snapshot

WO 2009143389 PDT PAT

Inventors	Yihan Wang, Wei-Sheng Huang, Shuangying Liu, William C. Shakespeare, R. Mathew Thomas, Jiwei Qi, Feng Li, Xiaotian Zhu, Anna Kohlmann, David C. Dalgarno, Jan Antoinette C. Romero, Dong Zou
Applicant	Ariad Pharmaceuticals, Inc.

Image result for Yihan Wang ARIAD

Yihan Wang

Dr. Wang founded Shenzhen TargetRx, Inc., in Aug 2014 and is now the President/CEO. He was the Associate Director of Chemistry at ARIAD Pharmaceuticals, Inc., until April 2013. Yihan Wang received his B.Sc. in chemistry from University of Science and Technology of China, and Ph.D. in chemistry from New York University. Yihan’s research has focused primarily on medicinal chemistry in the area of signal transduction drug discovery, integrating structure-based drug design, combinatorial chemistry, and both biological and pharmacological assays to identify small-molecule clinical candidates. His career at ARIAD includes innovative research in therapeutic areas involving bone diseases and cancer, and has been a key contributor to the discovery of several clinical drugs, including Ponatinib (iClusig^TM) (approved by the FDA for resistant CML in Dec 2012), Brigatinib (AP26113, Phase II for NSCLC), Ridoforolimus (Phase III for Sarcoma and multiple Phase II), and several pre-clinical compounds. Yihan is the primary author of approximately 90 peer-reviewed publications, patents, and invited meeting talks. Yihan is the editor of “Chemical Biology and Drug Design” and a reviewer for many professional journals.

Yihan is one of the co-founders of Chinese-American BioMedical Association (CABA) and currently on the Board of Directors.

EXAMPLE 19:

5-chloro-Λ’⁴-[4-(dimethylphosphoryl)phenyl]-Λ^r2-{2-methoxy-4-[4-(4-methylpiperazin-l- yl)piperidin-l-yI]phenyl}pyrimidine-2,4-diamine:

2,5-dichloro-N-[4-(dimethylphosphoryl)plienyl]pyrimiclin-4-amine: To a solution of 2,4,5- trichloropyrimindine (0.15ml, 1.31 mmol) in 1 mL of DMF was added 4- (dimethylphosphoryl)aniline (0.22 Ig, 1.31 mmol) and potassium carbonate (0.217g, 1.57mmol). The mixture was heated at 110 ⁰C for 4h. It was basified with saturated sodium bicarbonate solution. The suspension was filtered and washed with ethyl acetate to give the final product (0.15g, 36% yield). MS/ES+: m/z=316.

l-[l-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine: To a solution of 5- fluoro-2-nitroanisooIe (0.5g, 2.92 mmol) in 3 mL of DMF was added l-methyl-4- (piperidin)piperazine (0.536g, 2.92 mmol) and potassium carbonate (0.808, 5.84 mmol). The mixture was heated at 120 ⁰C for 18h. The mixture was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was purified by chromatography to give final product as yellow solid (0.95g, 95% yield). MS/ES+: m/z=334.

2-methoxy-4-[4-(4-methylpiperazin-l-yl)piperidin-l-yl]aniline: The a solution of 1 -[I -(3- methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine (0.3g, 0.90 mmol) in 10 mL of ethanol purged with argon was added 10% Palladium on carbon (0.06Og). The hydrogenation was finished under 30psi after 4h. The mixture was passed through Celite to a flask containing HCl in ethanol. Concentration of the filtrate gave the final product (0.15g, 88% yield). MS/ES+: m/z=334.

S-chloro-JSP-ft-ζdimethylphosphorytyphenyll-rf-ft-methoxy^-ft-ø-methylpiperazin-l- yl)piperidin-l-yl]phenyl}pyrimidine-2,4-diamine: To the compound 2,5-dichloro-N-[4-

(dimethylphosphoryl)phenyl]pyrimidin-4-amine (0.005g, O.lόmmol) in ImL of 2-methoxyethanol was added 2-methoxy-4-[4-(4-methylpiperazin-l-yl)piperidin-l-yl]aniline (0.7 Ig, 0.16 mmol). The mixture was stirred at 110⁰C for 18h. The mixture was basified with saturated sodium bicarbonate solution and extracted with limited amount of ethyl acetate. The aqueous layer was purified by chromatography to give the final product (0.015g, 20% yield). MS/ES+: m/z=583.

SYNTHESIS

WILL BE ADDED WATCH OUT………….

CONTD………..

SOME COLOUR

Dual ALK EGFR Inhibitor AP26113 is an orally available inhibitor of receptor tyrosine kinases anaplastic lymphoma kinase (ALK) and the epidermal growth factor receptor (EGFR) with potential antineoplastic activity. Brigatinib binds to and inhibits ALK kinase and ALK fusion proteins as well as EGFR and mutant forms. This leads to the inhibition of ALK kinase and EGFR kinase, disrupts their signaling pathways and eventually inhibits tumor cell growth in susceptible tumor cells. In addition, AP26113 appears to overcome mutation-based resistance. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development; ALK dysregulation and gene rearrangements are associated with a series of tumors. EGFR is overexpressed in a variety of cancer cell types.

Structures of select ALK inhibitors.

Brigatinib (previously known as AP26113) is an investigational small-molecule targeted cancer therapy being developed by ARIAD Pharmaceuticals, Inc.^[1] Brigatinib has exhibited activity as a potent dual inhibitor of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR).

ARIAD has begun a Phase 1/2 clinical trial of brigatinib based on cancer patients’ molecular diagnoses in September 2011.

ALK was first identified as a chromosomal rearrangement in anaplastic large cell lymphoma (ALCL). Genetic studies indicate that abnormal expression of ALK is a key driver of certain types of non-small cell lung cancer (NSCLC) and neuroblastomas, as well as ALCL. Since ALK is generally not expressed in normal adult tissues, it represents a highly promising molecular target for cancer therapy.

Epidermal growth factor receptor (EGFR) is another validated target in NSCLC. Additionally, the T790M “gatekeeper” mutation is linked in approximately 50 percent of patients who grow resistant to first-generation EGFR inhibitors.^[2] While second-generation EGFR inhibitors are in development, clinical efficacy has been limited due to toxicity thought to be associated with inhibiting the native (endogenous or unmutated) EGFR. A therapy designed to target EGFR, the T790M mutation but avoiding inhibition of native EGFR is another promising molecular target for cancer therapy.

Pre-clinical results

In 2010, ARIAD announced results of preclinical studies on brigatinib showing potent inhibition of the target protein and of mutant forms that are resistant to the first-generation ALK inhibitor, which currently is in clinical trials in patients with cancer. ARIAD scientists presented these data at the annual meeting of the American Association for Cancer Research (AACR) in Washington, D.C. in April.^[3]

In 2011, ARIAD announced preclinical studies showing that brigatinib potently inhibited activated EGFR or its T790M mutant, both in cell culture and in mouse tumor models following once daily oral dosing. Importantly, the effective oral doses in these preclinical models were similar to those previously shown to be effective in resistant ALK models. When tested against the native form of EGFR, brigatinib lacked activity, indicating a favorable selectivity for activated EGFR. These data were presented at the International Association for the Study of Lung Cancer (IASLC) 14th World Conference on Lung Cancer.^[4]

Brigatinib

Phase 3 ALTA 1L trial of brigatinib

In April 2015, ARIAD announced the initiation of a randomized, first-line Phase 3 clinical trial of brigatinib in adult patients with ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) who have not previously been treated with an ALK inhibitor. The ALTA 1L (ALK in Lung Cancer Trial of BrigAtinib in 1st Line) trial is designed to assess the efficacy of brigatinib in comparison to crizotinib based on evaluation of the primary endpoint of progression free survival (PFS). Read Full Press Release

Phase 2 ALTA trial of brigatinib (AP26113)

In March 2014, ARIAD announced the initiation of its global Phase 2 ALTA (ALK in Lung Cancer Trial of brigatinib (AP26113) in patients with locally advanced or metastatic NSCLC who test positive for the ALK oncogene and were previously treated with crizotinib. This trial has reached full enrollment of approximately 220 patients and explores two different dose levels. Read Full Press Release

Phase 1/2 study of oral ALK inhibitor brigatinib (AP26113)

The international Phase 1/2 clinical trial of brigatinib (AP26113) is being conducted in patients with advanced malignancies, including anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC). Patient enrollment in the trial is complete, with the last patient enrolled in July 2014. The primary endpoint in the Phase 2 portion of the trial is overall response rate. In April 2016, ARIAD announced updated clinical data from the trial. Read Full Press Release

Expanded Access Study of brigatinib

The purpose of this Expanded Access Program (EAP) is to provide brigatinib for those patients with locally advanced and/or metastatic patients with ALK+ NSCLC on an expanded access basis due to their inability to meet eligibility criteria for on-going recruiting trials, inability to participate in other clinical trials (e.g., poor performance status, lack of geographic proximity), or because other medical interventions are not considered appropriate or acceptable.

About Brigatinib

Brigatinib (AP26113) is an investigational, targeted cancer medicine discovered internally at ARIAD Pharmaceuticals, Inc. It is in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) non-small cell cancer (NSCLC) whose disease is resistant to crizotinib. Brigatinib is currently being evaluated in the global Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial that is anticipated to form the basis for its initial regulatory review. ARIAD has also initiated the Phase 3 ALTA 1L trial to assess the efficacy of brigatinib in comparison to crizotinib. In June 2016, an Expanded Access Study of brigatinib will begin. More information on brigatinib clinical trials, including the expanded access program (EAP) for ALK+ NSCLC can be found here.

Brigatinib was granted orphan drug designation by the U.S. Food and Drug Administration (FDA) in May 2016 for the treatment of certain subtypes of non-small cell lung cancer (NSCLC). The designation is for anaplastic lymphoma kinase-positive (ALK+), c-ros 1 oncogene positive (ROS1+), or epidermal growth factor receptor positive (EGFR+) non-small cell lung cancer (NSCLC). Brigatinib received breakthrough therapy designation from the FDA in October 2014 for the treatment of patients with ALK+ NSCLC whose disease is resistant to crizotinib. Both designations were based on results from an ongoing Phase 1/2 trial that showed anti-tumor activity of brigatinib in patients with ALK+ NSCLC, including patients with active brain metastases.

We are on track to file for approval of brigatinib in the U.S. in the third quarter of 2016.

PATENT

WO 2016065028

https://google.com/patents/WO2016065028A1?cl=ru

Brigatinib has the chemical formula C29H3₉QN7G2P which, corresponds to a formula weight of 584.09 g/moL Its chemical structure is shown below:

Brigatinib is a multi-targeted tyrosine-kinase inhibitor useful for the treatment of non-small cell lung cancer (NSCLC) and other diseases, it is a potent inhibitor of ALK (anaplastic lymphoma kinase} and is in clinical development for the treatment of adult patients with ALK-driven NSCLC. Crizotinib (XALKOR!^®) is an FDA approved drug for first-line treatment ^‘of ALK-positive NSCLC. “Despite initial responses to crizotinib, the majority of patients have a relapse within 12 months, owing to the development of resistance.” Shaw et al., New Eng. J. Med. 370:1 189-97 2014. Thus, a growing population of cancer patients are in need of new and effective therapies for ALK-positive cancers.

Brigatinib is also potentially useful for treating other diseases or conditions in which ALK or other protein kinases inhibited by brigatinib are implicated. Such kinases and their associated disorders or conditions are disclosed in WO 2009/143389, both of which are hereby incorporated herein by reference for all purposes.

FIG. 1 is a synthetic scheme for brigatinib,

FIG. 6 is an ¹H-Niv1R spectrum obtained for a sample of brigatinib dissolved in CD₃OD. Normalised intensity is shown on the vertical axis and chemical shift (ppm) is shown on the horizontal axis.

FIG. 7 is a ¹³C-NMR spectrum obtained for a sample of brigatinib dissolved in CDCi₃. Normalized intensity is shown on the vertical axis and chemical shift (ppm) is shown on the horizontal axis.

FIG. 8 is a mass spectral fragmentation pattern of a sample of brigatinib Form A. Relative abundance is shown on the vertical axis and atomic weight (m/z) is shown on the horizontal axis.

Table 2 summarizes the relevant chemical shift data of Form A obtained from

the ^‘Ή, and ¹³C-N R experiments. The number of signals and their relative intensity (integrals) confinri the number of protons and carbons in the structure of Form A of brigatinib. The ³¹P-NMR chemical shift for the single phosphorous atom in brigatinib was 43.6 ppm. These ¹H and ¹³C-NMR chemical shift data are reported according to the atom numbering scheme shown immediately below:

¹H-N R Assignments – ¹³C~N R Assignments

Table 2: ¹H and ³C Chemical Shift Data (in ppm) of Form A of Brigatinib

[00118] With reference to Figure 8, mass spectral experiments of Form A were carried out using an Agilsent eiectrospray time of fisght mass spectrometer (Model 6210} operating in positive son mode using flow injection sampie introduction. Samples of Form A were dissolved in methanol/water and were analyzed and the mass observed was m/ 584.263 ( +f-T) with the calculated exact mass being 584.2684 ( +H⁺). The observed moiecuiar mass is consistent with the elemental composition calculated from the molecular formula of brigatinib.

PAPER

Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase

ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States

J. Med. Chem., 2016, 59 (10), pp 4948–4964

DOI: 10.1021/acs.jmedchem.6b00306

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00306

*Phone: +1-617-621-2341. E-mail: Wei-Sheng.Huang@ariad.com.

Abstract

In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC₅₀s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.

(2-((5-Chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-pyrimidin-4-yl)amino)phenyl)dimethylphosphine Oxide (11q)

Mp 215 °C.

¹H NMR (400 MHz, CD₃OD) δ 8.33 (dd, J = 4.52, 8.03 Hz, 1H), 8.02 (s, 1H), 7.66 (d, J = 8.78 Hz, 1H), 7.59 (ddd, J = 1.51, 7.78, 14.05 Hz, 1H), 7.47–7.54 (m, 1H), 7.25 (ddt, J = 1.00, 2.26, 7.53 Hz, 1H), 6.65 (d, J = 2.51 Hz, 1H), 6.45 (dd, J = 2.51, 8.78 Hz, 1H), 3.84 (s, 3H), 3.69 (d, J = 12.30 Hz, 2H), 2.62–2.86 (m, 6H), 2.43–2.62 (m, 4H), 2.33–2.42 (m, 1H), 2.29 (s, 3H), 1.97–2.08 (m, 2H), 1.83 (d, J = 13.30 Hz, 6H), 1.66 (dq, J = 3.89, 12.09 Hz, 2H).

¹³C NMR (151 MHz, CDCl₃) δ 18.57 (d, J = 71.53 Hz), 28.28 (s), 46.02 (s), 49.01 (s), 50.52 (s), 55.46 (s), 55.65 (s), 61.79 (s), 101.07 (s), 106.01 (s), 108.41 (s), 120.25 (d, J = 95.73 Hz), 120.68 (s), 122.09 (s), 122.41 (d, J = 12.10 Hz), 123.13 (br d, J = 6.60 Hz), 129.48 (d, J = 11.00 Hz), 132.36 (s), 143.91 (d, J = 2.20 Hz), 147.59 (s), 149.38 (s), 154.97 (s), 155.91 (s), 157.82 (s).

³¹P NMR (162 MHz, CDCl₃) δ 43.55.

MS/ES+: m/z = 584.3 [M + H]⁺.

Anal. Calcd for C₂₉H₃₉ClN₇O₂P: C, 59.63; H, 6.73; Cl, 6.07; N, 16.79; O, 5.48; P, 5.30. Found: C, 59.26; H, 6.52; Cl, 6.58; N, 16.80.

PATENT

WO 2016089208

New Patent, Suzhou MiracPharma Technology Co Ltd, Brigatinib, WO 2017016410

WO-2017016410

Preparation method for antitumor drug AP26113

Suzhou MiracPharma Technology Co Ltd

SUZHOU MIRACPHARMA TECHNOLOGY CO., LTD [CN/CN]; Room 1305, Building 1,Lianfeng Commercial Plaza, Industrial District Suzhou, Jiangsu 215000 (CN)
XU, Xuenong; (CN)

Improved process for preparing brigatinib, useful for treating cancer eg non-small cell lung cancer (NSCLC). The present filing represents the first PCT patenting to be seen from Suzhou MiracPharma that focuses on brigatinib; In February 2017, brigatinib was reported to be in pre-registration phase.

Disclosed is a preparation method for an antitumor drug AP26113 (I). The method comprises the following preparation steps: cyclizing N-[2-methoxyl-4-[4-(dimethyl amino)piperid-1-yl]aniline]guanidine and N,N-dimethylamino acrylate, condensing N-[2-methoxyl-4-[4-(dimethyl amino)piperid-1-yl]aniline]guanidine and 4-(dimethyl phosphitylate)aniline, and chlorinating N-[2-methoxyl-4-[4-(dimethyl amino)piperid-1-yl]aniline]guanidine by means of a chlorinating agent, sequentially, so as to prepare AP26113 (I). The preparation method adopts easily-obtained raw materials, causes few side reactions, and is economical, environmentally-friendly, and suitable for industrial production.

AP26113 is an experimental drug developed by Ariad Pharmaceuticals to target small molecule tyrosine kinase inhibitors for the treatment of anaplastic lymphoma kinase-positive (ALK) metastases resistant to crizotinib Non-small cell lung cancer (NSCLC) patients. The drug was approved by the US Food and Drug Administration in August 2014 for breakthrough drug treatment. The current clinical data show that AP26113 on ALK-positive non-small cell lung cancer patients, including patients with brain metastases, have a sustained anti-tumor activity. And the inhibitory activity against ALK is about 10 times that of zolotriptan, which can inhibit all 9 kinds of identified mutations of kotatinib resistant ALK.

The chemical name of AP26113 is 5-chloro-N- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] -N4- [2- Phosphono) phenyl] -2,4-pyrimidinediamine (I) having the structural formula:

Methods for the preparation of AP26113 have been reported. AP26113 and its starting materials A and B are prepared by PCT Patent WO2009143389 of Ariad and U.S. Patent No. 20130225527, US20130225528 and US20140066406 of Ariad. The target compound AP26113 is prepared by substituting 2,4,5-trichloropyrimidine with the pyrimidine ring of starting materials A and B in turn.

Although the synthetic procedure is simple, the nucleophilic activity of the three chlorine atoms on 2,4,5-trichloropyrimidine is limited. When the same or similar aniline group is faced, its position Selectivity will inevitably produce interference, resulting in unnecessary side effects, thus affecting the quality of the product. At the same time, the reaction process for the use of precious metal palladium reagent also increased the cost of production is not conducive to the realization of its industrialization.

Therefore, how to use modern synthesis technology, the use of readily available raw materials, design and development of simple and quick, economical and environmentally friendly and easy to industrialization of the new synthesis route, especially customer service location on the pyrimidine ring side effects of selectivity, for the drug Economic and technological development is of great significance

The synthesis step comprises the following steps: N- [2-methoxy-4- [4- (dimethylamino) piperidin-1-yl] aniline] guanidine (II) and N, N-dimethylaminoacrylates Amino-4 (1H) -pyrimidinone (III) in the presence of a base such as N, N-dimethylformamide, N, N-dimethylformamide, (III) was reacted with 4- (dimethyl (dimethylamino) -1-piperidinyl) -2-methoxyphenyl] (A) is condensed under the action of a condensing agent and a base accelerator to obtain N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxybenzene (IV); the N2- [4- [4- (dimethylamino) -l- (4-fluorophenyl) (IV) with a chlorinating agent in the presence of a base such as sodium hydride, sodium hydride, sodium hydride, potassium hydride, AP26113 (I).

Example 1:

A solution of 2-methoxy-4- [4- (dimethylamino) piperidin-1-yl] aniline (24.9 g, 0.1 mol) and 250 mL of methanol was added to the reaction flask and the temperature was lowered to 0C (15 mL, 0.15 mol) and a 50% solution of cyanamide (10 mL, 0.15 mol) were added successively. The reaction was stirred for 12 to 14 hours and the reaction was complete by TLC. After cooling to 0-5 ° C, 250 mL of methyl tert-butyl ether was added to the reaction mixture. A solid precipitated and was filtered, washed successively with water and cold acetonitrile, and dried to give N- [2-methoxy- 16.3 g, yield 56.0%, FAB-MS m / z: 292 [M + H] ⁺ . [4- (Dimethylamino) piperidin-1-yl] aniline] guanidine (II)

Example 2:

A solution of N- [2-methoxy-4- [4- (dimethylamino) piperidin-1-yl] aniline] guanidine (II) (2.9 g, 10 mmol), N, Methyl methacrylate (1.8 g, 13.7 mmol) and toluene (50 mL). The mixture was heated to reflux and stirred for 24-26 hours. The reaction was complete by TLC. After cooling to room temperature, a solid precipitated. The filter cake was washed with cold methanol and dried in vacuo to give an off-white solid of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] 1H) -pyrimidinone (III), yield 77.3%, FAB-MS m / z: 344 [M + H] ⁺ .

Example 3:

A solution of N- [2-methoxy-4- [4- (dimethylamino) piperidin-1-yl] aniline] guanidine (II) (2.9 g, 10 mmol), N, (2.0 g, 14.0 mmol) and N, N-dimethylformamide (30 mL) was added and the temperature was raised to 115-125 ° C. The reaction was stirred for 22-24 hours and the reaction was complete by TLC. The mixture was concentrated under reduced pressure, and 50 mL of ethanol was added to the resulting residue. The mixture was cooled to room temperature while stirring to precipitate a solid. The filter cake was washed with cold ethanol and dried in vacuo to give an off-white solid of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] 1H) -pyrimidinone (III) in 79.6% yield, FAB-MS m / z: 344 [M + H] ⁺ .

Example 4:

A mixture of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] amino-4 (1H) -pyrimidinone III) (3.43 g, 10 mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (6.63 g, 15 mmol) and acetonitrile 100 mL. Diazabicyclo [5.4.0] -undec-7-ene (DBU) (2.28 g, 15 mmol) was added dropwise at room temperature for 12 hours. The temperature was raised to 60 ° C and the reaction was continued for 12 hours. The solvent was evaporated under reduced pressure, 100 mL of ethyl acetate was dissolved, and the mixture was washed with 20 mL of 2M sodium hydroxide and 20 mL of water. The organic layer was dried over anhydrous sodium sulfate, and 50 mL of tetrahydrofuran-dissolved 4- (dimethylphosphoranylidene) A) (2.2 g, 13 mmol) and sodium hydride (0.31 g, 13 mmol) was added and the temperature was raised to 50-55 ° C. The reaction was stirred for 6-8 hours and monitored by TLC. The reaction was quenched with saturated brine, the organic phase was separated, dried and the solvent was distilled off under reduced pressure. The crude product was recrystallized from ethanol to give an off-white solid of N2- [4- [4- (dimethylamino) -1-piperidine Yl] -2-methoxyphenyl] -N4- [2- (dimethylphosphono) phenyl] -2,4-pyrimidinediamine (IV) in a yield of 83.2%. FAB-MS m / z: 495 [M + H] ⁺ .

Example 5:

A mixture of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] amino-4 (1H) -pyrimidinone (Dimethylamino) phosphonium hexafluorophosphate (BOP) (6.63 g, 15 mmol), 4- (dimethylsulfamoyl) phosphonium hexafluorophosphate Phosphoryl) aniline (A) (2.2 g, 13 mmol) and N, N-dimethylformamide. Diazabicyclo [5.4.0] undec-7-ene (DBU) (2.28 g, 15 mmol) was added dropwise and reacted at room temperature for 12 hours. The temperature was raised to 60 ° C and the reaction was continued for 12 hours. The solvent was distilled off under reduced pressure, 100 mL of ethyl acetate was added to dissolve, and the mixture was washed with 2 M sodium hydroxide 20 mL. The organic phase was separated, dried and concentrated under reduced pressure. The residue was recrystallized from ethanol to give an off-white solid of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] -N4- [2- Phenylidene] -2,4-pyrimidinediamine (IV) was obtained in a yield of 48.6%. FAB-MS m / z: 495 [M + H] ⁺ .

Example 6:

A solution of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] -N4- [2- (dimethylphosphono) Phenyl] -2,4-pyrimidinediamine (IV) (4.9 g, 10 mmol) and 100 mL of acetonitrile were added and stirred at room temperature. N-Chlorosuccinimide (1.6 g, 12 mmol) was added in three portions, The reaction was allowed to proceed at room temperature for 4-6 hours, and the reaction was terminated by TLC. The reaction solution was poured into 50 mL of water to quench the reaction. Dichloromethane, and the combined organic layers were washed successively with saturated sodium bicarbonate solution, saturated brine and water. Dried over anhydrous sodium sulfate and concentrated. The resulting crude oil was recrystallized from ethyl acetate / n-hexane to give 3.5 g of a white solid AP26113 (I) in 66.3% yield, FAB-MS m / z: 529 [M + the H] ⁺ , ¹ the H NMR (CDCl ₃ ) 1.67 (m, 2H), 1.81 (S, 3H), 1.85 (S, 3H), 1.93 (m, 2H), 1.96 (m, 2H), 2.10 (m, 2H), 3.86 (s, 3H), 6.50 (m, 1H), 6.57 (m, 1H), 7.12 (m, 1H) ), 7.31 (m, 1H), 7.50 (m, 1H), 8.13 (m, 2H), 8.64 (m, 1H).

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017016410&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

////////////New Patent, Suzhou MiracPharma Technology Co Ltd, Brigatinib, WO 2017016410

References

Jump up^ Huang, Wei-Sheng; Liu, Shuangying; Zou, Dong; Thomas, Mathew; Wang, Yihan; Zhou, Tianjun; Romero, Jan; Kohlmann, Anna; Li, Feng. “Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase”. Journal of Medicinal Chemistry. 59: 4948–4964. doi:10.1021/acs.jmedchem.6b00306.
Jump up^ Sequist; et al. (2011). “Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors”. Sci Trans. Med. 3 (75): 75ra26. doi:10.1126/scitranslmed.3002003.
Jump up^ “ARIAD Presents Preclinical Data on Its Investigational ALK Inhibitor, AP26113, Demonstrating That It Can Overcome Mutation-Based Drug Resistance in Cancer Models”.
Jump up^ “ARIAD Announces Presentation on Its Investigational Lung Cancer Drug Candidate, AP26113, a Dual Inhibitor of ALK and EGFR, at World Conference on Lung Cancer”.

1 to 6 of 6

Patent ID	Patent Title	Submitted Date	Granted Date
US2015225436	PHOSPHOROUS DERIVATIVES AS KINASE INHIBITORS	2015-04-20	2015-08-13
US2014066406	Phosphorus Derivatives as Kinase Inhibitors	2013-03-15	2014-03-06
US2014024620	Methods for Inhibiting Cell Proliferation in EGFR-Driven Cancers	2011-10-14	2014-01-23
US2013225527	Phosphorus Derivatives as Kinase Inhibitors	2013-03-15	2013-08-29
US2013225528	Phosphorus Derivatives as Kinase Inhibitors	2013-03-15	2013-08-29
US2012202776	PHOSPHORUS DERIVATIVES AS KINASE INHIBITORS	2009-05-21	2012-08-09

Brigatinib
Names

IUPAC name (2-((5-Chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide
Other names AP26113
Identifiers
CAS Number	1197953-54-0
3D model (Jmol)	Interactive image
ChemSpider	34982928
PubChem	68165256
InChI [show]
SMILES [show]
Properties
Chemical formula	C₂₉H₃₉ClN₇O₂P
Molar mass	584.10 g·mol⁻¹
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

//////////Бригатиниб, بريغاتينيب , 布格替尼 , Brigatinib, AP26113, PHASE 2, ORPHAN DRUG, 1197953-54-0

CN1CCN(CC1)C2CCN(CC2)C3=CC(=C(C=C3)NC4=NC=C(C(=N4)NC5=CC=CC=C5P(=O)(C)C)Cl)OC

CPP 115

December 9, 2016 4:56 am / Leave a comment

(+)-(1S,4S)-4-Amino-3-(difluoromethylene)-1-cyclopentanecarboxylic acid

640897-20-7 CAS

PHASE 1

NORTHWESTERN UNIVERSITY .INNOVATORS

Sponsor:

CPP-115 free base; UNII-5TD9324Z2U; CHEMBL146927; 640897-20-7; (1S,3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic acid; (+)-(1S,4S)-4-Amino-3-(difluoromethylene)-1-cyclopentanecarboxylic acid
Molecular Formula:	C₇H₉F₂NO₂
Molecular Weight:	177.151 g/mol

Originator Northwestern University
Developer Catalyst Pharmaceutical Partners
Class Aminobutyric acids; Antiepileptic drugs; Small molecules
Mechanism of Action 4-aminobutyrate transaminase inhibitors

Orphan Drug Status Yes – Infantile spasms
On Fast track Drug abuse
Cocaine Dependency

Highest Development Phases

Phase I Gilles de la Tourette’s syndrome; Infantile spasms; Partial epilepsies
Preclinical Drug abuse

Most Recent Events

19 Sep 2016 Efficacy data from a phase I trial in Infantile spasms released by Catalyst Pharmaceuticals
16 Dec 2015 Top-line adverse events and pharmacodynamics data from a phase Ib trial in Healthy volunteers released by Catalyst Pharmaceuticals
13 Oct 2015Catalyst Pharmaceuticals receives patent allowance for CPP 115 in USA

Image result for SILVERMAN, Richard, B Richard B. Silverman, Ph.D.,
John Evans Professor of Chemistry, Northwestern University, Evanston, Illinois, USA.

Click here for structure editor

CPP 115 HCl salt, cas 760947-97-5

UNII-0285I2MVUA; CPP-115; 760947-97-5; (1S,3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic acid hydrochloride; Cyclopentanecarboxylic acid, 3-amino-4-(difluoromethylene)-, hydrochloride, (1S,3S)-; 0285I2MVUA
Molecular Formula:	C₇H₁₀ClF₂NO₂
Molecular Weight:	213.609 g/mol

Responsible Party:Catalyst Pharmaceuticals, Inc.ClinicalTrials.gov Identifier:NCT01493596 History of ChangesOther Study ID Numbers:CPP-115-0001 Study First Received:November 28, 2011Last Updated:May 10, 2012Health Authority:United States: Food and Drug Administration

Cpp-115: An Investigational Drug For Epilepsy

The fact that 1 in 12 people will have a seizure in their lifetime raises alarming signals to mitigate, prevent and cure epilepsy. The etiology is still unclear, but one of the pharmaceutical strategies to treat seizures is to replenish the local concentrations of GABA (gamma-aminobutyric acid, an inhibitory neurotransmitter in the human brain) that is degraded by an enzyme called GABA aminotransferase (GABA-AT). Mere consumption of GABA capsules is not effective, due to its inability to cross the blood-brain barrier (BBB). Therefore, an alternative strategy that involved stopping the function of GABA-AT was envisioned. Sabril is a first-in-class, FDA-approved antiepileptic drug; however, its daily dosage limit (1g – 3g) and adverse side effects, which include vision defects, call for further innovation.

Prof. Richard Silverman and his lab members at Northwestern University embarked on a scientific journey to identify BBB-penetrating antiepileptic compounds that would not cause visual defects. Through computational modeling and several cycles of optimization they discovered CPP-115 (chemical name: (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid; kinact/KI = 52 mM.min-1.)1 Mechanistically, CPP-115 binds to GABA-AT, undergoing product transformation that kills GABA-AT’s function. In rat studies, CPP-115 suppressed spasms at a much lower dose (0.1 mg/kg) than Sabril (>200 mg/kg) and exhibited better tolerance without visual defects.

CPP-115 (licensed to Catalyst Pharmaceuticals) elicited no cross-inhibition. It is metabolically more stable, with favorable PK characteristics (including rapid absorption and clearance). In a randomized, double-blind, single ascending dose phase I(a) study, CPP-115 was very well tolerated in all six doses (n=55 patients; maximum dose 500 mg, therapeutic dose 80 mg/day).2 Phase I(b) studies conducted in double-blind, placebo-controlled conditions demonstrated the safety and tolerability of CPP-115 in healthy volunteers. Intriguingly, an increase in brain GABA levels (150% to over 200%) was detected, accentuating CPP-115’s antiepileptic potential.2 Further clinical trials are currently in progress. CPP-115, with 12 years of unexpired patent life, has been granted orphan-drug designation in both the U.S. and EU for treating infantile spasms.

CPP-115 is one of a group of novel GABA-aminotransferase inhibitors discovered by scientists at Northwestern University. In 2009 Catalyst entered into a strategic collaboration with Northwestern University and in-licensed the worldwide rights to these inhibitors.

CPP-115 binds to GABA-AT (GABA-aminotransferase, also known as GABA transaminase or GABA-T), causing increased levels of GABA, gamma-aminobutyric acid, the chief inhibitory neurotransmitter in humans. It plays a role in regulating neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone.

In preclinical studies CPP-115 has been shown to have potentially significant advantages compared to the only approved and marketed current GABA-AT inhibitor (vigabatrin). CPP-115 may not cause the visual field defects associated with chronic administration of vigabatrin and it has been shown to be at least 200 times more potent in both in-vitro and animal model studies. The increased potency could enable the development of superior or alternative dosage forms and routes of administration. Catalyst hopes these important benefits will allow it to develop CPP-115 for a broad range of other central nervous system indications, such as infantile spasms, epilepsy, Tourette Syndrome and Post Traumatic Stress Disorder (PTSD). Additionally, Catalyst is exploring other selected diseases in which modulation of GABA levels might be beneficial. Catalyst believes that it controls all current intellectual property for GABA-aminotransferase inhibitors.

CPP-115 has received orphan drug designation in both the US and the EU for infantile spasms. Catalyst has begun the clinical development of CPP-115 by completing a randomized, double-blind, single ascending dose Phase I(a) study in normal healthy volunteers to evaluate the human safety characteristics of CPP-115, including CNS side effects and respiratory and cardiovascular safety. The Company reported results which indicated that CPP-115 was well tolerated at all six doses administered up to 500 mg, well above the anticipated therapeutic dose of up to 80 mg/day.

The hydrochloride salt of CPP-115 (PubChem CID 71252718) has been granted orphan drug designation by the EMA for the treatment of West syndrome, an epileptic disorder of young children which causes developmental problems. West syndrome is a long-term debilitating disease which may be life threatening as it can lead to severe damage to motor and cognitive functions. CPP-115 may have additional therapeutic applications for treating other neurological disorders, including drug addiction [4]. A single Phase I clinical trial has assessed CPP-115 as a treatment for cocaine addiction [3], but development has not progressed further.

Image result for CPP 115

Patent

WO 2016073983

NORTHWESTERN UNIVERSITY [–/US]; 633 Clark Street Evanston, IL 60208 (US)
Inventors:	SILVERMAN, Richard, B.; (US). ILAN, Yaron; (IL)

Example 8

[0067] (IS, 4S)-6-Difluoromethylenyl-2-(4′-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (13). At -78 °C, T uLi (1.7 M in pentane, 1.73 mL, 2.94 mmol) was slowly added to a stirred solution of diethyl (difluoromethyl)phosphonate (0.48 mL, 2.94 mmol) in anhydrous THF (15 mL). After being stirred for 0.5 h at -78 °C, 12 (0.60g, 2.45 mmol) in anhydrous THF (20 mL) was slowly added via syringe. Stirring continued for 1 h at – 78 °C , then the solution was allowed to warm to room temperature and heated to reflux for 24 h. Compound 12 is known and available in the art, and can be prepared as described in Qiu, J.; Silverman, R.B. A New Class of Conformationally Rigid Analogues of 4-Amino-5- halopentanoic Acids, Potent Inactivators of γ-Aminobutyric Acid Aminotransferase. J. Med. Chem. 2000, 43, 706-720. After the reaction had cooled down, THF was evaporated, and saturated NH₄C1 solution (20 mL) was added to the residue, which was extracted with EtOAc (3 x 20 mL). The organic layer was washed with brine (2 x 20 mL), dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified by flash column

chromatography, eluting with hexanes/ethyl acetate (2: 1) to give 13 (0.47 g, 68%) as a colorless oil: 1H NMR (400 MHz, CDC1₃) δ 7.18 (d, J 8.4 Hz, 2H), 6.07 (d, J 8.4 Hz, 2H), 4.63 (d, J 14.8 Hz, 1H), 4.14 (s, 1H), 3.80 (s, 3H), 3.78 (d, J 14.8 Hz, 1H), 3.00 (s, 1H), 2.50 (dt, J 15.2, 3.6 Hz, 1H), 2.27 (dd, J 15.2, 2.4 Hz, 1H), 2.00 (d, J 9.2 Hz, 1H), 1.53 (d, 9.6 Hz, 1H); ¹³C NMR (100 MHz, CDC1₃) δ 177.37, 159.13, 152.19 (dd, J 285.7, 281.2 Hz), 129.59, 128.47, 1 14.13, 88.95 (dd, J 25.6, 22.2 Hz), 58.38 (d, J 5.3 Hz), 55.50, 45.60, 44.59, 40.96, 27.43; ¹⁹F NMR (376 MHz, CDC1₃) δ 42.64 and 41.01 (2 dd, J 60.2, 2.3 Hz, 2F). HRMS (EI) Ci₅Hi₅N0₂F2 calcd M

279.1071 , found M 279.10701.

Example 10

(IS, 3S)-3-Amino-4-difluoromethylenyl-l-cyclopentanoic acid (15) (i.e., compound 10, CPP-115, Figure 2). To lactam 14 (20.0 mg, 0.13 mmol) was added 4 mL of 4 N HCl. The solution was stirred at 70 °C for 10 h. After being washed with ethyl acetate (3 x 4 mL), the water layer was evaporated under reduced pressure to give a yellow solid. Recrystallization with ethanol/ether gave a white solid, which was then loaded on a cation- exchange column (AG50W-X8) and eluted with 0.2 N ammonium hydroxide to give the free amino acid 15 as a white solid (16 mg, 72%). 1H NMR (400 MHz, D₂0) δ 4.44 (s, 1H), 2.92 (m, 1H), 2.74 (m, 1H), 2.57 (dd, J 16.4, 3.6 Hz, 1H), 2.34 (m, 1H), 2.02 (d, J 14.8 Hz, 1H); ¹³C NMR (126 MHz, D₂0) δ 186.08, 155.30 (t, J 288.7 Hz), 92.19 (m), 53.16 (d, J 3.8 Hz), 48.01, 37.89, 32.45; ¹⁹F NMR (376 MHz, D₂0) δ -8.43 and -9.02 (2d, J 46.3 Hz, 2F); MS (ESI) C₇H₉N0₂F₂ calcd M+H 178, found M+H 178.

PATENT

US 6794413

https://www.google.com/patents/US6794413

C₇H₁₁O₂N, H% 7.85 C% 59.56 N% 9.92, found H% 7.88 C% 59.23 N% 9.62.

Example 5

(1S, 4S)-6-Difluoromethylenyl-2-(4′-methoxybenzyl)-2-azabicyclo [2.2.1]heptan-3-one (13). At −78° C., ^tBuLi (1.7 M in pentane, 1.73 mL, 2.94 mmol) was slowly added to a stirred solution of diethyl (difluoromethyl)phosphonate (0.48 mL, 2.94 mmol) in anhydrous THF (15 mL). After being stirred for 0.5 h at −78° C., 12 (0.60 g, 2.45 mmol) in anhydrous THF (20 mL) was slowly added via syringe. Stirring continued for 1 h at −78° C., then the solution was allowed to warm to room temperature and heated to reflux for 24 h. Compound 12 is known and available in the, art, and can be prepared as described in Qiu, J.; Silverman, R. B. A New Class of. Conformationally Rigid Analogues of 4-Amino-5-halopentanoic Acids, Potent Inactivators of γ-Aminobutyric Acid Aminotransferase. J. Med. Chem. 2000, 43, 706-720. After the reaction had cooled down, THF was evaporated, and saturated NH₄Cl solution (20 mL) was added to the residue, which was extracted with EtOAc (3×20 mL). The organic layer was washed with brine (2×20 mL), dried4over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with hexanes/ethyl acetate (2:1) to give 13 (0.47 g, 68%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.18 (d, J 8.4 Hz, 2H), 6.07 (d, J 8.4 Hz, 2H), 4.63 (d, J 14.8 Hz, 1H), 4.14 (s. 1H), 3.80 (s, 3H), 3.78 (d, J 14.8 Hz, 1H), 3.00 (s, 1H), 2.50 (dt, J 15.2, 3.6 Hz, 1H), 2.27 (dd, J 15.2, 2.4 Hz, 1H), 2.00 (d, J 9.2 Hz, 1H) 1.53 (d, 9.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 177.37, 159.13, 152.19 (dd, J 285.7, 281.2 Hz), 129.59, 128.47, 114.13, 88.95 (dd, J 25.6, 22.2 Hz), 58.38 (d, J 5.3 Hz), 55.50, 45.60, 44.59, 40.96, 27.43; ¹⁹F NMR (376 MHz, CDCl₃) δ 42.64 and 41.01 (2 dd, J 60.2, 2.3 Hz, 2F). HRMS (EI) C₁₅H₁₅NO₂F₂calcd M 279.1071, found M 279.10701.

Example 6

(1S, 4S)-6-Difluoromethylenyl-2-azabicyclo[2.2.1]heptan-3-one (14). Compound 13 (86.9 mg, 0.31 mmol) was dissolved in CH₃CN (1.75 mL). A solution of ceric ammonium nitrate (512 mg, 0.93 mmol) in water (0.87 mL) was slowly added. The resulting solution was stirred at room temperature for 4 h. The reaction mixture was then diluted with ethyl acetate (20 mL), washed with brine (2×10 mL), and dried over anhydrous Na₂SO₄. After being concentrated under reduced pressure, the residue was purified by flash column chromatography, eluting with hexanes/ethyl acetate (1:1) to give the desired product as a colorless oil (33.6 mg, 68%). ¹H NMR (400 MHz, CDCl₃) δ 5.48 (br s, 1H), 4.40 (s, 1H), 2.93 (s, 1H), 2.54 (dd, J 15.2, 2.8 Hz, 1H), 2.32 (d, J 15.2 Hz, 1H), 2.15 (d, J 9.6 Hz, 1H), 1.64 (d, J 10.0 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ 42.85 and 40.00 (2d, J 60.2 Hz, 2F); HRMS (EI) C₇H₇NOF₂calcd M 159.0496, found M 159.04673.

Example 7

(1S, 3S)3-Amino-4-difluoromethylenyl-1-cyclopentanoic acid (15). To lactam 14 (20.0 mg, 0.13 mmol) was added 4 mL of 4 N HCl. The solution was stirred at 70° C. for 10 h. After being washed with ethyl acetate (3×4 mL), the water layer was evaporated under reduced pressure to give a yellow solid. Recrystallization with ethanol/ether gave a white solid, which was then loaded on a cation-exchange column (AG50W-X8) and eluted with 0.2 N ammonium hydroxide to give the free amino acid 15 as a white solid (16 mg, 72%). ¹H NMR (400 MHz, D₂O) δ 4.44 (s, 1H), 2.92 (m, 1H), 2.74 (m, 1H), 2.57 (dd, J 16.4, 3.6 Hz, 1H), 2.34 (m 1H), 2.02 (d, J 14.8 Hz, 1H); ¹³C NMR (126 MHz, D₂O) δ 186.08, 155.30 (t, J 288.7 Hz), 92.19 (m), 53.16 (d, J 3.8 Hz), 48.01, 37.89, 32.45; ¹⁹F NMR (376 MHz, D₂O) δ −8.43 and −9.02 (2d, J 46.3 Hz, 2F); MS (ESI) C₇H₉NO₂F₂calcd M+H 178, found M+H 178.

paper

Journal of Medicinal Chemistry (2003), 46(25), 5292-5293

Design, Synthesis, and Biological Activity of a Difluoro-Substituted, Conformationally Rigid Vigabatrin Analogue as a Potent γ-Aminobutyric Acid Aminotransferase Inhibitor

Yue Pan , Jian Qiu , and Richard B. Silverman *

Department of Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology, and Drug Discovery Program, Northwestern University, Evanston, Illinois 60208-3113

J. Med. Chem., 2003, 46 (25), pp 5292–5293

DOI: 10.1021/jm034162s

Publication Date (Web): November 11, 2003

http://pubs.acs.org/doi/abs/10.1021/jm034162s

Abstract

Previously it was found that a conformationally rigid analogue (2) of the epilepsy drug vigabatrin (1) did not inactivate γ-aminobutyric acid aminotransferase (GABA-AT). A cyclic compound with an exocyclic double bond (6) was synthesized and was found to inactivate GABA-AT, but only in the absence of 2-mercaptoethanol. The corresponding difluoro-substituted analogue (14) was synthesized and was shown to be a very potent time-dependent inhibitor, even in the presence of 2-mercaptoethanol.

1 to 6 of 6

Patent ID	Patent Title	Submitted Date	Granted Date
US2015196522	METHODS OF USING (1S, 3S)-3-AMINO-4-DIFLUOROMETHYLENYL-1-CYCLOPENTANOIC ACID	2015-03-02	2015-07-16
US8969413	Methods of using (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid	2011-02-25	2015-03-03
US2014336256	METHOD OF TREATING TOURETTE’S DISORDER WITH GABA-AMINOTRANSFERASE INACTIVATORS	2014-07-25	2014-11-13
US2011237554	Combination therapies: inhibitors of GABA transaminase and NKCC1	2011-09-29
US7381748	Compounds and related methods for inhibition of gamma-aminobutyric acid aminotransferase	2008-06-03
US6794413	Compounds and related methods for inhibition of gamma-aminobutyric acid aminotransferase	2004-09-21

RICHARD B. SILVERMAN

PROFESSOR

Research Statement

The research in my group can be summarized as investigations of the molecular mechanisms of action, rational design, and syntheses of potential medicinal agents, particularly for neurodegenerative diseases. Numerous drugs are known to function as specific inhibitors of particular enzymes. When little is known about the enzyme’s molecular mechanism of action, chemical model studies are designed to determine reasonable nonenzymatic pathways applicable to the enzyme. Based on the proposed mechanism of enzyme action, inhibitors are designed and synthesized. Organic synthesis is a primary tool for this work. The enzymes are isolated from either mammalian tissue or from overexpressed cells containing recombinant enzymes. Active site labeling studies utilize MALDI TOF and electrospray ionization mass spectrometry as well as radiolabeled inactivators and peptide mapping. We also are synthesizing compounds to act as receptor antagonists for important receptors related to neurodegenerative diseases.

Recent Publications

Lee, H.; Doud, E. H.; Wu, R.; Sanishvili, R.; Juncosa, J. I.; Liu, D.; Kelleher, N. L.; Silverman, R. B. Mechanism of inactivation of gamma-aminobutyric acid aminotransferase by (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115). J. Am. Chem. Soc. 2015, 137, 2628-2640.

Zigmond, E.; Ya’acov, A. B.; Lee, H.; Lichtenstein, Y.; Shalev, Z.; Smith, Y.; Zolotarov, L.; Ziv, E.; Kalman, R.; Le, H. V.; Lu, H.; Silverman, R. B.; Ilan, Y. Suppression of hepatocellular carcinoma by inhibition of overexpressed ornithine aminotransferase. ACS Med. Chem. Lett. 2015, 6, 840-844.

Tang, W.; Li, H.; Doud, E. H.; Chen, Y.; Choing, S.; Plaza, C.; Kelleher, N. L.; Poulos, T. L.; Silverman, R. B. Mechanism of inactivation of neuronal nitric oxide synthase by (S)-2-amino-5-(2-(methylthio)acetimidamido)pentanoic acid. J. Am. Chem. Soc. 2015, 137, 5980-5989.

Le, H. V.; Hawker, D. D.; Wu, R.; Doud, E.; Widom, J.; Sanishvili, R.; Liu, D.; Kelleher, N. L.; Silverman, R. B. Design and mechanism of tetrahydrothiophene-based GABA aminotransferase inactivators. J. Am. Chem. Soc. 2015, 137, 4525-4533.

Huang, H.; Li, H.; Yang, S.; Chreifi, G.; Martásek, P.; Roman, L. J.; Meyskens, F. L.; Poulos, T. L.; Silverman, R. B. Potent and Selective Double-headed Thiophene-2-carboximidamide Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma. J. Med. Chem. 2014, 57, 686-700.

Trippier, P. C.; Zhao, K. T.; Fox, S. G.; Schiefer, I. T.; Benmohamed, R.; Moran, J.; Kirsch, D. R.; Morimoto, R. I.; Silverman, R. B. Proteasome Activation is a Mechanism for Pyrazolone Small Molecules Displaying Therapeutic Potential in Amyotrophic Lateral Sclerosis. ACS Chem. Neurosci. 2014, 5, 823-829.

Holden, J. K.; Li, H.; Jing, Q.; Kang, S.; Richo, J.; Silverman, R. B.; Poulos, T. L. Structural and biological studies on bacterial nitric oxide synthase inhibitors. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 18127-18131.

Kang, S.; Cooper, G.; Dunne, S. F.; Dusel, B.; Luan, C.-H.; Surmeier, D. J.; Silverman, R. B. CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson’s disease. Nature Commun 2012, 3, 1146.

Silverman, R. B. The 2011 E. B. Hershberg Award for Important Discoveries in Medicinally Active Substances: (1S,3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a GABA Aminotransferase Inactivator and New Treatment for Drug Addiction and Infantile Spasms. J. Med. Chem. 2012, 55, 567-575.

Chen, T.; Benmohamed, R.; Kim, J.; Smith, K.; Amante, D.; Morimoto, R. I.; Kirsch, D. R.; Ferrante, R. J.; Silverman, R. B. ADME-Guided Design and Synthesis of Aryloxanyl Pyrazolone Derivatives to Block Mutant SOD1 Cytotoxicity and Protein Aggregation: Potential Application for the Treatment of Amyotrophic Lateral Sclerosis. J. Med. Chem. 2012, 55, 515-527.

Selected Honors/Awards

2014 Fellow of the National Academy of Inventors
2014 Northwestern University Trustee Medal for Faculty Innovation and Entrepreneurship
2014 iCON Innovator Award (iBIO Institute)
2014 Elected to American Academy of Arts & Sciences
2014 Excellence in Medicinal Chemistry Prize of the Israel Chemical Society
2013 Fellow of the Royal Society of Chemistry (UK)
2013 Centenary Prize of the Royal Society of Chemistry
2013 Bristol-Myers Squibb-Edward E. Smissman Award of the American Chemical Society (ACS)
2013 Roland T. Lakey Award from Wayne State University
2012 Sato Memorial International Award of the Pharmaceutical Society of Japan
2011 Fellow of the ACS
2011 E. B. Hershberg Award for Important Discoveries in Medicinally Active Substances of the ACS
2011 Alumni Hall of Fame, Central High School of Central High School of Philadelphia
2009 Medicinal Chemistry Hall of Fame of the American Chemical Society
2009 Perkin Medal, Society of Chemical Industry
2008 Alumni Fellow Award, Pennsylvania State University
2003 Arthur C. Cope Senior Scholar Award of the American Chemical Society
2000 Northwestern University Alumni Association Excellence in Teaching Award
1999 E. LeRoy Hall Award for Teaching Excellence
1999 Excellence in Chemistry Education Award from the Northwestern University Chapter of Alpha Chi Sigma Chemistry Fraternity
1990 Fellow of the American Association for the Advancement of Science
1985 Fellow of the American Institute of Chemists
1982 NIH Research Career Development Awardee
1981 Alfred P. Sloan Research Fellow
1976 Du Pont Young Faculty Fellow
Silverman describes the structure of pregabalin.

In recognition of his outstanding work in applied chemistry, the Society of Chemical Industry 2009 Perkin Medal has been awarded to Richard B. (Rick) Silverman, the John Evans Professor of Chemistry at Northwestern University. The Perkin Medal, which was first awarded just over one century ago, is recognized as one of the chemical industry’s most prestigious awards.

Silverman’s research primarily focuses on medicinal chemistry: studying the molecular basis of drug action, reaction mechanisms of enzymes, and design and synthesis of pharmaceutical agents. He has worked to deepen understanding of several diseases, including epilepsy, cancer, Parkinson’s, and cerebral palsy.

Among Silverman’s many scientific accomplishments, designing pregabalin and discovering the medicinal properties of that compound stand out for catapulting him and Northwestern to pharmaceutical fame and fortune. Pregabalin, a γ-aminobutyric acid analog, is the active substance in Lyrica, a pain and epilepsy medication commercialized by drug giant Pfizer.

In 2007, after Northwestern collected more than $70 million in royalties for the drug, the university sold a portion of its royalty rights for an additional $700 million (C&EN, March 10, 2008, page 56). Around the same time, Silverman and his family donated a portion of their earnings from the drug to fund construction of a new Northwestern science building. The facility, which is scheduled to open this fall, will house chemistry, biology, and engineering research groups devoted to biomedical science.

Silverman has published more than 250 papers in organic chemistry, medicinal chemistry, and enzymology. He is also the author of three books, including “The Organic Chemistry of Drug Design and Drug Action,” and holds 40 patents.

The Perkin Medal is named for Sir William Henry Perkin (1838–1907), who was honored by SCI in 1906 for developing the first synthetic dye, Perkin mauve. This year’s medal will be presented at SCI’s Perkin Medal banquet in Philadelphia in September.

The Legacy Of Lyrica

November 18, 2013

Northwestern’s Richard Silverman, professor of chemistry, developed pregabalin, the chemical that Pfizer now markets as Lyrica. The drug is one of the two approved treatments for fibromyalgia, epilepsy, and the most effective treatment for seizures as well.

In his laboratory, Silverman’s research team studied chemicals made in the brain. Of particular interest was GABA, a neurotransmitter that inhibits certain brain functions. When GABA levels fall too low in some people, it can trigger epileptic seizures. His group studied enzymes that affect GABA levels, looking for ways to keep GABA elevated. In 1989, the Parke-Davis unit of Warner-Lambert was interested in the research findings. Among the 17 chemical analogs that Silverman sent to Parke-Davis, only pregabalin showed effects in mice.

Serendipity played a huge part in shaping this success story, as most chemicals that affect cells in lab experiments do not survive inside an animal. Another outcome of the research was that the compound was effective for a reason entirely different from Silverman’s initial goal of producing more GABA. In another stroke of luck, the molecule happened to be of the right shape to be transported directly into the brain with nearly 90 percent efficacy.

Lyrica has been a tremendous medical and commercial success that has validated the nearly 15 year process from invention to market launch in 2005. In 2004 Lyrica was approved for use in adults for the treatment of various peripheral neuropathic pain indications as well as therapy for partial epilepsy in more than 60 countries outside of the United States. In 2006 Lyrica was also approved for the treatment of generalized anxiety disorder in Europe. The drug brought in $1.2 billion in sales in 2006 and in 2010 was approved in Europe to treat central neuropathic (nerve) pain. This is expected to push profits from the blockbuster drug to climb even higher.

Northwestern sold a sizeable amount of royalty interest in 2007 to Royalty Pharma, a company that specializes in acquiring cash-generating intellectual property, for $700 million to help the university’s endowment. This deal has been termed the largest sale ever of a royalty stream for a pharmaceutical product.

To learn more about Lyrica visit the product website at www.lyrica.com.

Originally Appeared:

Northwestern’s Innovation and New Ventures Office

////////Cocaine Dependency, CPP 115, PHASE 1, CATALYST, NORTHWESTERN UNIVERSITY, ORPHAN DRUG, 640897-20-7, 760947-97-5

C1C(CC(=C(F)F)C1N)C(=O)O

Pitolisant

August 26, 2016 1:28 pm / Leave a comment

Pitolisant

CAS 362665-56-3

FDA APPROVED 2019 AUG

1-(3-(3-(4-Chlorophenyl)propoxy)propyl)piperidine

MF C17H26ClNO
MW 295.1703

HBS-101
Pitolisant
Tiprolisant
UNII-4BC83L4PIY

(Wakix^®)

A histamine H3 receptor antagonist/inverse agonist used to treat narcolepsy.

BF-2649; BF-2.649; FUB-649, Ciproxidine, Tiprolisant

CAS 362665-56-3, 362665-57-4 (oxalate)

ChemSpider 2D Image | 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine hydrochloride (1:1) | C17H27Cl2NO

CAS 903576-44-3(Pitolisant Hydrochloride)

APPROVED IN EU, European Medicine Agency (EMA) on Mar 31, 2016.

BF 2.649
BF 2649
BF2.649
Ciproxidine
Pitolisant hydrochloride
Tiprolisant
UNII-YV33CH63HI

1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine hydrochloride (1:1)

Molecular Weight	332.31
Formula	C17H26ClNO ● HCl

Bioprojet INNOVATOR

Jean-Charles Schwartz, Jeanne-Marie Lecomte

OriginatorBioprojet; Ferrer
DeveloperAlium Medical; AOP Orphan Pharmaceuticals AG; Bioprojet; Ferox Therapeutics; Harmony Biosciences
ClassNootropics; Piperidines; Sleep disorder therapies
Mechanism of ActionHistamine H3 receptor antagonists; Histamine H3 receptor inverse agonists

Orphan Drug StatusYes – Narcolepsy
New Molecular EntityYes

Highest Development Phases

MarketedNarcolepsy
Phase IIIHypersomnia
Phase IDrug abuse; Type 1 diabetes mellitus

15 Aug 2019Registered for Narcolepsy in USA (PO)
15 Aug 2019Harmony Biosciences intends to market pitolisant for excessive daytime sleepiness in patients with Narcolepsy in USA, in 4Q of 2019
19 Jun 2019Phase-I clinical trials in Type 1 diabetes mellitus in USA (PO) (NCT04026750)
Pitolisant (INN), also known as tiprolisant (USAN),^[1] is a medication in the United States that was approved by the FDA in August 2019. It was granted orphan designation for the treatment of narcolepsy, Fast Track designation for the treatment of excessive daytime sleepiness (EDS) and cataplexy in patients with narcolepsy, and Breakthrough Therapy designation for the treatment of cataplexy in patients with narcolepsy. Pitolisant, a first-in-class medication, is a potent and highly selective Histamine 3 (H₃) receptorantagonist/inverse agonist; it enhances the activity of histaminergic neurons in the brain that function to improve a patient’s wakefulness and inhibit attacks of cataplexy. It was designed and developed by Bioprojet, who has marketed the product in Europe since its approval by the European Medicines Agency in 2016. Pitolisant represents the first new therapy in the U.S. in over 15 years for the treatment of both EDS and cataplexy in adult patients with narcolepsy.The NDA (New Drug Submission) submission is based on results from the clinical development program in narcolepsy, which included over 300 patients, some of whom were treated for up to five years. It also included safety data in over 1500 patients across multiple patient populations. [1]It was developed by Jean-Charles Schwartz, Walter Schunack, and colleagues after the former discovered the H₃ receptor.^[2] It was the first H₃ receptor inverse agonist to be tested in humans or introduced for clinical use.^[2]

Pitolisant (INN) or tiprolisant (USAN) is a histamine receptor inverse agonist/antagonist selective for the H₃ subtype.^[1] It hasstimulant and nootropic effects in animal studies,^[2] and may have several medical applications, having been researched for the treatment of narcolepsy, for which it has been granted orphan drug status in the EU and US.^[3]^[4] It is currently in clinical trials forschizophrenia and Parkinson’s disease.^[4]^[5]^[6]

Pitolisant hydrochloride was approved by European Medicine Agency (EMA) on Mar 31, 2016. It was developed and marketed as Wakix^® by Bioprojet in EU.

Pitolisant is being developed by Bioprojet for the oral treatment of central nervous system disorders. Pitolisant is a selective histamine H3-receptor antagonist/inverse agonist which enhances the activity of histaminergic neurons. Pitolisant has been launched in several countries for the treatment of narcolepsy, and is approved in the US, EU, Iceland and Liechtenstein. Clinical development is underway for type-1 diabetes, hypersomnia and drug abuse in countries worldwide.

Phase III development was also conducted for the treatment of hypersomnia in Switzerland. Phase II development for attention-deficit hyperactivity disorder was conducted in France. However, there were no recent reports on development identified. Development in epilepsy and obesity has been discontinued.

Ferrer and Bioprojet appeared to have a co-development agreement for pitolisant that allowed the mutual use of both companies’ technical and scientific resources; however, as per Ferrer’s communication dated June 2016, the drug is no longer in its portfolio.

Image result for Wakix®

Pitolisant hydrochloride is an antagonist/inverse agonist of the histamine H3 receptor, which is indicated in adults for the treatment of narcolepsy with or without cataplexy.

Wakix^® is available as tablet for oral use, containing 4.5 mg and 18 mg of Pitolisant hydrochloride. The initial dose of 9 mg (two 4.5 mg, tablets) per day, and it should be used at the lowest effective dose, depending on individual patient response and tolerance, according to an up-titration scheme, without exceeding the dose of 36 mg/day.

Pitolisant was developed by Jean-Charles Schwartz, Walter Schunack and colleagues after the former discovered H₃ receptors.^[7]Pitolisant was the first clinically used H₃ receptor inverse agonist.

Pitolisant, also known as Tiprolisant, is a histamine receptor inverse agonist/antagonist selective for the H3 subtype. It has stimulant and nootropic effects in animal studies, and may have several medical applications, having been researched for the treatment of narcolepsy, for which it has been granted orphan drug status in the EU and US. It is currently in clinical trials for schizophrenia and Parkinson’s disease. Pitolisant was the first clinically used H3 receptor inverse agonist.

Image result for pitolisant

The European Medicines Agency (EMA) has recommended granting marketing authorization for pitolisant (Wakix, Bioprojet Pharma) for narcolepsy with or without cataplexy, the agency announced today.

Narcolepsy is a rare sleep disorder that affects the brain’s ability to regulate the normal sleep-wake cycle, leading to excessive daytime sleepiness, including the sudden urge to sleep, and disturbed night-time sleep. Some patients also experience sudden episodes of cataplexy, potentially causing dangerous falls and increasing the risks for accidents, including car accidents. Symptoms of narcolepsy can be severe and significantly reduce quality of life.

Pitolisant “will add to the available treatment options for narcolepsy. It is a first-in-class medicine that acts on histamine H3 receptors in the brain. This leads to increased histamine release in the brain, thereby enhancing wakefulness and alertness,” the EMA notes in a news release.

The EMA recommendation for approval of pitolisant is based on an evaluation of all available safety and efficacy data conducted by the Committee for Medicinal Products for Human Use (CHMP). The data include two pivotal placebo-controlled trials involving 259 patients, as well as one uncontrolled, open-label study involving 102 patients with narcolepsy and one supportive study in 105 patients.

The studies showed that pitolisant was effective in reducing excessive daytime sleepiness in patients with narcolepsy. The beneficial effect of the drug on cataplexy was demonstrated in one of the pivotal studies as well as in the supportive study.

No major safety concerns with pitolisant emerged in testing. Insomnia, headache, and nausea were among the most common adverse effects observed in the clinical trials, and the CHMP decided on measures to mitigate these risks, the EMA said. The CHMP also requested the company conduct a long-term safety study to further investigate the safety of the drug when used over long periods.

Pitolisant for narcolepsy received orphan designation from the Committee for Orphan Medicinal Products in 2007. Orphan designation provides medicine developers access to incentives, such as fee reductions for scientific advice, with the aim of encouraging the development of treatments for rare disorders.

The CHMP opinion will now be sent to the European Commission for the adoption of a decision on a European Union–wide marketing authorization. Once that has been granted, each member state will decide on price and reimbursement based on the potential role/use of this medicine in the context of its national health system.

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Narcolepsy-cataplexy.

Narcolepsy-cataplexy, or Gelineau syndrome, is a rare but serious disorder characterized by excessive daytime sleepiness which can be an extreme hindrance to normal professional and social activities, and which is accompanied by more or less frequent attacks of cataplexy (a sudden loss of muscle tone triggered by emotions as varied as laughter or fear) and erratic episodes of REM sleep (during wakefulness and during sleep), sometimes associated with hypnagogic hallucinations. Moreover, individuals with narcolepsy have various degrees of cognitive impairment and tend to be obese (reviewed by Dauvilliers et al., Clin. Neurophysiol., 2003, 114, 2000; Baumann and Bassetti, Sleep Med. Rev., 2005, 9, 253).

The disorder is caused by the loss of a group of neurons in the brain which produce two peptides, orexins, also known as hypocretins, located in the anterior hypothalamus and projecting to the main groups of aminergic neurons which regulate wakefulness and sleep. Patients with the disorder generally have very low levels of orexins in cerebrospinal fluid. Orexin knock-out mice display many of the symptoms seen in narcoleptic subjects, confirming the role of these peptides and thereby providing an excellent animal model of the disease (Chemelli et al., Cell, 1999, 98, 437).

Several types of treatments which can improve the symptoms of narcolepsy already exist, although they do not completely relieve symptoms and, furthermore, can cause significant side effects limiting their usefulness.

For instance, amphetamines or analogues such as methylphenidate which release catecholamines are used to treated daytime sleepiness, but these agents induce a state of excessive excitation as well as cardiovascular disturbances and also carry a potential for drug addiction.

Modafinil, a drug whose mechanism of action is unclear, also improves daytime sleepiness without causing as many side effects as amphetamines. Nonetheless, its efficacy is limited and it can cause headaches and nausea, particularly at high doses. Moreover amphetamines and/or modafinil do not appear to improve some of the most disabling symptoms of the disease, particularly cataplexy attacks, cognitive deficits and weight gain. With regard to cataplexy, treatments include antidepressants and oxybate. Effectiveness of the former has not been demonstrated (Cochrane Database Syst. Rev., 2005, 20, 3), and the latter is a drug of illegal abuse and its use is restricted.

It has also been shown that histamine H3 receptor antagonists induce the activation of histaminergic neurons in the brain which release histamine, a neurotransmitter with a crucial role in maintaining wakefulness (Schwartz et al., Physiol. Rev. 1991, 71, 1).

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006084833&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Pharmaceutical products with histamine H3 receptor ligand properties and 0 subsequent pharmacological activities thereof are described in EP-980300. An especially important product among those disclosed is 1-[3-[3-(4- chlorophenyl)propoxy] propyl]-piperidine. This compound is disclosed as the free base and as the oxalate salt.

5 The use of 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine as the free base is limited because of its oily nature. On the contrary, 1-[3-[3-(4- chlorophenyl)propoxy]propyl]-piperidine oxalate is a crystalline substance but its low aqueous solubility (0.025 g/ml at 230C) also limits its use as a
pharmaceutical ingredient.
0
Subsequent patents EP-1100503 and EP-1428820 mention certain salts of 1- [3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine. However, the only one specifically described is the oxalate salt. The crystalline monohydrochloride salt is not described.

Example 1 : 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine

According to the method disclosed in EP-982300, Example 78, sodium 3-piperidinopropanolate (2.127 kg; 12.88 mol), 3-(4-chlorophenyl)propyl mesylate (1.121 kg; 4.51 mol) and 0.322 mol of 15-crown-5 in 4.5 kg of dry toluene were refluxed for 4 hours. The solvent was evaporated and the residue purified by column chromatography on silica gel (eluent: methylene chloride/methanol (90/10)). The obtained oil was distilled in a fractionating equipment at reduced pressure (0.3-0.7 mmHg) and with a heating jacket at 207-210⁰C. The head fractions and the distilled fraction at 0.001-0.010 mmHg with a jacket temperature of 180-200⁰C were collected. The obtained oil (1.0 kg; 3.38 mol) corresponds to 1-[3-[3-(4-chlorophenyl)propoxy] propyl]-piperidine. Yield 75%.

Example 2: 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine
monohydrochloride

Preparation

Distilled 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine (1.0 kg) and anhydrous ethyl acetate (4.5 kg) are transferred to a 10-L glass vessel fitted with a cooling bath and a gas inlet. A stream of gaseous hydrogen chloride is bubbled in the reaction mixture at 20-25⁰C.

The pH of the solution is checked by taking a 0.5 mL sample of the reaction mixture and diluting it with 5 mL of deionized water. The final pH must be about 3-4.

The mixture is cooled to -10°C-(-12°C) and stirred at this temperature for 1 h. The precipitate is filtered by using a sintered glass filter and washed with 0.5 L of anhydrous ethyl acetate previously cooled to 0-5⁰C. The product is dried in a vacuum oven at 5O⁰C for a minimum period of 12 hours. The resulting crude 1 -[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine monohydrochloride weighs 1.10 kg.

Purification

A mixture of the above-described crude, 3.98 kg of anhydrous ethyl acetate and 0.35 kg of /-propanol is heated slowly at 55-6O⁰C in a 10-L glass vessel fitted with a heating and cooling system. When the solution has been completed, it is filtered through a heat-isolated sintered glass filter, keeping the temperature at 55-6O⁰C. The solution is transferred to a 10 L glass vessel and the mass is slowly cooled to 0-5⁰C for about 1 hour. The mixture is stirred at this temperature for 1 hour and the precipitate is filtered through a sintered glass filter. The solid is washed with a mixture of 1.6 kg of anhydrous ethyl acetate and 0.14 kg of /-propanol cooled at 0-5⁰C. The solid is dried in a vacuum oven at 5O⁰C for a minimum period of 12 hours. M. p. 117-119⁰C. Yield 80%.
IR spectrum (KBr): bands at 1112 and 1101 (C-O Ether/ St. asym), 2936 and 2868 (Alkane CH(CH₂)) / St.), 1455 (Alkane CH(CH₂)) / Deform.), 2647 and 2551 (Amine Salt / St.), 1492 (Amine / St.), 802 (Aromatic / Deform.) cm^“1.

SEE

Eur. J. Pharm. Sci. 2001, 13, 249–259.

US2004220225A1.

CN101155793A

CN101171009A

References

Celanire S, Wijtmans M, Talaga P, Leurs R, de Esch IJ (December 2005). “Keynote review: histamine H3 receptor antagonists reach out for the clinic”. Drug Discov. Today. 10 (23-24): 1613–27. doi:10.1016/S1359-6446(05)03625-1. PMID 16376822.
Ligneau X, Perrin D, Landais L, Camelin JC, Calmels TP, Berrebi-Bertrand I, Lecomte JM, Parmentier R, Anaclet C, Lin JS, Bertaina-Anglade V, la Rochelle CD, d’Aniello F, Rouleau A, Gbahou F, Arrang JM, Ganellin CR, Stark H, Schunack W, Schwartz JC. BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: Preclinical pharmacology. Journal of Pharmacology and Experimental Therapeutics. 2007 Jan;320(1):365-75. PMID 17005916
Lin JS, Dauvilliers Y, Arnulf I, Bastuji H, Anaclet C, Parmentier R, Kocher L, Yanagisawa M, Lehert P, Ligneau X, Perrin D, Robert P, Roux M, Lecomte JM, Schwartz JC. An inverse agonist of the histamine H(3) receptor improves wakefulness in narcolepsy: studies in orexin-/- mice and patients. Neurobiology of Disease. 2008 Apr;30(1):74-83. PMID 18295497
^ Jump up to:^a ^b Prous Science: Molecule of the Month September 2011
Ligneau X, Landais L, Perrin D, Piriou J, Uguen M, Denis E, Robert P, Parmentier R, Anaclet C, Lin JS, Burban A, Arrang JM, Schwartz JC. Brain histamine and schizophrenia: potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649. Biochemical Pharmacology. 2007 Apr 15;73(8):1215-24. PMID 17343831
Stocking EM, Letavic MA (2008). “Histamine H3 antagonists as wake-promoting and pro-cognitive agents”. Current Topics in Medicinal Chemistry. 8 (11): 988–1002. doi:10.2174/156802608784936728. PMID 18673168.
Schwartz, Jean-Charles (May 2011). “The histamine H3 receptor: from discovery to clinical trials with pitolisant”. BPJ. doi:10.1111/j.1476-5381.2011.01286.x.

References

^ http://adisinsight.springer.com/drugs/800029451
^ Jump up to:^a ^b Schwartz JC (2011). “The histamine H3 receptor: from discovery to clinical trials with pitolisant”. Br. J. Pharmacol. 163(4): 713–21. doi:10.1111/j.1476-5381.2011.01286.x. PMC 3111674. PMID 21615387.

External links

Pitolisant – AdisInsight

REFERENCES

1: Leu-Semenescu S, Nittur N, Golmard JL, Arnulf I. Effects of pitolisant, a histamine H3 inverse agonist, in drug-resistant idiopathic and symptomatic hypersomnia: a chart review. Sleep Med. 2014 Jun;15(6):681-7. doi: 10.1016/j.sleep.2014.01.021. Epub 2014 Mar 18. PubMed PMID: 24854887.

2: Dauvilliers Y, Bassetti C, Lammers GJ, Arnulf I, Mayer G, Rodenbeck A, Lehert P, Ding CL, Lecomte JM, Schwartz JC; HARMONY I study group. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013 Nov;12(11):1068-75. doi: 10.1016/S1474-4422(13)70225-4. Epub 2013 Oct 7. PubMed PMID: 24107292.

3: Nirogi R, Ajjala DR, Kandikere V, Pantangi HR, Jonnala MR, Bhyrapuneni G, Muddana NR, Vurimindi H. LC-MS/MS method for the determination of pitolisant: application to rat pharmacokinetic and brain penetration studies. Biomed Chromatogr. 2013 Nov;27(11):1431-7. doi: 10.1002/bmc.2939. Epub 2013 Jun 13. PubMed PMID: 23760876.

4: Kasteleijn-Nolst Trenité D, Parain D, Genton P, Masnou P, Schwartz JC, Hirsch E. Efficacy of the histamine 3 receptor (H3R) antagonist pitolisant (formerly known as tiprolisant; BF2.649) in epilepsy: dose-dependent effects in the human photosensitivity model. Epilepsy Behav. 2013 Jul;28(1):66-70. doi: 10.1016/j.yebeh.2013.03.018. Epub 2013 May 8. PubMed PMID: 23665640.

5: Uguen M, Perrin D, Belliard S, Ligneau X, Beardsley PM, Lecomte JM, Schwartz JC. Preclinical evaluation of the abuse potential of Pitolisant, a histamine H₃ receptor inverse agonist/antagonist compared with Modafinil. Br J Pharmacol. 2013 Jun;169(3):632-44. doi: 10.1111/bph.12149. PubMed PMID: 23472741; PubMed Central PMCID: PMC3682710.

6: Brabant C, Charlier Y, Tirelli E. The histamine H₃-receptor inverse agonist pitolisant improves fear memory in mice. Behav Brain Res. 2013 Apr 15;243:199-204. doi: 10.1016/j.bbr.2012.12.063. Epub 2013 Jan 14. PubMed PMID: 23327739.

7: Zhang DD, Sisignano M, Schuh CD, Sander K, Stark H, Scholich K. Overdose of the histamine H₃ inverse agonist pitolisant increases thermal pain thresholds. Inflamm Res. 2012 Nov;61(11):1283-91. doi: 10.1007/s00011-012-0528-5. Epub 2012 Jul 21. PubMed PMID: 22820944.

8: Inocente C, Arnulf I, Bastuji H, Thibault-Stoll A, Raoux A, Reimão R, Lin JS, Franco P. Pitolisant, an inverse agonist of the histamine H3 receptor: an alternative stimulant for narcolepsy-cataplexy in teenagers with refractory sleepiness. Clin Neuropharmacol. 2012 Mar-Apr;35(2):55-60. doi: 10.1097/WNF.0b013e318246879d. PubMed PMID: 22356925.

9: Schwartz JC. The histamine H3 receptor: from discovery to clinical trials with pitolisant. Br J Pharmacol. 2011 Jun;163(4):713-21. doi: 10.1111/j.1476-5381.2011.01286.x. Review. PubMed PMID: 21615387; PubMed Central PMCID: PMC3111674.

Pitolisant
Clinical data

Trade names	Wakix
Synonyms	Tiprolisant; Ciproxidine; BF2.649
License data	EU EMA: by INN
Routes of administration	Oral
Drug class	Histamine H₃ receptor inverse agonists
ATC code	N07XX11 (WHO)
Identifiers
IUPAC name [show]
CAS Number	362665-56-3 903576-44-3 (hydrochloride) 362665-57-4 (oxalate)
PubChem CID	9948102
ChemSpider	8123714
UNII	4BC83L4PIY
KEGG	D10749
ChEBI	CHEBI:134709
ChEMBL	ChEMBL462605
Chemical and physical data
Formula	C₁₇H₂₆ClNO
Molar mass	295.851 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] C1CCN(CC1)CCCOCCCC2=CC=C(C=C2)Cl
InChI [hide] InChI=1S/C17H26ClNO/c18-17-9-7-16(8-10-17)6-4-14-20-15-5-13-19-11-2-1-3-12-19/h7-10H,1-6,11-15H2 Key:NNACHAUCXXVJSP-UHFFFAOYSA-N

//////////Pitolisant Hydrochloride, Wakix, histamine H3 receptor antagonist/inverse agonist, narcolepsy, orphan drug, tiprolisant, EU 2016, FDA 2019

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