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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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FDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome


FDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome

The U.S. Food and Drug Administration today expanded the approved use of Nucala (mepolizumab) to treat adult patients with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body. This new indication provides the first FDA-approved therapy specifically to treat EGPA. Continue reading.

December 12, 2017

Release

The U.S. Food and Drug Administration today expanded the approved use of Nucala (mepolizumab) to treat adult patients with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body. This new indication provides the first FDA-approved therapy specifically to treat EGPA.

According to the National Institutes of Health, EGPA (formerly known as Churg-Strauss syndrome) is a condition characterized by asthma, high levels of eosinophils (a type of white blood cell that helps fight infection), and inflammation of small- to medium-sized blood vessels. The inflamed vessels can affect various organ systems including the lungs, gastrointestinal tract, skin, heart and nervous system. It is estimated that approximately 0.11 to 2.66 new cases per 1 million people are diagnosed each year, with an overall prevalence of 10.7 to 14 per 1,000,000 adults.

“Prior to today’s action, patients with this challenging, rare disease did not have an FDA-approved treatment option,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research. “The expanded indication of Nucala meets a critical, unmet need for EGPA patients. It’s notable that patients taking Nucala in clinical trials reported a significant improvement in their symptoms.”

The FDA granted this application Priority Review and Orphan Drug designations. Orphan Drug designation provides incentives to assist and encourage the development of drugs for rare diseases.

Nucala was previously approved in 2015 to treat patients age 12 years and older with a specific subgroup of asthma (severe asthma with an eosinophilic phenotype) despite receiving their current asthma medicines. Nucala is an interleukin-5 antagonist monoclonal antibody (IgG1 kappa) produced by recombinant DNA technology in Chinese hamster ovary cells.

Nucala is administered once every four weeks by subcutaneous injection by a health care professional into the upper arm, thigh, or abdomen.

The safety and efficacy of Nucala was based on data from a 52-week treatment clinical trial that compared Nucala to placebo. Patients received 300 milligrams (mg) of Nucala or placebo administered subcutaneously once every four weeks while continuing their stable daily oral corticosteroids (OCS) therapy. Starting at week four, OCS was tapered during the treatment period. The primary efficacy assessment in the trial measured Nucala’s treatment impact on disease remission (i.e., becoming symptom free) while on an OCS dose less than or equal to 4 mg of prednisone. Patients receiving 300 mg of Nucala achieved a significantly greater accrued time in remission compared with placebo. A significantly higher proportion of patients receiving 300 mg of Nucala achieved remission at both week 36 and week 48 compared with placebo. In addition, significantly more patients who received 300 mg of Nucala achieved remission within the first 24 weeks and remained in remission for the remainder of the 52-week study treatment period compared with patients who received the placebo.

The most common adverse reactions associated with Nucala in clinical trials included headache, injection site reaction, back pain, and fatigue.

Nucala should not be administered to patients with a history of hypersensitivity to mepolizumab or one of its ingredients. It should not be used to treat acute bronchospasm or status asthmaticus. Hypersensitivity reactions, including anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, rash, have occurred. Patients should discontinue treatment in the event of a hypersensitivity reaction. Patients should not discontinue systemic or inhaled corticosteroids abruptly upon beginning treatment with Nucala. Instead, patients should decrease corticosteroids gradually, if appropriate.

Health care providers should treat patients with pre-existing helminth infections before treating with Nucala because it is unknown if Nucala would affect patients’ responses against parasitic infections. In addition, herpes zoster infections have occurred in patients receiving Nucala. Health care providers should consider vaccination if medically appropriate.

The FDA granted approval of Nucala to GlaxoSmithKline.

//////////////Nucala, mepolizumab, fda 2017, gsk,  Eosinophilic Granulomatosis, Polyangiitis, Churg-Strauss Syndrome, Priority Review, Orphan Drug

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VOXELOTOR


Image result for VOXELOTOR

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

  • 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.

Image result for VOXELOTORImage result for VOXELOTOR

Image result for VOXELOTOR

PATENT

WO 2013102142

Inventors Brian MetcalfChihyuan ChuangJeffrey WarringtonKumar PAULVANNANMatthew P. JacobsonLan HUABradley 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

 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.20178 (3), pp 321–326
DOI: 10.1021/acsmedchemlett.6b00491

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.

Abstract Image

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).

Figure

cheme 1. Synthesis of 36a

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.

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

[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

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

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

16

[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)

[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:

17

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.

18

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

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.

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.

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

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

Copanlisib


Copanlisib.svgChemSpider 2D Image | Copanlisib | C23H28N8O4

Copanlisib, BAY 80-6946, 

  • BAY 84-1236
  • Molecular FormulaC23H28N8O4
  • Average mass480.520 Da

Cas 1032568-63-0 [RN]

1402152-26-4 MONO HCL

UNII-WI6V529FZ9

FDA Approved September 2017

2-Amino-N-{7-methoxy-8-[3-(4-morpholinyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-5-pyrimidinecarboxamide
5-Pyrimidinecarboxamide, 2-amino-N-[2,3-dihydro-7-methoxy-8-[3-(4-morpholinyl)propoxy]imidazo[1,2-c]quinazolin-5-yl]-

Copanlisib (BAY 80-6946), developed by Bayer, is a selective Class I phosphoinositide 3-kinase inhibitor[1] which has shown promise in Phase I/II clinical trials for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia.[2]

Image result for copanlisib

Copanlisib is a selective pan-Class I phosphoinositide 3-kinase (PI3K/Phosphatidylinositol-4,5-bisphosphate 3-kinase/phosphatidylinositide 3-kinase) inhibitor that was first developed by Bayer Healthcare Pharmaceuticals, Inc. The drug targets the enzyme that plays a role in regulating cell growth and survival. Copanlisib was granted accelerated approval on September 14, 2017 under the market name Aliqopa for the treatment of adult patients with relapsed follicular lymphoma and a treatment history of at least two prior systemic therapies. Follicular lymphoma is a slow-growing type of non-Hodgkin lymphoma that is caused by unregulated proliferation and growth of lymphocytes. The active ingredient in Aliquopa intravenous therapy is copanlisib dihydrochloride.

Image result for copanlisib

Copanlisib dihydrochloride.pngCopanlisib dihydrochloride; UNII-03ZI7RZ52O; 03ZI7RZ52O; 1402152-13-9; BAY 80-6946 dihydrochloride;

Image result for copanlisib

1402152-46-8 CAS  X=4, 

1919050-77-3 CAS X=1

The FDA awarded copanlisib orphan drug status for follicular lymphoma in February 2015.[3]

Phase II clinical trials are in progress for treatment of endometrial cancer,[4] diffuse large B-cell lymphoma,[5] cholangiocarcinoma,[6]and non-Hodgkin lymphoma.[7] Copanlisib in combination with R-CHOP or R-B (rituximab and bendamustine) is in a phase III trial for relapsed indolent non-Hodgkin lymphoma (NHL).[8] Two separate phase III trials are investigating the use of copanlisib in combination with rituximab for indolent NHL[9] and the other using copanlisib alone in cases of rituximab-refractory indolent NHL.[10]

Copanlisib hydrochloride, a phosphatidylinositol 3-Kinase inhibitor developed by Bayer, was first approved and launched in 2017 in the U.S. for the intravenous treatment of adults with relapsed follicular lymphoma who have received at least two prior treatments.

In 2015, orphan drug designation was assigned in the U.S. for the treatment of follicular lymphoma. In 2017, additional orphan drug designations were granted in the U.S. for the treatment of splenic, nodal and extranodal marginal zone lymphoma.

SYN

WO 2017049983

PATENTS

WO 2008070150

Inventors Martin HentemannJill WoodWilliam ScottMartin MichelsAnn-Marie CampbellAnn-Marie BullionR. Bruce RowleyAniko RedmanLess «
Applicant Bayer Schering Pharma Aktiengesellschaft

Example 13

Preparation of 2-amino-N-r7-methoxy-8-(3-morpholin-4-ylpropoxy)-2.3- dihvdroimidazori^-clquinazolin-S-vHpvrimidine-S-carboxamide.

Figure imgf000084_0001

Step 1 : Preparation of 4-hvdroxy-3-methoxy-2-nitrobenzonitrile

Figure imgf000084_0002

4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (200 g, 1.01 mol) was dissolved in THF (2.5 L) and then ammonium hydroxide (2.5 L) was added followed by iodine (464 g, 1.8 mol). The resulting mixture was allowed to stir for 2 days at which time it was concentrated under reduced pressure. The residue was acidified with HCI (2 N) and extracted into diethyl ether. The organic layer was washed with brine and dried (sodium sulfate) and concentrated under reduced pressure. The residue was washed with diethyl ether and dried under vacuum to provide the title compound (166 g, 84%): 1H NMR (DMSO-cfe) δ: 11.91 (1 H, s), 7.67 (1 H, d), 7.20 (1 H, d), 3.88 (3H, s)

Step 2: Preparation of 3-methoxy-4-(3-morpholin-4-ylpropoxy)-2-nitrobenzonitrile

Figure imgf000084_0003

To a solution of 4-hydroxy-3-methoxy-2-nitrobenzonitrile (3.9 g, 20.1 mmol) in DMF (150 mL) was added cesium carbonate (19.6 g, 60.3 mmol) and Intermediate C (5.0 g, 24.8 mmol). The reaction mixture was heated at 75 0C overnight then cooled to room temperature and filtered through a pad of silica gel and concentrated under reduced pressure. The material thus obtained was used without further purification

Step 3: Preparation of 2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile

Figure imgf000085_0001

3-Methoxy-4-(3-morpholin-4-ylpropoxy)-2-nitrobenzonitrile (7.7 g, 24.1 mmol) was suspended in acetic acid (170 ml_) and cooled to 0 °C. Water (0.4 ml_) was added, followed by iron powder (6.7 g, 120 mmol) and the resulting mixture was stirred at room temperature for 4 h at which time the reaction mixture was filtered through a pad of Celite and washed with acetic acid (400 ml_). The filtrate was concentrated under reduced pressure to 100 mL and diluted with EtOAc (200 ml.) at which time potassium carbonate was added slowly. The resulting slurry was filtered through a pad of Celite washing with EtOAc and water. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution. The organic layer was separated and passed through a pad of silica gel. The resultant solution was concentrated under reduced pressure to provide the title compound (6.5 g, 92%): 1H NMR (DMSO-Cf6) δ: 7.13 (1 H1 d), 6.38 (1 H, d), 5.63 (2H1 br s), 4.04 (2H, t), 3.65 (3H, s), 3.55 (4H1 br t), 2.41 (2H, t), 2.38 (4H1 m), 1.88 (2H1 quint.).

Step 4: Preparation of 6-(4.5-dihvdro-1 H-imidazol-2-v0-2-methoxy-3-(3-morpholin- 4-ylpropoxy)aniline

Figure imgf000085_0002

To a degassed mixture of 2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile (6.5 g, 22.2 mmol) and ethylene diamine (40 mL) was added sulfur (1.8 g, 55.4 mmol). The mixture was stirred at 100 °C for 3 h at which time water was added to the reaction mixture. The precipitate that was formed was collected and washed with water and then dried overnight under vacuum to provide the title compound (3.2 g, 43%): HPLC MS RT = 1.25 min, MH+= 335.2; 1H NMR (DMSO-Cf6) δ: 7.15 (1H, d), 6.86 (2H, br s), 6.25 (1 H, d), 4.02 (2H, t), 3.66 (3H, s), 3.57 (8H, m), 2.46 (2H, t), 2.44 (4H, m), 1.89 (2H, quint.). Step 5: Preparation of 7-methoxy-8-(3-morpholin-4-ylpropoxy)-2.3- dihvdroimidazof1.2-clquinazolin-5-amine

Figure imgf000086_0001

Cyanogen bromide (10.9 g, 102.9 mmol) was added to a mixture of 6-(4,5-dihydro-1 H- imidazol-2-yl)-2-methoxy-3-(3-morpholin-4-ylpropoxy)aniline (17.2 g, 51.4 mmol) and TEA (15.6 g, 154.3 mmol) in DCM (200 ml_) precooled to 0 0C. After 1 h the reaction mixture was concentrated under reduced pressure and the resulting residue stirred with EtOAc (300 mL) overnight at rt. The resulting slurry was filtered to generate the title compound contaminated with triethylamine hydrobromide (26.2 g, 71%): HPLC MS RT = 0.17 min, MH+= 360.2.

Step 6: Preparation of 2-amino-N-r7-methoxy-8-(3-morpholin-4-ylpropoxy)-2.3- dihvdroimidazori ^-clquinazolin-S-vnpyrimidine-δ-carboxamide.

Figure imgf000086_0002

7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (100 mg, 0.22 mol) was dissolved in DMF (5 mL), and Intermediate B (46 mg, 0.33 mmol) was added. PYBOP (173 mg, 0.33 mmol) and diisopropylethylamine (0.16 mL, 0.89 mmol) were subsequently added, and the mixture was stirred at rt overnight. EtOAc was added, and the solids were isolated by vacuum filtration to give the title compound (42.7 mg, 40%): HPLC MS RT = 1.09 min, MH+= 481.2; 1H NMR (DMSO-Cf6 + 2 drops TFA-tf) δ: 9.01 (2H, s), 8.04 (1 H, d), 7.43 (1 H, d), 4.54 (2H, m), 4.34 (2H, br t), 4.23 (2H, m), 4.04 (2H, m), 4.00 (3H, s), 3.65 (2H, br t), 3.52 (2H, m), 3.31 (2H, m), 3.18 (2H, m), 2.25 (2H, m).

PATENT

CN 105130998

TRANSLATED

Example VI:

[0053] a nitrogen atmosphere, the reaction flask was added 7-methoxy-8- (3-morpholin-4-yl-propoxy) -2,3-dihydro-imidazo [l, 2-c] quinoline tetrazol-5-amine (V) (0 • 36g, lmmol), 2- amino-5-carboxylic acid (0 • 15g, l.lmmol) and acetonitrile 25mL, condensing agent added benzotriazole-1-yl yloxy-tris (dimethylamino) phosphonium hexafluorophosphate key (0.49g, 1. lmmol) and the base catalyst 1,5_-diazabicyclo [4. 3.0] – non-5-ene (0 . 50g, 4mmol), at room temperature for 12 hours.Then heated to 50-60 ° C, the reaction was stirred for 6-8 hours, TLC the reaction was complete. The solvent was distilled off under reduced pressure, cooled to room temperature, ethyl acetate was added solid separated. Filter cake washed with cold methanol and vacuum dried to give an off-white solid Kupannixi (1) 0.278, showing a yield of 56.3% -] \ ^ 111/2: 481 [] \ 1+ buckle + 1 111 bandit ? (square) (: 13). 5 2.05 (111,211), 2.48 (111,411), 2. 56 (m, 2H), 3 72 (t, 4H), 4 02 (s, 3H),. 4. 16 (m, 7H), 5. 36 (s, 2H), 6. 84 (d, 1H), 7. 08 (d, 1H), 9. 10 (s, 2H) square

PATENT

WO 2016071435

2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide (10), (which is hereinafter referred to as„copanlisib”), is a proprietary cancer agent with a novel mechanism of action, inhibiting Class I phosphatidylinositol-3-kinases (PI3Ks). This class of kinases is an attractive target since PI3Ks play a central role in the transduction of cellular signals from surface receptors for survival and proliferation. Copanlisib exhibits a broad spectrum of activity against tumours of multiple histologic types, both in vitro and in vivo.

Copanlisib may be synthesised according to the methods given in international patent application PCT/EP2003/010377, published as WO 04/029055 A1 on April 08, 2004, (which is incorporated herein by reference in its entirety), on pp. 26 et seq.

Copanlisib is published in international patent application PCT/US2007/024985, published as WO 2008/070150 A1 on June 12, 2008, (which is incorporated herein by reference in its entirety), as the compound of Example 13 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide.

Copanlisib may be synthesized according to the methods given in WO 2008/070150, pp. 9 et seq., and on pp. 42 et seq. Biological test data for said compound of formula (I) is given in WO 2008/070150 on pp. 101 to 107.

2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimid-azo[1 ,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride (1 1 ), (which is hereinafter referred to as „copanlisib dihydrochloride”) is published in international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 1 1 , 2012, (which is incorporated herein by reference in its entirety), as the compound of Examples 1 and 2 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dinydrochloride : it may be synthesized according to the methods given in said Examples 1 and 2.

Copanlisib may exist in one or more tautomeric forms : tautomers, sometimes referred to as proton-shift tautomers, are two or more compounds that are related by the migration of a hydrogen atom accompanied by the migration of one or more single bonds and one or more adjacent double bonds.

Copanlisib may for example exist in tautomeric form (la), tautomeric form (lb), or tautomeric form (Ic), or may exist as a mixture of any of these forms, as depicted below. It is intended that all such tautomeric forms are included within the scope of the present invention.

Copanlisib may exist as a solvate : a solvate for the purpose of this invention is a complex of a solvent and copanlisib in the solid state. Exemplary solvates include, but are not limited to, complexes of copanlisib with ethanol or methanol.

Copanlisib and copanlisib dihydrochloride may exist as a hydrate. Hydrates are a specific form of solvate wherein the solvent is water, wherein said water is a structural element of the crystal lattice of copanlisib or of copanlisib dihydrochloride. It is possible for the amount of said water to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric hydrates, a hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, or penta-hydrate of copanlisib or of copanlisib dihydrochloride is possible. It is also possible for water to be present on the surface of the crystal lattice of copanlisib or of copanlisib dihydrochloride. The present invention includes all such hydrates of copanlisib or of copanlisib dihydrochloride, in particular copanlisib dihydrochloride hydrate referred to as “hydrate I”, as prepared and characterised in the experimental section herein, or as “hydrate II”, as prepared and characterised in the experimental section herein.

As mentioned supra, copanlisib is, in WO 2008/070150, described on pp. 9 et seq., and may be synthesized according to the methods given therein on pp. 42 et seq., viz. :

Reaction Scheme 1 :

(I)

In Reaction Scheme 1 , vanillin acetate can be converted to intermediate (III) via nitration conditions such as neat fuming nitric acid or nitric acid in the presence of another strong acid such as sulfuric acid. Hydrolysis of the acetate in intermediate (III) would be expected in the presence of bases such as sodium

hydroxide, lithium hydroxide, or potassium hydroxide in a protic solvent such as methanol. Protection of intermediate (IV) to generate compounds of Formula (V) could be accomplished by standard methods (Greene, T.W.; Wuts, P.G.M.; Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999). Conversion of compounds of formula (V) to those of formula (VI) can be achieved using ammonia in the presence of iodine in an aprotic solvent such as THF or dioxane. Reduction of the nitro group in formula (VI) could be accomplished using iron in acetic acid or hydrogen gas in the presence of a suitable palladium, platinum or nickel catalyst. Conversion of compounds of formula (VII) to the imidazoline of formula (VIII) is best accomplished using ethylenediamine in the presence of a catalyst such as elemental sulfur with heating. The cyclization of compounds of formula (VIII) to those of formula (IX) is accomplished using cyanogen bromide in the presence of an amine base such as triethylamine, diisopropylethylamine, or pyridine in a halogenated solvent such as DCM or dichloroethane. Removal of the protecting group in formula (IX) will be dependent on the group selected and can be accomplished by standard methods (Greene, T.W.; Wuts, P.G.M.; Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999). Alkylation of the phenol in formula (X) can be achieved using a base such as cesium carbonate, sodium hydride, or potassium t-butoxide in a polar aprotic solvent such as DMF or DMSO with introduction of a side chain bearing an appropriate leaving group such as a halide, or a sulfonate group. Lastly, amides of formula (I) can be formed using activated esters such as acid chlorides and anhydrides or alternatively formed using carboxylic acids and appropriate coupling agents such as PYBOP, DCC, or EDCI in polar aprotic solvents.

Reaction Scheme 2 :

Reaction Scheme 3

Step A9: N-[3-(dimethylamino)propyl]-N’-ethylcarbodiimide hydrochloride (“EDCI”) is used as coupling reagent. Copanlisib is isolated by simple filtration.

Step A1 1 : Easy purification of copanlisib via its dihydrochloride

(dihydrochloride is the final product)

Hence, in a first aspect, the present invention relates to a method of preparing copanlisib (10) via the following steps shown in Reaction Scheme 3, infra :

Reaction Scheme 3 : 

Example 1 : Step A1 : Preparation of 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (2)

3.94 kg of nitric acid (65 w%) were added to 5.87 kg of concentrated sulfuric acid at 0°C (nitrating acid). 1 .5 kg of vanillin acetate were dissolved in 2.9 kg of dichloromethane (vanillin acetate solution). Both solutions reacted in a micro reactor with flow rates of app. 8.0 mL/min (nitrating acid) and app. 4.0 mL/min (vanillin acetate solution) at 5°C. The reaction mixture was directly dosed into 8 kg of water at 3°C. After 3h flow rates were increased to 10 mL/min (nitrating acid) and 5.0 mL/min (vanillin acetate solution). After additional 9 h the flow reaction was completed. The layers were separated at r.t., and the aqueous phase was extracted with 2 L of dichloromethane. The combined organic phases were washed with 2 L of saturated sodium bicarbonate, and then 0.8 L of water. The dichloromethane solution was concentrated in vacuum to app. 3 L, 3.9 L of methanol were added and app. the same volume was removed by distillation again. Additional 3.9 L of methanol were added, and the solution concentrated to a volume of app. 3.5 L. This solution of 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (2) was directly used in the next step.

Example 2 : Step A2 : Preparation of 4-hydroxy -3-methoxy-2-nitrobenzaldehyde (2-nitro-vanillin) (3)

To the solution of 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (2) prepared as described in example 1 (see above) 1 .25 kg of methanol were added, followed by 2.26 kg of potassium carbonate. The mixture was stirred at 30°C for 3h. 7.3 kg of dichloromethane and 12.8 kg of aqueous hydrochloric acid (10 w%) were added at < 30°C (pH 0.5 – 1 ). The mixture was stirred for 15 min, and the layers were separated. The organic layer was filtered, and the filter cake washed with 0.5 L of dichloromethane. The aqueous layer was extracted twice with 4.1 kg of

dichloromethane. The combined organic layers were concentrated in vacuum to app. 4 L. 3.41 kg of toluene were added, and the mixture concentrated to a final volume of app. 4 L. The mixture was cooled to 0°C. After 90 min the suspension was filtered. The collected solids were washed with cold toluene and dried to give 0.95 kg (62 %).

1H-NMR (400 MHz, de-DMSO): δ =3.84 (s, 3H), 7.23 (d, 1 H), 7.73 (d, 1 H), 9.74 (s, 1 H), 1 1 .82 (brs, 1 H).

NMR spectrum also contains signals of regioisomer 6-nitrovanillin (app. 10%): δ = 3.95 (s, 3H), 7.37 (s, 1 H), 7.51 (s, 1 H), 10.16 (s, 1 H), 1 1 .1 1 (brs, 1 H).

Example 3 : Step A3 : Preparation of 4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde (4) :

10 g of 3 were dissolved in 45 mL DMF at 25 °C. This solution was charged with 14 g potassium carbonate and the temperature did rise to app. 30 °C. Into this suspension 7.1 mL benzyl bromide was dosed in 15minutes at a temperature of 30 °C. The reaction mixture was stirred for 2 hours to complete the reaction. After cooling to 25 °C 125 mL water was added. The suspension was filtered, washed twice with 50 mL water and once with water / methanol (10 mL / 10 mL) and tried at 40 °C under reduced pressure. In this way 14.2 g (97% yield) of 4 were obtained as a yellowish solid.

1 H-NMR (500 MHz, d6-DMSO): 3.86 (s, 3H); 5.38 (s, 2 H); 7.45 (m, 5H); 7.62 (d, 2H); 7.91 (d, 2H); 9.81 (s, 1 H).

Example 4a : Step A4 : 2-[4-(benzyloxy)-3-methoxy-2-nitrophenyl]-4,5-dihydro-1 H-imidazole (5) : Method A

10 g of 4 were dissolved in 100 mL methanol and 2.5 g ethylenediamine were added at 20-25 °C. The reaction mixture was stirred at this temperature for one hour, cooled to 0°C and a solution of N- bromosuccinimide (8.1 g) in 60 mL

acetonitrile was added. Stirring was continued for 1 .5 h and the reaction mixture was warmed to 20 °C and stirred for another 60 minutes. The reaction was quenched with a solution of 8.6 g NaHCO3 and 2.2 g Na2SO3 in 100 mL water. After 10 minutes 230 mL water was added, the product was filtered, washed with 40 mL water and tried at 40 °C under reduced pressure. In this way 8.9 g (78% yield) of 5 was obtained as an white solid.

1 H-NMR (500 MHz, d6-DMSO): 3.31 (s, 4H); 3.83 (s, 3H); 5.29 (s, 2 H); 6.88 (s, 1 H); 7.37 (t, 1 H); 7.43 (m, 3H); 7.50 (m, 3H).

Example 4b : Step A4 : 2-[4-(benzyloxy)-3-methoxy-2-nitrophenyl]-4,5-dihydro-1 H-imidazole (5) : Method B

28.7 kg of compound 4 were dissolved in 231 kg dichloromethane at 20 °C and 8.2 kg ethylenediamine were added. After stirring for 60 minutes N-bromosuccinimide was added in 4 portions (4 x 5.8 kg) controlling that the temperature did not exceed 25°C. When the addition was completed stirring was continued for 90 minutes at 22 °C. To the reaction mixture 9 kg potassium carbonate in 39 kg water was added and the layers were separated. From the organic layer 150 kg of solvent was removed via distillation and 67 kg toluene was added. Another 50 kg solvent was removed under reduced pressure and 40 kg toluene was added. After stirring for 30 minutes at 35-45 °C the reaction was cooled to 20 °C and the product was isolated via filtration. The product was washed with toluene (19 kg), tried under reduced pressure and 26.6 kg (81 % yield) of a brown product was obtained.

Example 5 : Step A5 : 3-(benzyloxy)-6-(4,5-dihydro-1 H-imidazol-2-yl)-2-methoxyaniline (6) :

8.6 g of compound 5 were suspended in 55 mL THF and 1 .4 g of 1 %Pt/0.2% Fe/C in 4 mL water was added. The mixture was heated to 45 °C and hydrogenated at 3 bar hydrogen pressure for 30 minutes. The catalyst was

filtered off and washed two times with THF. THF was removed via distillation and 65 mL isopropanol/water 1/1 were added to the reaction mixture. The solvent remaining THF was removed via distillation and 86 mL isopropanol/water 1/1 was added. The suspension was stirred for one hour, filtered, washed twice with isopropanol/water 1/1 and dried under reduced pressure to yield 7.8g (99% yield) of an white solid.

1 H-NMR (500 MHz, d6-DMSO): 3.26 (t, 2H); 3.68 (s, 3H); 3.82 (t, 2H); 5.13 (s, 2 H); 6.35 (d, 1 H); 6.70 (s, 1 H); 6.93 (bs, 2 H); 7.17 (d, 1 H); 7.33 (t, 1 H); 7.40 (t, 2H); 7.45 (d, 2H).

Example 6a : Step A6 : 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (7) : Method A

10 g of 6 were suspended in 65 mL acetonitrile and 6.1 mL triethylamine were added. At 5-10 °C 8.4 mL bromocyanide 50% in acetonitrile were added over one hour and stirring was continued for one hour. 86 mL 2% NaOH were added and the reaction mixture was heated to 45 °C and stirred for one hour. The suspension was cool to 10 °C, filtered and washed with water/acetone 80/20. To further improve the quality of the material the wet product was stirred in 50 mL toluene at 20-25 °C. The product was filtered off, washed with toluene and dried under reduced pressure. In this way 8.8 g (81 % yield) of 7 was isolated as a white solid.

1 H-NMR (500 MHz, d6-DMSO): 3.73 (s, 3H); 3.87 (m, 4H); 5.14 (s, 2 H); 6.65 (bs, 2 H); 6.78 (d, 1 H); 7.33 (m, 1 H); 7.40 (m, 3 H); 7.46 (m, 2H).

Example 6b : Step A6 : 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (8) : Method B

20 kg of compound 6 were dissolved in 218 kg dichloromethane at 20 °C and the mixture was cooled to 5 °C. At this temperature 23.2 kg triethylamine was dosed in 15 minutes and subsequently 25.2 kg bromocyanide (3 M in

dichloromethane) was dosed in 60 minutes to the reaction mixture. After stirring for one hour at 22 °C the reaction was concentrated and 188 kg of solvent were removed under reduced pressure. Acetone (40 kg) and water (50 kg) were added and another 100 kg of solvent were removed via distillation. Acetone (40 kg) and water (150 kg) were added and stirring was continued for 30 minutes at 36°C. After cooling to 2 °C the suspension was stirred for 30 minutes, isolated, washed with 80 kg of cold water and tried under reduced pressure. With this procedure 20.7 kg (95% yield) of an off-white product was obtained.

Example 7a : Step A7 : Method A: preparation of 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol (8) :

A mixture of 2 kg of 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine, 203 g of 5% Palladium on charcoal (50% water wetted) and 31 .8 kg of Ν,Ν-dimethylformamide was stirred at 60°C under 3 bar of hydrogen for 18 h. The mixture was filtered, and the residue was washed with 7.5 kg of Ν,Ν-dimethylformamide. The filtrate (38.2 kg) was concentrated in vacuum (ap. 27 L of distillate collected and discarded). The remaining mixture was cooled from 50°C to 22°C within 1 h, during this cooling phase 14.4 kg of water were added within 30 min. The resulting suspension was stirred at 22°C for 1 h and then filtered. The collected solids were washed with water and dried in vacuum to yield 0.94 kg (65 %).

1H-NMR (400 MHz, de-DMSO): δ = 3.72 (s, 3H), 3.85 (m, 4H), 6.47 (d, 1 H), 6.59 (bs, 1 H), 7.29 (d, 1 H), 9.30 (bs, 1 H).

Example 7b : Step A7 Method B : preparation of 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol (8) :

222.8 g of trifluroacetic acid were added to a mixture of 600 g of 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine and 2850 g of DMF. 18 g of 5% Palladium on charcoal (50% water wetted) were added. The mixture

was stirred at under 3 bar of hydrogen overnight. The catalyst was removed by filtration and washed with 570 g of DMF. The filtrate was concentrated in vacuum (432 g of distillate collected and discarded). 4095 ml of 0.5 M aqueous sodium hydroxide solution was added within 2 hours. The resulting suspension was stirred overnight. The product was isolated using a centrifuge. The collected solids were washed with water. The isolated material (480.2g; containing app. 25 w% water) can be directly used in the next step (example 8b).

Example 8a : Step A8 : Method A : preparation of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (9) :

2.5 kg of potassium carbonate were added to a mixture of 1 .4 kg of 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol, 14 L of n-butanol, 1 .4 L of Ν,Ν-dimethylformamide and 1 .4 L of water. 1 .57 kg of 4-(3-chloropropyl)morpholine hydrochloride were added. The resulting suspension was heated to 90°C and stirred at this temperature for 5 h. The mixture was cooled to r.t.. At 50°C 8.4 kg of water were added. The mixture was stirred at r.t. for 15 min. After phase separation the aqueous phase was extracted with 12 L of n-butanol. The combined organic phases were concentrated in vacuum to a volume of ap. 1 1 L. 10.7 L of terf-butyl methyl ether were added at 50°C. The resulting mixture was cooled within 2 h to 0°C and stirred at this temperature for 1 h. The suspension was filtered, and the collected solids were washed with tert-butyl methyl ether and dried to give 1 .85 kg (86 %).

The isolated 1 .85 kg were combined with additional 0.85 kg of material produced according to the same process. 10.8 L of water were added and the mixture heated up to 60°C. The mixture was stirred at this temperature for 10 min, then cooled to 45°C within 30 min and then to 0°C within 1 h. The suspension was stirred at 0°C for 2 h and then filtered. The solids were washed with cold water and dried to yield 2.5 kg.

1H-NMR (400 MHz, de-DMSO): δ = 1 .88 (m, 4H), 2.36 (m, 4H), 2.44 (t, 2H), 3.57 (m, 4H), 3.70 (s, 3H), 3.88 (m, 4H), 4.04 (t, 2H), 6.63 (s, 2H), 6.69 (d, 1 H), 7.41 (d, 1 H).

HPLC: stationary phase: Kinetex C18 (150 mm, 3.0 mm ID, 2.6 μιτι particle size): mobile phase A: 0.5 ml_ trifluoro acetic acid / 1 L water; mobile phase B: 0.5 ml_ trifluoro acetic acid / L acetonitrile; UV detection at 256 nm; oven temperature: 40°C; injection volume: 2.0 μΙ_; flow 1 .0 mL/min; linear gradient in 4 steps: 0% B -> 6% B (20 min), 6 % B -> 16% B (5 min), 16% B -> 28 % B (5 min), 28 % B -> 80 % B (4 min), 4 minutes holding time at 80% B; purity: >99,5 % (Rt=1 1 .0 min), relevant potential by-products: degradation product 1 at RRT (relative retention time) of 0.60 (6.6 min) typically <0.05 %, 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol RRT 0.71 (7.8 min): typically <0.05 %, degradation product 2 RRT 1 .31 (14.4 min): typically <0.05 %, 7-methoxy-5-{[3-(morpholin-4-yl)propyl]amino}-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol RRT 1 .39 (15.3 min): typically <0.05 %, 9-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 1 .43 (15.7 min): typically <0.05 %, degradation product 3 RRT 1 .49 (16.4 min): typically <0.05 %, 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-N-[3-(morpholin-4-yl)propyl]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 1 .51 (16.7 min): typically <0.10 %, 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 2.56 (28.2 min): typically <0.05 %, 8-(benzyloxy)-7-methoxy-N-[3-(morpholin-4-yl)propyl]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 2.59 (28.5 min): typically <0.05 %.

Example 8b: : Step A8 (Method B): preparation of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (9) :

13.53 g of 5-amino-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-ol (containing app. 26 w% of water) were suspended in 1 10 g of n-butanol. The mixture was concentrated in vacuum (13.5 g of distillate collected and discarded). 17.9 g of potassium carbonate and 1 1 .2 g of 4-(3-chloropropyl)morpholine hydrochloride were added. The resulting mixture was heated to 90°C and stirred at this temperature for 4 hours. The reaction mixture was cooled to to 50°C, and 70 g of water were added. The layers were separated. The organic layer was concentrated in vacuum (54 g of distillate collected and discard). 90 g of terf-butyl methyl ether were added at 65°C. The resulting mixture was cooled to 0°C. The mixture was filtered, and the collected solids washed with terf-butyl methyl ether and then dried in vacuum to yield 13.4 g (86%).

13.1 g of the isolated material were suspended in 65.7 g of water. The mixture was heated to 60°C. The resulting solution was slowly cooled to 0°C. The precipitated solids were isolated by filtration, washed with water and dried in vacuum to yield 12.0 g (92%).

Example 9: Step A10 : Preparation of 2-aminopyrimidine-5-carboxylic acid (9b)

1 kg of methyl 3,3-dimethoxypropanoate was dissolved in 7 L of 1 ,4-dioxane. 1 .58 kg of sodium methoxide solution (30 w% in methanol) were added. The mixture was heated to reflux, and ap. 4.9 kg of distillate were removed. The resulting suspension was cooled to r.t., and 0.5 kg of methyl formate was added. The reaction mixture was stirred overnight, then 0.71 kg of guanidine hydrochloride was added, and the reaction mixture was stirred at r.t. for 2 h. The reaction mixture was then heated to reflux, and stirred for 2 h. 13.5 L of water were added, followed by 0.72 kg of aqueous sodium hydroxide solution (45 w%). The reaction mixture was heated at reflux for additional 0.5 h, and then cooled to 50°C. 0.92 kg of aqueous hydrochloric acid (25 w%) were added until pH 6 was reached. Seeding crystals were added, and additional 0.84 kg of aqueous hydrochloric acid (25 w%) were added at 50°C until pH 2 was reached. The mixture was cooled to 20°C and stirred overnight. The suspension was filtered, the collected solids washed twice with water, then twice with methanol, yielding 0.61 kg (65%).

Four batches produced according to the above procedure were combined (total 2.42 kg). 12 L of ethanol were added, and the resulting suspension was stirred at r.t. for 2.5 h. The mixture was filtered. The collected solids were washed with ethanol and dried in vacuum to yield 2.38 kg.

To 800 g of this material 2.5 L of dichloromethane and 4 L of water were added, followed by 1375 ml_ of dicyclohexylamine. The mixture was stirred for 30 min. at r.t. and filtered. The collected solids are discarded. The phases of the filtrate are separated, and the organic phase was discarded. 345 ml_ of aqueous sodium hydroxide solution (45 w%) were added to the aqueous phase. The aqueous phase was extracted with 2.5 L of ethyl acetate. The phases were separated and the organic phase discarded. The pH value of the aqueous phase was adjusted to pH 2 using app. 500 ml_ of hydrochloric acid (37 w%). The mixture was filtered, and the collected solids were washed with water and dried, yielding 405 g.

The 405 g were combined with a second batch of comparable quality (152 g). 2 L of ethyl acetate and 6 L of water were added, followed by 480 ml_ of aqueous sodium hydroxide solution (45 w%). The mixture was stirred at r.t. for 30 min.. The phases were separated. The pH of the aqueous phase was adjusted to pH 2 with ap. 770 ml_ of aqueous hydrochloric acid (37 w%). The mixture was filtered, and the collected solids washed with water and dried to yield 535 g.

1H-NMR (400 MHz, de-DMSO): δ = 7.46 (bs, 2H); 8.66 (s, 2H), 12.72 (bs, 1 H).

Example 10 : Step A9 : preparation of copanlisib (10)

A mixture of 1250 g of 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydro-imidazo[1 ,2-c]quinazolin-5-amine, 20.3 kg of N,N-dimethylformamide, 531 g of 2-aminopyrimidine-5-carboxylic acid, 425 g of Ν,Ν-dimethylaminopyridine and 1000 g of N-[3-(dimethylamino)propyl]-N’-ethylcarbodiimide hydrochloride was stirred at r.t. for 17 h. The reaction mixture was filtered. The collected solids were washed with Ν,Ν-dimethylformamide, then ethanol, and dried at 50°C to yield 1 .6 kg (96%). The isolated material was directly converted into the dihydrochloride.

Example 11 : Step A11 : preparation of copanlisib dihydrochloride (11)

To a mixture of 1 .6 kg of copanlisib and 4.8 kg of water were added 684 g of aqueous hydrochloric acid (32 w%) while maintaining the temperature between 20 to 25°C until a pH of 3 to 4 was reached. The resulting mixture was stirred for 10 min, and the pH was checked (pH 3.5). The mixture was filtered, and the filter cake was washed with 0.36 kg of water. 109 g of aqueous hydrochloric acid were added to the filtrate until the pH was 1 .8 to 2.0. The mixture was stirred for 30 min and the pH was checked (pH 1 .9). 7.6 kg of ethanol were slowly added within 5 h at 20 to 25°C, dosing was paused after 20 min for 1 h when crystallization started. After completed addition of ethanol the resulting suspension was stirred for 1 h. The suspension was filtered. The collected solids was washed with ethanol-water mixtures and finally ethanol, and then dried in vacuum to give 1 .57 kg of copansilib dihydrochloride (85 %).

1H-NMR (400 MHz, de-DMSO): δ = 2.32 (m, 2H), 3.1 1 (m, 2H), 3.29 (m, 2H),

3.47 (m, 2H), 3.84 (m, 2H), 3.96 (m, 2H), 4.01 (s, 3H), 4.19 (t, 2H), 4.37 (t, 2H),

4.48 (t, 2H), 7.40 (d, 1 H), 7.53 (bs, 2H), 8.26 (d, 1 H), 8.97 (s, 2H), 1 1 .28 (bs, 1 H), 12.75 (bs, 1 H), 13.41 (bs, 1 H).

HPLC: stationary phase: Kinetex C18 (150 mm, 3.0 mm ID, 2.6 μιτι particle size): mobile phase A: 2.0 ml_ trifluoro acetic acid / 1 L water; mobile phase B: 2.0 ml_ trifluoro acetic acid / L acetonitrile; UV detection at 254 nm switch after 1 minute to 282 nm; oven temperature: 60°C; injection volume: 2.0 μΙ_; flow 1 .7 mL/min; linear gradient after 1 minute isocratic run in 2 steps: 0% B -> 18% B (9 min), 18 % B -> 80% B (2.5 min), 2.5 minutes holding time at 80% B; purity: >99.8% (Rt=6.1 min), relevant potential by-products: 2-Aminopyrimidine-5-carboxylic acid at RRT (relative retention time) of 0.10 (0.6 min) typically <0.01 %, 4-dimethylaminopyrimidine RRT 0.26 (1 .6 min): typically <0.01 %, 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine RRT 0.40 (2.4 min): typically <0.03 %, by-product 1 RRT 0.93 (5.7 min): typically <0.05 %, by-product 6 RRT 1 .04 (6.4 min): typically <0.05 %, 2-amino- N-{3-(2-aminoethyl)-8-methoxy-7-[3-(morpholin-4-yl)propoxy]-4-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamicle RRT 1.12 (8.9 min); typically <0.10 %, 5-{[(2-aminopyrimidin-5-yl)carbonyl]amino}-7-methoxy-2,3-dihydroimidazo[ ,2-c]quinazolin-8-yl 2-aminopyrimidine-5-carboxylate RRT 1.41 (8.6 min): typically <0.01 %

Example 15 : Step A11 : further example of preparation of copanlisib dihydrochloride (11)

7.3 g of hydrochloric acid were added to a mixture of 12 g of copanlisib and 33 g of water at maximum 30°C. The resulting mixture was stirred at 25°C for 15 min, and the filtered. The filter residue was washed with 6 g of water. 1 1 .5 g of ethanol were added to the filtrate at 23°C within 1 hour. After the addition was completed the mixture was stirred for 1 hour at 23°C. Additional 59 g of ethanol were added to the mixture with 3 hours. After the addition was completed the mixture was stirred at 23°C for 1 hour. The resulting suspension was filtered. The collected crystals were washed three times with a mixture of 1 1 .9 g of ethanol and 5.0 g of water and the air dried to give 14.2 g of copanlisib dihydrochloride as hydrate I.

Purity by HPLC: > 99.8%; < 0.05% 2-amino-N-{3-(2-aminoethyl)-8-methoxy-7- [3-(morpholin-4-yl)propoxy]-4-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamide

Example 16 : Step A11 : further example of preparation of copanlisib dihydrochloride (11 )

9.1 kg of hydrochloric acid (25 w%) were added to a mixture of 14,7 kg of copanlisib and 41.9 kg of water at maximum temperature of 28°C. The resulting mixture was stirred at 23°C for 80 minutes until a clear solution was formed. The solution was transferred to a second reaction vessel, and the transfer lines rinsed with 6 kg of water, 14.1 kg of ethanol were slowly added within 70 minutes at 23°C. After the addition of ethanol was completed the mixture was stirred at 23°C for 1 hour. Additional 72.3 kg of ethanol were slowly added within 3.5 hours at 23°C, and resulting mixture stirred at this temperature for 1 hour. The suspension is filtered, and the collected solids were washed twice with 31 kg of an ethanol-water mixture (2.4: 1 (w w)). The product was dried in vacuum with a maximum jacket temperature of 40°C for 3.5 hours to yield 15.0 kg of copanlisib dihydrochloride as hydrate I.

Purity by HPLC: > 99.9 %; < 0.05% 2-amino-N-{3-(2-aminoethyl)-8-methoxy-7-[3-(morpholin-4-yl)propoxy]^-oxo-3,4-dihydroquinazolin-2-yl}pyrimidine-5-carboxamideLoss on drying: 14.7 w%

PATENT

WO 2017049983

Copanlisib is a novel oral phosphoinositide 3 kinase (PI3K) inhibitor developed by the German company Bayer. Existing clinical studies have shown that the drug inhibits the growth of cancer cells in patients with leukemia and lymphoma by blocking the PI3K signaling pathway. To further prove the promise of the drug, Bayer also conducted two more Phase III clinical studies in 2015: treating a rare non-Hodgkin’s lymphoma (NHL) by itself or in combination with Rituxan and using it alone The effect of Rituxan is compared. In addition, Bayer also plans to conduct a Phase II clinical trial of Copanlisib in the treatment of diffuse large B-cell lymphoma, a malignant NHL subtype. Because the drug does not yet have a standard Chinese translation, the applicant here transliterates “Kupanisi”.
The chemical name of Copanisibib (I) is 2-amino-N- [2,3-dihydro-7-methoxy- 8- [3- (4- morpholinyl) propoxy] Imidazo [1,2-c] quinazolin-5-yl] -5-pyrimidinecarboxamide of the formula:
PCT patent WO2008070150 from the original company discloses the preparation of cupanatinib and its analogs. The document altogether refers to the following five possible synthetic routes.
Synthetic Route 1:
Synthetic route two:
Synthetic route three:

Synthetic route four:
Synthetic route five:

Example 6:
In a nitrogen atmosphere, 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2,3-dihydroimidazo [1,2-c] quinazoline- (V) (0.36 g, 1 mmol), 2-aminopyrimidine-5-carboxylic acid (0.15 g, 1.1 mmol) and acetonitrile were added 25 mL of a condensing agent benzotriazol- (0.49 g, 1.1 mmol) and base catalyst 1,5-diazabicyclo [4.3.0] -non-5-ene (0.50 g, 4 mmol) were added and the mixture was stirred at room temperature for 12 hours . Then warmed to 50-60 ℃, the reaction was stirred for 6-8 hours, TLC detection reaction was completed. The solvent was evaporated under reduced pressure, cooled to room temperature, ethyl acetate was added and a solid precipitated. Filter cake washed with cold methanol, and dried in vacuo to give an off-white solid Kupannixi (I) 0.27g, yield% 56.3; the MS-EI m / Z: 481 [M + H] + , . 1 H NMR (CDCl3 3 ) 62.05 (m, 2H), 2.48 (m, 4H), 2.56 (m, 2H), 3.72 (t, 4H), 4.02 (s, 3H), 4.16 (m, , 6.84 (d, 1H), 7.08 (d, 1H), 9.10 (s, 2H).

PAPER

http://web.a.ebscohost.com/ehost/pdfviewer/pdfviewer?vid=1&sid=49a5a4d4-00a3-4f4a-8630-0277f78d630f%40sessionmgr4010

 ChemMedChem (2016), 11(14), 1517-1530.

2-Amino-N-{7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide (BAY 80-6946, 39i):

Amine 36 (80% purity; 100 mg, 0.22 mmol) was dissolved in DMF (5 mL), and acid 39i’ (46 mg, 0.33 mmol) was added. PyBOP (173 mg, 0.33 mmol) and DIPEA (0.16 mL, 0.89 mmol) were sequentially added, and the mixture was stirred at RT overnight. EtOAc was added, and the solids were isolated by vacuum filtration to give 39i (42.7 mg, 40%):

1H NMR ([D6 ]DMSO+ 2 drops [D]TFA): d=2.25 (m, 2H), 3.18 (m, 2H), 3.31 (m, 2H), 3.52 (m, 2H), 3.65 (brt, 2H), 4.00 (s, 3H), 4.04 (m, 2H), 4.23 (m, 2H), 4.34 (brt, 2H), 4.54 (m, 2H), 7.43 (d, 1H), 8.04 (d, 1H), 9.01 (s, 2H);

1H NMR of the bis-HCl salt (500 MHz, [D6 ]DMSO): d=2.30–2.37 (m, 2H), 3.11 (brs, 2H), 3.25–3.31 (m, 2H), 3.48 (d, J=12.1 Hz, 2H), 3.83–3.90 (m, 2H), 3.95–4.00 (m, 2H), 4.01 (s, 3H), 4.17–4.22 (m, 2H), 4.37 (t, J=6.0 Hz, 2H), 4.47 (t, J=9.7 Hz, 2H), 7.40 (d, J= 9.2 Hz, 1H), 7.54 (s, 2H), 8.32 (d, J=9.2 Hz, 1H), 8.96 (s, 2H), 11.46 (brs, 1H), 12.92 (brs, 1H), 13.41 (brs, 1H);

13C NMR (125 MHz, [D6 ]DMSO): d=23.09, 45.22, 46.00, 51.21, 53.38, 61.54, 63.40, 67.09, 101.18, 112.55, 118.51, 123.96, 132.88, 134.35, 148.96, 157.25, 160.56, 164.96, 176.02 ppm;

MS (ESI+) m/z: 481 [M+H]+ .

References

  1. Jump up^ “Phase II Data of Bayer’s Novel Cancer Drug Candidate Copanlisib to be Presented”. Retrieved 3 March 2015.
  2. Jump up^ Loguidice, Christina (8 December 2014). “Copanlisib Continues to Show Promise for Treating Indolent Lymphomas”. Rare Disease Report. Retrieved 3 March 2015.
  3. Jump up^ HealthCare, Bayer. “Bayer Advances Clinical Development Program for Investigational Cancer Drug Copanlisib”http://www.prnewswire.com.
  4. Jump up^ “Copanlisib in Treating Patients With Persistent or Recurrent Endometrial Cancer – Full Text View – ClinicalTrials.gov”.
  5. Jump up^ “Phase II Copanlisib in Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL) – Full Text View – ClinicalTrials.gov”.
  6. Jump up^ “Copanlisib (BAY 80-6946) in Combination With Gemcitabine and Cisplatin in Advanced Cholangiocarcinoma – Full Text View – ClinicalTrials.gov”.
  7. Jump up^ “Open-label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin’s Lymphomas – Full Text View – ClinicalTrials.gov”.
  8. Jump up^ “Study of Copanlisib in Combination With Standard Immunochemotherapy in Relapsed Indolent Non-Hodgkin’s Lymphoma (iNHL) – Full Text View – ClinicalTrials.gov”.
  9. Jump up^ “Copanlisib and Rituximab in Relapsed Indolent B-cell Non-Hodgkin’s Lymphoma (iNHL) – Full Text View – ClinicalTrials.gov”.
  10. Jump up^ “Phase III Copanlisib in Rituximab-refractory iNHL – Full Text View – ClinicalTrials.gov”.
Patent ID

Patent Title

Submitted Date

Granted Date

US2016303136 COMBINATION OF PI3K-INHIBITORS
2014-11-28
US2015141420 USE OF SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINES FOR THE TREATMENT OF MYELOMA
2014-09-29
2015-05-21
Patent ID

Patent Title

Submitted Date

Granted Date

US2016058770 USE OF SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINES FOR TREATING LYMPHOMAS
2014-04-04
2016-03-03
US2015254400 GROUPING FOR CLASSIFYING GASTRIC CANCER
2013-09-18
2015-09-10
US2011251191 USE OF SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINES FOR THE TREATMENT OF MYELOMA
2011-10-13
US2013184270 SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINE-CONTAINING COMBINATIONS
2011-04-14
2013-07-18
US2014072529 SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINE SALTS
2012-03-29
2014-03-13
Patent ID

Patent Title

Submitted Date

Granted Date

US2014243295 USE OF SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINES
2012-03-29
2014-08-28
US2017056336 CO-TARGETING ANDROGEN RECEPTOR SPLICE VARIANTS AND MTOR SIGNALING PATHWAY FOR THE TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER
2016-05-09
US2015320754 COMBINATION THERAPIES
2015-04-15
2015-11-12
US2015320755 COMBINATION THERAPIES
2015-04-15
2015-11-12
US2016113932 TREATMENT OF CANCERS USING PI3 KINASE ISOFORM MODULATORS
2014-05-30
2016-04-28
Patent ID

Patent Title

Submitted Date

Granted Date

US8466283 Substituted 2, 3-dihydroimidazo[1, 2-c]quinazoline Derivatives Useful for Treating Hyper-Proliferative Disorders and Diseases Associated with Angiogenesis
2011-04-14
US9636344 SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINE SALTS
2016-01-07
2016-07-07
US2014377258 Treatment Of Cancers Using PI3 Kinase Isoform Modulators
2014-05-30
2014-12-25
US2015283142 TREATMENT OF CANCERS USING PI3 KINASE ISOFORM MODULATORS
2013-11-01
2015-10-08
US2013261113 SUBSTITUTED 2, 3-DIHYDROIMIDAZO[1, 2-C]QUINAZOLINE DERIVATIVES USEFUL FOR TREATING HYPER-PROLIFERATIVE DISORDERS AND DISEASES ASSOCIATED WITH ANGIOGENESIS
2013-06-03
2013-10-03
Copanlisib
Copanlisib.svg
Names
IUPAC name

2-Amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide
Other names

BAY 80-6946
Identifiers
3D model (JSmol)
ChemSpider
KEGG
MeSH 2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo(1,2-c)quinazolin-4-yl)pyrimidine-5-carboxamide
UNII
Properties
C23H28N8O4
Molar mass 480.53 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

////////////copanlisib, BAY 80-6946, BAYER, orphan drug status,  follicular lymphoma, FDA 2017, BAY 84-1236

COC1=C(C=CC2=C1N=C(N3C2=NCC3)NC(=O)C4=CN=C(N=C4)N)OCCCN5CCOCC5

 

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

FDA approves new treatment Hemlibra (emicizumab-kxwh) to prevent bleeding in certain patients with hemophilia A


FDA approves new treatment to prevent bleeding in certain patients with hemophilia A

The U.S. Food and Drug Administration today approved Hemlibra (emicizumab-kxwh) to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.Continue reading.

 

 

November 16, 2017

Summary

FDA approves new treatment to prevent or reduce frequency of bleeding episodes in patients with hemophilia A who have Factor VIII inhibitors.

Release

The U.S. Food and Drug Administration today approved Hemlibra (emicizumab-kxwh) to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.

“Reducing the frequency or preventing bleeding episodes is an important part of disease management for patients with hemophilia. Today’s approval provides a new preventative treatment that has been shown to significantly reduce the number of bleeding episodes in patients with hemophilia A with Factor VIII inhibitors,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “In addition, patients treated with Hemlibra reported an improvement in their physical functioning.”

Hemophilia A is an inherited blood-clotting disorder that primarily affects males. According to the National Institutes of Health, hemophilia affects one in every 5,000 males born in the United States, approximately 80 percent of whom have hemophilia A. Patients with hemophilia A are missing a gene which produces Factor VIII, a protein that enables blood to clot. Patients may experience repeated episodes of serious bleeding, primarily into their joints, which can be severely damaged as a result. Some patients develop an immune response known as a FVIII inhibitor or antibody. The antibody interferes with the effectiveness of currently available treatments for hemophilia.

Hemlibra is a first-in-class therapy that works by bridging other Factors in the blood to restore blood clotting for these patients. Hemlibra is a preventative (prophylactic) treatment given weekly via injection under the skin (subcutaneous).

The safety and efficacy of Hemlibra was based on data from two clinical trials. The first was a trial that included 109 males aged 12 and older with hemophilia A with FVIII inhibitors. The randomized portion of the trial compared Hemlibra to no prophylactic treatment in 53 patients who were previously treated with on-demand therapy with a bypassing agent before enrolling in the trial. Patients taking Hemlibra experienced approximately 2.9 treated bleeding episodes per year compared to approximately 23.3 treated bleeding episodes per year for patients who did not receive prophylactic treatment. This represents an 87 percent reduction in the rate of treated bleeds. The trial also included patient-reported Quality of Life metrics on physical health. Patients treated with Hemlibra reported an improvement in hemophilia-related symptoms (painful swellings and joint pain) and physical functioning (pain with movement and difficulty walking) compared to patients who did not receive prophylactic treatment.

The second trial was a single arm trial of 23 males under the age of 12 with hemophilia A with FVIII inhibitors. During the trial, 87 percent of the patients taking Hemlibra did not experience a bleeding episode that required treatment.

Common side effects of Hemlibra include injection site reactions, headache, and joint pain (arthralgia).

The labeling for Hemlibra contains a boxed warning to alert healthcare professionals and patients that severe blood clots (thrombotic microangiopathy and thromboembolism) have been observed in patients who were also given a rescue treatment (activated prothrombin complex concentrate) to treat bleeds for 24 hours or more while taking Hemlibra.

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

The FDA granted the approval of Hemlibra to Genentech, Inc.

///////Hemlibra, emicizumab-kxwh, FDA 2017, hemophilia A, Priority Review and Breakthrough Therapy designation,  Orphan Drug designation

 

 

“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


Tafamidis skeletal.svgChemSpider 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

Image result for Vyndaqel tafamidis meglumine

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)

Image result for The Scripps Research Institute

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 Kdi = 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

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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.

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

Image result for TAFAMIDIS

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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/

str1

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 (Kds ∼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).

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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)

str1

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

  1. 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.
  2. Jump up^ Ando, Y., and Suhr, O.B. (1998). Autonomic dysfunction in familial amyloidotic polyneuropathy (FAP). Amyloid, 5, 288-300.
  3. Jump up^ Benson, M.D. (1989). “Familial Amyloidotic polyneuropathy”. Trends in Neurosciences, 12.3, 88-92, PMID 2469222doi:10.1016/0166-2236(89)90162-8.
  4. Jump up^ http://www.businesswire.com/news/home/20111117005505/en/Pfizer%E2%80%99s-Vyndaqel%C2%AE-tafamidis-Therapy-Approved-European-Union
  5. Jump up^ Clinical trial number NCT00409175 for “Safety and Efficacy Study of Fx-1006A in Patients With Familial Amyloidosis” at ClinicalTrials.gov
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Jump up^ Coelho, T. (1996). “Familial amyloid polyneuropathy: new developments in genetics and treatment”. Current Opinion in Neurology, 9, 355-359.
  11. 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.
  12. 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.
  13. 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
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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
Tafamidis skeletal.svg
Clinical data
Trade names Vyndaqel
License data
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
Formula C14H7Cl2NO3
Molar mass 308.116 g/mol
3D model (JSmol)

//////////////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

Pracinostat


Pracinostat.svg

ChemSpider 2D Image | Pracinostat | C20H30N4O2

Pracinostat.png

2D chemical structure of 929016-96-6

Pracinostat

  • Molecular Formula C20H30N4O2
  • Average mass 358.478 Da
2-Propenamide, 3-[2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl]-N-hydroxy-, (2E)-
929016-96-6 [RN]
SB939
(2E)-3-{2-butyl-1-[2-(diethylamino)ethyl]-1,3-benzodiazol-5-yl}-N-hydroxyprop-2-enamide
N-hydroxy-1-[(4-methoxyphenyl)methyl]-1H-indole-6-carboxamide
PCI 34051,  UNII: GPO2JN4UON
929016-98-8 DI HCl salt, C20 H30 N4 O2 . 2 Cl H, 431.4
929016-96-6 (free base)
929016-97-7 (trifluoroacetate)
S*BIO (Originator)
Leukemia, acute myeloid, phase 3, helsinn
Image result for S*BIO
str1
CAS 929016-98-8 DI HCl salt, C20 H30 N4 O2 . 2 Cl H, 431.4
E)-3-[2-Butyl-1-(2-diethylaminoethyl)-1H-benzimidazol-5-yl]-N-hydroxyacrylamide Dihydrochloride Salt

Pracinostat (SB939) is an orally bioavailable, small-molecule histone deacetylase (HDAC) inhibitor based on hydroxamic acid with potential anti-tumor activity characterized by favorable physicochemical, pharmaceutical, and pharmacokinetic properties.

WO-2017192451  describes Novel polymorphic crystalline forms of pracinostat (designated as Form 3) and their hydrates, processes for their preparation and compositions and combination comprising them are claimed. Also claimed is their use for inhibiting histone deacetylase and treating cancer, such as myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), breast cancer, colon cancer, prostate cancer, pancreas cancer, leukemia, lymphoma, ovary cancer, melanoma and neuroblastoma.

See WO2014070948 ,  Helsinn , under sub-license from MEI Pharma (under license from S*Bio), is developing pracinostat, an oral HDAC inhibitor, for treating hematological tumors, including AML, MDS and myelofibrosis.

The oncolytic agent pracinostat hydrochloride is an antagonist of histone deacetylase 1 (HDAC1) and 2 (HDAC2) that was discovered by the Singapore-based company S*BIO. Helsinn obtained the exlusive development and commercialization rights in July 2016, and is conducting phase III clinical trials in combination with azacitidine in adults with newly diagnosed acute myeloid leukemia. Phase II trials are also under way for the treatment of previously untreated intermediate-2 or high risk myelodysplastic syndrome patients and for the treatment of primary or post essential thrombocythemia/polycythemia vera) in combination with ruxolitinib.In North America, S*BIO had been conducting phase II clinical trials of pracinostat hydrochloride in patients with solid tumors and for the treatment of myeloproliferative diseases and phase I clinical trials in patients with leukemia; however, recent progress reports are not available at present. The University of Queensland had been evaluating the compound in preclinical studies for malaria.

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University of Queensland

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MEI Pharma

The Canadian Cancer Society Research Institute (the research branch of the Canadian Cancer Society upon its integration with the National Cancer Institute of Canada to form the new Canadian Cancer Society) is conducting phase II clinical trials in Canada for the treatment of recurrent or metastatic prostate cancer.

Image result for Canadian Cancer Society Research Institute

Canadian Cancer Society Research Institute

In 2012, the product was licensed to MEI Pharma by S*BIO on a worldwide basis. In 2016, MEI Pharma and Helsinn entered into a licensing, development and commercialization agreement by which Helsinn obtained exclusive worldwide rights (including manufacturing and commercialization rights).

Image result for HELSINN

HELSINN

In 2014, the FDA assigned an orphan drug designation to MEI Pharma for the treatment of acute myeloid leukemia. In 2016, the product received breakthrough therapy designation in the U.S. in combination with azacitidine for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are older than 75 years of age or unfit for intensive chemotherapy.

Pracinostat is an orally available, small-molecule histone deacetylase (HDAC) inhibitor with potential antineoplastic activity. Pracinostat inhibits HDACs, which may result in the accumulation of highly acetylated histones, followed by the induction of chromatin remodeling; the selective transcription of tumor suppressor genes; the tumor suppressor protein-mediated inhibition of tumor cell division; and, finally, the induction of tumor cell apoptosis. This agent may possess improved metabolic, pharmacokinetic and pharmacological properties compared to other HDAC inhibitors.

Pracinostat is a novel HDAC inhibitor with improved in vivo properties compared to other HDAC inhibitors currently in clinical trials, allowing oral dosing. Data demonstrate that Pracinostat is a potent and effective anti-tumor drug with potential as an oral therapy for a variety of human hematological and solid tumors

SYNTHESIS

Figure

Clinically tested HDAC inhibitors.

Activity

Pracinostat selectively inhibits HDAC class I,II,IV without class III and HDAC6 in class IV,[1] but has no effect on other Zn-binding enzymes, receptors, and ion channels. It accumulates in tumor cells and exerts a continuous inhibition to histone deacetylase,resulting in acetylated histones accumulation, chromatin remodeling, tumor suppressor genes transcription, and ultimately, apoptosis of tumor cells.[2]

Clinical medication

Clinical studies suggests that pracinostat has potential best pharmacokinetic properties when compared to other oral HDAC inhibitors.[3]In March 2014, pracinostat has granted Orphan Drug for acute myelocytic leukemia (AML) and for the treatment of T-cell lymphoma by the Food and Drug Administration.

Clinical Trials

CTID Title Phase Status Date
NCT03151304 A Safety and Efficacy Study of Pracinostat and Azacitidine in Patients With High Risk Myelodysplastic Syndromes 2 Recruiting
2017-10-27
NCT03151408 An Efficacy and Safety Study Of Pracinostat In Combination With Azacitidine In Adults With Acute Myeloid Leukemia 3 Recruiting
2017-10-17
NCT02267278 Ruxolitinib and Pracinostat Combination Therapy for Patients With Myelofibrosis (MF) 2 Active, not recruiting
2017-04-27
NCT01873703 Phase 2 Study of Pracinostat With Azacitidine in Patients With Previously Untreated Myelodysplastic Syndrome 2 Active, not recruiting
2017-04-21
NCT02118909 Evaluate the Effects of Itraconazole and Ciprofloxacin on Single-Dose PK of Pracinostat in Healthy Nonsmoking Subjects 1 Completed
2017-02-22
NCT02058784 Study to Evaluate the Food Effect of Single-dose Bioavailability of Pracinostat in Healthy Adult Subjects 1 Completed
2017-02-22
NCT01993641 Phase 2 Study Adding Pracinostat to a Hypomethylating Agent (HMA) in Patients With MDS Who Failed to Respond to Single Agent HMA 2 Completed
2017-02-22
NCT01112384 A Study of SB939 in Patients With Translocation-Associated Recurrent/Metastatic Sarcomas 2 Completed
2016-11-25
NCT01184274 A Phase I Study of SB939 in Pediatric Patients With Refractory Solid Tumours and Leukemia 1 Completed
2014-01-16
NCT01200498 Study of SB939 in Subjects With Myelofibrosis 2 Completed
2013-12-13

PATENT

WO2005028447

Inventors Dizhong ChenWeiping DengKanda SangthongpitagHong Yan SongEric T. SunNiefang YuYong Zou
Applicant S*Bio Pte Ltd

Scheme I

Figure imgf000041_0001

Scheme II

Figure imgf000042_0001Scheme III

Figure imgf000043_0001Scheme IV

Figure imgf000044_0001 Scheme V

Figure imgf000045_0001

PAPER

Discovery of (2E)-3-{2-Butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an Orally Active Histone Deacetylase Inhibitor with a Superior Preclinical Profile

Chemistry Discovery, Biology Discovery, and §Pre-Clinical Development, S*BIO Pte Ltd., 1 Science Park Road, No. 05-09 The Capricorn, Singapore Science Park II, Singapore 117528, Singapore
J. Med. Chem.201154 (13), pp 4694–4720
DOI: 10.1021/jm2003552
Phone: +65-68275019. Fax: +65-68275005. E-mail: haishan_wang@sbio.com.

Abstract

Abstract Image

A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC50), liver microsomal stability (t1/2), cytochrome P450 inhibitory (3A4 IC50), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.

(E)-3-[2-Butyl-1-(2-diethylaminoethyl)-1H-benzimidazol-5-yl]-N-hydroxyacrylamide Dihydrochloride Salt (3)

The freebase of 3 was prepared according to procedure D. The hydroxamic acid moiety was identified by 1H–15N HSQC (DMSO-d6) with δN = 169.0 ppm (CONHOH). Other nitrogens in 3were identified by 1H–15N HMBC (DMSO-d6) with δN of 241.4 ppm for N3 of the benzimidazole ring, 152.3 ppm for N1, and 41.3 ppm for the diethylamino group (reference to nitromethane δN = 380.0 ppm in CDCl3). The dihydrochloride salt of 3 was prepared according to procedure D as white or off-white solid or powder in ∼60% yield from 9 in two steps. LC–MS m/z 359.2 ([M + H]+).
1H NMR (DMSO-d6) δ 11.79 (brs, 1H, NH or OH), 10.92 (very br s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 15.8 Hz, 1H), 6.65 (d, J = 15.8 Hz, 1H), 5.01 (t-like, J = 7.7 Hz, 2H), 3.48 (m, 2H), 3.30–3.19 (m, 6H), 1.87 (quintet, J = 7.8 Hz, 2H), 1.47 (sextet, J = 7.5 Hz, 2H), 1.29 (t, J = 7.2 Hz, 6H), 0.97 (t, J = 7.3 Hz, 3H);
13C NMR (DMSO-d6) δ 162.3, 156.0, 137.3 (CH), 132.8, 132.3, 132.0 (br, identified by HMBC), 124.7 (CH), 120.2 (CH), 113.1 (2 × CH), 48.2, 46.3, 39.0, 28.1, 25.0, 21.7, 13.6, 8.3.
Anal. (C20H30N4O2·2HCl·0.265H2O) C, H, N, Cl. Water content = 1.09% (Karl Fisher method). HRMS (ESI) m/z [M + H]+ calcd for C20H31N4O2, 359.2442; found, 359.2449.

PATENT

WO 2007030080

http://google.com/patents/WO2007030080A1?cl=en

 
Inventors Dizhong ChenWeiping DengKen Chi Lik LeePek Ling LyeEric T. SunHaishan WangNiefang Yu
Applicant S*Bio Pte Ltd

SEE

WO 2008108741

WO 2014070948

Patent

WO-2017192451

References

  1. Jump up^ “In vitro enzyme activity of SB939 and SAHA”. 22 Aug 2014.
  2. Jump up^ “The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML”. Blood Cancer Journaldoi:10.1038/bcj.2012.14.
  3. Jump up^ Veronica Novotny-Diermayr; et al. (March 9, 2010). “SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer”Mol Cancer Therdoi:10.1158/1535-7163.MCT-09-0689.
PATENT 
Cited Patent Filing date Publication date Applicant Title
WO2005028447A1 * Sep 21, 2004 Mar 31, 2005 S*Bio Pte Ltd Benzimidazole derivates: preparation and pharmaceutical applications
US20050137234 * Dec 14, 2004 Jun 23, 2005 Syrrx, Inc. Histone deacetylase inhibitors
Reference
1 None
2 See also references of EP1937650A1
Citing Patent Filing date Publication date Applicant Title
WO2009084544A1 * Dec 24, 2008 Jul 9, 2009 Idemitsu Kosan Co., Ltd. Nitrogen-containing heterocyclic derivative and organic electroluminescent device using the same
WO2010043953A2 * Oct 14, 2009 Apr 22, 2010 Orchid Research Laboratories Ltd. Novel bridged cyclic compounds as histone deacetylase inhibitors
WO2010043953A3 * Oct 14, 2009 Mar 24, 2011 Orchid Research Laboratories Ltd. Novel bridged cyclic compounds as histone deacetylase inhibitors
WO2017030938A1 * Aug 12, 2016 Feb 23, 2017 Incyte Corporation Heterocyclic compounds and uses thereof
DE102007037579A1 Aug 9, 2007 Feb 19, 2009 Emc Microcollections Gmbh Neue Benzimidazol-2-yl-alkylamine und ihre Anwendung als mikrobizide Wirkstoffe
US8865912 Jan 27, 2014 Oct 21, 2014 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9024029 Sep 3, 2013 May 5, 2015 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9062003 Sep 9, 2014 Jun 23, 2015 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9156797 May 15, 2015 Oct 13, 2015 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9402829 Feb 20, 2015 Aug 2, 2016 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9717713 Jun 10, 2016 Aug 1, 2017 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
Patent ID

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2015-04-09
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2014-10-10
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2015-07-09
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2012-05-24
2014-08-21
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2012-10-15
2013-04-25
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2013-02-01
2013-05-30
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2012-06-01
2014-11-27
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2015-05-29
Patent ID

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US9387263 RbAp48 TRANSGENIC MICE FOR DRUG DISCOVERY IN AGE-RELATED MEMORY DECLINE
2012-08-02
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2012-03-09
2014-02-20
US2010098691 COMBINATION OF BENZIMIDAZOLE ANTI-CANCER AGENT AND A SECOND ANTI-CANCER AGENT
2010-04-22
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2014-04-08
2016-03-10
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2012-10-31
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Patent ID

Patent Title

Submitted Date

Granted Date

US2017049784 METHOD OF TREATING ACUTE MYELOID LEUKEMIA AND/OR ACUTE LYMPHOBLASTIC LEUKEMIA USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2015-05-01
US2017095484 METHOD OF TREATING RESISTANT NON-HODGKIN LYMPHOMA, MEDULLOBLASTOMA, AND/OR ALK+NON-SMALL CELL LUNG CANCER USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2015-05-01
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2014-11-26
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2013-10-30
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2013-06-24
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Pracinostat
Pracinostat.svg
Names
IUPAC name

(E)-3-(2-Butyl-1-(2-(diethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
Other names

Pracinostat
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
Properties
C20H30N4O2
Molar mass 358.49 g·mol−1
Density 1.1±0.1 g/cm3
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

//////////////Pracinostat, PCI 34051, SB939, orphan drug designation, Leukemia, acute myeloid, phase 3, helsinn

CCCCC1=NC2=C(N1CCN(CC)CC)C=CC(=C2)C=CC(=O)NO

 

“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


imgImage 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

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

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

Funapide, TV 45070, XEN-402, фунапид فونابيد 呋纳匹特


Image result for TV 450702D chemical structure of 1259933-16-8

ChemSpider 2D Image | Funapide | C22H14F3NO5Funapide.png

Funapide TV 45070,  XEN-402,  Funapide, (+)-

фунапид
فونابيد
呋纳匹特
  • Molecular FormulaC22H14F3NO5
  • Average mass429.345 Da

(S)-1′-[(5-Methyl-2-furyl)methyl]spiro[6H-furo[3,2-f][1,3]benzodioxole-7,3′-indoline]-2′-one

Spiro(furo(2,3-F)-1,3-benzodioxole-7(6H),3′-(3H)indol)-2′(1’H)-one, 1′-((5-(trifluoromethyl)-2-furanyl)methyl)-, (3’S)-

(3’S)-1′-((5-(Trifluoromethyl)furan-2-yl)methyl)-2H,6H-spiro(furo(2,3-F)(1,3)benzodioxole-7,3′-indol)-2′(1’H)-one

Spiro[furo[2,3-f]-1,3-benzodioxole-7(6H),3′-[3H]indol]-2′(1’H)-one, 1′-[[5-(trifluoromethyl)-2-furanyl]methyl]-, (7S)-
TV-45070
UNII-A5595LHJ2L
XEN-401-S
XEN402
(3’S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2H-6H-spiro[furo[2,3-f]-1,3-benzodioxole-7,3′-indol]-2′(1’H)-one
(7S)-1′-{[5-(Trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1’H)-one
1259933-16-8 CAS
UNII-A5595LHJ2L

Phase II clinical trials for Postherpetic neuralgia (PHN)

Treatment of Neuropathic Pain

  • Originator Xenon Pharmaceuticals
  • Developer Teva Pharmaceutical Industries; Xenon Pharmaceuticals
  • Class Benzodioxoles; Fluorobenzenes; Furans; Indoles; Non-opioid analgesics; Small molecules; Spiro compounds
  • Mechanism of Action Nav1.7-voltage-gated-sodium-channel-inhibitors; Nav1.8 voltage-gated sodium channel inhibitors
  • Orphan Drug Status Yes – Erythromelalgia

Highest Development Phases

  • Phase II Erythromelalgia; Postherpetic neuralgia
  • No development reported Dental pain; Pain
  • Discontinued Musculoskeletal pain

Most Recent Events

  • 09 May 2017 Teva Pharmaceutical Industries completes a phase IIb trial for Postherpetic neuralgia in USA (Topical) (NCT02365636)
  • 26 Sep 2016 Adverse events data from a phase II trial in Musculoskeletal pain presented at the 16th World Congress on Pain (PAN – 2016)
  • 19 Aug 2015 No recent reports of development identified – Phase-I for Pain (In volunteers) in Canada (PO)

MP 100 – 102 DEG CENT EP2538919

S ROT  ALPHA 0.99 g/100ml, dimethyl sulfoxide, 14.04, US 20110087027

Funapide (INN) (former developmental code names TV-45070 and XEN402) is a novel analgesic under development by Xenon Pharmaceuticals in partnership with Teva Pharmaceutical Industries for the treatment of a variety of chronic pain conditions, including osteoarthritisneuropathic painpostherpetic neuralgia, and erythromelalgia, as well as dental pain.[1][2][3][4] It acts as a small-moleculeNav1.7 and Nav1.8 voltage-gated sodium channel blocker.[1][2][4] Funapide is being evaluated in humans in both oral and topicalformulations, and as of July 2014, has reached phase IIb clinical trials.[1][3]

Image result for TV 45070

Sodium channels play a diverse set of roles in maintaining normal and pathological states, including the long recognized role that voltage gated sodium channels play in the generation of abnormal neuronal activity and neuropathic or pathological pain. Damage to peripheral nerves following trauma or disease can result in changes to sodium channel activity and the development of abnormal afferent activity including ectopic discharges from axotomised afferents and spontaneous activity of sensitized intact nociceptors. These changes can produce long-lasting abnormal hypersensitivity to normally innocuous stimuli, or allodynia. Examples of neuropathic pain include, but are not limited to, post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, and pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias.

There have been some advances in treating neuropathic pain symptoms by using medications, such as gabapentin, and more recently pregabalin, as short-term, first-line treatments. However, pharmacotherapy for neuropathic pain has generally had limited success with little response to commonly used pain reducing drugs, such as NSAIDS and opiates. Consequently, there is still a considerable need to explore novel treatment modalities.

There remain a limited number of potent effective sodium channel blockers with a minimum of adverse events in the clinic. There is also an unmet medical need to treat neuropathic pain and other sodium channel associated pathological states effectively and without adverse side effects. PCT Published Patent Application No. WO 2006/110917, PCT Published Patent Application No. WO 2010/045251 , PCT Published Patent Application No. WO 2010/045197, PCT Published Patent Application No. WO 2011/047174 and PCT Published Patent Application No. WO 2011/002708 discloses certain spiro-oxindole compounds. These compounds are disclosed therein as being useful for the treatment of sodium channel-mediated diseases, preferably diseases related to pain, central nervous conditions such as epilepsy, anxiety, depression and bipolar disease;

cardiovascular conditions such as arrhythmias, atrial fibrillation and ventricular fibrillation; neuromuscular conditions such as restless leg syndrome; neuroprotection against stroke, neural trauma and multiple sclerosis; and channelopathies such as erythromelalgia and familial rectal pain syndrome.

Methods of preparing these compounds and pharmaceutical compositions containing them are also disclosed in PCT Published Patent Application No. WO 2006/110917, PCT Published Patent Application No. WO 2010/045251 , PCT

Published Patent Application No. WO 2010/045197, PCT Published Patent Application No. WO 2011/047174 and PCT Published Patent Application No. WO 2011/002708.

Postherpetic neuralgia (PHN) is a rare disorder that is defined as significant pain or abnormal sensation 120 days or more after the presence of the initial rash caused by shingles. This pain persists after the healing of the associated rash. Generally, this affliction occurs in older individuals and individuals suffering from immunosuppression. There are about one million cases of shingles in the US per year, of which 10–20% will result in PHN.
Topical analgesics such as lidocaine and capsaicin are traditionally used to treat this disorder. Both lidocaine and TV-45070 have a mechanism of action that involves the inhibition of voltage-gated sodium ion channels.
TV-45070 (formerly XEN-402) was in-licensed by Teva from Xenon Pharmaceuticals and is reported to be an antagonist of the Nav1.7 sodium ion channel protein.
It is currently in Phase II clinical trials for PHN. Interestingly, the loss of function of the Nav1.7 sodium ion channel was reported to result in the inability to experience pain as a hereditary trait in certain individuals.
Primary erythromelalgia is another rare disease where alterations in Nav1.7 or mutations in the corresponding encoding gene SCN9A have been reported to result in chronic burning pain that can last for hours or even days. Thus, compounds which regulate this protein have potential therapeutic value as analgesics for chronic pain.
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PATENT
US 20100331386
WO 2011106729
US 20110087027
US 20110086899
US 20130143941
US 20130210884
WO 2013154712
 US 20150216794
WO 2016127068
WO 2016109795
CN 106518886
US 20170239183
SYNTHESIS
WO 2013154712
 CONTD…….
Synthesis
CN 106518886
PATENT
US 20100331386
Preparation of the (S)-Enantiomer of the Invention
The (S)-enantiomer of the invention and the corresponding (R)-enantiomer are prepared by the resolution of the compound of formula (I), as set forth above in the Summary of the Invention, using either chiral high pressure liquid chromatography methods or by simulated moving bed chromatography methods, as described below in the following Reaction Scheme wherein “chiral HPLC” refers to chiral high pressure liquid chromatography and “SMB” refers to simulated moving bed chromatography:
Figure US20100331386A1-20101230-C00006
The compound of formula (I) can be prepared by the methods disclosed in PCT Published Patent Application No. WO 2006/110917, by methods disclosed herein, or by methods known to one skilled in the art.
One of ordinary skill in the art would recognize variations in the above Reaction Scheme which are appropriate for the resolution of the individual enantiomers.
Alternatively, the (S)-enantiomer of formula (I-S) and the (R)-enantiomer of formula (I-R), can be synthesized from starting materials which are known or readily prepared using process analogous to those which are known.
Preferably, the (S)-enantiomer of the invention obtained by the resolution methods disclosed herein is substantially free of the (R)-enantiomer or contains only traces of the (R)-enantiomer.
The following Synthetic Examples serve to illustrate the resolution methods disclosed by the above Reaction Schemes and are not intended to limit the scope of the invention.
Synthetic Example 1Synthesis of 1-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (Compound of formula (I))
Figure US20100331386A1-20101230-C00007
To a suspension of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.0 g, 3.6 mmol), which can be prepared according to the methods disclosed in PCT Published Patent Application No. WO 2006/110917, and cesium carbonate (3.52 g, 11 mmol) in acetone (50 mL) was added 2-bromomethyl-5-trifluoromethylfuran (1.13 g, 3.9 mmol) in one portion and the reaction mixture was stirred at 55-60° C. for 16 hours. Upon cooling to ambient temperature, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography, eluting with ethyl acetate/hexane (1/9-1/1) to afford 1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1 ′H)-one, i.e., the compound of formula (I), (1.17 g, 76%) as a white solid: mp 139-141° C.;
1H NMR (300 MHz, CDCl3) δ 7.32-6.97 (m, 5H), 6.72 (d, J=3.3 Hz, 1H), 6.66 (s, 1H), 6.07 (s, 1H), 5.90-5.88 (m, 2H), 5.05, 4.86 (ABq, JAB=16.1 Hz, 2H), 4.91 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.9, 155.7, 153.5, 148.8, 142.2, 141.9, 140.8, 140.2, 139.7, 139.1, 132.1, 129.2, 124.7, 124.1, 123.7, 121.1, 120.1, 117.6, 114.5, 114.4, 110.3, 109.7, 103.0, 101.9, 93.8, 80.0, 57.8, 36.9;
MS (ES+) m/z 430.2 (M+1), 452.2 (M+23); Cal’d for C22H14F3NO5: C, 61.54%; H, 3.29%; N, 3.26%; Found: C, 61.51%; H, 3.29%; N, 3.26%.
Synthetic Example 2Resolution of Compound of Formula (I) by Chiral HPLC
The compound of formula (I) was resolved into the (S)-enantiomer of the invention and the corresponding (R)-enantiomer by chiral HPLC under the following conditions:

Column: Chiralcel® OJ-RH; 20 mm I.D.×250 mm, 5 mic; Lot: OJRH CJ-EH001 (Daicel Chemical Industries, Ltd)

Eluent: Acetonitrile/Water (60/40, v/v, isocratic)

Flow rate: 10 mL/min

Run time: 60 min

Loading: 100 mg of compound of formula (I) in 1 mL of acetonitrileTemperature: Ambient

Under the above chiral HPLC conditions, the (R)-enantiomer of the compound of formula (I), i.e., (R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]-benzodioxole-7,3′-indol]-2′(1′H)-one, was isolated as the first fraction as a white solid; ee (enantiomeric excess)>99% (analytical OJ-RH, 55% acetonitrile in water); mp 103-105° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.32-6.99 (m, 5H), 6.71 (d, J=3.4 Hz, 1H), 6.67 (s, 1H), 6.05 (s, 1H), 5.89 (d, J=6.2 Hz, 2H), 5.13, 5.02 (ABq, JAB=16.4 Hz, 2H), 4.82, 4.72 (ABq, JAB=9.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 177.2, 155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0, 129.1, 123.9, 120.6, 119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6, 93.5, 80.3, 58.2, 36.9; MS (ES+) m/z 430.2 (M+1), [α]D−17.46° (c 0.99, DMSO).

The (S)-enantiomer of the compound of formula (I), i.e., (S)-1′-{[5-(trifluoromethypfuran-2-yl]methyl}spiro-[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was isolated as the second fraction as a white solid; ee >99% (analytical OJ-RH, 55% acetonitrile in water); mp 100-102° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.32-6.99 (m, 5H), 6.71 (d, J=3.4 Hz, 1H), 6.67 (s, 1H), 6.05 (s, 1H), 5.89 (d, J=6.3 Hz, 2H), 5.12, 5.02 (ABq, JAB=16.4 Hz, 2H), 4.82, 4.72 (ABq, JAB=9.4 Hz, 2H); 13C NMR (75MHz, CDCl3) δ 177.2, 155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0, 129.1, 123.9, 120.6, 119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6, 93.5, 80.3, 58.2, 36.9; MS (ES+) m/z 430.2 (M+1), [α]D+14.04° (c 0.99, DMSO)

Synthetic Example 3Resolution of Compound of Formula (I) by SMB Chromatography

The compound of formula (I) was resolved into the (S)-enantiomer of the invention and the corresponding (R)-enantiomer by SMB chromatography under the following conditions:

Extract: 147.05 mL/min, Raffinate: 76.13 mL/min Eluent: 183.18 mL/min Feed: 40 mL/min Recycling: 407.88 mL/min Run Time: 0.57 min Temperature: 25° C. Pressure: 46 bar

The feed solution (25 g of compound of formula (I) in 1.0 L of mobile phase (25:75:0.1 (v:v:v) mixture of acetonitrile/methanol/trifluoroacetic acid)) was injected continuously into the SMB system (Novasep Licosep Lab Unit), which was equipped with eight identical columns in 2-2-2-2 configuration containing 110 g (per column, 9.6 cm, 4.8 cm I.D.) of ChiralPAK-AD as stationary phase. The first eluting enantiomer (the (R)-enantiomer of the compound of formula (I)) was contained in the raffinate stream and the second eluting enantiomer (the (S)-enantiomer of the compound of formula (I)) was contained in the extract stream. The characterization data of the (S)-enantiomer and the (R)-enantiomer obtained from the SMB resolution were identical to those obtained above utilizing chiral HPLC.

The compound of formula (I) was resolved into its constituent enantiomers on a Waters preparative LCMS autopurification system. The first-eluting enantiomer from the chiral column was brominated (at a site well-removed from the stereogenic centre) to give the corresponding 5′-bromo derivative, which was subsequently crystallized to generate a single crystal suitable for X-ray crystallography. The crystal structure of this brominated derivative of the first-eluting enantiomer was obtained and its absolute configuration was found to be the same as the (R)-enantiomer of the invention. Hence, the second-eluting enantiomer from the chiral column is the (S)-enantiomer of the invention. Moreover, the material obtained from the extract stream of the SMB resolution had a specific optical rotation of the same sign (positive, i.e. dextrorotatory) as that of the material obtained from the aforementioned LC resolution.

Patent

WO 2013154712

EXAMPLE 8

Synthesis of (7S)-1 ‘-{[5-(trifluoromethyl)furan-2- yllmethylJspirotfurop.S-flll .Sl enzoclioxole-y.S’-indoll-Zil ‘Wi-one

Compound of formula (ia1 )

Figure imgf000095_0001

To a cooled (0 °C) solution of (3S)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3- (hydroxymethyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1 ,3-dihydro-2H-indol-2-one prepared according to the procedure described in Example 7 (16.4 mmol) and 2- (diphenylphosphino)pyridine (5.2 g, 20 mmol) in anhydrous tetrahydrofuran (170 mL) was added di-ferf-butylazodicarboxylate (4.5 g, 20 mmol). The mixture was stirred for 2 h at 0 °C, then the reaction was diluted with ethyl acetate (170 mL), washed with 3 N hydrochloric acid (7 x 50 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol (80 mL), decolorizing charcoal (15 g) was added and the mixture was heated at reflux for 1 h. The mixture was filtered while hot through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue triturated in a mixture of diethyl ether/hexanes to afford (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro- [furo[2,3-/][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (1.30 g) as a colorless solid in 18% yield. The mother liquor from the trituration was concentrated in vacuo, trifluoroacetic acid (20 mL) was added and the mixture stirred for 3 h at ambient temperature. The mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride (100 mL), 3 N hydrochloric acid (4 x 60 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of ethyl acetate in hexanes to afford further (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro- [furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (2.6 g) as a colorless solid (37% yield, overall yield 55% over 2 steps): H NMR (300 MHz, CDCI3) £7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz, 1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1 ); ee (enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert- butyl ether).

EXAMPLE 9

Synthesis of 1-(diphenylmethyl)-1 H-indole-2,3-dione

Compound of formula (15a)

Figure imgf000096_0001

A. To a suspension of hexanes-washed sodium hydride (34.0 g, 849 mmol) in anhydrous Λ/,/V-dimethylformamide (400 mL) at 0 °C was added a solution of isatin (99.8 g, 678 mmol) in anhydrous Λ/,/V-dimethylformamide (400 mL) dropwise over 30 minutes. The reaction mixture was stirred for 1 h at 0 °C and a solution of benzhydryl bromide (185 g, 745 mmol) in anhydrous N-dimethylformamide (100 mL) was added dropwise over 5 minutes. The reaction mixture was allowed to warm to ambient temperature, stirred for 16 h and heated at 60 °C for 2 h. The mixture was cooled to 0 °C and water (500 mL) was added. The mixture was poured into water (2 L), causing a precipitate to be deposited. The solid was collected by suction filtration and washed with water (2000 mL) to afford 1-(diphenylmethyl)-1H-indole-2,3- dione (164 g) as an orange solid in 77% yield.

B. Alternatively, to a mixture of isatin (40.0 g, 272 mmol), cesium carbonate (177 g, 543 mmol) and A/./V-dimethylformamide (270 mL) at 80 °C was added dropwise a solution of benzhydryl bromide (149 g, 544 mmol) in N,N- dimethyiformamide (200 mL) over 30 minutes. The reaction mixture was heated at 80 °C for 3 h, allowed to cool to ambient temperature and filtered through a pad of diatomaceous earth. The pad was rinsed with ethyl acetate (1000 mL). The filtrate was washed with saturated aqueous ammonium chloride (4 x 200 mL), 1 N

hydrochloric acid (200 mL) and brine (4 x 200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to afford 1 -(diphenylmethyl)-1 H-indole-2,3-dione (59.1 g) as an orange solid in 69% yield. The mother liquor from the trituration was concentrated in vacuo and the residue triturated in diethyl ether to afford a further portion of 1-(diphenylmethyl)-1 H- indole-2,3-dione (8.2 g) in 10% yield: 1H NMR (300 MHz, CDCI3) £7.60 (d, J = 7.4 Hz, 1 H), 7.34-7.24 (m, 1 1 H), 7.05-6.97 (m, 2H), 6.48 (d, J = 8.0 Hz, 1 H); MS (ES+) m/z 313.9 (M + 1 ).

C. Alternatively, a mixture of isatin (500 g, 3.4 mol) and anhydrous N,N- dimethylformamide (3.5 L) was stirred at 15-35 °C for 0.5 h. Cesium carbonate (2.2 kg, 6.8 mol) was added and the mixture stirred at 55-60 °C for 1 h. A solution of benzhydryl bromide (1.26 kg, 5.1 mol) in anhydrous N, A/-dimethylformamide (1.5 L) was added and the resultant mixture stirred at 80-85 °C for 1 h, allowed to cool to ambient temperature and filtered. The filter cake was washed with ethyl acetate (12.5 L). To the combined filtrate and washes was added 1 N hydrochloric acid (5 L). The phases were separated and the aqueous phase was extracted with ethyl acetate (2.5 L). The combined organic extracts were washed with 1 N hydrochloric acid (2 * 2.5 L) and brine (3 χ 2.5 L) and concentrated in vacuo to a volume of approximately 750 mL. Methyl ferf-butyl ether (2 L) was added and the mixture was cooled to 5-15 °C, causing a solid to be deposited. The solid was collected by filtration, washed with methyl ferf- butyl ether (250 mL) and dried in vacuo at 50-55 °C for 16 h to afford 1- (diphenylmethyl)-1 H-indole-2,3-dione (715 g) as an orange solid in 67% yield: 1H NMR (300 MHz, CDCI3) 7.60 (d, J = 7.4 Hz, H), 7.34-7.24 (m, 1 H), 7.05-6.97 (m, 2H), 6.48 (d, J = 8.0 Hz, 1 H); MS (ES+) m/z 313.9 (M + 1 ).

EXAMPLE 10

Synthesis of 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3- dihydro-2H-indol-2-one

Compound of formula (16a1 )

Figure imgf000097_0001

A. To a solution of sesamol (33.1 g, 239 mmol) in anhydrous

tetrahydrofuran (500 mL) at 0 °C was added dropwise a 2 M solution of

isopropylmagnesium chloride in tetrahydrofuran (104 mL, 208 mmol), followed by 1 – (diphenylmethyl)-1H-indole-2,3-dione (50.0 g, 160 mmol) and tetrahydrofuran (100 mL). The reaction mixture was stirred at ambient temperature for 5 h, diluted with ethyl acetate (1500 mL), washed with saturated aqueous ammonium chloride (400 mL) and brine (2 x 400 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford 1- (diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-in

2- one (70.7 g) as a colorless solid in 98% yield: 1H NMR (300 MHz, CDCI3) <59.12 (br s, 1 H), 7.45-7.43 (m, 1 H), 7.30-7.22 (m, 10H), 7.09-7.07 (m, 2H), 6.89 (s, 1 H), 6.56- 6.55 (m, 1 H), 6.47-6.46 (m, 1 H), 6.29-6.28 (m, 1 H), 5.86 (s, 2H), 4.52 (br s, 1 H); MS (ES+) m/z 433.7 (M – 17).

B. Alternatviely, a mixture of sesamol (0.99 kg, 7.2 mol) and anhydrous tetrahydrofuran (18 L) was stirred at 15-35 °C for 0.5 h and cooled to -5-0 °C.

Isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran, 3.1 L, 6.2 mol) was added, followed by 1-(diphenylmethyl)-1 H-indole-2,3-dione (1.50 kg, 4.8 mol) and further anhydrous tetrahydrofuran (3 L). The mixture was stirred at 15-25 °C for 5 h. Ethyl acetate (45 L) and saturated aqueous ammonium chloride (15 L) were added. The mixture was stirred at 15-25 °C for 0.5 h and was allowed to settle for 0.5 h. The phases were separated and the organic phase was washed with brine (2.3 L) and concentrated in vacuo to a volume of approximately 4 L. Methyl ferf-butyl ether (9 L) was added and the mixture concentrated in vacuo to a volume of approximately 4 L. Heptane (6 L) was added and the mixture was stirred at 15-25 °C for 2 h, causing a solid to be deposited. The solid was collected by filtration, washed with methyl tert- butyl ether (0.3 L) and dried in vacuo at 50-55 °C for 7 h to afford 1-(diphenylmethyl)-3- hydroxy-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (2.12 kg) as an off-white solid in 98% yield: 1H NMR (300 MHz, CDCI3) 9.12 (br s, 1 H), 7.45-7.43 (m, 1 H), 7.30-7.22 (m, 10H), 7.09-7.07 (m, 2H), 6.89 (s, 1 H), 6.56-6.55 (m, 1 H), 6.47-6.46 (m, 1 H), 6.29-6.28 (m, 1 H), 5.86 (s, 2H), 4.52 (br s, 1 H); MS (ES+) m/z 433.7 (M – 17).

EXAMPLE 1 1

Synthesis of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3- dihydro-2H-indol-2-one

Compound of formula (17a1)

Figure imgf000098_0001

A. A mixture of 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1 ,3- benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (30.0 g, 66.5 mmol), benzyl bromide (8.3 mL, 70 mmol), and potassium carbonate (18.4 g, 133 mmol) in anhydrous N,N- dimeihylformamide (100 mL) was stirred at ambient temperature for 16 h. The reaction mixture was filtered and the solid was washed with /V,A/-dimethylformamide (100 mL). The filtrate was poured into water (1000 mL) and the resulting precipitate was collected by suction filtration and washed with water to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol- 5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (32.0 g) as a beige solid in 83% yield: 1H NMR (300 MHz, CDCI3) 7.42-7.28 (m, 9H), 7.22-7.14 (m, 6H), 7.10- 6.93 (m, 3H), 6.89-6.87 (m, 2H), 6.53 (d, J = 7.6 Hz, 1 H), 6.29 (br s, 1 H), 5.88 (s, 1 H), 5.85 (s, 1 H), 4.66 (d, J = 14.2 Hz, 1 H), 4.51 (d, J = 14.1 Hz, 1 H), 3.95 (s, 1 H); MS (ES+) m/z 542.0 (M + 1), 523.9 (M – 17).

B. Alternatively, to a solution of 1-(diphenylmethyl)-3-hydroxy-3-(6- hydroxy-1 ,3-benzodioxol-5-yl)-1 ,3-dihydro-2H-indol-2-one (2.1 kg, 4.6 mol) in anhydrous A/,A/-dimethylformamide (8.4 L) at 20-30 °C was added potassium carbonate (1.3 kg, 9.2 mol), followed by benzyl bromide (0.58 L, 4.8 mol). The mixture was stirred at 20-30 °C for 80 h and filtered. The filter cake was washed with

A/,/V-dimethylformamide (0.4 L) and the filtrate was poured into water (75 L), causing a solid to be deposited. The mixture was stirred at 15-25 °C for 7 h. The solid was collected by filtration, washed with water (2 L) and dried in vacuo at 50-60 °C for 48 h to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1-(diphenylmethyl)-3-hydroxy-1 ,3- dihydro-2H-indol-2-one (2.1 1 kg) as an off-white solid in 84% yield; 1H NMR (300

MHz, CDCI3) £7.42-7.28 (m, 9H), 7.22-7.14 (m, 6H), 7.10-6.93 (m, 3H), 6.89-6.87 (m, 2H), 6.53 (d, J = 7.6 Hz, 1 H), 6.29 (br s, 1 H), 5.88 (s, 1 H), 5.85 (s, 1 H), 4.66 (d, J = 14.2 Hz, 1 H), 4.51 (d, J = 14.1 Hz, 1 H), 3.95 (s, 1 H); MS (ES+) m/z 542.0 (M + 1 ).

EXAMPLE 12

Synthesis of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1 -(diphenylmethyl)-l ,3-dihydro-2H- indol-2-one

Compound of formula (18a1 )

Figure imgf000099_0001

A. To a solution of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1- (diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (32.0 g, 57.7 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (50 mL) followed by triethylsilane (50 mL). The reaction mixture was stirred at ambient temperature for 2 h and concentrated in vacuo. The residue was dissolved in ethyi acetate (250 mL), washed with saturated aqueous ammonium chloride (3 x 100 mL) and brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to afford 3-[6-(benzyloxy)-1 ,3-benzodioxol-5- yl]-1-(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (19.0 g) as a colorless solid in 61 % yield: 1H NMR (300 MHz, CDCI3) 7.31 -7.23 (m, 15H), 7.10-6.88 (m, 4H), 6.50-6.45 (m, 3H), 5.86 (s, 2H), 4.97-4.86 (m, 3H); MS (ES+) m/z 525.9 (M + 1).

B. Alternatively, to a solution of 3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-1- (diphenylmethyl)-3-hydroxy-1 ,3-dihydro-2H-indol-2-one (2.0 kg, 3.7 mol) in

dichloromethane (7 L) at 20-30 °C was added trifluoracetic acid (2.5 L), followed by triethylsilane (3.1 L). The mixture was stirred at 15-35 °C for 4 h and concentrated in vacuo to dryness. To the residue was added ethyl acetate (16 L) and the mixture was stirred at 15-35 °C for 0.5 h, washed with saturated aqueous ammonium chloride (3 x 7 L) and brine (3 χ 7 L) and concentrated in vacuo to a volume of approximately 7 L. Methyl ferf-butyl ether (9 L) was added and the mixture concentrated in vacuo to a volume of approximately 9 L and stirred at 10-20 °C for 2.5 h, during which time a solid was deposited. The solid was collected by filtration, washed with methyl te/t-butyl ether (0.4 L) and dried in vacuo at 50-55 °C for 7 h to afford 3-[6-(benzyloxy)-1 ,3- benzodioxol-5-yl]-1-(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1 .26 kg) as an off-white solid in 65% yield: 1H NMR (300 MHz, CDCI3) £7.31 -7.23 (m, 15H), 7.10- 6.88 (m, 4H), 6.50-6.45 (m, 3H), 5.86 (s, 2H), 4.97-4.86 (m, 3H); MS (ES+) m/z 525.9 (M + 1).

EXAMPLE 13

Synthesis of (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1 –

(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one

Compound of formula (19a1 )

Figure imgf000100_0001

A. To a nitrogen-degassed mixture of 50% w/w aqueous potassium hydroxide (69.6 mL, 619 mmol), toluene (100 mL), and (9S)-1 -(anthracen-9- ylmethyl)cinchonan-1 -ium-9-ol chloride (0.50 g, 0.95 mmol) cooled in an ice/salt bath to an internal temperature of -18 °C was added a nitrogen-degassed solution of 3-[6- (benzyloxy)-l ,3-benzodioxol-5-yl]-1 -(diphenylmethyl)-l ,3-dihydro-2H-indol-2-one (10.0 g, 19.0 mmol) and benzyl chloromethyl ether (2.9 mL, 21 mmol) in

toluene/tetrahydrofuran (1 :1 v/v, 80 mL) dropwise over 1 h. The reaction mixture was stirred for 3.5 h and diluted with ethyl acetate (80 mL). The organic phase was washed with 1 N hydrochloric acid (3 x 150 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford (3S)-3-[6-(benzyloxy)-1 ,3- benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1-(diphenylmethyl)-1 ,3-dihydro-2/-/-indol-2-one (12.6 g) as a colorless solid in quantitative yield: 1H NMR (300 MHz, CDCI3) 7.42 (d, 2H), 7.24-6.91 (m, 21 H), 6.69-6.67 (m, 2H), 6.46 (d, J = 7.7 Hz, 1 H), 6.15 (s, 1 H), 5.83- 5.81 (m, 2H), 4.53-4.31 (m, 3H), 4.17-4.09 (m, 3H); MS (ES+) m/z 646.0 (M + 1); ee (enantiomeric excess) 90% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert-butyl ether).

B. Alternatively, a mixture of 50% w/v aqueous potassium hydroxide (4.2 kg), toluene (12 L) and (9S)-1 -(anthracen-9-ylmethyl)cinchonan-1 -ium-9-ol chloride (0.06 kg, 0.1 mol) was degassed with dry nitrogen and cooled to -18 to -22 °C. To this mixture was added a cold (-18 to -22 °C), nitrogen-degassed solution of 3-[6-

(benzyloxy)-l ,3-benzodioxol-5-yl]-1 ~(diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1.2 kg, 2.3 mol) and benzyl chloromethyl ether (0.43 kg, 2.8 mol) in toluene (10 L) and tetrahydrofuran (10 L) at -18 to 22 °C over 3 h. The mixture was stirred at -18 to -22 °C for 5 h, allowed to warm to ambient temperature and diluted with ethyl acetate (10 L). The phases were separated and the organic layer was washed with 1 N

hydrochloric acid (3 χ 8 L) and brine (2 χ 12 L) and concentrated in vacuo to dryness to afford (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1- (diphenylmethyl)-1 ,3-dihydro-2H-indol-2-one (1.5 kg) as a colorless solid in quantitative yield: 1H NMR (300 MHz, CDCI3) £7.42 (d, 2H), 7.24-6.91 (m, 21 H), 6.69-6.67 (m, 2H), 6.46 (d, J = 7.7 Hz, 1 H), 6.15 (s, 1 H), 5.83-5.81 (m, 2H), 4.53-4.31 (m, 3H), 4.17- 4.09 (m, 3H); MS (ES+) m/z 646.0 (M + 1); ee (enantiomeric excess) 90% (HPLC, ChiralPak IA). EXAMPLE 14

Synthesis of (3S)-1-(diphenylmethyl)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3- (hydroxymethyl)-1 ,3-dihydro-2/-/-indol-2-one

Compound of formula (20a1)

Figure imgf000102_0001

A. A mixture of (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3- [(benzyloxy)methyl]-1 -(diphenylmethyl)-1 ,3-dihydro-2/-/-indol-2-one (8.8 g, 14 mmol), 10% w/w palladium on carbon (50% wetted powder, 3.5 g, 1.6 mmol), and acetic acid (3.9 ml_, 68 mmol) in a nitrogen-degassed mixture of ethanol/tetrahydrofuran (1 : 1 v/v, 140 mL) was stirred under hydrogen gas (1 atm) at ambient temperature for 4 h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was rinsed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to afford (3S)-1-(diphenylmethyl)-3-(6-hydroxy-1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3- dihydro-2H-indol-2-one as a colorless solid that was carried forward without further purification: H NMR (300 MHz, CDCI3) 9.81 (br s, 1 H), 7.35-7.24 (m, 1 1 H), 7.15- 7.01 (m, 3H), 6.62 (s, 1 H), 6.54-6.47 (m, 2H), 5.86-5.84 (m, 2H), 4.76 (d, J = 1 1.0 Hz, 1 H), 4.13-4.04 (m, 1 H), 2.02 (s, 1 H); MS (ES+) m/z 465.9 (M + 1); ee (enantiomeric excess) 93% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl ie t-butyl ether).

B. Alternatively, a glass-lined hydrogenation reactor was charged with (3S)-3-[6-(benzyloxy)-1 ,3-benzodioxol-5-yl]-3-[(benzyloxy)methyl]-1 -(diphenylmethyl)- 1 ,3-dihydro-2H-indol-2-one (0.1 kg, 0.15 mol), tetrahydrofuran (0.8 L), ethanol (0.4 L), acetic acid (0.02 L) and 20% w/w palladium (li) hydroxide on carbon (0.04 kg). The reactor was purged three times with nitrogen. The reactor was then purged three times with hydrogen and was then pressurized to 50-55 lb/in2 with hydrogen. The mixture was stirred at 20-30 °C for 5 h under a 50-55 lb/in2 atmosphere of hydrogen. The reactor was purged and the mixture was filtered. The filtrate was concentrated in vacuo to a volume of approximately 0.2 L and methyl te/t-butyl ether (0.4 L) was added. The mixture was concentrated in vacuo to a volume of approximately 0.2 L and methyl ie/t-butyl ether (0.2 L) was added, followed by heptane (0.25 L). The mixture was stirred at ambient temperature for 2 h, during which time a solid was deposited. The solid was collected by filtration, washed with heptane (0.05 L) and dried in vacuo at a temperature below 50 °C for 8 h to afford (3S)-1 -(diphenylmethyl)-3-(6-hydroxy- 1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2H-indol-2-one (0.09 kg) as a colorless solid in 95% yield: 1H NMR (300 MHz, CDCI3) 9.81 (br s, 1 H), 7.35-7.24 (m, 1 1 H), 7.15-7.01 (m, 3H), 6.62 (s, 1 H), 6.54-6.47 (m, 2H), 5.86-5.84 (m, 2H), 4.76 (d, J = 1 1.0 Hz, 1 H), 4.13-4.04 (m, 1 H), 2.02 (s, 1 H); MS (ES+) m/z 465.9 (M + 1); ee (enantiomeric excess) 91% (HPLC, ChiralPak IA).

EXAMPLE 15

Synthesis of (7S)-1′-(diphenylmethyl)spiro[furo[2,3-/][1 ,3]benzodioxole-7,3′-indol]-

2′(1 ‘tf)-one

Compound of formula (21 a1 )

Figure imgf000103_0001

A. To a cooled (0 °C) solution of (3S)-1 -(diphenylmethyl)-3-(6-hydroxy-1 ,3- benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2H-indol-2-one prepared according to the procedure described in Example 14 (13.6 mmol) and 2-

(diphenylphosphino)pyridine (4.3 g, 16 mmol) in anhydrous tetrahydrofuran (140 mL) was added di-tert-butylazodicarboxylate (3.8 g, 17 mmol). The reaction mixture was stirred at 0 °C for 3 h, diluted with ethyl acetate (140 mL), washed with 3 N

hydrochloric acid (6 * 50 mL) and brine (2 χ 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford (7S)-1 ‘-(diphenylmethyl)spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)-one (4.55 g) as a colorless solid in a 75% yield over 2 steps: 1H NMR (300 MHz, CDCI3) 7.34-7.24 (m, 10H), 7.15-7.13 (m, 1 H), 7.04 (s, 1 H), 6.99-6.95 (m, 2H), 6.50-6.48 (m, 2H), 6.06 (s, 1 H), 5.85-5.83 (m, 2H), 4.96 (d, J = 8.9 Hz, 1 H), 4.69 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 447.9 (M + 1); ee

(enantiomeric excess) 93% (HPLC, Chiraipak IA, 2.5% acetonitrile in methyl te/f-butyl ether).

B. Alternativel, to a cooled (0-5 °C) solution of (3S)-1-(diphenylmethyl)-3- (6-hydroxy-1 ,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1 ,3-dihydro-2 -/-indol-2-one (1 .0 kg, 2.1 mol) and 2-(diphenylphosphino)pyridine (0.66 kg, 2.5 mol) in anhydrous tetrahydrofuran (20 L) was added over 2 h a solution of di-terf-butylazodicarboxylate (0.62 kg, 2.7 mmol) in anhydrous tetrahydrofuran (5 L). The mixture was stirred for 4 h at 0-5 °C and was allowed to warm to ambient temperature. The mixture was diluted with ethyl acetate (20 L), washed with 3 N hydrochloric acid (6 * 8 L) and brine (2 x 12 L) and concentrated in vacuo to a volume of approximately 1.5 L. Methyl rert-butyl ether (4 L) was added and the mixture concentrated in vacuo to a volume of

approximately 1.5 L. Methyl terf-butyl ether (2 L) and heptane (2 L) were added and the mixture was stirred at ambient temperature for 2 h, during which time a solid was deposited. The solid was collected by filtration, washed with heptane (0.5 L) and dried in vacuo below 50 °C for 8 h to afford (7S)-1′-(diphenylmethyl)spiro[furo[2,3- f][1 ,3]benzodioxole-7,3′-indol]-2′(1’H)-one (0.76 kg) as a colorless solid in 79% yield: 1H NMR (300 MHz, CDCI3) 7.34-7.24 (m, 10H), 7.15-7.13 (m, 1 H), 7.04 (s, 1 H), 6.99- 6.95 (m, 2H), 6.50-6.48 (m, 2H), 6.06 (s, 1 H), 5.85-5.83 (m, 2H), 4.96 (d, J = 8.9 Hz, 1 H), 4.69 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 447.9 (M + 1 ); ee (enantiomeric excess) 92% (HPLC, ChiralPak IA).

EXAMPLE 16

Synthesis of (7S)-spiro[furo[2,3-f][1 ,3]benzodioxole-7,3′-indol]-2′(1 ‘H)-one

Compound of formula (22a1)

Figure imgf000104_0001

A. To a solution of (7S)-1′-(diphenylmethyl)spiro[furo[2,3- f][1 ,3]benzodioxole-7,3′-indol]-2′(1’H)-one (4.55 g, 10.2 mmol) in trifluoroacetic acid (80 ml_) was added triethylsilane (7 ml_). The reaction mixture was heated at reflux for 2.5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and hexanes to afford

(7S)-spiro[furo[2,3-/][1 ,3]benzodioxole-7,3,-indol]-2′(1’W)-one (2.30 g) as a colorless solid in 80% yield: 1H NMR (300 MHz, CDCI3) £8.27 (br s, 1 H), 7.31-7.26 (m, 1 H), 7.17-7.15 (m, 1 H), 7.07-7.02 (m, 1 H), 6.96-6.94 (m, 1 H), 6.53-6.52 (m, 1 H), 6.24-6.23 (m, 1 H), 5.88-5.87 (m, 2H), 4.95 (d, J = 8.6 Hz, 1 H), 4.68 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 281.9 (M + 1 ); ee (enantiomeric excess) 99% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl fert-butyl ether). B. Alternatively, a mixture of (7S)-1 ‘-(diphenylmethyl)spiro[furo[2,3- /Kl^benzodioxole^-indol^ r^-one (0.70 kg, 1.6 mol), trifluoroacetic acid (12 L) and triethylsilane (1.1 L) was heated at reflux under nitrogen atmosphere for 3 h, allowed to cool to ambient temperature and concentrated in vacuo to dryness. To the residue was added ethyl acetate (0.3 L), methyl fert-butyl ether (1 L) and heptane (3.5 L), causing a solid to be deposited. The solid was collected by filtration, taken up in dichloromethane (3 L), stirred at ambient temperature for 1 h and filtered. The filtrate was concentrated in vacuo to dryness. The residue was taken up in ethyl acetate (0.3 L), methyl ferf-butyl ether (1 L) and heptane (3.5 L), causing a solid to be deposited. The solid was collected by filtration and dried in vacuo below 50 °C for 8 h to afford (7S)-spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘ -/)-one (0.40 kg) as a colorless solid in 91 % yield: 1H NMR (300 MHz, CDCI3) 8.27 (br s, 1 H), 7.31-7.26 (m, 1 H), 7.17-7.15 (m, 1 H), 7.07-7.02 (m, 1 H), 6.96-6.94 (m, 1 H), 6.53-6.52 (m, 1 H), 6.24-6.23 (m, 1 H), 5.88-5.87 (m, 2H), 4.95 (d, J = 8.6 Hz, 1 H), 4.68 (d, J = 8.9 Hz, 1 H); MS (ES+) m/z 281.9 (M + 1); ee (enantiomeric excess) 98.6% (HPLC, ChiralPak IA).

EXAMPLE 17

Synthesis of of (7S)-1 ‘-{[5-(trifluoromethyl)furan-2- yl]methyl}spiro[furo[2,3- ][1 ,3]benzodioxole-7,3’-indol]-2′(rH)-one

Compound of formula (Ia1)

Figure imgf000105_0001

A. To a mixture of (7S)-6H-spiro[[1 ,3]dioxolo[4,5-f]benzofuran-7,3′-indolin]- 2′-one (1.80 g, 6.41 mmol) and 2-(bromomethyl)-5-(trifluoromethyl)furan (1.47 g, 6.41 mmol) in acetone (200 mL) was added cesium carbonate (3.13 g, 9.61 mmol). The reaction mixture was heated at reflux for 2 h and filtered while hot through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to afford (7S)-1′-{[5- (trifluoromethyOfuran^-yllmethy^spiroIfurop.S- ltl .Slbenzodioxole^.S’-indol^ rH)- one (2.71 g) as a colorless solid in quantitative yield (97% purity by HPLC). The product was crystallized from a mixture of methanol and hexanes to afford (7S)-1 ‘-{[5- (trifluoromethy furan^-yllmethylJspirotfuro^.S- lfl .Slbenzodioxole^.S’-indoll^ rH)- one (1.46 g) as colorless needles in 53% yield. The mother liquor was concentrated in vacuo and subjected to a second crystallization in methanol and hexanes to afford further (7S)-1 ‘-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-/][1 ,3]benzodioxole- 7,3’-indol]-2′(1 ‘H)-one (0.469 g) as a colorless solid in 17% yield (total yield 70%): 1H NMR (300 MHz, CDCI3) δ 7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz, 1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1); ee (enantiomeric excess) >99.5% (HPLC, Chiralpak IA, 2.5% acetonitrile in methyl tert-butyl ether).

B. Alternatively, to a solution of (7S)-spiro[furoI2,3-f][1 ,3]benzodioxole-7,3′- indol]-2′(1’H)-one (0.40 kg, 1.4 mol) in anhydrous N, W-dimethylformamide (5 L) was added cesium carbonate (1.2 kg, 3.4 mol), followed by 2-(bromomethyl)-5- (trifluromethyl)furan (0.24 L, 1.7 mol). The mixture was heated at 80-85 °C for 3 h, allowed to cool to ambient temperature and filtered through a pad of diatomaceous earth. The pad was washed with ethyl acetate (8 L). The combined filtrate and washes were washed with water (4 L), saturated aqueous ammonium chloride (2 * 4 L) and brine (2 * 4 L) and concentrated in vacuo to dryness. The residue was purified by recrystallization from te/t-butyl methyl ether (0.4 L) and heptane (0.8 L), followed by drying of the resultant solid in vacuo at 40-50 °C for 8 h to afford (7S)-1 ‘-{[5- (trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1 ,3]benzodioxole-7,3’-indol]-2′(1 ‘H)- one (0.37 kg) as a colorless solid in 61% yield: 1H NMR (300 MHz, CDCI3) δ 7.29-6.96 (m, 4H), 6.73 (s, 1 H), 6.50 (s, 1 H), 6.38 (s, 1 H), 6.09 (s, 1 H), 5.85 (br s, 2H), 5.06 (d, J = 16.0 Hz,1 H), 4.93-4.84 (m, 2H), 4.68-4.65 (m, 1 H); MS (ES+) m/z 429.8 (M + 1 ); ee (enantiomeric excess) > 99% (HPLC, Chiralpak IA).

PATENT
CadieuxJ.-J.ChafeevM.ChowdhuryS.FuJ.JiaQ.AbelS.El-SayedE.HuthmannE.IsarnoT. Synthetic Methods For Spiro-Oxindole Compounds. U.S. Patent 8,445,696, May 21, 2013.
PATENT
SunS.FuJ.ChowdhuryS.HemeonI. W.GrimwoodM. E.MansourT. S. Asymmetric Syntheses of Spiro-Oxindole Compounds Useful As Therapeutic Agents. U.S. Patent 9,487,535, Nov 08, 2016.
PAPER
Abstract Image

TV-45070 is a small-molecule lactam containing a chiral spiro-ether that has been reported as a potential topical therapy for pain associated with the Nav1.7 sodium ion channel encoded by the gene SCN9A. A pilot-scale synthesis is presented that is highlighted by an asymmetric aldol coupling at ambient temperature, used to create a quaternary chiral center. Although only a moderate ee is obtained, the removal of the undesired isomer is achieved through preferential precipitation of a near racemic mixture from the reaction, leaving the enantiopure isomer in solution. Cyclization to form the final API uses an uncommon diphenylphosphine-based leaving group which proved successful on the neopentyl system when other traditional leaving groups failed.

The First Asymmetric Pilot-Scale Synthesis of TV-45070

Chemical Process Research and Development, Analytical Research and Development, Teva Branded Pharmaceutical Products R&D Inc., 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00237
Publication Date (Web): September 8, 2017
Copyright © 2017 American Chemical Society

*E-mail: jasclafan@yahoo.com.

(S)-1′-[(5-Methyl-2-furyl)methyl]spiro[6H-furo[3,2-f][1,3]benzodioxole-7,3′-indoline]-2′-one (1)

1H NMR (DMSO, 400 MHz) δ 7.32 (t, J = 7.7 Hz, 1H), 7.20 (m, 3H), 7.07 (t, J = 7.3 Hz, 1H), 6.77 (d, J= 3.3 Hz, 1H), 6.72 (s, 1H), 6.10 (s, 1H), 5.94 (d, J = 9.1 Hz, 1H), 5.94 (d, J = 9.1 Hz, 1H), 5.13 (d, J = 16.5 Hz, 1H), 5.02 (d, J = 16.5 Hz, 1H), 4.82 (d, J = 9.5 Hz, 1H), 4.73 (d, J = 9.5 Hz, 1H).
13C NMR (100 MHz, DMSO-d6): 176.48, 155.28, 153.02, 148.40, 141.80, 141.51, 139.54 (q, JCF = 41.9 Hz), 131.63, 128.79, 123.64, 123.29, 119.69, 118.92 (q, JCF = 266.4 Hz), 114.01 (q, JCF = 2.9 Hz) 109.86, 109.21, 102.55, 101.44, 93.31, 79.52, 57.41, 36.44.

References

  1. Jump up to:a b c Bagal, Sharan K.; Chapman, Mark L.; Marron, Brian E.; Prime, Rebecca; Ian Storer, R.; Swain, Nigel A. (2014). “Recent progress in sodium channel modulators for pain”. Bioorganic & Medicinal Chemistry Letters24 (16): 3690–9. ISSN 0960-894XPMID 25060923doi:10.1016/j.bmcl.2014.06.038.
  2. Jump up to:a b Stephen McMahon; Martin Koltzenburg; Irene Tracey; Dennis C. Turk (1 March 2013). Wall & Melzack’s Textbook of Pain: Expert Consult – Online. Elsevier Health Sciences. p. 508. ISBN 0-7020-5374-0.
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US2017095449 PHARMACEUTICAL COMPOSITIONS OF SPIRO-OXINDOLE COMPOUND FOR TOPICAL ADMINISTRATION AND THEIR USE AS THERAPEUTIC AGENTS 2016-10-11
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US9682033 METHODS OF TREATING POSTHERPETIC NEURALGIA WITH A TOPICAL FORMULATION OF A SPIRO-OXINDOLE COMPOUND 2016-02-05 2016-08-11
US2016166541 Methods For Identifying Analgesic Agents 2016-01-27 2016-06-16
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US8445696 SYNTHETIC METHODS FOR SPIRO-OXINDOLE COMPOUNDS 2011-04-14
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US8883840 14 Sep 2012 11 Nov 2014 Xenon Pharmaceuticals Inc. Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents
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Funapide
Funapide.svg
Clinical data
Routes of
administration
By mouthtopical
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C22H14F3NO5
Molar mass 429.34547 g/mol
3D model (JSmol)
//////////TV 45070,  XEN 402, TEVA, XENON, Postherpetic neuralgia, PHN, PHASE 2, Funapide, фунапид , فونابيد , 呋纳匹特 , Orphan Drug Status
C1C2(C3=CC=CC=C3N(C2=O)CC4=CC=C(O4)C(F)(F)F)C5=CC6=C(C=C5O1)OCO6

Enasidenib, Энасидениб , إيناسيدينيب ,伊那尼布 ,


Enasidenib.svg

ChemSpider 2D Image | Enasidenib | C19H17F6N7OEnasidenib.png

AG-221 (Enasidenib), IHD2 Inhibitor

Enasidenib

  • Molecular Formula C19H17F6N7O
  • Average mass 473.375
2-Propanol, 2-methyl-1-[[4-[6-(trifluoromethyl)-2-pyridinyl]-6-[[2-(trifluoromethyl)-4-pyridinyl]amino]-1,3,5-triazin-2-yl]amino]-[ACD/Index Name]
  • 2-Methyl-1-[[4-[6-(trifluoromethyl)-2-pyridinyl]-6-[[2-(trifluoromethyl)-4-pyridinyl]amino]-1,3,5-triazin-2-yl]amino]-2-propanol
  • 2-Methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)propan-2-ol
AG-221
CC-90007
1446502-11-9[RN]
enasidenib
Enasidenib
énasidénib
enasidenibum
UNII:3T1SS4E7AG
Энасидениб[Russian]
إيناسيدينيب[Arabic]
伊那尼布[Chinese]
2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol
2-methyl-1-[[4-[6-(trifluoromethyl)pyridin-2-yl]-6-[[2-(trifluoromethyl)pyridin-4-yl]amino]-1,3,5-triazin-2-yl]amino]propan-2-ol
2-methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)propan-2-ol
Originator Agios Pharmaceuticals
Developer Celgene Corporation
Mechanism Of Action Isocitrate dehydrogenase 2 inhibitor
Who Atc Codes L01 (Antineoplastic Agents)
Ephmra Codes L1 (Antineoplastics)
Indication Cancer

2D chemical structure of 1650550-25-6

Enasidenib mesylate [USAN]
RN: 1650550-25-6
UNII: UF6PC17XAV

Molecular Formula, C19-H17-F6-N7-O.C-H4-O3-S

Molecular Weight, 569.4849

2-Propanol, 2-methyl-1-((4-(6-(trifluoromethyl)-2-pyridinyl)-6-((2-(trifluoromethyl)-4-pyridinyl)amino)-1,3,5-triazin-2-yl)amino)-, methanesulfonate (1:1)

Enasidenib (AG-221) is an experimental drug in development for treatment of cancer. It is a small molecule inhibitor of IDH2 (isocitrate dehydrogenase 2). It was developed by Agios Pharmaceuticals and is licensed to Celgene for further development.

Image result for Enasidenib

LC MS

https://file.medchemexpress.com/batch_PDF/HY-18690/Enasidenib_LCMS_18195_MedChemExpress.pdf

NMR FROM INTERNET SOURCES

SEE http://www.medkoo.com/uploads/product/Enasidenib__AG-221_/qc/QC-Enasidenib-TZC60322Web.pdf

see also

https://file.medchemexpress.com/batch_PDF/HY-18690/Enasidenib_HNMR_18195_MedChemExpress.pdf ……….NMR CD3OD

str1

NMR FROM INTERNET SOURCES

SEE http://www.medkoo.com/uploads/product/Enasidenib__AG-221_/qc/QC-Enasidenib-TZC60322Web.pdf

Patent

http://www.google.com/patents/US20130190287

Compound 409—2-methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)propan-2-ol

Figure US20130190287A1-20130725-C00709

1H NMR (METHANOL-d4) δ 8.62-8.68 (m, 2H), 847-8.50 (m, 1H), 8.18-8.21 (m, 1H), 7.96-7.98 (m, 1H), 7.82-7.84 (m, 1H), 3.56-3.63 (d, J=28 Hz, 2H), 1.30 (s, 6H). LC-MS: m/z 474.3 (M+H)+.

The FDA granted fast track designation and orphan drug status for acute myeloid leukemia in 2014.[1]

An orally available inhibitor of isocitrate dehydrogenase type 2 (IDH2), with potential antineoplastic activity. Upon administration, AG-221 specifically inhibits IDH2 in the mitochondria, which inhibits the formation of 2-hydroxyglutarate (2HG). This may lead to both an induction of cellular differentiation and an inhibition of cellular proliferation in IDH2-expressing tumor cells. IDH2, an enzyme in the citric acid cycle, is mutated in a variety of cancers; It initiates and drives cancer growth by blocking differentiation and the production of the oncometabolite 2HG.

Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., a-ketoglutarate). These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer.

IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial) is also known as IDH; IDP; IDHM; IDPM; ICD-M; or mNADP-IDH. The protein encoded by this gene is the

NADP(+)-dependent isocitrate dehydrogenase found in the mitochondria. It plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with the pyruvate dehydrogenase complex. Human IDH2 gene encodes a protein of 452 amino acids. The nucleotide and amino acid sequences for IDH2 can be found as GenBank entries NM_002168.2 and NP_002159.2 respectively. The nucleotide and amino acid sequence for human IDH2 are also described in, e.g., Huh et al., Submitted (NOV-1992) to the

EMBL/GenBank/DDBJ databases; and The MGC Project Team, Genome Res.

14:2121-2127(2004).

Non-mutant, e.g., wild type, IDH2 catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate (a- KG) thereby reducing NAD+ (NADP+) to NADH (NADPH), e.g., in the forward reaction:

Isocitrate + NAD+ (NADP+)→ a-KG + C02 + NADH (NADPH) + H+.

It has been discovered that mutations of IDH2 present in certain cancer cells result in a new ability of the enzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). 2HG is not formed by wild- type IDH2. The production of 2HG is believed to contribute to the formation and progression of cancer (Dang, L et al, Nature 2009, 462:739-44).

The inhibition of mutant IDH2 and its neoactivity is therefore a potential therapeutic treatment for cancer. Accordingly, there is an ongoing need for inhibitors of IDH2 mutants having alpha hydroxyl neoactivity.

Mechanism of action

Isocitrate dehydrogenase is a critical enzyme in the citric acid cycle. Mutated forms of IDH produce high levels of 2-hydroxyglutarate and can contribute to the growth of tumors. IDH1 catalyzes this reaction in the cytoplasm, while IDH2 catalyzes this reaction in mitochondria. Enasidenib disrupts this cycle.[1][2]

Development

The drug was discovered in 2009, and an investigational new drug application was filed in 2013. In an SEC filing, Agios announced that they and Celgene were in the process of filing a new drug application with the FDA.[3] The fast track designation allows this drug to be developed in what in markedly less than the average 14 years it takes for a drug to be developed and approved.[4]

PATENT

WO 2013102431

Image result

Agios Pharmaceuticals, Inc.

Giovanni Cianchetta
Giovanni Cianchetta
Associate Director/Principal Scientist at Agios Pharmaceuticals
Inventors Giovanni CianchettaByron DelabarreJaneta Popovici-MullerFrancesco G. SalituroJeffrey O. SaundersJeremy TravinsShunqi YanTao GuoLi Zhang
Applicant Agios Pharmaceuticals, Inc.

Compound 409 –

2-methyl-l-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2-(trifluoromethyl)pyri^

ίαζίη-2- lamino ropan-2-ol

Figure imgf000135_0001

1H NMR (METHANOL-d4) δ 8.62-8.68 (m, 2 H), 847-8.50 (m, 1 H), 8.18-8.21 (m, 1 H), 7.96-7.98 (m, 1 H), 7.82-7.84 (m, 1 H), 3.56-3.63 (d, J = 28 Hz, 2 H), 1.30 (s, 6 H). LC-MS: m/z 474.3 (M+H)+.

WO 2017066611

WO 2017024134

WO 2016177347

PATENT

WO 2016126798

Example 1: Synthesis of compound 3

Example 1, Step 1: preparation of 6-trifluoromethyl-pyridine-2-carboxylic acid

Diethyl ether (4.32 L) and hexanes (5.40 L) are added to the reaction vessel under N2 atmosphere, and cooled to -75 °C to -65 °C. Dropwise addition of n-Butyl lithium (3.78 L in 1.6 M hexane) under N2 atmosphere at below -65 °C is followed by dropwise addition of dimethyl amino ethanol (327.45 g, 3.67 mol) and after 10 min. dropwise addition of 2-trifluoromethyl pyridine (360 g, 2.45 mol). The reaction is stirred under N2 while maintaining the temperature below -65 °C for about 2.0-2.5 hrs. The reaction mixture is poured over crushed dry ice under N2, then brought to a temperature of 0 to 5 °C while stirring (approx. 1.0 to 1.5 h) followed by the addition of water (1.8 L). The reaction mixture is stirred for 5-10 mins and allowed to warm to 5-10 °C. 6N HC1 (900 mL) is added dropwise until the mixture reached pH 1.0 to 2.0, then the mixture is stirred for 10-20 min. at 5-10 °C. The reaction mixture is diluted with ethyl acetate at 25-35 °C, then washed with brine solution. The reaction is concentrated and rinsed with n-heptane and then dried to yield 6-trifluoromethyl-pyridine-2-carboxylic acid.

Example 1, Step 2: preparation of 6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester Methanol is added to the reaction vessel under nitrogen atmosphere. 6-trifluoromethyl- pyridine-2-carboxylic acid (150 g, 0.785 mol) is added and dissolved at ambient temperature. Acetyl chloride (67.78 g, 0.863 mol) is added dropwise at a temperature below 45 °C. The reaction mixture is maintained at 65-70 °C for about 2-2.5 h, and then concentrated at 35-45 °C under vacuum and cooled to 25-35 °C. The mixture is diluted with ethyl acetate and rinsed with saturated NaHC03 solution then rinsed with brine solution. The mixture is concentrated at temp 35-45 °C under vacuum and cooled to 25-35 °C, then rinsed with n-heptane and concentrated at temp 35-45 °C under vacuum, then degassed to obtain brown solid, which is rinsed with n-heptane and stirred for 10-15 minute at 25-35 °C. The suspension is cooled to -40 to -30 °C while stirring, and filtered and dried to provide 6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester.

Example 1, Step 3: preparation of 6-(6-Trifluoromethyl-pyridin-2-yl)-lH-l,3,5-triazine-2,4-dione

1 L absolute ethanol is charged to the reaction vessel under N2 atmosphere and Sodium Metal (11.2 g, 0.488 mol) is added in portions under N2 atmosphere at below 50 °C. The reaction is stirred for 5-10 minutes, then heated to 50-55 °C. Dried Biuret (12.5 g, 0.122 mol) is added to the reaction vessel under N2 atmosphere at 50-55 °C temperature, and stirred 10-15 minutes. While maintaining 50-55 °C 6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (50.0 g, 0.244 mol) is added. The reaction mixture is heated to reflux (75-80 °C) and maintained for 1.5-2 hours. Then cooled to 35-40 °C, and concentrated at 45-50 °C under vacuum. Water is added and the mixture is concentrated under vacuum then cooled to 35-40 °C more water is added and the mixture cooled to 0 -5 °C. pH is adjusted to 7-8 by slow addition of 6N HC1, and solid precipitated out and is centrifuged and rinsed with water and centrifuged again. The off white to light brown solid of 6-(6-Trifluoromethyl-pyridin-2-yl)-lH-l,3,5-triazine-2,4-dione is dried under vacuum for 8 to 10 hrs at 50 °C to 60 °C under 600mm/Hg pressure to provide 6-(6-Trifluoromethyl-pyridin-2-yl)-lH-l,3,5-triazine-2,4-dione.

Example 1, Step 4: preparation of 2, 4-Dichloro-6-(6-trifluoromethyl-pyridin-2-yl)-l, 3, 5-triazine

POCI3 (175.0 mL) is charged into the reaction vessel at 20- 35 °C, and 6-(6-Trifluoromethyl-pyridin-2-yl)-lH-l,3,5-triazine-2,4-dione (35.0 g, 0.1355 mol) is added in portions at below 50 °C. The reaction mixture is de-gassed 5-20 minutes by purging with N2 gas. Phosphorous pentachloride (112.86 g, 0.542 mol) is added while stirring at below 50 °C and the resulting slurry is heated to reflux (105-110 °C) and maintained for 3-4 h. The reaction mixture is cooled to 50-55 °C, and concentrated at below 55 °C then cooled to 20-30 °C. The reaction mixture is rinsed with ethyl acetate and the ethyl acetate layer is slowly added to cold water (temperature ~5 °C) while stirring and maintaining the temperature below 10 °C. The mixture is stirred 3-5 minutes at a temperature of between 10 to 20 °C and the ethyl acetate layer is collected. The reaction mixture is rinsed with sodium bicarbonate solution and dried over anhydrous sodium sulphate. The material is dried 2-3 h under vacuum at below 45 °C to provide 2, 4-Dichloro-6-(6-trifluoromethyl-pyridin-2-yl)-l, 3, 5-triazine. Example 1, Step 5: preparation of 4-chloro-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoro-methyl)- pyridin-4-yl)-l,3,5-triazin-2-amine

A mixture of THF (135 mL) and 2, 4-Dichloro-6-(6-trifluoromethyl-pyridin-2-yl)-l, 3, 5-triazine (27.0 g, 0.0915 mol) are added to the reaction vessel at 20 – 35 °C, then 4-amino-2-(trifluoromethyl)pyridine (16.31 g, 0.1006 mol) and sodium bicarbonate (11.52 g, 0.1372 mol) are added. The resulting slurry is heated to reflux (75-80 °C) for 20-24 h. The reaction is cooled to 30-40 °C and THF evaporated at below 45 °C under reduced pressure. The reaction mixture is cooled to 20-35 °C and rinsed with ethyl acetate and water, and the ethyl acetate layer collected and rinsed with 0.5 N HC1 and brine solution. The organic layer is concentrated under vacuum at below 45 °C then rinsed with dichloromethane and hexanes, filtered and washed with hexanes and dried for 5-6h at 45-50 °C under vacuum to provide 4-chloro-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoro-methyl)- pyridin-4-yl)-l,3,5-triazin-2-amine.

Example 1, Step 6: preparation of 2-methyl-l-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2-(trifluoromethyl)- pyridin-4-ylamino)-l,3,5-triazin-2-ylamino)propan-2-ol

THF (290 mL), 4-chloro-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoro-methyl)-pyridin-4-yl)-l,3,5-triazin-2-amine (29.0 g, 0.06893 mol), sodium bicarbonate (8.68 g, 0.1033 mol), and 1, 1-dimethylaminoethanol (7.37 g, 0.08271 mol) are added to the reaction vessel at 20-35 °C. The resulting slurry is heated to reflux (75-80 °C) for 16-20 h. The reaction is cooled to 30-40 °C and THF evaporated at below 45 °C under reduced pressure. The reaction mixture is cooled to 20-35 °C and rinsed with ethyl acetate and water, and the ethyl acetate layer collected. The organic layer is concentrated under vacuum at below 45 °C then rinsed with dichlorom ethane and hexanes, filtered and washed with hexanes and dried for 8-1 Oh at 45-50 °C under vacuum to provide 2-methyl-l-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2-(trifluoromethyl)- pyridin-4-ylamino)-l,3,5-triazin-2-ylamino)propan-2-ol.

PATENT

US 20160089374

PATENT

WO 2015017821


References

  1. Jump up to:a b “Enasidenib”AdisInsight. Retrieved 31 January 2017.
  2. Jump up^ https://pubchem.ncbi.nlm.nih.gov/compound/Enasidenib
  3. Jump up^ https://www.sec.gov/Archives/edgar/data/1439222/000119312516758835/d172494d10q.htm
  4. Jump up^ http://www.xconomy.com/boston/2016/09/07/celgene-plots-speedy-fda-filing-for-agios-blood-cancer-drug/
  5. 1 to 3 of 3
    Patent ID

    Patent Title

    Submitted Date

    Granted Date

    US2013190287 THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE 2013-01-07 2013-07-25
    US2016089374 THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE 2015-09-28 2016-03-31
    US2016194305 THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE 2014-08-01 2016-07-07
 Image result for Enasidenib
08/01/2017
The U.S. Food and Drug Administration today approved Idhifa (enasidenib) for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a specific genetic mutation. The drug is approved for use with a companion diagnostic, the RealTime IDH2 Assay, which is used to detect specific mutations in the IDH2 gene in patients with AML.

The U.S. Food and Drug Administration today approved Idhifa (enasidenib) for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a specific genetic mutation. The drug is approved for use with a companion diagnostic, the RealTime IDH2 Assay, which is used to detect specific mutations in the IDH2 gene in patients with AML.

“Idhifa is a targeted therapy that fills an unmet need for patients with relapsed or refractory AML who have an IDH2 mutation,” 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. “The use of Idhifa was associated with a complete remission in some patients and a reduction in the need for both red cell and platelet transfusions.”

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of abnormal white blood cells in the bloodstream and bone marrow. The National Cancer Institute at the National Institutes of Health estimates that approximately 21,380 people will be diagnosed with AML this year; approximately 10,590 patients with AML will die of the disease in 2017.

Idhifa is an isocitrate dehydrogenase-2 inhibitor that works by blocking several enzymes that promote cell growth. If the IDH2 mutation is detected in blood or bone marrow samples using the RealTime IDH2 Assay, the patient may be eligible for treatment with Idhifa.

The efficacy of Idhifa was studied in a single-arm trial of 199 patients with relapsed or refractory AML who had IDH2 mutations as detected by the RealTime IDH2 Assay. The trial measured the percentage of patients with no evidence of disease and full recovery of blood counts after treatment (complete remission or CR), as well as patients with no evidence of disease and partial recovery of blood counts after treatment (complete remission with partial hematologic recovery or CRh). With a minimum of six months of treatment, 19 percent of patients experienced CR for a median 8.2 months, and 4 percent of patients experienced CRh for a median 9.6 months. Of the 157 patients who required transfusions of blood or platelets due to AML at the start of the study, 34 percent no longer required transfusions after treatment with Idhifa.

Common side effects of Idhifa include nausea, vomiting, diarrhea, increased levels of bilirubin (substance found in bile) and decreased appetite. Women who are pregnant or breastfeeding should not take Idhifa because it may cause harm to a developing fetus or a newborn baby.

The prescribing information for Idhifa includes a boxed warning that an adverse reaction known as differentiation syndrome can occur and can be fatal if not treated. Sign and symptoms of differentiation syndrome may include fever, difficulty breathing (dyspnea), acute respiratory distress, inflammation in the lungs (radiographic pulmonary infiltrates), fluid around the lungs or heart (pleural or pericardial effusions), rapid weight gain, swelling (peripheral edema) or liver (hepatic), kidney (renal) or multi-organ dysfunction. At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor patients closely until symptoms go away.

Idhifa was granted Priority Review designation, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition. Idhifa also received Orphan Drugdesignation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Idhifa to Celgene Corporation. The FDA granted the approval of the RealTime IDH2 Assay to Abbott Laboratories

 1H AND 13C NMR PREDICT

///////// fda 2017, Idhifa, enasidenib, Энасидениб , إيناسيدينيب ,伊那尼布 , AG 221, fast track designation,  orphan drug status ,  acute myeloid leukemiaCC-90007

CC(C)(CNC1=NC(=NC(=N1)NC2=CC(=NC=C2)C(F)(F)F)C3=NC(=CC=C3)C(F)(F)F)O

Enasidenib
Enasidenib.svg
Identifiers
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
Formula C19H17F6N7O
Molar mass 473.38 g·mol−1
3D model (JSmol)

FDA approves new treatment Endari (L-glutamine oral powder) for sickle cell disease


Image result for sickle cell disease
07/07/2017
The U.S. Food and Drug Administration today approved Endari (L-glutamine oral powder) for patients age five years and older with sickle cell disease to reduce severe complications associated with the blood disorder.

July 7, 2017

Release

The U.S. Food and Drug Administration today approved Endari (L-glutamine oral powder) for patients age five years and older with sickle cell disease to reduce severe complications associated with the blood disorder.

“Endari is the first treatment approved for patients with sickle cell disease in almost 20 years,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “Until now, only one other drug was approved for patients living with this serious, debilitating condition.”

Sickle cell disease is an inherited blood disorder in which the red blood cells are abnormally shaped (in a crescent, or “sickle,” shape). This restricts the flow in blood vessels and limits oxygen delivery to the body’s tissues, leading to severe pain and organ damage. According to the National Institutes of Health, approximately 100,000 people in the United States have sickle cell disease. The disease occurs most often in African-Americans, Latinos and other minority groups. The average life expectancy for patients with sickle cell disease in the United States is approximately 40 to 60 years.

The safety and efficacy of Endari were studied in a randomized trial of patients ages five to 58 years old with sickle cell disease who had two or more painful crises within the 12 months prior to enrollment in the trial. Patients were assigned randomly to treatment with Endari or placebo, and the effect of treatment was evaluated over 48 weeks. Patients who were treated with Endari experienced fewer hospital visits for pain treated with a parenterally administered narcotic or ketorolac (sickle cell crises), on average, compared to patients who received a placebo (median 3 vs. median 4), fewer hospitalizations for sickle cell pain (median 2 vs. median 3), and fewer days in the hospital (median 6.5 days vs. median 11 days).  Patients who received Endari also had fewer occurrences of acute chest syndrome (a life-threatening complication of sickle cell disease) compared with patients who received a placebo (8.6 percent vs. 23.1 percent).

Common side effects of Endari include constipation, nausea, headache, abdominal pain, cough, pain in the extremities, back pain and chest pain.

Endari received Orphan Drug designation for this use, which provides incentives to assist and encourage the development of drugs for rare diseases.  In addition, development of this drug was in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and/or effectiveness of products for use in rare diseases or conditions.

The FDA granted the approval of Endari to Emmaus Medical Inc.

Image result for Emmaus Medical Inc

Image result for sickle cell disease

/////////////FDA2017, Endari, Orphan Drug designation,  Emmaus Medical Inc., L-glutamine oral powder

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