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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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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 29 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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 cancer treatment for any solid tumor with a specific genetic feature


05/23/2017
The U.S. Food and Drug Administration today granted accelerated approval to a treatment for patients whose cancers have a specific genetic feature (biomarker). This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated

May 23, 2017

Release

The U.S. Food and Drug Administration today granted accelerated approval to a treatment for patients whose cancers have a specific genetic feature (biomarker). This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated.

Keytruda (pembrolizumab) is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This indication covers patients with solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and patients with colorectal cancer that has progressed following treatment with certain chemotherapy drugs.

“This is an important first for the cancer community,” 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, the FDA has approved cancer treatments based on where in the body the cancer started—for example, lung or breast cancers. We have now approved a drug based on a tumor’s biomarker without regard to the tumor’s original location.”

MSI-H and dMMR tumors contain abnormalities that affect the proper repair of DNA inside the cell. Tumors with these biomarkers are most commonly found in colorectal, endometrial and gastrointestinal cancers, but also less commonly appear in cancers arising in the breast, prostate, bladder, thyroid gland and other places. Approximately 5 percent of patients with metastatic colorectal cancer have MSI-H or dMMR tumors.

Keytruda works by targeting the cellular pathway known as PD-1/PD-L1 (proteins found on the body’s immune cells and some cancer cells). By blocking this pathway, Keytruda may help the body’s immune system fight the cancer cells. The FDA previously approved Keytruda for the treatment of certain patients with metastatic melanoma, metastatic non-small cell lung cancer, recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma.

Keytruda was approved for this new indication using the Accelerated Approvalpathway, under which the FDA may approve drugs for serious conditions where there is unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further study is required to verify and describe anticipated clinical benefits of Keytruda, and the sponsor is currently conducting these studies in additional patients with MSI-H or dMMR tumors.

The safety and efficacy of Keytruda for this indication were studied in patients with MSI-H or dMMR solid tumors enrolled in one of five uncontrolled, single-arm clinical trials. In some trials, patients were required to have MSI-H or dMMR cancers, while in other trials, a subgroup of patients were identified as having MSI-H or dMMR cancers by testing tumor samples after treatment began. A total of 15 cancer types were identified among 149 patients enrolled across these five clinical trials. The most common cancers were colorectal, endometrial and other gastrointestinal cancers. The review of Keytruda for this indication was based on the percentage of patients who experienced complete or partial shrinkage of their tumors (overall response rate) and for how long (durability of response). Of the 149 patients who received Keytruda in the trials, 39.6 percent had a complete or partial response. For 78 percent of those patients, the response lasted for six months or more.

Common side effects of Keytruda include fatigue, itchy skin (pruritus), diarrhea, decreased appetite, rash, fever (pyrexia), cough, difficulty breathing (dyspnea), musculoskeletal pain, constipation and nausea. Keytruda can cause serious conditions known as immune-mediated side effects, including inflammation of healthy organs such as the lungs (pneumonitis), colon (colitis), liver (hepatitis), endocrine glands (endocrinopathies) and kidneys (nephritis). Complications or death related to allogeneic hematopoietic stem cell transplantation after using Keytruda has occurred.

Patients who experience severe or life-threatening infusion-related reactions should stop taking Keytruda. Women who are pregnant or breastfeeding should not take Keytruda because it may cause harm to a developing fetus or newborn baby. The safety and effectiveness of Keytruda in pediatric patients with MSI-H central nervous system cancers have not been established.

The FDA granted this application 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.

The FDA granted accelerated approval of Keytruda to Merck & Co.

///////////Keytruda, pembrolizumab, BIO MARKER, MERCK, FDA 2017

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FDA approves first drug Actemra (tocilizumab) to specifically treat giant cell arteritis


Image result for actemra logo
05/22/2017
The U.S. Food and Drug Administration today expanded the approved use of subcutaneous Actemra (tocilizumab) to treat adults with giant cell arteritis. This new indication provides the first FDA-approved therapy, specific to this type of vasculitis.

May 22, 2017

Release

The U.S. Food and Drug Administration today expanded the approved use of subcutaneous Actemra (tocilizumab) to treat adults with giant cell arteritis. This new indication provides the first FDA-approved therapy, specific to this type of vasculitis.

“We expedited the development and review of this application because this drug fulfills a critical need for patients with this serious disease who had limited treatment options,” 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.

Giant cell arteritis is a form of vasculitis, a group of disorders that results in inflammation of blood vessels. This inflammation causes the arteries to narrow or become irregular, impeding adequate blood flow. In giant cell arteritis, the vessels most involved are those of the head, especially the temporal arteries (located on each side of the head). For this reason, the disorder is sometimes called temporal arteritis. However, other blood vessels, including large ones like the aorta, can become inflamed in giant cell arteritis. Standard treatment involves high doses of corticosteroids that are tapered over time.

The efficacy and safety of subcutaneous (injected under the skin) Actemra for giant cell arteritis were established in a double-blind, placebo-controlled study with 251 patients with giant cell arteritis. The primary efficacy endpoint was the proportion of patients achieving sustained remission from Week 12 through Week 52. Sustained remission was defined as the absence of symptoms of giant cell arteritis, normalization of inflammatory laboratory tests, and tapering the use of prednisone (a steroid drug). A greater proportion of patients receiving subcutaneous Actemra with standardized prednisone regimens achieved sustained remission from Week 12 through Week 52 as compared to patients receiving placebo with standardized prednisone regimens. The cumulative prednisone dose was lower in treated patients with Actemra relative to placebo.

The overall safety profile observed in the Actemra treatment groups was generally consistent with the known safety profile of Actemra. Actemra carries a Boxed Warning for serious infections. Patients treated with Actemra who develop a serious infection should stop that treatment until the infection is controlled. Live vaccines should be avoided during treatment with Actemra. Actemra should be used with caution in patients at increased risk of gastrointestinal perforation. Hypersensitivity reactions, including anaphylaxis and death, have occurred. Laboratory monitoring is recommended due to potential consequences of treatment-related changes in neutrophils (type of white blood cell), platelets, lipids and liver function tests.

Subcutaneous Actemra was previously approved for the treatment of moderate to severely active rheumatoid arthritis. Intravenous Actemra was also previously approved for the treatment of moderate to severely active rheumatoid arthritis, systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis. Intravenous administration is not approved for giant cell arteritis.

The FDA granted this application a Breakthrough Therapy designation and a Priority Review.

The FDA granted the supplemental approval of Actemra to Hoffman La Roche, Inc.

//////////Actemra, tocilizumab, fda 2017, Breakthrough Therapy designation, Priority Review,  supplemental approval, Hoffman La Roche, Inc.

FDA expands approved use of Kalydeco IVACAFTOR to treat additional mutations of cystic fibrosis


05/17/2017 04:14 PM EDT
The U.S. Food and Drug Administration today expanded the approved use of Kalydeco (ivacaftor) for treating cystic fibrosis. The approval triples the number of rare gene mutations that the drug can now treat, expanding the indication from the treatment of 10 mutations, to 33. The agency based its decision, in part, on the results of laboratory testing, which it used in conjunction with evidence from earlier human clinical trials. The approach provides a pathway for adding additional, rare mutations of the disease, based on laboratory data.

For Immediate Release

May 17, 2017

Release

The U.S. Food and Drug Administration today expanded the approved use of Kalydeco (ivacaftor) for treating cystic fibrosis. The approval triples the number of rare gene mutations that the drug can now treat, expanding the indication from the treatment of 10 mutations, to 33. The agency based its decision, in part, on the results of laboratory testing, which it used in conjunction with evidence from earlier human clinical trials. The approach provides a pathway for adding additional, rare mutations of the disease, based on laboratory data.

“Many rare cystic fibrosis mutations have such small patient populations that clinical trial studies are not feasible,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “This challenge led us to using an alternative approach based on precision medicine, which made it possible to identify certain gene mutations that are likely to respond to Kalydeco.

Cystic fibrosis affects the cells that produce mucus, sweat and digestive juices. These secreted fluids are normally thin and slippery due to the movement of sufficient ions (chloride) and water in and out of the cells. People with the progressive disease have a defective cystic fibrosis transmembrane conductance regulator (CFTR) gene that can’t regulate the movement of ions and water, causing the secretions to become sticky and thick. The secretions build up in the lungs, digestive tract and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes.

Results from an in vitro cell-based model system have been shown to reasonably predict clinical response to Kalydeco. When additional mutations responded to Kalydeco in the laboratory test, researchers were thus able to extrapolate clinical benefit demonstrated in earlier clinical trials of other mutations. This resulted in the addition of gene mutations for which the drug is now indicated.

Kalydeco, available as tablets or oral granules taken two times a day with fat-containing food, helps the protein made by the CFTR gene function better and as a result, improves lung function and other aspects of cystic fibrosis, including weight gain. If the patient’s genotype is unknown, an FDA-cleared cystic fibrosis mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.

Cystic fibrosis is a rare disease that affects about 30,000 people in the United States.Kalydeco is indicated for patients aged 2 and older who have one mutation in the CFTR gene that is responsive to drug treatment based on clinical and/or in vitro (laboratory) data. The expanded indication will affect another 3 percent of the cystic fibrosis population, impacting approximately 900 patients. Kalydeco serves as an example of how successful patient-focused drug development can provide greater understanding about a disease. For example, the Cystic Fibrosis Foundation maintains a 28,000-patient registry, including genetic data, which it makes available for research.

Common side effects of Kalydeco include headache; upper respiratory tract infection (common cold) including sore throat, nasal or sinus congestion, or runny nose; stomach (abdominal) pain; diarrhea; rash; nausea; and dizziness. Kalydeco is associated with risks including elevated transaminases (various enzymes produced by the liver) and pediatric cataracts. Co-administration with strong CYP3A inducers (e.g., rifampin, St. John’s wort) substantially decreases exposure of Kalydeco, which may diminish effectiveness, and is therefore not recommended.

Kalydeco is manufactured for Boston-based Vertex Pharmaceuticals Inc.

BMS 986205


ChemSpider 2D Image | BMS 986205 | C24H24ClFN2Oimg

BMS 986205

(2R)-N-(4-Chlorophenyl)-2-[cis-4-(6-fluoro-4-quinolinyl)cyclohexyl]propanamide
Cyclohexaneacetamide, N-(4-chlorophenyl)-4-(6-fluoro-4-quinolinyl)-α-methyl-, cis-
Cyclohexaneacetamide, N-(4-chlorophenyl)-4-(6-fluoro-4-quinolinyl)-α-methyl-, cis-(αR)-
(i?)-N-(4-chlorophenyl)-2- c 5-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide

CAS: 1923833-60-6

Phase 1 cancer

BMS-986205, ONO-7701,  F- 001287

  • Molecular Formula C24H24ClFN2O
  • Average mass 410.912 Da
  • Originator Bristol-Myers Squibb
  • Class Antineoplastics
  • 01 Feb 2016 Phase-I/II clinical trials in Cancer (Combination therapy, Late-stage disease, Second-line therapy or greater) in Canada (PO) (NCT02658890)
  • 31 Jan 2016 Preclinical trials in Cancer in USA (PO) before January 2016
  • 01 Jan 2016 Bristol-Myers Squibb plans a phase I/IIa trial for Cancer (Late-stage disease, Combination therapy, Second-line therapy or greater) in USA, Australia and Canada (PO) (NCT02658890)
Inventors Hilary Plake Beck, Juan Carlos Jaen, Maksim OSIPOV, Jay Patrick POWERS, Maureen Kay REILLY, Hunter Paul SHUNATONA, James Ross WALKER, Mikhail ZIBINSKY, James Aaron Balog, David K Williams, Jay A MARKWALDER, Emily Charlotte CHERNEY, Weifang Shan, Audris Huang
Applicant Flexus Biosciences, Inc.

Hilary Beck

Hilary Beck

FLX Bio, Inc.EX Principal Investigator, Company NameFLX Bio, Inc., 

CURRENTLY Director, Medicinal Chemistry at IDEAYA Biosciences, IDEAYA Biosciences, The University of Texas at Austin

Image result for Flexus Biosciences, Inc.

Brian Wong

Brian Wong

Chief Executive Officer at FLX Bio, Inc.

Bristol-Myers Squibb, following its acquisition of Flexus Biosciences, is developing BMS-986205 (previously F- 001287), the lead from an immunotherapy program of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors for the potential treatment of cancer. In February 2016, a phase I/IIa trial was initiated .

BMS-986205 (ONO-7701) is being evaluated at Bristol-Myers Squibb in phase I/II clinical trials for the oral treatment of adult patients with advanced cancers in combination with nivolumab. Early clinical development is also ongoing at Ono in Japan for the treatment of hematologic cancer and for the treatment of solid tumors.

In April 2017, data from the trial were presented at the 108th AACR Annual Meeting in Washington DC. As of February 2017, the MTD had not been reached, but BMS-986205 plus nivolumab treatment was well tolerated, with only two patients discontinuing treatment due to DLTs. The most commonly reported treatment-related adverse events (TRAEs) were decreased appetite, fatigue, nausea, diarrhea, and vomiting. Grade 3 TRAEs were reported in three patients during the combination therapy; however, no grade 3 events were reported during BMS-986205 monotherapy lead-in. No grade 4 or 5 TRAEs were reported with BMS-986205 alone or in combination with nivolumab

Indoleamine 2,3-dioxygenase (IDO; also known as IDOl) is an IFN-γ target gene that plays a role in immunomodulation. IDO is an oxidoreductase and one of two enzymes that catalyze the first and rate-limiting step in the conversion of tryptophan to N-formyl-kynurenine. It exists as a 41kD monomer that is found in several cell populations, including immune cells, endothelial cells, and fibroblasts. IDO is relatively well-conserved between species, with mouse and human sharing 63% sequence identity at the amino acid level. Data derived from its crystal structure and site-directed mutagenesis show that both substrate binding and the relationship between the substrate and iron-bound dioxygenase are necessary for activity. A homolog to IDO (ID02) has been identified that shares 44% amino acid sequence homology with IDO, but its function is largely distinct from that of IDO. (See, e.g., Serafini P, et al, Semin. Cancer Biol, 16(l):53-65 (Feb. 2006) and Ball, H.J. et al, Gene, 396(1):203-213 (Jul. 2007)).

IDO plays a major role in immune regulation, and its immunosuppressive function manifests in several manners. Importantly, IDO regulates immunity at the T cell level, and a nexus exists between IDO and cytokine production. In addition, tumors frequently manipulate immune function by upregulation of IDO. Thus, modulation of IDO can have a therapeutic impact on a number of diseases, disorders and conditions.

A pathophysiological link exists between IDO and cancer. Disruption of immune homeostasis is intimately involved with tumor growth and progression, and the production of IDO in the tumor microenvironment appears to aid in tumor growth and metastasis. Moreover, increased levels of IDO activity are associated with a variety of different tumors (Brandacher, G. et al, Clin. Cancer Res., 12(4): 1144-1151 (Feb. 15, 2006)).

Treatment of cancer commonly entails surgical resection followed by chemotherapy and radiotherapy. The standard treatment regimens show highly variable degrees of long-term success because of the ability of tumor cells to essentially escape by regenerating primary tumor growth and, often more importantly, seeding distant metastasis. Recent advances in the treatment of cancer and cancer-related diseases, disorders and conditions comprise the use of combination therapy incorporating immunotherapy with more traditional chemotherapy and radiotherapy. Under most scenarios, immunotherapy is associated with less toxicity than traditional chemotherapy because it utilizes the patient’s own immune system to identify and eliminate tumor cells.

In addition to cancer, IDO has been implicated in, among other conditions, immunosuppression, chronic infections, and autoimmune diseases or disorders (e.g. , rheumatoid arthritis). Thus, suppression of tryptophan degradation by inhibition of IDO activity has tremendous therapeutic value. Moreover, inhibitors of IDO can be used to enhance T cell activation when the T cells are suppressed by pregnancy, malignancy, or a virus (e.g., HIV). Although their roles are not as well defined, IDO inhibitors may also find use in the treatment of patients with neurological or neuropsychiatric diseases or disorders (e.g., depression).

Small molecule inhibitors of IDO have been developed to treat or prevent IDO-related diseases. For example, the IDO inhibitors 1-methyl-DL-tryptophan; p-(3-benzofuranyl)-DL-alanine; p-[3-benzo(b)thienyl]-DL-alanine; and 6-nitro-L-tryptophan have been used to modulate T cell-mediated immunity by altering local extracellular concentrations of tryptophan and tryptophan metabolites (WO 99/29310). Compounds having IDO inhibitory activity are further reported in WO 2004/094409.

In view of the role played by indoleamine 2,3-dioxygenase in a diverse array of diseases, disorders and conditions, and the limitations (e.g., efficacy) of current IDO inhibitors, new IDO modulators, and compositions and methods associated therewith, are needed.

In April 2017, preclinical data were presented at the 108th AACR Annual Meeting in Washington DC. BMS-986205 inhibited kynurenine production with IC50 values of 1.7, 1.1 and > 2000 and 4.6, 6.3 and > 2000 nM in human (HeLa, HEK293 expressing human IDO-1 and tryptophan-2, 3-dioxygenase cell-based assays) and rat (M109, HEK293 expressing mouse ID0-1 and -2 cell-based assays) respectively. In human SKOV-3 xenografts (serum and tumor) AUC (0 to 24h; pharmacokinetic and pharmacodynamic [PK and PD])) was 0.8, 4.2 and 23 and 3.5, 11 and 40 microM h, respectively; area under the effect curve (PK and PD) was 39, 32 and 41 and 60, 63 and 76% kyn, at BMS-986205 (5, 25 and 125 mg/kg, qd×5), respectively

In April 2017, preclinical data were presented at the 253rd ACS National Meeting and Exhibition in San Francisco, CA. BMS-986205 showed potent and selective inhibition of IDO-1 enzyme (IC50 = 1.7nM) and potent growth inhibition in cellular assays (IC50 = 3.4 nM) in SKOV3 cells. A good pharmacokinetic profile was seen at oral and iv doses in rats, dogs and monkeys. The compound showed good oral exposure and efficacy in in vivo assays

Preclinical studies were performed to evaluate the activity of BMS-986205, a potent and selective optimized indoleamine 2, 3-dioxygenase (IDO)- 1inhibitor, for the treatment of cancer. BMS-986205 inhibited kynurenine production with IC50 values of 1.7, 1.1 and > 2000 and 4.6, 6.3 and > 2000 nM in human (HeLa, HEK293 expressing human IDO-1 and tryptophan-2, 3-dioxygenase cell-based assays) and rat (M109, HEK293 expressing mouse ID0-1 and -2 cell-based assays) respectively. BMS-986205 was also found to be potent when compared with IDO-1from other species (human < dog equivalent monkey equivalent mouse > rat). In cell-free systems, incubation of inhibitor lead to loss of heme absorbance of IDO-1 which was observed in the presence of BMS-986205 (10 microM), while did not observed with epacadostat (10 microM). The check inhibitory activity and check reversibility (24 h after compound removal) of BMS-986205 was found to be < 1 and 18% in M109 (mouse) and < 1 and 12% SKOV3 (human) cells, respectively. In human whole blood IDO-1, human DC mixed lymphocyte reaction and human T cells cocultured with SKOV3 cells- cell based assays, BMS-986205 showed potent cellular effects (inhibition of kynurenine and T-cell proliferation 3H-thymidine) with IC50 values of 2 to 42 (median 9.4 months), 1 to 7 and 15 nM, respectively. In human SKOV-3 xenografts (serum and tumor) AUC (0 to 24h; pharmacokinetic and pharmacodynamic [PK and PD])) was 0.8, 4.2 and 23 and 3.5, 11 and 40 microM h, respectively; area under the effect curve (PK and PD) was 39, 32 and 41 and 60, 63 and 76% kyn, at BMS-986205 (5, 25 and 125 mg/kg, qd×5), respectively. In vivo human-SKOV3 and hWB-xenografts, IC50 values of BMS-986205 were 3.4 and 9.4 NM, respectively. The ADME of BMS-986205 at parameters iv/po dose was 0.5/2, 0.5/1.5 and 0.5/1.2 mg/kg, respectively; iv/clearance was 27, 25 and 19 ml, min/kg, respectively; iv Vss was 3.8, 5.7 and 4.1 l/kg, respectively; t1/2 (iv) was 3.9, 4.7 and 6.6 h, respectively; fraction (po) was 64, 39 and 10%, respectively. At the time of presentation, BMS-986205 was being evaluated in combination with nivolumab.

The chemical structure and preclinical profile was presented for BMS-986205 ((2R)-N-(4-Chlorophenyl)-2-[cis-4-(6-fluoroquinolin-4-yl)cyclohexyl]propanamide), a potent IDO-1 inhibitor in phase I for the treatment of cancer. This compound showed potent and selective inhibition of IDO-1 enzyme (IC50 = 1.7nM) and potent growth inhibition in cellular assays (IC50 = 3.4 nM) in SKOV3 cells. The pharmacokinetic profile in rats dosed at 0.5 mg/kg iv and 2 mg/kg po, with clearance, Vss, half-life and bioavailability of 27 ml/min/kg, 3.8 l/kg, 3.9 h and 4%, respectively; in dogs at 0.5 iv and 1.5 po mg/kg dosing results were 25 ml/min/kg, 5.7 l/kg, 4.7 h and 39%; and, in cynomolgus monkeys with the same doses as dogs results were 19 ml/min/kg, 4.1 l/kg, 6.6 h and 10%, respectively. The compound showed good oral exposure and efficacy in in vivo assays.

BMS-986158: a BET inhibitor for cancerAshvinikumar Gavai of Bristol Myers Squibb (BMS) gave an overview of his company’s research into Bromodomian and extra-terminal domain (BET) as oncology target for transcriptional suppression of key oncogenes, such as MYC and BCL2. BET inhibition has been defined as strong rational strategy for the treatment of hematologic malignancies and solid tumors. From crystal-structure guided SAR studies, BMS-986158, 2-{3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol, was chosen as a potent BET inhibitor, showing IC50 values for BRD2, BRD3 and BRD4 activity of 1 nM; it also inhibited Myc oncogene (IC50 = 0.5 nM) and induced chlorogenic cancer cell death. In vitro the compound also displayed significant cytotoxicity against cancer cells.  When administered at 0.25, 0.5 and 1 mg/kg po, qd to mice bearing human lung H187 SCLC cancer xenograft, BMS-986158 was robust and showed efficacy as a anticancer agent at low doses. In metabolic studies, it showed t1/2 of 36, 40 and 24 min in human, rat and mice, respectively, and it gave an efflux ratio of 3 in Caco-2 permeability assay. In phase 1/II studies, BMS-986158 was well tolerated at efficacious doses and regimens, and drug tolerable toxicity at efficacy doses and regimens. Selective Itk inhibitors for inflammatory disordersThe development of highly selective Itk inhibitors for the treatment of diseases related to T-cell function, such as inflammatory disorders, was described by Shigeyuki Takai (Ono Pharmaceutical). Inhibitory properties of a hit compound, ONO-8810443, were modified via X-ray structure and Molecular Dynamics stimulation to get ONO-212049 with significant kinase selectivity (140-fold) against Lck, a tyrosine kinase operating upstream of Itk in the TCR cascade. Further modifications identified final lead compound ONO-7790500 (N-[6-[3-amino-6-[2-(3-methoxyazetidin-1-yl)pyridin-4-yl]pyrazin-2-yl]pyridin-3-yl]-1-(3-methoxyphenyl)-2,3-dimethyl-5-oxopyrazole-4-carboxamide), which selectively inhibited Itk (IC50 = < 0.004 microM) over Lck (IC50 = 9.1 microM; SI 2000-fold) and suppressed Jurkat T-cell proliferation (IC50 = 0.014 microM). This compound suppressed alphaCD3/CDP28 CD4+T-cell stimulation (IC50 = 0.074 microM) with selectivity over PMA/Ionomycin (IC50 = > 10 microM). ONO-7790500 also exhibited in vivo IL-2 inhibitory properties (62% inhibition at 30 mg/kg po) in mice. In pharmacokinetic studies in balb/c mice, the compound administered orally (10 mg/kg) showed a Cmax of 1420 ng/ml, AUClast of 11,700 ng*h/ml, t1/2 of 5.3 h and oral bioavailability of 68%. Administration iv at 0.3 mg/kg gave an AUC last of 610 ng*h/ml, t1/2 of 3.8 h, Vss of 1260 ml/kg and Cl of 5.1 ml/min/kg. ADMET data showed ONO-7790500 did not have relevant activity in cytochromes and hERG channels (IC50 > 10 microM) in toxicological studies, and gave a PAMPA value of 5.0 x 10(-6) cm/s. Fused imidazole and pyrazole derivatives as TGF-beta inhibitorsDual growth and differentiation factor-8 (GDF-8; also known as myostatin) and TGF-beta inhibitors were described. Both targets belong to TGF-beta superfamily consisting of a large group of structurally related cell regulatory proteins involved in fundamental biological and pathological processes, such as cell proliferation or immunomodulation. Myostatin (GDF8) is a negative regulator negative regulator of skeletal muscle growth and has also been related to bone metabolism. Investigators at Rigel Pharmaceuticals found that compounds designed to be GDF-8 inhibitors were able to inhibit TGF-beta as well, this could be an advantage for the treatment of diseases associated with muscle and adipose tissue disorders, as well as potentially immunosuppressive disorders. Jiaxin Yu from the company described  new fused imidazole derivatives, of which the best compound was 6-[2-(2,4,5-Trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl]quinoxaline. This compound was very potent at TGF-beta Receptor Type-1 (ALK5) inhibition with an IC50 value of 1nM. In an in vivo mouse assay this compound showed good activity at 59.7 mg/kg, po, and good plasma exposure; inhibition of GDF-8 and TGFbeta growth factors was 90 and 81.6 %, respectively.Rigel’s Ihab Darwish described a series of fused pyrazole derivatives, with the best compound being 6-[2-(2,4-Difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl][1,2,4]triazolo[1,5-a]pyridine. This compound showed an IC50 of 0.06 and 0.23 microM for GDF-8 and TGFbeta, respectively, in the pSMAD (MPC-11) signaling inhibition test. The compound had a good pharmacokinetic profile, with 40% of bioavailability in mice after a 5-mg/kg po dose. An iv dose of 1 mg/kg showed t1/2 of 0.7 h and Vss of 1.0 l/h/kgDiscovery of selective inhibitor of IDO BMS-986205 for cancerIndoleamine-2,3-dioxygenase (IDO)-1 enzyme initiates and regulates the first step of the kynurenine pathway (KP) of tryptophan metabolism, and evidence has shown that overexpression of IDO-1 in cancer tumors is a crucial mechanism facilitating tumor immune evasion and persistence. The chemical structure and preclinical profile of BMS-986205 was presented by Aaron Balog from BMS. BMS-986205 ((2R)-N-(4-Chlorophenyl)-2-[cis-4-(6-fluoroquinolin-4-yl)cyclohexyl]propanamide),  is a potent IDO-1 inhibitor in phase I for the treatment of cancer. This compound showed potent and selective inhibition of IDO-1 enzyme (IC50 = 1.7nM) and potent growth inhibition in cellular assays (IC50 = 3.4 nM) in SKOV3 cells. The pharmacokinetic profile in rats dosed at 0.5 mg/kg iv and 2 mg/kg po, with clearance, Vss, half-life and bioavailability of 27 ml/min/kg, 3.8 l/kg, 3.9 h and 4%, respectively; in dogs at 0.5 iv and 1.5 po mg/kg dosing results were 25 ml/min/kg, 5.7 l/kg, 4.7 h and 39%; and, in cynomolgus monkeys with the same doses as dogs results were 19 ml/min/kg, 4.1 l/kg, 6.6 h and 10%, respectively. The compound showed good oral exposure and efficacy in in vivo assays.Three further reports have been published from this meeting .The website for this meeting can be found at https://www.acs.org/content/acs/en/meetings/spring-2017.html.

SYNTHESIS

1 Wittig  NaH

2 REDUCTION H2, Pd, AcOEt, 4 h, rt, 50 psi

3 Hydrolysis HCl, H2O, Me2CO, 2 h, reflux

4  4-Me-2,6-(t-Bu)2-Py, CH2Cl2, overnight, rt

5 SUZUKI AcOK, 72287-26-4, Dioxane, 16 h, 80°C

6  Heck Reaction,  Suzuki Coupling, Hydrogenolysis of Carboxylic Esters, Reduction of Bonds, HYDROGEN

7 Et3N, THF, rt – -78°C , Pivaloyl chloride, 15 min, -78°C; 1 h, 0°C ,THF, 0°C – -78°C, BuLi, Me(CH2)4Me, 15 min, -78°C, R:(Me3Si)2NH •Na, THF, 10 min, -50°C , HYDROLYSIS,  (PrP(=O)O)3, C5H5N, AcOEt, 5 min, rt

Patent

WO2016073770

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=289DBE79BEFC6ADC558C89E7A74B19DB.wapp2nB?docId=WO2016073770&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 19

(i?)-N-(4-chlorophenyl)-2- c 5-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide

Example 19 : (i?)-N-(4-chlorophenyl)-2-(cz5-4-(6-fluoroquinolin-4- yl)cyclohexyl)propanamide

[0277] Prepared using General Procedures K, B, E, L, M, N, and O. General Procedure L employed 2-(4-(6-fluoroquinolin-4-yl)-cyclohexyl)acetic acid (mixture of

diastereomers), and ( ?)-2-phenyl-oxazolidinone. General Procedure M employed the cis product and iodomethane. The auxiliary was removed following General Procedure N and the desired product formed employing General Procedure O with 4-chloroaniline.

Purified using silica gel chromatography (0% to 100% ethyl acetate in hexanes) to afford Example 19. 1H NMR of czs-isomer (400 MHz; CDC13): δ 9.14 (s, 1H), 8.70 (d, J= 4.6 Hz, 1H), 8.06 (dd, J= 9.2 Hz, J= 5.6 Hz, 1H), 7.58-7.64 (m, 3H), 7.45 (ddd, J= 9.3 Hz, J= 7.8 Hz, J= 2.7 Hz, 1H), 7.19-7.24 (m, 2H), 7.15 (d, J= 4.6Hz, 1H), 3.16-3.26 (m, 1H), 2.59-2.69 (m, 1H), 2.08-2.16 (m, 1H), 1.66-1.86 (m, 7H), 1.31-1.42 (m, 1H), 1.21 (d, J= 6.8Hz, 3H) ppm. m/z 411.2 (M+H)+.

REFERENCES

23-Feb-2015
Bristol-Myers Squibb To Expand Its Immuno-Oncology Pipeline with Agreement to Acquire Flexus Biosciences, Inc
Bristol-Myers Squibb Co; Flexus Biosciences Inc

17-Dec-2014
Flexus Biosciences, a Cancer Immunotherapy Company Focused on Agents for the Reversal of Tumor Immunosuppression (ARTIS), Announces $38M Financing
Flexus Biosciences Inc

2015106thApril 21Abs 4290
Potent and selective next generation inhibitors of indoleamine-2,3-dioxygenase (IDO1) for the treatment of cancer
American Association for Cancer Research Annual Meeting
Jay P. Powers, Matthew J. Walters, Rajkumar Noubade, Stephen W. Young, Lisa Marshall, Jan Melom, Adam Park, Nick Shah, Pia Bjork, Jordan S. Fridman, Hilary P. Beck, David Chian, Jenny V. McKinnell, Maksim Osipov, Maureen K. Reilly, Hunter P. Shunatona, James R. Walker, Mikhail Zibinsky, Juan C. Jaen

2017108thApril 04Abs 4964
Structure, in vitro biology and in vivo pharmacodynamic characterization of a novel clinical IDO1 inhibitor
American Association for Cancer Research Annual Meeting
John T Hunt, Aaron Balog, Christine Huang, Tai-An Lin, Tai-An Lin, Derrick Maley, Johnni Gullo-Brown, Jesse Swanson, Jennifer Brown

2017253rdApril 05Abs MEDI 368
Discovery of a selective inhibitor of indoleamine-2,3-dioxygenase for use in the therapy of cancer
American Chemical Society National Meeting and Exposition
Aaron Balog

April 2-62017
American Chemical Society – 253rd National Meeting and Exhibition (Part IV) – OVERNIGHT REPORT, San Francisco, CA, USA
Casellas J, Carceller V

Juan Jaen

Juan Jaen

Jordan Fridman

Jordan Fridman

Chief Scientific Officer at FLX Bio, Inc.

Rekha Hemrajani

Rekha Hemrajani

Chief Operating Officer at FLX Bio, Inc

Max Osipov

Max Osipov

////////////////PHASE 1, BMS 986205, 1923833-60-6, BMS-986205, ONO-7701,Bristol-Myers Squibb,  Antineoplastics,  F- 001287

 C[C@H]([C@H]1CC[C@@H](C2=CC=NC3=CC=C(F)C=C23)CC1)C(NC4=CC=C(Cl)C=C4)=O

Wrapping up ‘s 1st time disclosures is Aaron Balog of @bmsnews talking about an IOD-1 inhibitor to treat cancer

str0

USA Viewership touched 3 lakhs on New Drug Approvals


str0

USA Viewership touched 3 lakhs on New Drug Approvals

https://newdrugapprovals.org/

Total 16.9 lakhs in 213 countries

Metopimazine


Metopimazine.svg

Metopimazine

RP-9965, EXP-999, NG-101

l-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide

CAS 14008-44-7
MF C22 H27 N3 O3 S2
MW 445.60
4-Piperidinecarboxamide, 1-[3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl]-
  • Isonipecotamide, 1-[3-[2-(methylsulfonyl)phenothiazin-10-yl]propyl]- (7CI,8CI)
  • 1-[3-[2-(Methylsulfonyl)-10H-phenothiazin-10-yl]propyl]-4-piperidinecarboxamide
  • 1-[3-[2-(Methylsulfonyl)phenothiazin-10-yl]propyl]-4-piperidinecarboxamide
  • 1-[3-[2-(Methylsulfonyl)phenothiazin-10-yl]propyl]isonipecotamide
  • 2-Methylsulfonyl-10-[3-(4-carbamoylpiperidino)propyl]phenothiazine
  • EXP 999
  • Metopimazine
  • RP 9965
  • Vogalene
  • metopimazine (gastroparesis), Neurogastrx

Sanofi (Originator)
Teva

Treatment of Nausea and Vomiting, APPROVED

Dopamine D3 receptor antagonist; Dopamine D2 receptor antagonist

Gastroprokinetic

Metopimazine (INN) is a phenothiazine antiemetic.

Metopimazine is an established antiemetic that has been approved and marketed for many years in Europe for the treatment of acute conditions. The compound does not cross the blood-brain-barrier, and is therefore free from central side effects, and is not associated with cardiovascular side effects

In May 2016, preclinical data were presented at the 2016 DDW in San Diego, CA. In rats, po NG-101 and domperidone did not penetrate the brain at therapeutically relevant concentrations, unlike metoclopramide. In dogs, the amplitude and frequency of antral contractions were increased by NG-101, whereas in rats, po metopimazine resulted in an increase in gastric emptying of solid foods. The blood-brain barrier was not readily crossed and there was no interaction with 5-HT3 or 5-HT4 receptors by NG-101 unlike metoclopramide and domperidone, respectively

Neurogastrx is investigating repurposed metopimazine (NG-101), a selective and peripherally restricted dopamine D2/D3 receptor antagonist, for the potential oral treatment of gastroparesis. By July 2014, preclinical studies were underway . SE BELOW REF

WO-2014105655: Methods for treating GI tract disorders
In May 2016, preclinical data were presented [SEE BELOW].

2016 May 24Abs 1079
NG101: A Potent and Selective Dopamine D2 Receptor Antagonist as a Potential Alternative to Metoclopramide and Domperidone for the Treatment of Gastroparesis
Digestive Disease Week
Cyril De Colle, Marieke van der Hart, Jiande Chen, Arash Rassoulpour, Pankaj J Pasricha

In July 2014, preclinical data were published. Metopimazine at 1mg/kg increased gastric motility in hound dogs. In studies in rodents, metopimazine at 3 and 10 mg/kg increased gastric emptying by 18 and 40%, respectively, compared with vehicle control

There is an increasing demand for antiemetic agents because of the most troublesome adverse effects of chemotherapy-induced nausea and emesis during cancer treatment.

However, the objective of complete prevention of emesis in all patients remains elusive. Therefore, there is a great demand for both development of (i) new antiemetic agents and (ii) new manufacturing processes for existing antiemetic agents. Metopimazine is an existing dopamine D2-receptor antagonist with potent antiemetic properties. It is chemically known as l-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide , which belongs to nitrogen- and sulfur-containing tricyclic compounds (phenothiazine class of drugs) with interesting biological and pharmacological activities.

Recently, it has been found that Metopimazine plays a key role as an alternative to Ondansetron in the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderate to high emetogenic noncisplatin-based chemotherapy.It has been used in France for many years for the prevention and treatment of nausea and vomiting under the brand name of Vogalene

In 1959, the first synthesis and manufacture process of Metopimazine  was reported by Jacob et al.The synthesis starts from the protection of 2-(Methylsulfanyl)-10H-phenothiazine..Jacob, R. M.; Robert, J. G. German Patent No. DE1092476, 1959.

Later, in 1990, Sindelar et al. reported a modified process , which starts from synthesis of 4-(2-fluorophenylthio)-3-nitrophenylmethylsulfone..Sindelar, K.; Holubek, J.; Koruna, I.; Hrubantova, M.; Protiva, M. Collect. Czech. Chem. Commun. 1990, 55, 15861601, DOI: 10.1135/cccc19901586

In 2010, Satyanarayana Reddy et al. reported a modified synthetic route which starts from either N-protection using acetyl chloride or N-alkylation using dihalopropane of 2-(methylsulfanyl)-10H-phenothiazine ..Satyanarayana Reddy, M.; Eswaraiah, S.; Satyanarayana, K. Indian Patent No. 360/CHE/2010 A, Aug 19, 2011.

Synthesis of 1-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)piperidine-4- carboxamide (1)-Metopimazine: Pale yellow color solid, yield. 65% (82 g), DSC 189 °C.

str1 str2 str3

1H NMR (400 MHz, DMSO-d6, δ/ppm): 7.44 (d, 1H, arom H, J = 8.8 Hz), 7.37 (d, 2H, arom H, J = 8.0 Hz), 7.24 (t, 1H, arom H, J = 7.6 Hz), 7.16 (m, 2H, -NH2), 7.1 (d, 1H, arom H, J = 8.4 Hz), 6.99 (t, 1H, arom H, J = 7.6 Hz), 6.68 (s, 1H, arom H), 3.99 (t, 2H, -NCH2, J = 6.4 Hz), 3.23 (s, 3H, -S-CH3), 2.8-2.73 (m, 2H, -CH2-), 2.36 (t, 2H, -CH2-, J = 6.8 Hz), 2.02-1.96 (m, 1H, -CH-), 1.84-1.78 (m, 4H, 2-CH2-), 1.61-1.58 (m, 2H, -CH2-), 1.48-1.44 (m, 2H, – CH2-).

13C NMR (100 MHz, DMSO-d6, δ/ppm): 176.52, 145.41, 143.5, 140.12, 130.47, 128.03, 127.50, 127.25, 123.23, 122.16, 120.59, 116.38, 113.24, 54.82, 52.97, 44.64, 43.47, 41.7, 28.59, 23.52.

MS m/z (ESI): 446.21 (M+H)+.

SYNTHESIS

ChemSpider 2D Image | Metopimazine | C22H27N3O3S2

Image result for Metopimazine, SYNTHESIS

PATENT

IN 201641043070

IN 2013CH05689

IN 2013CH00361

IN 2010CH00360

DE 1092476/US 3130194

PAPER

A Simple and Commercially Viable Process for Improved Yields of Metopimazine, a Dopamine D2-Receptor Antagonist

Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, Fourth Phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore, Karnataka 560 105, India
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00052
*E-mail: pramodkumar@microlabs.in. Tel: 0811 0415647, ext. 245. Mobile No.: +91 9008448247., *E-mail: gmadhusudanrao@yahoo.com.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.7b00052

Abstract Image

An efficient, practical, and commercially viable manufacturing process was developed with ≥99.7% purity and 31% overall yield (including four chemical reactions and one recrystallization) for an active pharmaceutical ingredient, called Metopimazine (1), an antiemetic drug used to prevent emesis during chemotherapy. The development of two in situ, one-pot methods in the present synthetic route helped to improve the overall yield of 1 (31%) compared with earlier reports (<15%). For the first time, characterization data of API (1), intermediates, and also possible impurities are presented. The key process issues and challenges were addressed effectively and achieved successfully.

Synthesis of 1-(3-[2-(Methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide (1), Metopimazine

In ………………….. The obtained compound (1) was dried in a hot air oven at 50 °C.
Pale yellow color solid, yield. 65% (82 g),
DSC 189 °C.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 7.44 (d, 1H, arom H, J = 8.8 Hz), 7.37 (d, 2H, arom H, J = 8.0 Hz), 7.24 (t, 1H, arom H, J = 7.6 Hz), 7.16 (m, 2H, −NH2), 7.1 (d, 1H, arom H, J = 8.4 Hz), 6.99 (t, 1H, arom H, J = 7.6 Hz), 6.68 (s, 1H, arom H), 3.99 (t, 2H, −NCH2, J = 6.4 Hz), 3.23 (s, 3H, −S–CH3), 2.8–2.73 (m, 2H, −CH2−), 2.36 (t, 2H, −CH2–, J = 6.8 Hz), 2.02–1.96 (m, 1H, −CH−), 1.84–1.78 (m, 4H, 2–CH2−), 1.61–1.58 (m, 2H, −CH2−), 1.48–1.44 (m, 2H, −CH2−).
13C NMR (100 MHz, DMSO-d6, δ/ppm): 176.52, 145.41, 143.5, 140.12, 130.47, 128.03, 127.50, 127.25, 123.23, 122.16, 120.59, 116.38, 113.24, 54.82, 52.97, 44.64, 43.47, 41.7, 28.59, 23.52.
MS m/z (ESI): 446.21 (M + H)+.
 
Regulatory
  • Vogalene
  • metopimazina (Italian, Portuguese)
  • metopimazin (Danish, Swedish)
  • metopimazine (Dutch)
  • metopimatsiini (Finnish)

Regulatory List Number

  • EC No.: 237-818-4
  • EINECS No.: 237-818-4
  • Harmonized Tariff Code

    293430

REFERENCES
Metopimazine
Metopimazine.svg
Clinical data
AHFS/Drugs.com International Drug Names
ATC code
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
ECHA InfoCard 100.034.367
Chemical and physical data
Formula C22H27N3O3S2
Molar mass 445.6 g/mol
3D model (Jmol)

//////////////Metopimazine, Dopamine D2-Receptor Antagonist, 14008-44-7, sanofi, teva, RP-9965, Nausea and Vomiting, EXP-999, NG-101, metopimazine, gastroparesis, Neurogastrx

NC(=O)C1CCN(CC1)CCCN2c4ccccc4Sc3ccc(cc23)S(C)(=O)=O

FDA approves drug to treat ALS, Radicava (Edaravone) , эдаравон, إيدارافون , 依达拉奉 ,ラジカット,


Edaravone.svg

05/05/2017
The U.S. Food and Drug Administration today approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease.

May 5, 2017

Release

The U.S. Food and Drug Administration today approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease.

“After learning about the use of edaravone to treat ALS in Japan, we rapidly engaged with the drug developer about filing a marketing application in the United States,” said Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This is the first new treatment approved by the FDA for ALS in many years, and we are pleased that people with ALS will now have an additional option.”

ALS is a rare disease that attacks and kills the nerve cells that control voluntary muscles. Voluntary muscles produce movements such as chewing, walking, breathing and talking. The nerves lose the ability to activate specific muscles, which causes the muscles to become weak and leads to paralysis. ALS is progressive, meaning it gets worse over time. The Centers for Disease Control and Prevention estimates that approximately 12,000-15,000 Americans have ALS. Most people with ALS die from respiratory failure, usually within three to five years from when the symptoms first appear.

Radicava is an intravenous infusion given by a health care professional. It is administered with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period. Subsequent treatment cycles consist of dosing on 10 of 14 days, followed by 14 days drug-free.

The efficacy of edaravone for the treatment of ALS was demonstrated in a six-month clinical trial conducted in Japan. In the trial, 137 participants were randomized to receive edaravone or placebo. At Week 24, individuals receiving edaravone declined less on a clinical assessment of daily functioning compared to those receiving a placebo.

The most common adverse reactions reported by clinical trial participants receiving edaravone were bruising (contusion) and gait disturbance.

Radicava is also associated with serious risks that require immediate medical care, such as hives, swelling, or shortness of breath, and allergic reactions to sodium bisulfite, an ingredient in the drug. Sodium bisulfite may cause anaphylactic symptoms that can be life-threatening in people with sulfite sensitivity.

The FDA granted this drug orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Radicava to Mitsubishi Tanabe Pharma America, Inc,

ChemSpider 2D Image | Edaravone | C10H10N2O

1-Phenyl-3-methyl-5-pyrazolone
3H-Pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl- [ACD/Index Name]
89-25-8 [RN]
эдаравон [Russian]
إيدارافون [Arabic]
依达拉奉 [Chinese]
ラジカット,
MCI-186

Edaravone (brand name ラジカット, Radicut) is a nootropic and neuroprotective agent used for the purpose of aiding neurological recovery following acute brain ischemia and subsequent cerebral infarction.[1] It acts as a potent antioxidant and strongly scavenges free radicals, protecting against oxidative stress and neuronal apoptosis.[2][3][4] It has been marketed solely in Japan by Mitsubishi Pharma since 2001.[1] It is also marketed in India by Edinburgh Pharmaceuticals by the brand name Arone.

On June 26, 2015, Mitsubishi Tanabe Pharma Corporation announced it has received approval to market Radicut for treatment of ALS in Japan. The phase III clinical trial began in 2011 in Japan. The company was awarded Orphan Drug Designation for Radicut by the FDA and EU in 2015. Radicut is an intravenous drug and administrated 14 days followed by 14 days drug holiday.

The biotech company Treeway is developing an oral formulation of edaravone (TW001) and is currently in clinical development. Treeway was awarded orphan drug designation for edaravone by the EMA in November 2014 and FDA in January 2015.

Edaravone has been shown to attenuate methamphetamine– and 6-OHDA-induced dopaminergic neurotoxicity in the striatum and substantia nigra, and does not affect methamphetamine-induced dopamine release or hyperthermia.[5][6] It has also been demonstrated to protect against MPTP-mediated dopaminergic neurotoxicity to the substantia nigra, though notably not to the striatum.[7][8][9]

Image result for edaravone synthesis

Edaravone (CAS NO.: 89-25-8), with other name of 3-Methyl-1-phenyl-2-pyrazolin-5-one, could be produced through many synthetic methods.

Following is one of the synthesis routes: By direct cyclization of phenylhydrazine (I) with ethyl acetoacetate (II) in refluxing ethanol.

SYNTHESIS

Edaravone, chemical name: 3-methyl-1-phenyl-2-pyrazoline-5-one, of the formula: Formula: CiciHltlN2O, molecular weight: 174.20, the formula:

 

Figure CN101830852BD00031

[0004] Edaravone is a brain-protecting agent (free radical scavenger). Clinical studies suggest that N- acetyl aspartate (NAA) is a specific sign of the survival of nerve cells, dramatically reducing the initial content of cerebral infarction. In patients with acute cerebral infarction Edaravone suppressed reduce peri-infarct regional cerebral blood flow, so that the first concept of days after the onset of brain NAA glycerol content than the control group significantly increased. Preclinical studies suggest that rats after ischemia / reperfusion of ischemic intravenous edaravone, can prevent the progress of cerebral edema and cerebral infarction, and relieve the accompanying neurological symptoms, suppress delayed neuronal death. Mechanism studies suggest that edaravone can scavenge free radicals, inhibiting lipid peroxidation, thereby inhibiting brain cells, endothelial cells, oxidative damage nerve cells.

For the synthesis of edaravone reported some use of benzene and methyl ethyl ketone amide corpus obtained, but methyl ethyl ketone amide difficult to obtain and slow reaction, which now has basically been abandoned; some use benzene corpus and ethyl acetoacetate in ethanol (see US4857542A, Synthesis Example 1) or water (Dykhanov NN Ethyl and butyl acetoacetates, Med Prom SSSR, 1961,15 (1):. 42-45) refluxing the reaction of the reaction The resulting purity edaravone poor, and the yield is not high, only about 70%.

Edaravone, chemical name: 2,4_-dihydro-5-methyl-2-phenyl pyrazole -3H- – one, of the formula: CiciHltlN2O, molecular weight: 174.20, the formula:

Figure CN102285920BD00031

edaravone is a clear cerebral infarction harmful factors (free radicals), protection of new therapeutic agents for cerebral infarction nerve cells. Clinical studies have shown that N- acetyl aspartate (NAA) is a specific sign of the survival of nerve cells, dramatically reducing the initial content of cerebral infarction. When patients with acute cerebral infarction Edaravone, peri-infarct rCBF decrease has improved, and the first 28 days after the onset of brain NAA content was significantly higher than that in the control group glycerol. Mechanism studies suggest that edaravone can clear the brain is highly cytotoxic hydroxyl radicals, inhibiting the synthesis of lipids free radicals, which can suppress brain infarction after reperfusion edema, protecting brain from damage and improve nerve impairment symptoms, and the delayed neuronal death inhibition, to protect the brain.

 The first is by phenylhydrazine and methyl ethyl ketone amide (National API process compilation, 1980.737-739) condensation reaction in water at 50 ° C, a yield of up to 97%, but the raw material ketone amide ( CH3C0CH2C0NH2) are not readily available. Formula I

Edaravone synthetic route for the reaction:

Figure CN102285920BD00032

[0008] The second is to phenylhydrazine and ethyl acetoacetate in ethanol or water at reflux the reaction, sodium bisulfite as the preparation of the catalyst. From the perspective of the chemical reaction, acetyl ethyl ketone amide more than hydrazine reacted with benzene and ethyl acetoacetate more readily available, the price is cheaper, but lower reaction yield of about 70%. Formula 2 for the synthesis route Edaravone reaction formula:

Figure CN102285920BD00041

PATENT

https://www.google.com/patents/CN101830852B?cl=en

Figure CN101830852BD00041

1 Edaravone Synthesis Example [0023] Example

[0024] (1) Weigh benzene hydrochloride corpus 13. 5g (94mmol), was added to IOOml water, stirred for 0.5 hours, sodium hydroxide was added an equimolar 3. 76g, stirred for 0.5 hours; [0025] ( 2) To the reaction solution was added dropwise ethyl acetoacetate 11. 7g (90mmol), the reaction exotherm, the reaction was heated to reflux for 2.5 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 15. 5g;

[0026] (3) The crude product was added 30ml volume ratio of 2: 1 isopropanol – water, 2g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature a white solid was precipitated to give 14 a white crystalline powder. 8g, yield 90%, mpU9 ° C, with a purity of 99.9% 0

2 Edaravone Synthesis Example [0027] Example

[0028] (1) Weigh 15g of benzene hydrochloride corpus (I (Mmmol), was added to 120ml of water and stirred for 0.5 hours, sodium hydroxide was added an equimolar 4. 16g, stirred for 0.5 hours;

[0029] (2) To the reaction solution was added dropwise 13g of ethyl acetoacetate (lOOmmol), the reaction exotherm, the reaction was heated to reflux for 2.5 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 16. 7g;

(3) The crude product was added 40ml volume ratio of 2: 1 isopropanol – water, 2. 5g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature to precipitate a white solid, as a white crystalline powder 16. lg, a yield of 88.9%, mpU8 ° C, with a purity of 99.9% 0

3 Edaravone Synthesis Example [0031] Example

[0032] (1) Weigh 22g of benzene hydrochloride corpus (152mm0l), was added to 200ml of water and stirred for 0.5 hours, sodium hydroxide was added an equimolar 6. 08g, stirred for 0.5 hours;

[0033] (2) To the reaction solution was added dropwise 19g of ethyl acetoacetate (146mm0l), the reaction exotherm, the reaction was heated to reflux for 3 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 24. Sg;

[0034] (3) The crude product was added 50ml volume ratio of 2: 1 isopropanol – water, 3g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature a white solid was precipitated to give 23 a white crystalline powder. 2g, a yield of 87. 8%, mpU8 ° C, with a purity of 99.9% 0

[0035] Comparative Example

[0036] The ethyl acetoacetate 65g (0. 5mol) and 180ml of anhydrous ethanol mixed, with stirring at 50 ° C was added dropwise benzyl corpus 54g (0. 5mol) and a solution consisting of 30ml absolute ethanol, dropwise at reflux for 2 Bi hours, ethanol was distilled off 60ml, cooled, suction filtered, washed crystals with cold absolute ethanol twice, and dried in vacuo to give pale yellow crystals 70g. Recrystallized twice from absolute ethanol to give pale yellowish white crystals 56g (yield 65%).

PATENT

https://www.google.com/patents/CN102285920B?cl=en

Example 1: Preparation of phenylhydrazine edaravone.

[0024] a. Weigh 5.1g phenylhydrazine (47mmol), was added under stirring to water containing 45mL round-bottom flask, take appropriate concentrated hydrochloric acid solution was adjusted to pH 6.0 with PH meter.

[0025] b. To the above solution was slowly added dropwise ethyl acetoacetate 5.85g (45mmol), the reaction exotherm, was added 1.5g sodium dithionite (Na2S2O6), heated to 105 ° C to room temperature until reflux After 3h, heating was stopped, and then stirred, cooling, filtration, and dried to give a pale yellow granular edaravone crude.

[0026] c. With anhydrous ethanol recrystallization, filtration, and dried to obtain a white crystalline powder that is refined edaravone, 85% yield, 99.2% purity 0

[0027] Example 2: Preparation of phenylhydrazine hydrochloride edaravone.

[0028] a. Weigh 6.8g phenylhydrazine hydrochloride (47mmol), was added under stirring to water containing 45mL round-bottomed flask, the pH of the solution adjusted to 6.0 with aqueous ammonia.

[0029] b. To the above solution was slowly added dropwise ethyl acetoacetate 5.85g (45mmol), the reaction exotherm, 1.25g was added sodium dithionite (Na2S2O6), heated to 105 ° C to room temperature until reflux After 3h, heating was stopped, and then stirred, cooling, filtration, and dried to give a pale yellow granular edaravone crude.

[0030] c. With anhydrous ethanol recrystallization, filtration, and dried to obtain a white crystalline powder that is refined edaravone, 84% yield, with a purity of 99.2%. [0031] Comparative Example:

Under the [0032] state of agitation will phenylhydrazine 10.2g (94mmol) added to a round bottom flask equipped with IOOmL water in an appropriate amount of concentrated hydrochloric acid was dubbed the volume ratio of 1: 1 aqueous hydrochloric acid, with a PH adjusting pH of the solution was measured 6.0. After weighing Ethylacetoacetate 11.7g (90mmol) added to the reaction mixture, the reaction was exothermic and cooling to room temperature, sodium bisulfite (NaHSO3), heated to 105 ° C under reflux for 3h, the hot solution Water was added into the beaker and mechanical stirring, cooling, filtration, and dried to give the yellow edaravone crude, 73% yield, with a purity of 99.1%.

Figure CN102285920BD00042

CLIP

http://www.rsc.org/suppdata/books/184973/9781849739634/bk9781849739634-chapter%204.2.3.pdf

Edaravone:

IR (KBr) max/cm-1 : 3431, 3129, 1602, 1599, 1580;

1 H NMR (300 MHz, CDCl3): δ 7.86 (d, J = 7.5 Hz, 2H, ArH), 7.40 (m, 2H, ArH), 7.18 (m, 1H, ArH), 3.41 (d, J =0.6 Hz, 2H, CH2), 2.19 (s, 3H, CH3);

13C NMR (75 MHz, CDCl3): 170.6, 156.4, 130.1, 128.8, 125.0, 118.9, 43.1, 17.0;

1 H NMR (300 MHz, DMSO-d6): δ 11.5 (bs, 1H, NH), 7.71 (m, 2H, ArH), 7.40 (m, 2H, ArH), 7.22 (m, 1H, ArH), 5.36 (s, 1H, CH), 2.12 (s, 3H, CH3);

13C NMR (75 MHz, DMSO-d6):171.7, 158.9, 148.7, 139.2, 138.6, 129.3,125.4, 124.8, 118.4, 43.5, 17.1, 14.2.

These values are in accordance with the previous published in literature1 .

In the carbon spectrum in DMSO presented in Figure SM 4.2.3.1.8 is evident the presence of the two major tautomeric structures of edaravone, signals are identified by different colours in both structures in the figure. Also in the IR analysis of the solid material (Figure SM 4.2.3.1.9) is possible to see either the NH form (max/cm-1, 3129), the OH form (max/cm- 1 , 3431) and the C=O (max/cm-1, 1599) of the enol and keto tautomeric forms of edaravone.

1. S. Pal, J. Mareddy and N. S. Devi, J.  Braz. Chem. Soc., 2008, 19, 1207.

CLIP

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532008000600023

We have shown that the short reaction time, in combination with good yields can make microwave assisted reaction of hydrazines with β-ketoesters ideal for a rapid entry to pyrazolones. All the compounds synthesized are characterized by spectroscopic (1H NMR, IR and MS) data. While determination of tautomeric composition of compound 3 is quite challenging as eight possible tautomeric forms need to be considered, interestingly, two major tautomeric forms of compound 3a was observed in two different solvents. For example, it exists as 1,2-dihydro pyrazolone (T-1Figure 2) in DMSO and 2,4-dihydro form (T-2Figure 2) in chloroform as indicated by 1H NMR spectra (Figure 3). The olefinic proton of T-1 appeared at 5.36 δ whereas the methylene hydrogens appeared at 3.43 δ in case of T-2. Additionally, the NH proton of T-1 at 11.40 δ was not observed incase of T-2 confirmed the absence of NH in the 2,4-dihydro form. Existence of two major tautomeric forms was also observed in case compound 3b (see 1H NMR data in the experimental section). However, X-ray study on single crystal of 2-(4-chlorophenyl)-5-methyl-1,2-dihydro pyrazol-3-one (3i) indicates that 2-aryl pyrazol-3-ones e.g. 3a-b3e-f and 3i exist as 1,2-dihydro form in crystal state. 27 It is mention worthy that the aryl ring of all these 2-aryl pyrazol-3-ones remain twisted with respect to the pyrazole plane as indicated by the crystallographic data of 3i [the dihedral angle between the pyrazole and benzene ring planes was found to be 15.81 (11)º].27

 

 

 

5-Methyl-2-phenyl-1,2-dihydro pyrazol-3-one (3a)

mp 125-127 ºC (lit21 126-130 ºC); 

IR (KBr) νmax/cm-1: 3127, 1597, 1525, 1498, 1454;

 1H NMR (400 MHz, DMSO-d6δ 11.40 (bs, 1H), 7.71-7.69 (m, 2H), 7.42-7.38 (m, 2H), 7.21-7.18 (m, 1H), 5.36 (s, 1H), 2.10 (s, 3H); 

13C NMR (50 MHz, DMSO-d6δ 170.6, 156.2, 138.1, 128.8 (2C), 124.9, 118.9 (2C), 43.1, 16.9; 

Mass (CI, m/z) 175 (M+1, 100).

1H NMR (400 MHz, CDCl3)δ 7.85 (d, J 8.3 Hz, 2H), 7.40-7.37 (m, 2H), 7.24-7.18 (m, 1H), 3.43 (s, 2H), 2.20 (s, 3H).

21. Makhija, M. T.; Kasliwal, R. T.; Kulkarni, V. M.; Neamati, N.; Bioorg. Med. Chem. 200412, 2317.         [ Links ]

CN101830852A Mar 22, 2010 Sep 15, 2010 海南美兰史克制药有限公司 Edaravone compound synthesized by new method
CN102060771A Nov 18, 2009 May 18, 2011 南京长澳制药有限公司 Edaravone crystal form and preparation method thereof
CN102180834A Mar 24, 2011 Sep 14, 2011 江苏正大丰海制药有限公司 Preparation method for edaravone

References

  1. ^ Jump up to:a b Doherty, Annette M. (2002). Annual Reports in Medicinal Chemistry, Volume 37 (Annual Reports in Medicinal Chemistry). Boston: Academic Press. ISBN 0-12-040537-7.
  2. Jump up^ Watanabe T, Tanaka M, Watanabe K, Takamatsu Y, Tobe A (March 2004). “[Research and development of the free radical scavenger edaravone as a neuroprotectant]”. Yakugaku Zasshi (in Japanese). 124 (3): 99–111. doi:10.1248/yakushi.124.99. PMID 15049127.
  3. Jump up^ Higashi Y, Jitsuiki D, Chayama K, Yoshizumi M (January 2006). “Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger, for treatment of cardiovascular diseases”. Recent Patents on Cardiovascular Drug Discovery. 1 (1): 85–93. doi:10.2174/157489006775244191. PMID 18221078.
  4. Jump up^ Yoshida H, Yanai H, Namiki Y, Fukatsu-Sasaki K, Furutani N, Tada N (2006). “Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury”. CNS Drug Reviews. 12 (1): 9–20. doi:10.1111/j.1527-3458.2006.00009.x. PMID 16834755.
  5. Jump up^ Yuan WJ, Yasuhara T, Shingo T, et al. (2008). “Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons”. BMC Neuroscience. 9: 75. doi:10.1186/1471-2202-9-75. PMC 2533664Freely accessible. PMID 18671880.
  6. Jump up^ Kawasaki T, Ishihara K, Ago Y, et al. (August 2006). “Protective effect of the radical scavenger edaravone against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum”. European Journal of Pharmacology. 542 (1-3): 92–9. doi:10.1016/j.ejphar.2006.05.012. PMID 16784740.
  7. Jump up^ Kawasaki T, Ishihara K, Ago Y, Baba A, Matsuda T (July 2007). “Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a radical scavenger, prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the substantia nigra but not the striatum”. The Journal of Pharmacology and Experimental Therapeutics. 322 (1): 274–81. doi:10.1124/jpet.106.119206. PMID 17429058.
  8. Jump up^ Yokoyama H, Takagi S, Watanabe Y, Kato H, Araki T (June 2008). “Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice”. Journal of Neural Transmission (Vienna, Austria : 1996). 115 (6): 831–42. doi:10.1007/s00702-008-0019-6. PMID 18235988.
  9. Jump up^ Yokoyama H, Yano R, Aoki E, Kato H, Araki T (September 2008). “Comparative pharmacological study of free radical scavenger, nitric oxide synthase inhibitor, nitric oxide synthase activator and cyclooxygenase inhibitor against MPTP neurotoxicity in mice”. Metabolic Brain Disease. 23 (3): 335–49. doi:10.1007/s11011-008-9096-3. PMID 18648914.

External links

Edaravone
Edaravone.svg
Edaravone ball-and-stick model.png
Clinical data
Trade names Radicut
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
  • Rx-only (JP)
Identifiers
Synonyms MCI-186
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.001.719
Chemical and physical data
Formula C10H10N2O
Molar mass 174.20 g/mol
3D model (Jmol)
////////// Radicava, edaravone, fda 2017, Lou Gehrig’s disease, amyotrophic lateral sclerosis,  Mitsubishi Tanabe, orphan drug designation89-25-8, эдаравон, إيدارافون , 依达拉奉 ,ラジカット,
O=C1CC(=NN1c1ccccc1)C

TEV-37440, CEP-37440


str1
str1
TEV-37440, CEP-37440
CAS 1391712-60-9
Benzamide, 2-[[5-chloro-2-[[(6S)-6,7,8,9-tetrahydro-6-[4-(2-hydroxyethyl)-1-piperazinyl]-1-methoxy-5H-benzocyclohepten-2-yl]amino]-4-pyrimidinyl]amino]-N-methyl-
MW  C30 H38 Cl N7 O3
Molecular Weight, 580.12
2-[(5-Chloropyrimidin-4-yl)amino]-N-methyl-benzamide; 2-[4-[(6S)-1-Methoxy-2-(methylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl]piperazin-1-yl]ethanol
2-[[5-Chloro-2-[[(6S)-6,7,8,9-tetrahydro-6-[4-(2-hydroxyethyl)-1-piperazinyl]-1-methoxy-5H-benzocyclohepten-2-yl]amino]-4-pyrimidinyl]amino]-N-methylbenzamide

2-[[5-chloro-2-[[(6S)-6-[4-(2-hydroxyethyl)piperazin- 1 -yl]- 1 -methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]amino]pyrimidin-4-yl]amino]-N-methyl-benzamide, and is also known as CEP-37440.

Image result

Applicants: CEPHALON, INC. [US/US]; 41 Moores Road P.O. Box 4011 Frazer, Pennsylvania 19355 (US)
Inventors: COURVOISIER, Laurent; (US).
JACOBS, Martin J.; (US).
OTT, Gregory R.; (US).
ALLWEIN, Shawn P.; (US)

Anaplastic Lymphoma Kinase (ALK) is a cell membrane-spanning receptor tyrosine kinase, which belongs to the insulin receptor subfamily. The most abundant expression of ALK occurs in the neonatal brain, suggesting a possible role for ALK in brain development (Duyster, J. et al, Oncogene, 2001, 20, 5623-5637).

ALK is also implicated in the progression of certain tumors. For example, approximately sixty percent of anaplastic large cell lymphomas (ALCL) are associated with a chromosome mutation that generates a fusion protein consisting of nucleophosmin (NPM) and the intracellular domain of ALK. (Armitage, J.O. et al., Cancer: Principle and Practice of Oncology, 6th edition, 2001, 2256-2316; Kutok J.L. & Aster J.C., J. Clin. Oncol, 2002, 20, 3691-3702). This mutant protein, NPM- ALK, possesses a constitutively active tyrosine kinase domain that is responsible for its oncogenic property through activation of downstream effectors. (Falini, B. et al, Blood, 1999, 94, 3509-3515; Morris, S.W. et al, Brit. J. Haematol, 2001, 113, 275-295; Duyster et al; Kutok & Aster). In addition, the transforming EML4-ALK fusion gene has been identified in non-small-cell lung cancer (NSCLC) patients (Soda, M., et al, Nature, 2007, 448, 561 – 566) and represents another in a list of ALK fusion proteins that are promising targets for ALK inhibitor therapy. Experimental data have demonstrated that the aberrant expression of constitutively active ALK is directly implicated in the pathogenesis of ALCL and that inhibition of ALK can markedly impair the growth of ALK+ lymphoma cells (Kuefer, Mu et al. Blood, 1997, 90, 2901-2910; Bai, R.Y. et al, Mol. Cell Biol, 1998, 18, 6951-6961; Bai, R.Y. et al, Blood, 2000, 96, 4319-4327; Ergin, M. et al, Exp. Hematol, 2001, 29, 1082-1090; Slupianek, A. et al, Cancer Res., 2001, 61, 2194-2199; Turturro, F. et al, Clin. Cancer Res., 2002, 8, 240-245). The constitutively activated chimeric ALK has also been demonstrated in about 60% of inflammatory myofibroblastic tumors (IMTs), a slow-growing sarcoma that mainly affects children and young adults. (Lawrence, B. et al., Am. J. Pathol, 2000, 157, 377-384; Duyster et al).

In addition, ALK and its putative ligand, pleiotrophin, are overexpressed in human glioblastomas (Stoica, G. et al, J. Biol. Chem., 2001, 276, 16772-16779). In mouse studies, depletion of ALK reduced glioblastoma tumor growth and prolonged animal

survival (Powers, C. et al, J. Biol. Chem., 2002, 277, 14153-14158; Mentlein, R. et al, J. Neurochem., 2002, 83, 747-753).

An ALK inhibitor would be expected to either permit durable cures when combined with current chemotherapy for ALCL, IMT, proliferative disorders,

glioblastoma and possible other solid tumors, or, as a single therapeutic agent, could be used in a maintenance role to prevent cancer recurrence in those patients. Various ALK inhibitors have been reported, such as indazoloisoquinolines (WO 2005/009389), thiazole amides and oxazole amides (WO 2005/097765), pyrrolopyrimidines (WO 2005080393), and pyrimidinediamines (WO 2005/016894).

WO 2008/051547 discloses fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors. The lead drug candidate disclosed in the ‘547 application is CEP-28122, a potent ALK inhibitor with oral efficacy against SUP-M2 and Karpas-299 ALK-dependent tumors in mouse xenograft models. CEP-28122 progressed to IND-enabling studies until its development was terminated due to the unexpected occurrence of severe lung toxicity in CEP-28122-treated monke s.

CEP-28122

Focal adhesion kinase (FAK) is an evolutionarily conserved non-receptor tyrosine kinase localized at focal adhesions, sites of cellular contact with the ECM (extra-cellular matrix) that functions as a critical transducer of signaling from integrin receptors and multiple receptor tyrosine kinases, including EGF-R, HER2, IGF-R1, PDGF-R and VEGF-R2 and TIE-2 (Parsons, JT; Slack-Davis, J; Tilghman, R; Roberts, WG. Focal adhesion kinase: targeting adhesion signaling pathways for therapeutic intervention. Clin. Cancer Res., 2008, 14, 627-632; Kyu-Ho Han, E; McGonigal, T. Role of focal adhesion kinase in human cancer – a potential target for drug discovery. Anti-cancer Agents Med. Chem., 2007, 7, 681-684). The integrin-activated FAK forms a binary complex with Src which can phosphorylate other substrates and trigger multiple signaling pathways. Given the central role of FAK binding and phosphorylation in mediating signal transduction with multiple SH2- and SH3- domain effector proteins (Mitra, SK; Hanson, DA; Schlaeper, DD. Focal adhesion kinase: in command and control of cell motility. Nature Rev. Mol.

Cell Biol, 2005, 6, 56-68), activated FAK plays a central role in mediating cell adhesion, migration, morphogenesis, proliferation and survival in normal and malignant cells (Mitra et al. 2005; McLean, GW; Carragher, NO; Avizzienyte, E; et al. The role of focal adhesion kinase in cancer – a new therapeutic opportunity. Nature Reviews Cancer, 2005, 5, 505-515; and Kyu-Ho Han and McGonigal, 2007). In tumors, FAK activation mediates anchorage-independent cell survival, one of the hallmarks of cancer cells. Moreover, FAK over expression and activation appear to be associated with an enhanced invasive and metastatic phenotype and tumor angiogenesis in these malignancies (Owens, LV; Xu, L; Craven, RJ; et al. Over expression of the focal adhesion kinase (pi 25 FAK) in invasive human tumors. Cancer Res., 1995, 55, 2752-2755; Tremblay, L; Hauck, W. Focal adhesion kinase (ppl25FAK) expression, activation and association with paxillin and p50CSK in human metastatic prostate carcinoma. Int. J. Cancer, 1996, 68, 164-171; Kornberg, IJ. Focal adhesion kinase in oral cancers. Head and Neck, 1998, 20: 634-639; Mc Clean et al 2005; Kyu-Ho Han and McGonigal, 2007) and correlated with poor prognosis and shorter metastasis-free survival.

Multiple proof-of-concept studies conducted in various solid tumors using siRNA

(Haider, J; Kamat ,AA; Landen, CN; et al. Focal adhesion kinase targeting using in vivo short interfering RNA delivery in neutral liposomes for ovarian carcinoma therapy. Clin. Cancer Res., 2006, 12, 4916-4924), dominant-negative FAK, and small molecule FAK inhibitors (Haider, J; Lin, YG; Merritt, WM; et al. Therapeutic efficacy of a novel focal adhesion kinase inhibitor, TAE226 in ovarian carcinoma. Cancer Res., 2007, 67, 10976-10983; Roberts, WG; Ung, E; Whalen, P; et al. Anti-tumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res., 2008, 68, 1935-1944; Bagi CM; Roberts GW; and Andersen CJ. Dual focal adhesion kinse/Pyk2 inhibitor has positive effects on bone tumors – implications for bone metastases. Cancer, 2008, 112, 2313-2321) have provided pre-clinical support for the therapeutic utility of FAK inhibition as an anti-tumor/anti-angiogenic strategy, particularly for androgen-independent prostate cancers, breast cancers, and HNSCCs. In preclinical models of human breast cancer (MDA-MB-231) in nude rats, administration of a small molecule FAK inhibitor (PF-562,271) inhibited primary tumor growth and intra-tibial tumor spread, and restored tumor-induced bone loss (Bagi et al, 2008). Roberts et al, (2008) showed that PF-562,271 inhibited bone metastases, prevented bone resorption, and increased osteogenesis in breast and androgen-independent prostate cancer patients with and without bone metastases, supporting an additional benefit of FAK inhibition in these specific malignancies.

In summary, there is clear genetic and biological evidence that links aberrant ALK activation and constitutive activation of FAK with the onset and progression of certain types of cancer in humans. Considerable evidence indicates that ALK- and FAK-positive tumor cells require these oncogenes to proliferate and survive, and in the case of FAK, to invade and metastasize to distant sites, while inhibition of both ALK and FAK signaling leads to tumor cell growth arrest or apoptosis, resulting in objective cytoreductive effects. Inhibition of FAK also results in attenuation of tumor motility, invasiveness, and metastatic spread, particularly in specific cancers characterized by bone metastatic dissemination and osteolytic disease. FAK activation protects tumor cells from

chemotherapy-induced apoptosis, contributing to tumor resistance; modulation of FAK activity (by siRNA or pharmacologically) potentiates efficacy of chemotherapeutic agents in vivo (e.g., doxorubicin, docetaxel and gemcitabine), suggesting the utility for rational combination therapies in specific cancers. ALK and FAK are minimally expressed in most normal tissues in the healthy adult and are activated and/or dysregulated in specific cancers during oncogenesis and/or during early stages of malignant progression.

Consequently, the on-target effects of treatment with a dual ALK and FAK inhibitor against normal cells should be minimal, creating a favorable therapeutic index.

A need exists for additional safe and effective ALK and/or FAK inhibitors for the treatment of cancer.

In 2012, the development of a new route to our lead anaplastic lymphoma kinase (ALK) inhibitor CEP-28122 (1) was disclosed.  This route utilized some unique synthetic approaches that included a selective nitration through a para-blocking group strategy, a one-pot amination-transfer hydrogenation to effect four reductions nearly simultaneously, an enzymatic resolution, and the leveraging of an in situ generated mixed mesylate hydrochloride salt to form the final active pharmaceutical ingredient (API). While this process development was occurring, efforts from Discovery identified TEV-37440 (2) as a suitable backup with many pharmaceutical advantages over the lead compound. The most notable of these advantages was the dual kinase selectivity for both ALK and focal adhesion kinase (FAK). Having this dual kinase effect made TEV-37440 an ideal candidate for drug development, targeting nonsmall-cell lung cancer (NSCLC). From a synthetic point of view, TEV-37440 contains numerous structural similarities to its lead development candidate CEP-28122 . The core ring system is again made up of three primary fragments with an identical central B-ring. While the C-ring is different, the challenging A-ring again contains chirality around a secondary amine of a similar 6–7 fused ring system. These similarities allow for many of the same strategies identified for CEP-28122 to be applied in the route development of TEV-37440. Described herein is the phase-appropriate development of the oncology development candidate TEV-37440. Highlights of this development include the use of a novel ring-expansion reaction, a selective nitration through a para-blocking group strategy, a single-pot amination–hydrogenation, a diastereomeric salt resolution, a through-process step to avoid a hazardous intermediate, and a practical formation of a trihydrochloride dihydrate salt.
Figure
ALK inhibitor CEP-28122 and ALK/FAK dual inhibitor TEV-37440.
Synthesis will be updated watch this space………..

CONTD……….
contd…………….
PATENT

The present invention rovides a compound of formula (I)

or a salt form thereof.

The compound of formula (I) has ALK and FAK inhibitory activity, and may be used to treat ALK- or FAK-mediated disorders or conditions.

The present invention further provides a pharmaceutical composition comprising at least one compound of the present invention together with at least one pharmaceutically acceptable excipient.

CEP-37440

The synthesis of 2-(5-chloro-2-{(S)-6-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-l-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino}-pyrimidin-4-ylamino)-N-methyl-benzamide can be carried out according Fig. 1, following the procedures outlined in Steps 1-8.

Stepl : 5-Methoxy-l-methylene-l,2,3,4-tetrahydro-naphthalene: To a slurry of 5- Methoxy-3,4-dihydro-2H-naphthalen-l-one (25 g, 0.14 mol) and methyltriphenylphos-phonium iodide (1.13 eq) in THF (250 mL) at RT was added potassium t-butoxide (1.6 eq) at such a rate as to maintain a temperature no higher than warm to the touch. The reaction was stirred for one hour and concentrated. The reaction was then azeotroped with three volumes of hexane to remove excess t-butanol. Fresh hexane was added the solution was let to stand overnight to effect trituration. The red-brown solid was removed by filtration and the filtratewas washed twice with water and was concentrated. Purification by

chromatography on ISCO (330g Si02 cartridge: stepwise hexane and then DCM) affords the title compound as a pale yellow oil (24 g, 99%). 1H-NMR (400 MHz, CDC13) 7.29 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.49 (s, 1H), 4.98 (s, 1H), 3.85 (s, 3H), 2.77 (t, J = 6.4 Hz, 2H), 2.53-2.50 (m, 2H), 1.93-1.87 (m, 2H).

Step 2: l-Methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one: 5-Methoxy-l-methylene-l,2,3,4-tetrahydro-naphthalene (23.8 g, 0.137 mol) in 150 mL MeOH added in one portion to freshly prepared solution of thallium(III)nitrate trihydrate (1.0 eq) in 300 mL MeOH. Stirred one minute and 400 mL chloroform added. The solution was filtered and the organics partitioned between dichloromethane and water. The organics were dried (MgS04) and concentrated. Purification by chromatography (ISCO, 330g silica cartridge; stepwise elution hexane (5 min) then 7 minute gradient to 100% dicloromethane (20 min) affords the title compound as the most polar of the products as a pale yellow oil (26g, 97%). 1H-NMR (400 MHz, CDC13) 7.16 (t, J = 7.9 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 7.5 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 2H), 3.05-3.01 (m, 2H), 2.55 (t, J = 7.0 Hz, 2H), 2.01-1.96 (m, 2H). LC/MS (ESI+) m/z = 191 (M+H)+

Step 3: l-Methoxy-2-nitro-5,7,8,9-tetrahydro-benzocyclohepten-6-one: To potassium nitrate in acetonitrile (50 mL) and trifluoroacetic anhydride (100 mL) at 0°C was added dropwise l-methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one (25 g, 0.131 mol) in 50 mL acetonitrile. The reaction was stirred for 2.5 hours while warming to RT. The reaction was concentrated without heat on a rotary evaporator. MeOHwas added and stirred briefly. Reconcentrated and worked-up by partitioning between dichloromethane and sat. sq. sodium bicarbonate solution. The organic layer was separated and dried (Mg2S04), concentrated and purified by chromatography ISCO (330g silica cartridge: gradient elution – 10 to 50% EA:HEX over 60 minutes) affording two isomers. The title compound was the later eluting (10.7 grams, 34.6% yield). 1H-NMR (400 MHz, CDC13) 7.70 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 2H), 3.13-3.09 (m, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.10-2.03 (m, 2H).

Step 4: 2-[4-(l-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-piperazin-l-yl]-ethanol: l-Methoxy-2-nitro-5,7,8,9-tetrahydro-benzocyclohepten-6-one (15.09 g, 64.15 mmol) in methylene chloride (870 ml)treated with 2-Piperazin-l-yl-ethanol (3 eq) followed by acetic acid (10 eq). The mixture was stirred at 50°C for 2 hrs and cooled to 0°C and sodium triacetoxyborohydride (4 eq) was added, then warmed to RT and stirred. After a few hours starting material was still present. Added

0.4 eq further of sodium triacetoxyborohydride, then again after 6 hours. Stirred overnight. Poured into a solution of sat. aq. Sodium bicarbonate and ice and made basic to pH 10 with IN sodium hydroxide, extracted 2X dichloromethane, dried MgS04, filtered and concentrated. This material was taken up into ethanol and HC1/

ethanol was added. The resulting precipitate was triturated for 2 hours then filtered. The solid was free-based using NaOH followed by sodium bicarbonate and extracted into dichloromethane to give the title compound (19g, 85% yield). 1H-NMR (400 MHz, CDCI3) 7.56 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 3.82 (s, 3H), 3.63-3.06 (m, 2H), 3.29-3.24 (m, 1H), 3.00-2.86 (m, 3H), 2.72-2.67 (m, 2H), 2.60-2.51 (m, 8H), 2.46-2.37 (m, 2H), 2.12-2.07 (m, 2H), 1.87-1.78 (m,lH), 1.37-1.29 (m, 1H). LC/MS (ESI+) m/z = 350 (M+H)+

Step 5 : 2-[4-(2-Amino- 1 -methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-piperazin- 1 -yl]-ethanol. 2-[4-(l -Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-piperazin-l-yl]-ethanol (19.0 g, 54.4 mmol) was

split into two batches and dissolved in a total of Ethanol (232 mL). 10 % Pd/C (

1.74 g, 1.64 mmol) was divided in half and the reaction was hydrogenated for 3-4 hours at 50 psi. Each reaction mixture was filtered through celite to remove Pd. The filtrates were combined and then concentrated and the title compound isolated as a foamy solid (17.25g, 99% yield). 1H-NMR (400 MHz, CDC13) 6.76 (d, J = 7.9 Hz, 1H), 6.53 (d, J = 7.9 Hz, 1H), 3.72 (broad s, 3H), 3.71 (s, 3H),3.64 (t, J = 5.4 Hz, 2H), 3.26-3.20 (m, 1H), 2.84- 2.72 (m, 5H), 2.62-2.56 (m, 8H), 2.42-2.35 (m, 2H), 2.40-2.37 (m, 1H), 1.81-1.74 (m, 1H), 1.70 (broad s,lH), 1.41-1.33 (m, 1H). LC/MS (ESI+) m/z = 320 (M+H)+

Step 6 : 2-[4-((S)-2-Amino- 1 -methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-piperazin-l-yl] -ethanol: 34 grams of racemic 2-[4-(2 -Amino- l-methoxy-6, 7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-piperazin-l-yl]-ethanol were separated using SFC (supercritical fluid C02) chromatography using a Chiralcel OJ-H (3 x 15 cm) 808041 column with 15% methanol(0.2% DEA)/C02, 100 bar eluent at 80 mL/min flow rate monitoring the wavelength of 220 nm with an injection volume: 0.5 mL, 20 mg/mL ethanol. 16.9 grams of the (R)-enantiomer and 17 grams of the titled compound were isolated with a chemical purity >99% and an enantiomeric excess (ee) >99% (measured using a Chiralcel OJ-H analytical column). NMR and mass were equivalent to the racemic material. The absolute configurationof the first eluting isomer was unambiguously assigned as the (R)-configuration via small-molecule X-ray using anomalous dispersion of the bis-p-bromobenzyl derivative: 4-bromo-benzoic acid 2-{4-[(R)-2-(4-bromo-

benzoylamino)- 1 -methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-piperazin-l -yl} -ethyl ester. Thus, the second eluting enantiomer was determined to be (S)-configuration.

Step 7: 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide: 2-Amino-N-methyl-benzamide (24.4 g, 0.16 mol) in DMF (0.5 L) was added 2,4,5-Trichloro-pyrimidine (39 g, 1.3 eq) and Potassium carbonate (1.3 eq). Stired under argon at 75 °C for 5 hrs and then at RT overnight. Poured into 1 L water and precipitate isolated by filtration and washed 1 : 1 acetonitrile: water followed by drying in air stream and under vacuum to afford the title compound as a yellow solid (38 g, 78% yield). 11.70 (s, 1H), 8.74 (d, J = 8.2 Hz, 1H), 8.24 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.16 (t, J = 8.4 Hz, 1H), 6.28 (s, 1H), 3.06 (d, J = 4.7 Hz, 3H).

Step 8 : 2-(5-Chloro-2- {(S)-6-[4-(2-hydroxy-ethyl)-piperazin-l -yl]- 1 -methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino}-pyrimidin-4-ylamino)-N-methyl-benzamide: To a sealed vessel 2-[4-((S)-2-Amino-l-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-piperazin-l-yl]-ethano (2.69 g, 8.41 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (2.00 g, 6.73 mmol) were combined in 1-methoxy-2-propanol (120 mL, 1200 mmol) followed by the addition of Methanesulfonic acid (2.44 mL, 37.7 mmol). The reaction was then heated at 90°C for 18 hours.

The reaction mixture was added to a separatory funnel and diluted with sat. bicarb until a cloudy ppt formed. This was extracted with dichloromethane 3x. The organic

layer was then washed with brine, dried over MgS04, filtered and concentrated. The residue was pumped dry then chromatographed on ISCO flash column. It was injected in dichloromethane onto a normal phase column and eluted on a gradient of 0-10%

(dichloromethane: 10%NH4OH in MeOH). The desired product eluted around 9-10% and the 10% gradient was held until product eluted completely. Mixed fractions concentrated and were chromatographed on the Gilson reverse-phase HPLC gradient elution 0-40%

CH3CN. Chromatogrpahy was repeated using normal phase silica and reverse phase HPLC to effect further purification as desired. Following neutralization and concentration of all the material, the resulting solid was obtained by taking the foam up into EtOAc and concentrating to dryness several times to give the title compound (1.1 g, 28%>). 11.02 (s, 1H), 8.69 (d, J = 8.9 Hz, 1H), 8.13 (s, 1H), 8.08 (d, J = 8.4 Hz, 1Η),7.59-7.50 (m, 2H),

7.41 (s, 1H), 7.13 (t, J = 7.4 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.21 (s, 1H), 3.74 (m, 3H), 3.66-3.63 (m, 2H), 3.29-3.23 (m, 1H), 3.06 (d, J = 4.3 Hz, 3H), 2.92-2.72 (m, 5H), 2.66-2.55 (m, 8H), 2.48-2.39 (m, 2H), 2.16-2.10 (m, 2H), 1.87-1.77 (m, 1H), 1.42-1.32 (m, 1H).LC/MS (ESI+) m/z = 580 (M+H)+

CEP-37440 amorphous HC1 salt

2-(5-Chloro-2- {6-[4-(2-hydroxy-ethyl)-piperazin- 1 -yl]- 1 -methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino}-pyrimidin-4-ylamino)-N-methyl-benzamide hydrochloride: 2-(5-Chloro-2-{6-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-l-methoxy-6, 7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino}-pyrimidin-4-ylamino)-N-methyl-benzamide (4.90 g, 8.45 mmol) and 2.5 M of HC1 in ethanol (13.5 niL, 33.8 mmol) were heated until they dissolved in ethanol (164 mL). The reaction was concentrated two times from ethanol, then warmed in a small amount of ethanol until completely dissolved. This solution was allowed to cool slowly with a stirring (<100 rpm). A solid preciptate formed quickly before the solution had cooled. This mixture was allowed to stir until ambient temperature was achieved and then filtered. The solid was washed with ethanol followed by ether then directly pumped dry under high vac to give 2-(5-chloro-2-{6-[4-(2-hydroxy-ethyl)-piperazin-l -yl]- 1 -methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino} -pyrimidin-4-ylamino)-N-methyl-benzamide hydrochloride (5.3 grams, quantitative yield). 1H-NMR (MeOD, 400 MHz) δ 8.55 (s, 1H), 8.17 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 6.8 Hz, 1H), 7.46 (broad s, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 4.00-3.95 (m, 4H), 3.83-3.72 (m, 5H), 3.73 (s, 3H), 3.65-3.59 (m, 2H), 3.47-3.38 (m, 5H), 2.95 (s, 3H), 2.72-2.65 (m, 1H), 2.44-2.38 (m, 1H), 2.29-2.28 (m, 1H), 2.19-2.12 (m, 1H), 1.59-1.49 (m, 1H). LC/MS (ESI+) m/z = 580 (M+H)+.

PATENT

2-[[5-chloro-2-[[(6S)-6-[4-(2-hydroxyethyl)piperazin-l-yl]-l-methoxy-6,7,8,9-tetrahydro-5Hbenzo[7]annulen-2-yl]amino]pyrimidin-4-yl]amino]-N-methyl-benzamide (CEP-37440) is an orally available dual kinase inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) and focal adhesion kinase (FAK) with antineoplastic activity. See, e.g., WO 2013/134353.

H


CEP-37440

[0003] In view of the surprising and unexpected properties observed with CEP-37440, improved methods for its preparation in high enantiomeric purity are needed.

CEP-37825 CEP-38063-tartrate salt

Scheme 2

CEP-37440

[0059] Preferred methods for asymmetrically producing an intermediate for the formation of CEP-37440 according to the disclosure are depicted in Scheme 3.

Scheme 3

4

[0060] Preferred methods for asymmetrically producing an intermediate for the formation of CEP-37440 according to the disclosure are depicted in Scheme 4.

[0061] The following examples are provided to illustrate the compositions, processes, and properties of the present disclosure. The examples are merely illustrative and are not intended to limit the disclosure to the materials, conditions, or process parameters set forth therein.

EXAMPLES

Chiral HPLC method:

CHIRALCEL AD column

eluent: heptane/isopropanol (90:10)

flow: 1.2 mL/min

detection: 220 nm and 254 nm.

Example 1

5-methoxytetralone CEP-41158

[0063] To a 12L 4-neck round bottom flask was added methoxytetralone (500 g, 2830 mmol, 1 eq) and Pti3PCH3I (1320 g, 3264 mmol, 1.15 eq) as solids via a powder funnel. THF (5 L) was added and the mixture was stirred with overhead stirring at 19 °C. tBuO (525 g, 4683, 1.65 eq) was added portion-wise over 2 hours to maintain a maximum reaction temperature of 47 °C. A THF solution of tBuOK can also be used with similar results. The funnel was washed with additional THF as needed. The resulting slurry was stirred for an additional hour at 30 °C. HPLC analysis showed < 0.5% starting material.

[0064] The reaction was transferred to a single neck flask and concentrated by roto-evaporator and solvent switched to heptanes (approximately 2.5L, removing as much THF as possible). The slurry was filtered, washing with an additional 0.5 L heptanes. The combined filtrant and wash (approximately 3 L) was washed 2 times with water (2 x 250 mL). The water layers were back extracted 1 time with 0.5 L heptanes which was combined with the other organic layers (total volume was approximately 3.5L).

[0065] To remove the residual amounts of Pl^PO, the solution can be dried and cooled (overnight in the cold room) to precipitate out the triphenylphosphine oxide. Filtration results in a clean product stream that can be concentrated to an oil. Alternatively, the initial heptane product stream may be passed through a plug of S1O2 followed by concentration to an oil.

Example 2

[0066] CEP-41 158 (Limiting Reagent, see Example 1 ) was charged to a reaction vessel followed by methyl tertiary butyl ether (MTBE) (6.3 volumes), isopropanol (3.3 volumes),

Triton X (0.1 volumes), water (6.3 volumes), and 2-iodo-5-methylbenzenesulfonic acid (0.125 eq). While holding the batch at 20-25 °C, oxone (0.65 eq) was added portion-wise over

approximately 1.5 h and then continued to stir at room temperature. HPLC was used to monitor reaction conversion. A typical reaction time was 4 h but the reaction can be stirred overnight, as well.

[0067] The reaction was quenched by the slow addition of sodium sulfite (0.5 eq) over 10 minutes. Peroxide test strips were used to confirm no peroxides remained. NaOH (5N) was then added at <30 °C to obtain a pH of 8 (typically this was approximately 2 volumes of 5N NaOH). Celite was added and the solution was filtered. The aqueous layer was removed and the organics were washed with brine before being concentrated to an oil.

[0068] Bisulfite adduct formation: The above oil was taken up in isopropanol (7 volumes) before adding water (4 volumes). To this solution was slowly added a freshly prepared aqueous sodium bisulfite solution (6.4 M, 2 eq) at ambient temperature. The resulting slurry was stirred overnight then filtered. The solids were washed with isopropanol and then dried at 40 °C in a vacuum oven with a nitrogen bleed.

Example 3

CEP -41609 CEP-41159

[0069] Unless otherwise noted all volumes and equivalents are based on the wt% corrected charge of CEP-41609. To a nitrogen purged 2.0 L jacketed reactor equipped with an anchor overhead stirrer, and a thermocouple probe was charged 1 17.8 g of CEP-41609 (84.9 wt%, 100.0 g, 0.3398 mol). 500 mL of acetonitrile (5 volumes) was then introduced and the jacket was set to 15 °C. 300 mL of deionized H2O (3 volumes) was then charged and the slurry cooled from -17 °C to 10 °C with stirring at 130 RPM. HC1 (86.4 mL, 1 1.8M, 1.019 mol, 3 equiv.) was added in one portion with the slurry at 10 °C. The mixture exothermed to 17.3 °C and the jacket was adjusted to 22 °C. The slurry cooled to 13.8 °C before being warmed back up to 20 °C in 13 minutes. The stirring was turned up to 175 RPM to improve mixing while completing a 30 minute age. The solids had dissolved after 30 minutes. At 57 minutes the stirring was stopped and the biphasic solution was allowed to settle and sit overnight (15 h).

[0070] After sitting overnight, stirring (175 RPM) was reinitiated and the jacket was set to -40 °C. It took 28 minutes for the mixture to reach -15 °C and in that time the jacket was adjusted to -20 °C. With the jacket at -20 and the reaction at -15 °C the first charge of N-chlorosuccinimide (NCS) was done (28.4 g, 0.2127 mol, 0.626 equiv.). The reaction exothermed to -1.2 °C in 1.5 minutes. 4 minutes later with the reaction cooled to -6.9 °C and the jacket still at -20 °C the second charge of NCS was done (85.0 g, 0.6367 mol, 1.874 equiv.). The reaction exothermed to 2.2 °C in 1.5 minutes. The reaction was then cooled to 0 °C in 1 minute and held at 0 ± 2 °C. Acetonitrile (ACN) (25 mL, 0.25 volumes vs wt% corrected CEP-41609) was used to rinse residual NCS off the wall of the reactor and into the reaction just after the second charge. After 2 hours at 0 ± 2 °C an IPC was taken from the organic layer and the HPLC showed undetectable levels of CEP-41608.

[0071] At 2 hours 22 minutes the work up began with the addition of MTBE (650 mL, 6.5 volumes) over 6 minutes at 0 to 1.7 °C. The mixture was stirred at 175 RPM (complete mixing achieved) for 2.5 minutes then stirring was stopped and the layers settled in 2.5 minutes. 280 mL of an aqueous layer was then cut at -1.6 °C. To the remaining 1500 mL of organic solution was charged 650 mL NaCl solution (6.5 volumes, 24 wt% NaCl; 189.2 g NaCl mixed with 599.25 g D.I. H20) over 8 minutes at -1.3 to 1.7 °C. Stirring was increased to 325 RPM to achieve complete mixing. The solution was allowed to stir for 1.5 minutes before stopping the stirring and allowing the layers settle in 3 minutes. 1000 mL of aqueous layer was cut at -0.4 °C. To the remaining 1 100 mL of organic layer was charged 650 mL NaHCC solution (6.5 volumes, 7.5 wt% NaHC03; 53 g NaHC03 mixed with 655.5 g D.I. H20) over 9 minutes at -0.3 to 2.6 °C with stirring at 325 RPM to achieve complete mixing. The solution was allowed to stir for 5 minutes and then the stirring was stopped and the layers settled in 4 minutes. 800 mL of an aqueous layer (pH = 8) was cut at 0.2 °C.

[0072] The remaining organic layer (1000 mL) was checked by HPLC (70.2 A% CEP-41 159, 17.5 A% impurity 1, 5.9 A% impurity 2, 2.9 A% impurity 3). Thejacket was set to 10 °C while a solution of Na2S204 (33.4 g @ 85 wt%, 0.1631 mol, in 326 mL DI H20) was prepared in a capped imax jar. 50 minutes after cutting the NaHCC layer the organic layer was at 8.8 °C. With thejacket at 10 °C the Na2S204 solution was added in one portion with the stirring at 250 RPM. The mixture warms to 15.4 °C and the jacket was adjusted to maintain the reaction at 15 ± 1 °C for 15 minutes. Stirring was then stopped and an HPLC was taken from the organic layer while holding the biphasic solution at 15 °C. The HPLC showed no detectable impurity 1 (76.1 A% CEP-41 159, 6.4 A% impurity 2, 3.1 A% impurity 3, 0.54 A% CEP-41608). After a total of 39 minutes contact time with Na2S204 solution the aqueous layer was cut leaving 925 mL of organic layer. This solution was held overnight with the jacket at 20 °C.

[0073] After 16 hours 1 1 minutes the organic solution was drained into a round bottom flask, rinsing with 100 mL MTBE (1 volume). The solution was then concentrated at 120 mbar

with the bath temperature at 35 °C. Once 590 mL (5.9 volumes vs. wt% corrected CEP-41609) was removed the remaining solution was diluted with 550 mL AcOH (5.5 volumes vs. wt% corrected CEP-41609). This solution was then concentrated again at 65 mbar with the bath temperature at 45 °C. Once 320 mL (3.2 volumes vs. wt% corrected CEP-41609) was removed the distillation was stopped and the remaining solution was weighted (523.39 g) and checked by HPLC and Ή NMR. HPLC showed 66.31 g (87.0% yield) of CEP-41 159 in solution, and the NMR showed 96.0 wt% AcOH (3.1 wt% ACN, 0.9 wt% MTBE; 93 wt% AcOH desired). The desired AcOH solution mass was calculated from the HPLC assay of CEP-41 159 (9 x 66.3 lg = 596.79 g) and the amount of AcOH needed to dilute to this mass was also calculated (596.79-523.39 = 73.4 g x (lmL/1.049g) = 70 mL AcOH). The AcOH solution was then transferred back to the 2 L JLR (which had been rinsed with H2O and dried with an N2 sweep and 40 °C jacket) and 70 mL of AcOH was used to rinse out the round bottom flask and dilute the solution.

[0074] After sitting at 20 °C for 2.5 hours this solution was diluted with 199 mL DI H20 (3 volumes vs. CEP-41 159) while setting the stirring at 225 RPM and the jacket at -30 °C. The resulting homogeneous solution was cooled to -10 °C in 21 minutes. The stirring was set to 324 RPM and after 1 minute at -10 °C seed (249.4 mg, Lot # 3292-1 1 1-Pl ) was added to the solution. A thick slurry formed in <2 minutes (exotherms to -8.6 °C) but the stir speed allowed for good mixing. After 29 minutes added 332 mL DI H2O (5 volumes vs. CEP-41 159) over 12 minutes at -10 to -8 °C. Held the slurry for 28 minutes at -10 °C and then filtered a sample to check the mother liquor losses. Losses looked good at 7.7 mg/g (desired <9 mg g). After 50 minutes at -10 °C with all water added the slurry was filtered. Filtration was quick, taking <1 minute. The flask and cake were washed with 265.3 mL of ambient temperature 25 vol% ACOH H2O (4 volumes vs. CEP-41 159). The resulting mother liquors and wash were assayed and found to contain 6.7% losses (4.0 mg/g CEP-41 159). The solids were held on the filter with the vacuum pulling air across them and with aluminum foil keeping light from them.

[0075] After 67 hours and the solids were then left on the filter for another 48 hours. A total of 58.08 g of white cottony solids were recovered and were checked by HPLC and Ή NMR. HPLC indicates the solids were 100 A% and 102.7 wt% while the NMR showed only trace levels of AcOH. Based on this data the solids were deemed 100% pure and the yield was 76.2%.

Example 4

CEP -41159 CEP-41160

All volumes and equivalents are based on the wt% corrected charge of CEP-41 159 unless other wise stated. Potassium nitrate (22.99 g, 0.2274 mol, 1.02 equivalents) was dissolved in trifluoroacetic acid (TFA) (125 mL, 2.5 volumes). This dissolution took ~5 minutes with vigorous stirring. CEP-41 159 (50.0 g, 0.2229 mol, 1.00 equivalents) was taken up in TFA (125 mL, 2.5 volumes) at 22 °C. This solution was cooled to -13 °C over 21 minutes and then the addition of the potassium nitrate/TFA solution was started. This solution was added in four equal portions. After each portion was added an HPLC was run on a sample of the reaction to evaluate if the reaction had progressed. The sample was diluted in ACN before it could warm up as a temperature rise would likely cause further reaction to occur. The HPLC after the first addition was completed (addition took 13 min at -13 to -6.2 °C) showed 20.9 % conversion. The batch was cooled to -13 °C and the second addition was done over 5 minutes at -13 to -1.2 °C. HPLC after the second addition showed 43.6% conversion. After the reaction was cooled back to -13 °C the third addition was started. This third addition was done over 5 minutes at -13 to -2.7 °C, and the HPLC showed 70.1% conversion. After the reaction was cooled back to -13 °C the final addition was started. This final addition was done over 3 minutes at -13 to -7.5 °C, and the HPLC showed 98.9% conversion. The reaction was held at -13 °C while sodium acetate (22.85 g, 0.2787 mol, 1.25 equivalents) was taken up in DI water (600 mL, 12.0 volumes). After 19 minutes at -14 to -13 °C the reaction was diluted with half of the sodium acetate solution over 3 minutes while allowing the reaction to warm from -14 °C to 14.5 °C. The resulting solution was warmed to 22 °C over 14 minutes and seeded with CEP-41 160 (50 mg, 0.001 x CEP-41 159). The resulting slurry was allowed to stir overnight. After 15 hours 51 minutes the second half of the sodium acetate solution was added over 12 minutes at 21.6-22.6 °C. The resulting slurry was stirred for 34 minutes and then assayed for losses. The losses were at 2.88mg/g. The slurry was then filtered 1 hour 07 minutes after final sodium acetate solution addition was done. The reaction vessel and cake were washed with Dl water (200 mL, 4.0 volumes). The mother liquors and wash were combined and assayed by HPLC to determine they contain 4.3% of the product. The solids were dried in the filter open to air with the vacuum pulling on the bottom of the filter. After 4 hours 52 minutes of drying 52.985g of CEP-41 160 was recovered. These were bright

yellow sandy solids which were 100 A% and 100.8 wt% (@ 238 nm). This is 88.3% yield of CEP-41 160.

Example 5

CEP-37825 CEP-3B063-Tartrate Salt

(A-Ring)

[0076] A glass jar was charged with CEP-37825 (17.0 g physical, 16.7 g corrected, 52.3m mol, 1.00 equiv, Johnson Matthey 4239.A.13.2), MeOH (167 mL) and H20 (40.5 g). The mixture was stirred at ambient temperature until complete dissolution occurred. The resulting solution was filtered over a sintered glass funnel into a 500 mL jacketed reactor, rinsing with MeOH (85 mL). The reactor was evacuated and filled with N2. The solution was heated to 35 °C (internal temperature). A solution of L-tartaric acid (7.85 g, 52.3 mmol, 1.00 equiv) in MeOH (84 mL) was added via addition funnel over 1 1 minutes. Additional MeOH (30 mL) was used as a rinse. The solution was seeded with a slurry of CEP-38063 L-tartrate (50.0 mg) in MeOH (2.5 mL). The vial containing the slurry was rinsed with additional MeOH (1.2 mL). A slurry gradually formed, and the mixture was aged at 33-34 °C for 90 min. The internal temperature was decreased to 29 °C and agitated for 63 min after which the mixture was cooled to 20-25 °C and stirred overnight.

[0077] After stirring overnight at ambient temperature, the mixture was filtered, rinsing with a solution of H20 (2.6 mL) in MeOH (49 mL). The mixture was dried at room temperature overnight under vacuum. Crude CEP-38063 L-tartrate (10.07 g) was obtained in 87.6% de (93.8% dr). The CEP-38063 free base content was 64.2%. The yield was 36% from CEP-37825 racemate.

[0078] Recrystallization: A 1 L OptiMax vessel was charged with two lots of crude CEP-38063 L-tartrate (18.9 g, 89.3% dr, 9.47 g, 88.6% de, 57.1 mmol total). Methanol (346 mL) and H20 (38.8 g) were added and the reactor was placed under nitrogen. The slurry was heated to 66.5 °C during which time the solids dissolved. The solution was then cooled to 55 °C and seeded with a slurry of CEP-38063 L-tartrate (106.9 mg) in MeOH (5.4 mL). The vial containing the slurry was rinsed with additional MeOH (2.6 mL). The slurry was agitated at 53- 54 °C for 82 min. It was then cooled to 48.5 °C over 60 minutes. It was agitated for 1 h, then cooled to 20 °C over 60 minutes.

[0079] After stirring overnight at ambient temperature, the mixture was filtered, rinsing with a solution of H2O (5.7 mL) in MeOH (107 mL). The mixture was dried under vacuum at room temperature overnight. CEP-38063 L-tartrate (21.4 g) was obtained in >99 A%, 99.4% de (99.7% dr) . The CEP-38063 free base content was 65.3%.

Example 6: Procedure for CEP-19036 (amidation and coupling step)

[0084] Into a 20-L jacketed glass reactor were charged isatoic anhydride (500 g, 3.06 mol,) and ethanol (2500 mL). This was followed by the controlled addition of 30 wt% methylamine in ethanol (378.5 g, 3.98 mol) further diluted with ethanol (330 mL) over 70 minutes from an addition funnel at 20±5 °C. The resulting mixture was stirred at 20±5 °C for 60 min and checked by HPLC for reaction completion (<1 A% S ). Upon completion, 13% NaCl

(prepared by dissolving 390 g of NaCl in 2610 mL of DI water) was added over 20.0 min. The resulting mixture was agitated at 20±5 °C for 10 min then allowed to settle for 10 min. The bottom aqueous layer was removed. The organic layer was washed with 26% NaCl (prepared by dissolving 792 g of NaCl in 2210 mL of DI water). The combined aqueous washes were extracted with ethyl acetate (5100 mL). The ethyl acetate extract was combined with the batch and concentrated under reduced pressure (50-80 mmHg) at 30-40 °C in a 12-L round-bottomed flask until the batch volume was approximately 1.5 L (3x the weight of isatoic anhydride). To the residue was added ethyl acetate (5100 mL), which was then concentrated under reduced pressure (50-80 mmHg), a second time, to approximately 1.5L (3 x the weight of isatoic anhydride). To the concentrated batch was added 5.0 L of acetonitrile. The resulting mixture was stirred at room temperature for 60 min, and filtered through a pad of Celite in a sintered glass funnel with fine porosity. The pad was rinsed with acetonitrile (500 mL) and the rinse was combined with the batch. The clear filtrate was transferred to a 20-L jacketed glass reactor. Hunig’s base (712.6 g) and 2,4,5-trichloropyrimidine (657.3 g) were added. The resulting solution was heated to 73±3 °C and agitated at 73±3 °C until the reaction was complete as indicated by an in-process test. The reaction mixture was then cooled to 0±5 °C over 30 min and stirred at this temperature for 1 -2 hrs. The product was collected by vacuum filtration on a sintered glass funnel. The cake was rinsed with acetonitrile (1240 mL) and pulled dry under vacuum with a nitrogen bleed until the residual water and acetonitrile content were less than 1 wt% by NMR analysis and KF titration. A total of 746.3 g (81.9% overall yield) of CEP- 19036 was obtained as a light tan solid with the following quality attributes: 99.8 A%, 98.99 wt%, 0.1 wt% NaCl, 0.1 wt% H20, 0.1 wt% acetonitrile.

Example 7

[0085] CEP-38063-tartrate salt (30.1 g of salt, Limiting Reagent) was charged to a vessel along with 10 volumes of water and 10 volumes of dichloromethane. At room temperature NaOH (10 N aqueous solution, 2 equiv) was added and stirred for 15 minutes. The bottom organic layer was removed and the aqueous layer was washed a second time with 10 volumes of dichloromethane. The combined organics were washed with brine (5 volumes) then concentrated under vacuum by distillation. To the concentrate, l-methoxy-2-propanol (12.7 volumes) was added along with CEP- 19036 (1.25 equiv) and methanesulfonic acid (2.75 eq). The resulting mixture was heated to 70 °C for approximately 48 hours then cooled to room temperature. Water (14 volumes) and dichloromethane (14 volumes) was added and stirred for 15 minutes. The bottom organic layer was cut to waste prior to adding an additional 14 volumes of dichloromethane and NaOH (ION, 3.6 equiv). The bottom organic layer was removed and the aqueous was washed with an additional 14 volumes of dichloromethane. The organic layers were combined, washed with brine and concentrated under vacuum by distillation. Isopropanol (30 volumes) and water (0.6 volumes) was added and heated to 70 °C. The resulting solution was cooled to 50 °C before adding additional water (5.8 volumes) which results in

crystallization. The slurry was then cooled to room temperature, filtered and dried at 60 °C to afford a 74% yield of product with >99% purity.

Example 8: Procedure for CEP-37440-3HCl-2H2O (salt formation)

[0086] Combined free base (145.83 g, 251.4 mmol) into a 5 L 3-neck round bottom flask equipped with overhead stirring and an addition funnel. To these solids was added nBuOH which resulted in a yellow cloudy solution (free of large solids) after stirring for 40 minutes. Precipitation occurred immediately and a slight exotherm to 23 °C was observed. The resulting slurry was heated to 85 °C over 45 minutes. Near 60 °C, the solids went into solution. Once the heating reached 80 °C, HC1 (2.5 M in 1 : 1 : 1 MeOH/EtOH/water, 307 mL, 767 mmol) was added via addition over 4 minutes and seed crystals (CEP-37440 H2A3, 1.7 g) were added. The seed held and more solids formed during a 1 h age at 85 °C. The solution was then cooled to room temperature over 1 h then further cooled to 2 °C over an additional 30 minutes. The slurry was stirred at 0-5 °C for lh then filtered, washing with 0 °C nBuOH (400 mL). Initial cake dimensions (cylinder) were 6.0 cm high with a diameter of 13.5 cm. After wash, compressed cake was 4.3 cm high. Losses to the mother liquor were approximately 0.5%. The resulting solids were dried in a vacuum oven at 60 °C for 24 h (with N2 purging after the first 16 h) to give 162 g of the desired product (98.8 HPLC purity, 88% isolated yield assuming 100 wt% starting material, 0.5% residual nBuOH by NMR, XRPD and m.p. confirmed H2A3 salt form).

Example 9: Enamine formation and hydrogenatlon

[0087] To CEP-41 160 (10 g) was added MgS04 (2.5 g, 25 wt%) and dichloromethane (8 volumes wrt CEP-41 160) at room temperature and stirred for 4 days. The resulting slurry was filtered and the filtrant was concentrated to an oil. The oil was then taken up into MTBE (70 mL, 7 volumes) which resulted in crystallization. The slurry was cooled to 0 °C and the product was filtered washing with cold MTBE. The product was dried with nitrogen under vacuum to afford 10.5 g of the product (68%). Additional MTBE crystallizations could be applied to increase purity as desired.

[0088] Prior to the reaction, the NaBArF was dried by co-evaporation with dry toluene (3 times) to remove traces of water. Trifluoroethanol was dried over molecular sieves (Union Carbide, Type 13X). In a pre-dried Schlenk, the appropriate amount of [Ir(COE)2Cl]2 precursor and RD81 was dissolved in dry DCM. After stirring the solution for 30 minutes, the NaBArF was added and stirred for an additional 30 minutes. In a separate Schlenk, the appropriate amount of substrate was dissolved in dry trifluoroethanol and stirred for 30 minutes. To a pre-dried high-pressure autoclave both the catalyst solution and substrate solution were transferred under a gentle stream of dry nitrogen. The autoclave was closed and pressurized to 50 bars of hydrogen and stirred for the desired reaction time. Then, the autoclave was vented and the reaction mixture collected. Work-up of the samples: all volatiles were removed in vacuo.

[

Example 10

I II

[0090] Preparation of hydrogenation substrate was accomplished by condensation of the ketone (1 eq.) and amide (1.1 eq. – 1.3 eq) catalyzed by TsOH (0.05 eq. to 0.1 eq.) in toluene.

[0091] To a solution of I (4.7 g, 20 mmol) in toluene (30 mL, 7 vol) was added acetamide (1.54 g, 26 mmol, 1.3 equiv) and TsOH.H20 (0.02 g, 1 mmol, 0.05 equiv.). The mixture was refluxed under N2 equipped with a Dean-Stark apparatus to remove H20. The progress of the reaction was monitored by TLC. When the reaction was completed, the mixture was cooled down. The solution was washed with H20, dried over Na2S04 and concentrated. The residue was purified by silica gel column chromatography with hexane/ethyl acetate (5/l→ 1/1, v/v) as eluent to give the desired product as a yellow solid (5.0 g, 90% yield).

Example 11

Π m

[0092] Asymetric hydrogenations were conducted using catalytic Ru(R-C3-TunePhos)(acac)2 in methanol with 0.25 eq. of H3P04 (20 mg/mL), at about 30, 50, and 70 °C using 10, 20, 35, 50, and 70 atm of H2. Reaction times were about 15 – 18 h.Conversions of >99% were achieved. Enantiomeric excesses (%) of 67% – 82% were observed.

Example 12

Π m

[0093] Asymetric hydrogenations were conducted using catalytic Ru(S-Cs-TunePhos)(acac)2 in methanol or ethanol with 0.063 eq., 0.125 eq. 0.25 eq., and 0.5 eq. of H3PO4 (20 mg/mL), at about 50, 70, and 90 °C using 20, 50, 70,and 75 atm of H2. Reaction times were about 15 – 18 h.Conversions of >99% were achieved. Enantiomeric excesses (%) of 79% – 86% were observed.

Example 13

π m

[0094] In a glove box, to a hydrogenator (with glass liner) were added the substrate (4.14 g, 15 mmol), Ru(S-C5-TunePhos)(acac)2 (13.8 mg, 0.015 mmol, TONI OOO), Η3ΡΟ» (9 mL, 20 mg/mL in CH3OH, 0.125 equiv), CH3OH (19 mL, 7 vol) and a magnetic stirring bar. The hydrogenator was sealed and taken out of the glove box. The hydrogenator was charged with hydrogen to 50 atm. and put in an oil bath. The reaction mixture was stirred under 50 atm. at 50 °C for 48 h. After hydrogen was released carefully, the reaction mixture was concentrated.

Recrystallization from CH3OH (55 mL) gave the desired product as an off-white solid (2.29 g, 55% yield).

References:

Allwein, S.P et al., Org. Process Res. Dev. 2012, 16, 148-155.

Purohit, V.C. Org. Lett. 2013, 15, 1650-1653.

WO2008/051547

PAPER

Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK)

Teva Branded Pharmaceutical Products R&D, 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States
Champions Oncology, Inc., One University Plaza, Suite 307, Hackensack, New Jersey 07601, United States
§ Thomas Jefferson University, 233 South 10th Street, 1002 BLSB, Philadelphia, Pennsylvania 19107, United States
J. Med. Chem., 2016, 59 (16), pp 7478–7496
DOI: 10.1021/acs.jmedchem.6b00487
*Telephone: 1-610-738-6861. E-mail: gregory.ott@tevapharm.com.
Abstract Image
Journal of Medicinal Chemistry (2016), 59(16), 7478-7496
Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein

(27b) 2-[[5-Chloro-2-[[(6S)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-1-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]amino]pyrimidin-4-yl]amino]-N-methylbenzamide

 27b (1.1 g, 28%) as an off-white foamy solid.
LC/MS (ESI+) m/z = 580.0 (M + H)+;
1H NMR (400 MHz, CDCl3) δ 11.02 (s, 1H), 8.69 (d, J = 8.9 Hz, 1H), 8.13 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.59–7.50 (m, 2H), 7.41 (s, 1H), 7.13 (t, J = 7.4 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.21 (s, 1H), 3.74 (m, 3H), 3.66–3.63 (m, 2H), 3.29–3.23 (m, 1H), 3.06 (d, J = 4.3 Hz, 3H), 2.92–2.72 (m, 5H), 2.66–2.55 (m, 8H), 2.48–2.39 (m, 2H), 2.16–2.10 (m, 2H), 1.87–1.77 (m, 1H), 1.42–1.32 (m, 1H).
13C NMR (101 MHz, DMSO-d6) δ 168.9, 158.5, 155.0, 154.7, 149.0, 139.3, 137.3, 135.6, 131.4, 130.3, 127.9, 124.4, 121.8, 121.3, 120.5, 104.8, 63.1, 61.0, 60.4, 58.5, 53.8, 47.7, 38.1, 33.9, 26.4, 26.3, 25.7, 25.5.
High resolution mass spectrum m/z 580.2807 [(M + H)+ calcd for C30H39ClN7O3 580.2803]. HPLC purity: 99 A%.
PAPER

Development of a Process Route to the FAK/ALK Dual Inhibitor TEV-37440

Chemical Process Research & Development, Analytical Development, Teva Pharmaceuticals, 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00070
Abstract Image

The development of a scalable route to TEV-37440, a dual inhibitor of focal adhesion kinase (FAK) and anaplastic lymphoma kinase (ALK), is presented. The medicinal chemistry route used to support this target through nomination is reviewed, along with the early process chemistry route to support IND (inversigational new drug) enabling activities within CMC (Chemistry, Manufacturing, and Controls). The identification and development of an improved route that was performed in the pilot plant to supply early phase clinical supplies are discussed. Details surrounding the use of a novel ring expansion, a selective nitration through a para-blocking group strategy, a single-pot amination–hydrogenation, a diastereomeric salt resolution, a through-process step to avoid a hazardous intermediate, and a practical formation of a trihydrochloride dihydrate salt are disclosed.

str1 str2str3 str4

2-[(5-Chloropyrimidin-4-yl)amino]-N-methyl-benzamide; 2-[4-[(6S)-1-Methoxy-2-(methylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl]piperazin-1-yl]ethanol (2, Free Base)

 2 (75% yield) as the free base with >99.6 A% purity.
1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.74 (dd, J = 8.7, 4.1 Hz, 1H), 8.6 (d, J = 8.4 Hz, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 7.73 (dd, J = 7.9, 1.4 Hz, 1H), 7.54 (d, J = 8.1, 1H), 7.37 (ddd, J = 7.8, 7.8, 1.1, 1H), 7.10 (ddd, J = 7.6, 7.6, 1.0, 1H), 6.91 (d, J = 8.2 Hz, 1H), 4.35 (s, 1H), 3.59 (s, 3H), 3.49 (dd, J = 6.1, 6.1 Hz, 2H), 3.36 (br. s, 3H), 3.13–3.08 (m, 1H), 2.86–2.80 (part. ob. m, 1H), 2.80 (d, J = 4.5 Hz, 3H), 2.67–2.61 (m, 2H), 2.54–2.33 (m, 5H), 2.29–2.23 (m, 1H), 2.05–1.93 (m, 2H), 1.81–1.72 (m, 1H), 1.27–1.16 (m, 1H), 1.04 (d, J = 6.1 Hz, 2H);
13C NMR (100 MHz, DMSO-d6) δ 168.9, 158.4, 155.0, 154.6, 148.7, 139.3, 137.1, 135.5, 131.3, 130.2, 127.8, 124.4, 121.7, 121.2, 121.0, 120.5, 104.9, 63.0, 62.0, 60.9, 60.4, 58.5, 53.7, 47.6, 38.1, 33.8, 26.3, 25.4;
HRMS (ESI) calcd for C30H39ClN7O3 [M + H]+: 580.2797, found 580.2813.

2-[(5-Chloropyrimidin-4-yl)amino]-N-methyl-benzamide; 2-[4-[(6S)-1-Methoxy-2-(methylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl]piperazin-1-yl]ethanol Trihydrochloride Dihydrate Salt (2, Salt)

TEV-37440 trihydrochloride-dihydrate (2–3HCl·2H2O) with >99.6 A% purity and >99.5% ee. HPLC was used to determine ee with the following method: Chiralpak IC, 5 μm, 250 × 4.6 mm column, 25 °C, 1 mL/min, isocratic with 48% hexane/48% dichloromethane/2% ethanol/2% methanol/0.1% diethylamine, 20 min.
1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 12.20–11.60 (br. s, 1H), 9.96 (s, 1H), 9.04 (d, J = 4.5 Hz, 1H), 8.53 (s, 1H), 8.39 (d, J = 3.3 Hz, 1H), 7.88 (dd, J = 7.9, 1.1 Hz, 1H), 7.59 (d, J = 8.1, 1H), 7.47 (t, J = 8.1, 1H), 7.29 (ddd, J = 7.6, 7.6, 0.7 Hz, 1H) 7.05 (d, J = 7.6 Hz, 1H), 5.80–4.80 (br. s, 2H), 3.98–3.61 (m, 11H), 3.66 (part. ob. s, 3H), 3.42–3.14 (m, 7H), 2.81 (d, J = 4.5, 3H), 2.36–2.28 (m, 1H), 2.20–2.12 (m, 1H), 2.04–1.92 (m, 1H), 1.40–1.28 (m, 1H);
13C NMR (100 MHz, DMSO-d6) δ 168.4, 156.3, 152.8, 149.5, 144.2, 137.3, 136.2, 135.2, 131.4, 128.8, 128.2, 125.1, 124.3, 122.4, 122.2, 122.0, 105.5, 63.8, 61.8, 58.0, 55.3, 48.7, 43.1, 35.7, 29.4, 26.3, 24.7;
HRMS (ESI) calcd for C30H39ClN7O3 [M + H]+: 580.2797, found 580.2776. Heavy metals <20 ppm. Palladium <5 ppm.
References
  1. Allwein, S. P.; Roemmele, R. C.; Haley, J. J.; Mowrey, D. R.; Petrillo, D. E.; Reif, J. J.; Gingrich, D. E.;Bakale, R. P. Org. Process Res. Dev. 2012, 16, 148155, DOI: 10.1021/op200313v

  2. 2.Ott, G. R.; Cheng, M.; Learn, K. S.; Wagner, J.; Gingrich, D. E.; Lisko, J. G.; Curry, M.; Mesaros, E. F.;Ghose, A. K.; Quail, M. R.; Wan, W.; Lu, L.; Dobrzanski, P.; Albom, M. S.; Angeles, T. S.; Wells-Knecht, K.;Huang, Z.; Aimone, L. D.; Bruckheimer, E.; Anderson, N.; Friedman, J.; Fernandez, S. V.; Ator, M. A.;Ruggeri, B. A.; Dorsey, B. D. J. Med. Chem. 2016, 59, 74787496, DOI: 10.1021/acs.jmedchem.6b00487

///////////////////TEV-37440, TEV 37440, CEP-37440, CEP 37440

CNC(=O)c5ccccc5Nc1nc(ncc1Cl)Nc3ccc2C[C@H](CCCc2c3OC)N4CCN(CC4)CCO

NVP-LXS196


SCHEMBL17506262.png

str1

NVP-LXS196

CAS 1874276-76-2

3-amino-N-[3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl]-6-[3-(trifluoromethyl)pyridin-2-yl]pyrazine-2-carboxamide

  • 3-Amino-N-[3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl]-6-[3-(trifluoromethyl)pyridin-2-yl]pyrazine-2-carboxamide
Molecular Formula: C22H23F3N8O
Molecular Weight: 472.476 g/mol
Inventors Michael Joseph Luzzio, Julien Papillon,Michael Scott Visser
Applicant Novartis Ag

Michael Luzzio

Michael Joseph Luzzio

Julien Papillon

Julien Papillon,

Mike Visser

Michael Scott Visser

Image result

SYNTHESIS

Uveal melanoma (UM) is the most common cancer of the eye in adults (Singh AD. et al., Ophthalmology. 201 1 ; 1 18: 1881-5). Most UM patients develop metastases for which no curative treatment has been identified so far. The majority of UM tumors have mutations in the genes GNAQ (guanine nucleotide-binding protein G(q) subunit alpha) and GNA11 (guanine nucleotide-binding protein G(q) subunit 1 1 ), which encode for small GTPases (Harbour JW. Pigment Cell Melanoma Res. 2012;25: 171-81). Both of these mutations lead to activation of the protein kinase C (PKC) pathway. The up-regulation of PKC pathway has downstream effects which leads to constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway that has been implicated in causing uncontrolled cell growth in a number of proliferative diseases.

Whilst anti-proliferative effects have been observed with certain PKC pathway inhibitors, no sustained MAPK pathway inhibition has been observed. Thus far, PKC inhibitors (PKCi) have had limited efficacy as single agents in patients (Mochly-Rosen D et al., Nat Rev Drug Discov. 2012 Dec;1 1 (12):937-57). Moreover, inhibition of PKC alone was unable to trigger cell death in vitro and/or tumor regression in vivo (Chen X, et al., Oncogene. 2014;33:4724-34).

The protein p53 is a transcription factor that controls the expression of a multitude of target genes involved in DNA damage repair, apoptosis and cell cycle arrest, which are all important phenomena counteracting the malignant growth of tumors. The TP53 gene is one of the most frequently mutated genes in human cancers, with approximately half of all cancers having inactivated p53. Furthermore, in cancers with a non-mutated TP53 gene, typically the p53 is functionally inactivated at the protein level. One of the mechanisms of p53 inactivation is through its interaction with human homolog of MDM2 (Mouse double minute 2) protein. MDM2 protein functions both as an E3 ubiquitin ligase, that leads to proteasomal degradation of p53, and an inhibitor of p53 transcriptional activation. Therefore, MDM2 is an important negative regulator of the p53 tumor suppressor. MDM2 inhibitors can prevent interaction between MDM2 and p53 and thus allow the p53 protein to exert its effector functions. Whilst TP53 mutations are not common in UM, there are reports suggesting the p53 pathway is inactivated by either high expression of MDM2 protein or downregulation of the PERP protein in UM patients.

A combination of an MDM2 inhibitor (Nutlin-3) has been shown to act synergistically with reactivation of p53 and induction of tumor cell apoptosis (RITA) and Topotecan to cause growth inhibition in UM cell lines (De Lange J. et al., Oncogene. 2012;31 :1 105-16). However, Nutlin-3 and Topotecan delayed in vivo tumor growth only in a limited manner.

PATENT

WO 2017029588

PATENT

WO 2016020864

Example 9: 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)- 6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Synthesis of tert-butyl (4-meth l-l-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate

To a solution of 3-fluoro-2-nitropyridine (11.2 g, 81 mmol) in dioxane (200 mL) was added tert-butyl (4-methylpiperidin-4-yl)carbamate (26 g, 121 mmol). Huenig’s Base (28.3 mL,

162 mmol) was added and the mixture was heated to 85 °C for 18 hrs. The reaction was cooled to RT and concentrated to give a brown solid. The solids were washed with 200 mL of 4: 1 heptane:EtOAc. Slurry was concentrated to half volume and filtered to collect (26.2 g, 78 mmol, 96%) brown solid. LC-MS (Acidic Method): ret.time= 1.46 min, M+H = 337.4

Step 2: Synthesis of tert-butyl (4-meth l-l-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate

To a solution of tert-butyl (4-methyl-l-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate (11.6 g, 37.2 mmol) in ethyl acetate (200 mL). 10% Pd-C (3.48 g) was added and stirred under H2 balloon pressure at RT for 4h. A small amount of MgS04 was added to the reaction and then the reaction mixture was filtered through a pad of cellite, then washed with ethyl acetate (100 mL) and the filtrate was concentrated to afford a brown solid (8.54 g, 27.9 mmol, 85%). LC-MS (Acidic Method): ret.time= 0.91 min, M+H = 307.4.

Step 3: Synthesis of tert-butyl (l-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-meth lpiperidin-4-yl)carbamate

To a solution of 3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylic acid in dimethyl formamide (125 mL) was added ((lH-benzo[d][l,2,3]triazol-l- yl) oxy)

tris(dimethylamino) phosphonium hexafluorophosphate(V) (1.8g, 4.24 mmol) and 4-methylmorpholine (1 mL, 9.79 mmol). Reaction stirred at RT for 40 minutes. Tert-butyl (l-(2-aminopyridin-3-yl)-4-methylpiperidin-4-yl) carbamate in dimethylformamide (25 mL) was added and reaction stirred for 16 hrs at RT. The reaction mixture was diluted with EtOAc and was washed with NaHC03(aq) (3 x 200mL) and brine (lx 200mL). The organic phase was dried with Na2S04, filtered and concentrated. The crude product was taken up in acetonitrile (30 mL) and mixture was allowed to stand at RT for a period of time. Yellow solid collected by filtration (1.39g, 74%). LC-MS (Acidic Method): ret.time= 1.13 mm, M+H = 573.3.

Step 4: Synthesis of 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

A solution of tert-butyl (l-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate (l -39g, 2.06 mmol) in dichloromethane (10 mL) was cooled to 0 °C. 2,2,2-trifluoroacetic acid (2.4 ml, 31 mmol) was added dropwise to the solution. The mixture was allowed to warm to 22 °C and stirred for 4 hrs. Reaction mixture was concentrated to remove DCM and excess TFA. A red oil was produced, which was taken up in 100 mL CHCI3/IPA 3: 1 and saturated aq. NaHCC was added to neutralize the solution. The mixture was then stirred at 22°C for 16 hrs. The mixture transfered to separatory funnel and aqueous layers were washed with CHCI3/IPA 3: 1 (3X 100 mL). Combined organic phases were dried with Na2S04, filtered and concentrated to afford a yellow solid. The crude product was recrystallized from acetonitrile. A yellow solid was collected by filtration (0.82g, 83%). LC-MS (Acidic Method ): ret.time= 0.75 mm, M+H = 473.2. 1H NMR (400 MHz, Methanol-^) δ 8.92 (dd, J = 5.1, 1.4 Hz, 1H), 8.68 (s, 1H), 8.47 – 8.27 (m, 1H), 8.12 (dd, J = 4.9, 1.6 Hz, 1H), 7.83 – 7.50 (m, 2H), 7.18 (dd, J = 7.9, 4.9 Hz, 1H), 3.02 – 2.65 (m, 4H), 1.54 – 1.24 (m, 4H), 0.74 (s, 3H).

REFERENCES

Visser, M.; Papillon, J.; Fan, J.; et al.
NVP-LXS196, a novel PKC inhibitor for the treatment of uveal melanoma
253rd Am Chem Soc (ACS) Natl Meet (April 2-6, San Francisco) 2017, Abst MEDI 366

Patent ID Patent Title Submitted Date Granted Date
US2016046605 PROTEIN KINASE C INHIBITORS AND METHODS OF THEIR USE 2015-08-05 2016-02-18

//////////////NVP-LXS196, NVP-LXS 196, 1874276-76-2, Michael Joseph Luzzio, Julien Papillon,Michael Scott Visser, NOVARTIS, PKC inhibitor,  uveal melanoma

FC(F)(F)c1cccnc1c2cnc(N)c(n2)C(=O)Nc3ncccc3N4CCC(C)(N)CC4

http://sanfrancisco2017.acs.org/i/803418-253rd-american-chemical-society-national-meeting-expo/289

Michael Visser of @Novartis talking now in 1st time disclosures about a PKC inhibitor to treat uveal melanoma str0

FDA approves new combination treatment for acute myeloid leukemia, Rydapt (midostaurin)


MIDOSTAURIN

04/28/2017
The U.S. Food and Drug Administration today approved Rydapt (midostaurin) for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation called FLT3, in combination with chemotherapy. The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.

April 28, 2017

Release

The U.S. Food and Drug Administration today approved Rydapt (midostaurin) for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation called FLT3, in combination with chemotherapy. The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of white blood cells in the bloodstream. The National Cancer Institute estimated that approximately 19,930 people would be diagnosed with AML in 2016 and 10,430 were projected to die of the disease.

“Rydapt is the first targeted therapy to treat patients with AML, in combination with chemotherapy,” 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. “The ability to detect the gene mutation with a diagnostic test means doctors can identify specific patients who may benefit from this treatment.”

Rydapt is a kinase inhibitor that works by blocking several enzymes that promote cell growth. If the FLT3 mutation is detected in blood or bone marrow samples using the LeukoStrat CDx FLT3 Mutation Assay, the patient may be eligible for treatment with Rydapt in combination with chemotherapy.

The safety and efficacy of Rydapt for patients with AML were studied in a randomized trial of 717 patients who had not been treated previously for AML. In the trial, patients who received Rydapt in combination with chemotherapy lived longer than patients who received chemotherapy alone, although a specific median survival rate could not be reliably estimated. In addition, patients who received Rydapt in combination with chemotherapy in the trial went longer (median 8.2 months) without certain complications (failure to achieve complete remission within 60 days of starting treatment, progression of leukemia or death) than patients who received chemotherapy alone (median three months).

Common side effects of Rydapt in patients with AML include low levels of white blood cells with fever (febrile neutropenia), nausea, inflammation of the mucous membranes (mucositis), vomiting, headache, spots on the skin due to bleeding (petechiae), musculoskeletal pain, nosebleeds (epistaxis), device-related infection, high blood sugar (hyperglycemia) and upper respiratory tract infection. Rydapt should not be used in patients with hypersensitivity to midostaurin or other ingredients in Rydapt. Women who are pregnant or breastfeeding should not take Rydapt because it may cause harm to a developing fetus or a newborn baby. Patients who experience signs or symptoms of lung damage (pulmonary toxicity) should stop using Rydapt.

Rydapt was also approved today for adults with certain types of rare blood disorders (aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm or mast cell leukemia). Common side effects of Rydapt in these patients include nausea, vomiting, diarrhea, swelling (edema), musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, fever, headache and shortness of breath.

The FDA granted this application Priority Review, Fast Track (for the mastocytosis indication) and Breakthrough Therapy (for the AML indication) designations.

The FDA granted the approval of Rydapt to Novartis Pharmaceuticals Corporation. The FDA granted the approval of the LeukoStrat CDx FLT3 Mutation Assay to Invivoscribe Technologies Inc.

MIDOSTAURIN

(9S,10R,11R,13R)-2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiamzonine-1-one

N-[(9S,10R,11R,13R)-2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiazonin-11-yl]-N-methylbenzamide

N-((9S,10R,11R,13R)-2,3,9,10,11,12-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo(1,2,3-gh:3′,2′,1′-lm)pyrrolo(3,4-j)(1,7)benzodiazonin-11-yl)-N-methyl-,

N-[(2R,4R,5R,6S)-5-methoxy-6-methyl-18-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14(28),15(19),20(27),21(26),22,24-nonaen-4-yl]-N-methylbenzamide hydrate

N-benzoyl staurosporine

NOVARTIS ONCOLOGY ORIGINATOR

Chemical Formula: C35H30N4O4

Exact Mass: 570.22671

Molecular Weight: 570.63710

Elemental Analysis: C, 73.67; H, 5.30; N, 9.82; O, 11.22

Tyrosine kinase inhibitors

PKC 412。PKC412A。CGP 41251。Benzoylstaurosporine;4′-N-Benzoylstaurosporine;Cgp 41251;Cgp 41 251.

120685-11-2 CAS

PHASE 3

  • 4′-N-Benzoylstaurosporine
  • Benzoylstaurosporine
  • Cgp 41 251
  • CGP 41251
  • CGP-41251
  • Midostaurin
  • PKC 412
  • PKC412
  • UNII-ID912S5VON

Midostaurin is an inhibitor of tyrosine kinase, protein kinase C, and VEGF. Midostaurin inhibits cell growth and phosphorylation of FLT3, STAT5, and ERK. It is a potent inhibitor of a spectrum of FLT3 activation loop mutations.

it  is prepared by acylation of the alkaloid staurosporine (I) with benzoyl chloride (II) in the presence of diisopropylethylamine in chloroform.Production Route of Midostaurin

Midostaurin is a synthetic indolocarbazole multikinase inhibitor with potential antiangiogenic and antineoplastic activities. Midostaurin inhibits protein kinase C alpha (PKCalpha), vascular endothelial growth factor receptor 2 (VEGFR2), c-kit, platelet-derived growth factor receptor (PDGFR) and FMS-like tyrosine kinase 3 (FLT3) tyrosine kinases, which may result in disruption of the cell cycle, inhibition of proliferation, apoptosis, and inhibition of angiogenesis in susceptible tumors.

MIDOSTAURIN

Derivative of staurosporin, orally active, potent inhibitor of FLT3 tyrosine kinase (fetal liver tyrosine kinase 3). In addition Midostaurin inhibits further molecular targets such as VEGFR-1 (Vascular Endothelial Growth Factor Receptor 1), c-kit (stem cell factor receptor), H-and K-RAS (Rat Sarcoma Viral homologue) and MDR (multidrug resistance protein).

Midostaurin inhibits both wild-type FLT3 and FLT3 mutant, wherein the internal tandem duplication mutations (FLT3-ITD), and the point mutation to be inhibited in the tyrosine kinase domain of the molecule at positions 835 and 836.Midostaurin is tested in patients with AML.

Midostaurin, a protein kinase C (PKC) and Flt3 (FLK2/STK1) inhibitor, is in phase III clinical development at originator Novartis for the oral treatment of acute myeloid leukemia (AML).

Novartis is conducting phase III clinical trials for the treatment of aggressive systemic mastocytosis or mast cell leukemia. The National Cancer Institute (NCI) is conducting phase I/II trials with the drug for the treatment of chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS).

Massachusetts General Hospital is conducting phase I clinical trials for the treatment of adenocarcinoma of the rectum in combination with radiation and standard chemotherapy.

MIDOSTAURIN

Midostaurin (PKC412) is a multi-target protein kinase inhibitor being investigated for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). It is a semi-synthetic derivative of staurosporine, an alkaloid from the bacterium Streptomyces staurosporeus, and is active in patients with mutations of CD135 (FMS-like tyrosine kinase 3 receptor).[1]

After successful Phase II clinical trials, a Phase III trial for AML has started in 2008. It is testing midostaurin in combination with daunorubicin and cytarabine.[2] In another trial, the substance has proven ineffective in metastatic melanoma.[3]

Midostaurin has also been studied at Johns Hopkins University for the treatment of age-related macular degeneration (AMD), but no recent progress reports for this indication have been made available. Trials in macular edema of diabetic origin were discontinued at Novartis.

In 2004, orphan drug designation was received in the E.U. for the treatment of AML. In 2009 and 2010, orphan drug designation was assigned for the treatment of acute myeloid leukemia and for the treatment of mastocytosis, respectively, in the U.S. In 2010, orphan drug designation was assigned in the E.U. for the latter indication.

MIDOSTAURIN

References

  1.  Fischer, T.; Stone, R. M.; Deangelo, D. J.; Galinsky, I.; Estey, E.; Lanza, C.; Fox, E.; Ehninger, G.; Feldman, E. J.; Schiller, G. J.; Klimek, V. M.; Nimer, S. D.; Gilliland, D. G.; Dutreix, C.; Huntsman-Labed, A.; Virkus, J.; Giles, F. J. (2010). “Phase IIB Trial of Oral Midostaurin (PKC412), the FMS-Like Tyrosine Kinase 3 Receptor (FLT3) and Multi-Targeted Kinase Inhibitor, in Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome with Either Wild-Type or Mutated FLT3”. Journal of Clinical Oncology 28 (28): 4339–4345. doi:10.1200/JCO.2010.28.9678PMID 20733134edit
  2.  ClinicalTrials.gov NCT00651261 Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
  3.  Millward, M. J.; House, C.; Bowtell, D.; Webster, L.; Olver, I. N.; Gore, M.; Copeman, M.; Lynch, K.; Yap, A.; Wang, Y.; Cohen, P. S.; Zalcberg, J. (2006). “The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study”British Journal of Cancer 95 (7): 829–834. doi:10.1038/sj.bjc.6603331PMC 2360547PMID 16969355.
    1. Midostaurin product page, Fermentek
    2.  Wang, Y; Yin, OQ; Graf, P; Kisicki, JC; Schran, H (2008). “Dose- and Time-Dependent Pharmacokinetics of Midostaurin in Patients With Diabetes Mellitus”. J Clin Pharmacol 48 (6): 763–775. doi:10.1177/0091270008318006PMID 18508951.
    3.  Ryan KS (2008). “Structural studies of rebeccamycin, staurosporine, and violacein biosynthetic enzymes”Ph.D. Thesis. Massachusetts Institute of Technology.

Bioorg Med Chem Lett 1994, 4(3): 399

US 5093330

EP 0657164

EP 0711556

EP 0733358

WO 1998007415

WO 2002076432

WO 2003024420

WO 2003037347

WO 2004112794

WO 2005027910

WO 2005040415

WO 2006024494

WO 2006048296

WO 2006061199

WO 2007017497

WO 2013086133

WO 2012016050

WO 2011000811

8-1-2013
Identification of potent Yes1 kinase inhibitors using a library screening approach.
Bioorganic & medicinal chemistry letters
 
3-1-2013
Evaluation of potential Myt1 kinase inhibitors by TR-FRET based binding assay.
European journal of medicinal chemistry
2-23-2012
Testing the promiscuity of commercial kinase inhibitors against the AGC kinase group using a split-luciferase screen.
Journal of medicinal chemistry
 
1-26-2012
VX-322: a novel dual receptor tyrosine kinase inhibitor for the treatment of acute myelogenous leukemia.
Journal of medicinal chemistry
1-1-2012
H2O2 production downstream of FLT3 is mediated by p22phox in the endoplasmic reticulum and is required for STAT5 signalling.
PloS one
10-27-2011
Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase.
Journal of medicinal chemistry
 
6-1-2011
Discovery, synthesis, and investigation of the antitumor activity of novel piperazinylpyrimidine derivatives.
European journal of medicinal chemistry
3-1-2010
Colony stimulating factor-1 receptor as a target for small molecule inhibitors.
Bioorganic & medicinal chemistry
7-18-2012
Staurosporine Derivatives as Inhibitors of FLT3 Receptor Tyrosine Kinase Activity
6-13-2012
Crystal form of N-benzoyl-staurosporine
12-14-2011
COMPOSITIONS FOR TREATMENT OF SYSTEMIC MASTOCYTOSIS
7-6-2011
Staurosporine derivatives as inhibitors of flt3 receptor tyrosine kinase activity
7-6-2011
Staurosporine Derivatives for Use in Alveolar Rhabdomyosarcoma
12-10-2010
Pharmaceutical Compositions for treating wouds and related methods
11-5-2010
COMBINATIONS OF JAK INHIBITORS
7-23-2010
COMBINATIONS COMPRISING STAUROSPORINES
3-5-2010
COMBINATION OF IAP INHIBITORS AND FLT3 INHIBITORS
1-29-2010
ANTI-CANCER PHOSPHONATE ANALOGS
1-13-2010
Therapeutic phosphonate compounds
11-20-2009
Use of Staurosporine Derivatives for the Treatment of Multiple Myeloma
7-17-2009
KINASE INHIBITORY PHOSPHONATE ANALOGS
6-19-2009
Organic Compounds
3-20-2009
Use of Midostaurin for Treating Gastrointestinal Stromal Tumors
11-21-2008
PHARMACEUTICAL COMPOSITIONS COMPRISING A POORLY WATER-SOLUBLE ACTIVE INGREDIENT, A SURFACTANT AND A WATER-SOLUBLE POLYMER
11-19-2008
Anti-cancer phosphonate analogs
9-12-2008
Multi-Functional Small Molecules as Anti-Proliferative Agents
9-5-2008
Sensitization of Drug-Resistant Lung Caners to Protein Kinase Inhibitors
8-29-2008
Organic Compounds
8-27-2008
Kinase inhibitory phosphonate analogs
4-25-2008
Treatment Of Gastrointestinal Stromal Tumors With Imatinib And Midostaurin
12-28-2007
Pharmaceutical Uses of Staurosporine Derivatives
12-7-2007
Kinase Inhibitor Phosphonate Conjugates
8-17-2007
Combinations comprising staurosporines
10-13-2006
Staurosporine derivatives for hypereosinophilic syndrome
7-15-2005
Phosphonate substituted kinase inhibitors
10-20-2004
Staurosporin derivatives

MIDOSTAURIN HYDRATE

Midostaurin according to the invention is N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiazonin-11-yl]-N-methylbenzamide of the formula (II):

Figure US20090075972A1-20090319-C00002

or a salt thereof, hereinafter: “Compound of formula II or midostaurin”.

Compound of formula II or midostaurin [International Nonproprietary Name] is also known as PKC412.

Midostaurin is a derivative of the naturally occurring alkaloid staurosporine, and has been specifically described in the European patent No. 0 296 110 published on Dec. 21, 1988, as well as in U.S. Pat. No.  5093330 published on Mar. 3, 1992, and Japanese Patent No. 2 708 047.

………………….

https://www.google.co.in/patents/EP0296110B1

The nomenclature of the products is, on the complete structure of staurosporine ([storage]-NH-CH ₃derived, and which is designated by N-substituent on the nitrogen of the methylamino group

Figure imgb0028

Example 18:

     N-Benzoyl-staurospor

  • A solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of N, N-diisopropylethylamine in 2 ml of chloroform is added at room temperature with 0.035 ml (0.3 mmol) of benzoyl chloride and 10 stirred minutes.The reaction mixture is diluted with chloroform, washed with sodium bicarbonate, dried over magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (eluent methylene chloride / ethanol 30:1), mp 235-247 ° with brown coloration.
  • cut paste may not be ok below

Staurosporine the formula [storage]-NH-CH ₃ (II) (for the meaning of the rest of [storage] see above) as the basic material of the novel compounds was already in 1977, from the cultures of Streptomyces staurosporeus AWAYA, and TAKAHASHI

O ¯

Figure imgb0003

MURA, sp. nov. AM 2282, see Omura, S., Iwai, Y., Hirano, A., Nakagawa, A.; awayâ, J., Tsuchiya, H., Takahashi, Y., and Masuma, R. J. Antibiot. 30, 275-281 (1977) isolated and tested for antimicrobial activity. It was also found here that the compound against yeast-like fungi and microorganisms is effective (MIC of about 3-25 mcg / ml), taking as the hydrochloride = having a LD ₅ ₀ 6.6 mg / kg (mouse, intraperitoneal). Stagnated recently it has been shown in extensive screening, see Tamaoki, T., Nomoto, H., Takahashi, I., Kato, Y, Morimoto, M. and Tomita, F.: Biochem. and Biophys. Research Commun. 135 (No. 2), 397-402 (1986) that the compound exerts a potent inhibitory effect on protein kinase C (rat brain)

…………………

https://www.google.co.in/patents/US5093330

EXAMPLE 18 N-benzoyl-staurosporine

0.035 ml (0.3 mmol) of benzoyl chloride is added at room temperature to a solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of N,N-diisopropylethylamine in 2 ml of chloroform and the whole is stirred for 10 minutes. The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation. The crude product is chromatographed on silica gel (eluant:methylene chloride/ethanol 30:1); m.p. 235

…………………….

Bioorg Med Chem Lett 1994, 4(3): 399

http://www.sciencedirect.com/science/article/pii/0960894X94800049

Full-size image (2 K)

……………………

http://www.google.com/patents/WO1998007415A2

A variety of PKC inhibitors are available in the art for use in the invention. These include bryostatin (U.S. Patent 4,560,774), safinogel (WO 9617603), fasudil (EP 187371), 7- hydoxystaurosporin (EP 137632B), various diones described in EP 657458, EP 657411 and WO9535294, phenylmethyl hexanamides as described in WO9517888, various indane containing benzamides as described in WO9530640, various pyrrolo [3,4-c]carbazoles as described in EP 695755, LY 333531 (IMSworld R & D Focus 960722, July 22, 1996 and Pharmaprojects Accession No. 24174), SPC-104065 (Pharmaprojects Accession No. 22568), P-10050 (Pharmaprojects Accession No. 22643), No. 4432 (Pharmaprojects Accession No. 23031), No. 4503 (Pharmaprojects Accession No. 23252), No. 4721 (Pharmaprojects Accession No. 23890), No. 4755 (Pharmaprojects Accession No. 24035), balanol (Pharmaprojects Accession No. 20376), K-7259 (Pharmaprojects Accession No. 16649), Protein kinase C inhib, Lilly (Pharmaprojects Accession No. 18006), and UCN-01 (Pharmaprojects Accession No. 11915). Also see, for example, Tamaoki and Nakano (1990) Biotechnology 8:732-735; Posada et al. (1989) Cancer Commun. 1:285-292; Sato et al. (1990) Biochem Biophys. Res. Commun. 173:1252-1257; Utz et al. (1994) Int. J. Cancer 57:104-110; Schwartz et al. (1993) J. Na . Cancer lnst. 85:402-407; Meyer et al. (1989) Int. J. Cancer 43:851-856; Akinaga et al. (1991) Cancer Res. 51:4888-4892, which disclosures are herein incorporated by reference. Additionally, antisense molecules can be used as PKC inhibitors. Although such antisense molecules inhibit mRNA translation into the PKC protein, such antisense molecules are considered PKC inhibitors for purposes of this invention. Such antisense molecules against PKC inhibitors include those described in published PCT patent applications WO 93/19203, WO 95/03833 and WO 95/02069, herein incorporated by reference. Such inhibitors can be used in formulations for local delivery to prevent cellular proliferation. Such inhibitors find particular use in local delivery for preventing rumor growth and restenosis.

N-benzoyl staurosporine is a benzoyl derivative of the naturally occurring alkaloid staurosporine. It is chiral compound ([a]D=+148.0+-2.0°) with the formula C35H30R1O4 (molecular weight 570.65). It is a pale yellow amorphous powder which remains unchanged up to 220°C. The compound is very lipophilic (log P>5.48) and almost insoluble in water (0.068 mg/1) but dissolves readily in DMSO.

……………………….

staurosporine

Staurosporine (antibiotic AM-2282 or STS) is a natural product originally isolated in 1977 from the bacterium Streptomyces staurosporeus. It was the first of over 50 alkaloids to be isolated with this type of bis-indole chemical structure. The chemical structure of staurosporine was elucidated by X-ray analysis of a single crystal and the absolute stereochemical configuration by the same method in 1994.

Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive. The interest in these activities resulted in a large investigative effort in chemistry and biology and the discovery of the potential for anti-cancer treatment

Synthesis of Staurosporine

Staurosporine is the precursor of the novel protein kinase inhibitor midostaurin(PKC412). Besides midostaurin, staurosporine is also used as a starting material in the commercial synthesis of K252c (also called staurosporine aglycone). In the natural biosynthetic pathway, K252c is a precursor of staurosporine.

Indolocarbazoles belong to the alkaloid sub-class of bisindoles. Of these carbazoles the Indolo(2,3-a)carbazoles are the most frequently isolated; the most common subgroup of the Indolo(2,3-a)carbazoles are the Indolo(2,3-a)pyrrole(3,4-c)carbazoles which can be divided into two major classes – halogenated (chlorinated) with a fully oxidized C-7 carbon with only one indole nitrogen containing a β-glycosidic bond and the second class consists of both indole nitrogen glycosilated, non-halogenated, and a fully reduced C-7 carbon. Staurosporine is part of the second non-halogenated class.

The biosynthesis of staurosporine starts with the amino acid L-tryptophan in its zwitterionic form. Tryptophan is converted to an imineby enzyme StaO which is an L-amino acid oxidase (that may be FAD dependent). The imine is acted upon by StaD to form an uncharacterized intermediate proposed to be the dimerization product between 2 imine molecules. Chromopyrrolic acid is the molecule formed from this intermediate after the loss of VioE (used in the biosynthesis of violacein – a natural product formed from a branch point in this pathway that also diverges to form rebeccamycin. An aryl aryl coupling thought to be catalyzed by a cytochrome P450enzyme to form an aromatic ring system occurs

Staurosporine 2

This is followed by a nucleophilic attack between the indole nitrogens resulting in cyclization and then decarboxylation assisted by StaC exclusively forming staurosporine aglycone or K252c. Glucose is transformed to NTP-L-ristoamine by StaA/B/E/J/I/K which is then added on to the staurosporine aglycone at 1 indole N by StaG. The StaN enzyme reorients the sugar by attaching it to the 2nd indole nitrogen into an unfavored conformation to form intermediated O-demethyl-N-demethyl-staurosporine. Lastly, O-methylation of the 4’amine by StaMA and N-methylation of the 3′-hydroxy by StaMB leads to the formation of staurosporine

US4107297 * 28 Nov 1977 15 Aug 1978 The Kitasato Institute Antibiotic compound
US4735939 * 27 Feb 1987 5 Apr 1988 The Dow Chemical Company Insecticidal activity of staurosporine
ZA884238A * Title not available
////////FDA 2017, acute myeloid leukemia, Rydapt, midostaurin, Novartis Pharmaceuticals Corporation, LeukoStrat CDx FLT3 Mutation Assay,  Invivoscribe Technologies Inc, Priority Review, Fast Track, (for the mastocytosis indication, Breakthrough Therapy

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