MYSELF

DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 36Yrs Exp. in the feld of Organic Chemistry,Working for AFRICURE PHARMA as ADVISOR earlier with 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

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 AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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 Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, 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 38 lakh plus views on New Drug Approvals Blog in 227 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 He has total of 32 International and Indian awards

Verified Services

View Full Profile →

Iptakalim Hydrochloride 盐酸埃他卡林

December 4, 2015 12:28 pm / Leave a comment

Iptakalim Hydrochloride 盐酸埃他卡林

A K(ir) 6.1/SUR2B activator potentially for the treatment of pulmonary arterial hypertension.

179.7, C9H21N.HCl

CAS No. 642407-44-1(Iptakalim)

642407-63-4(Iptakalim Hydrochloride)

N-(1-methylethyl)-2,3-dimethyl-2-butylamine

	Catholic Healthcare West (D/B/A/ St. Joseph’s Hospital And Medical Center)

Catholic Healthcare West (D/B/A/ St. Joseph’s Hospital And Medical Center)

Hypertension is a multifactorial disorder, and effective blood pressure control is not achieved in most individuals. According to the most recent report of the American Heart Association, for 2010, the estimated direct and indirect financial burden for managing hypertension is estimated to be $76.6 billion. Overall, almost 75% of adults with cardiovascular diseases/comorbidities have hypertension, which is associated with a shorter overall life expectancy. Alarmingly, rates of prehypertension and hypertension are increasing among children and adolescents due, in part, to the obesity epidemic we currently face. There is also the problem of an aging population and the growing rates of diabetes and obesity in adults, all factors that are associated with high blood pressure.Thus, the need is great for novel drugs that target the various contributing causes of hypertension and the processes leading to end organ damage.

Iptakalim (IPT), chemically 2, 3–dimethyl-N-(1-methylethyl)-2-butanamine hydrochloride, is novel adenosine triphosphate–sensitive potassium (K_ATP) channel opener. K_ATP channels are composed of discrete pore-forming inward rectifier subunits (Kir6.1s) and regulatory sulphonylurea subunits (SUR).IPT shows high selectivity for cardiac K_ATP (SUR2A/Kir6.2) and vascular K_ATP (SUR2B/Kir6.1 or SUR6B/Kir6.2). Because of this high selectivity, IPT does not exhibit the adverse side effects associated with the older nonspecific K⁺ channel openers, which limit their use to the treatment of severe or refractory hypertension. IPT produces arteriolar and small artery vasodilatation, with no significant effect on capacitance vessels or large arteries. Vasodilatation is induced by causing cellular hyperpolarization via the opening of K⁺ channels, which in turn decreases the opening probability of L-type Ca²⁺ channels. Of particular note, IPT is very effective in lowering the blood pressure of hypertensive humans but not of those with normal blood pressure.

The present compd relates generally to a novel method for decreasing a human’s cravings for cigarettes and reducing instances of relapse during detoxification once smoking abstinence has been achieved, and more specifically, to a method for decreasing nicotine use by treating a human with a novel type of nicotinic acetylcholine receptor antagonist, iptakalim hydrochloride (IPT).

Cigarette smoking is a prevalent, modifiable risk factor for increased morbidity and mortality in the United States, and perhaps in the world. Smokers incur medical risks attributable to direct inhalation. Bystanders, termed passive smokers, also incur medical risks from second-hand smoke. Society, as a whole, also bears the economic costs associated with death and disease attributable to smoking. Although the majority of smokers have tried repeatedly to quit smoking, eighty percent of smokers return to tobacco in less than two years after quitting. Therefore, tobacco dependence is a health hazard for millions of Americans.
Nicotine is the biologically active substance that is thought to promote the use of tobacco products by approximately one-quarter of the world populations. Tobacco-related disease is personally and economically costly to the any nation. Unfortunately, once use of tobacco has begun, it is hard for a smoker to quit because of nicotinic dependence and addiction.
The initiation and maintenance of tobacco dependence in a human is due to certain bio-behavioral and neuromolecular mechanisms. Nicotinic acetylcholine receptors (nAChRs) in humans are the initial binding sites for nicotine. The binding of nicotine to nAChRs is thought to modulate the brain’s “reward” function by triggering dopamine release in the human brain. The nAChRs exist as a diverse family of molecules composed of different combinations of subunits derived from at least sixteen genes. nAChRs are prototypical members of the ligand-gated ion channel superfamily of neurotransmitter receptors. nAChRs represent both classical and contemporary models for the establishment of concepts pertaining to mechanisms of drug action, synaptic transmission, and structure and function of transmembrane signaling molecules.
Basic cellular mechanisms of nicotinic dependence also involve the functional state changes during repeated nicotinic agonists exposure and receptor changes in the number of receptors during chronic nicotinic exposure. nAChRs can exist in many different functional states, such as resting, activated, desensitized or inactivated The activation and/or desensitization of nAChRs plays an important role in initiating nicotinic tolerance and dependence. Recovery from receptor activation and/or desensitization contributes to nicotinic withdrawal symptoms.
The most abundant form of nAChRs in the brain contains α4 and β2 subunits. α4β2-nAChRs bind nicotine with high affinity and respond to levels of nicotine found in the plasma of smokers. α4β2-nAChR also have been implicated in nicotine self-administration, reward, and dependence. Therefore, selective drug action at nAChRs, especially at those containing α4 subunits, is thought to be an ideal way for nicotine cessation and reducing nicotine withdrawal syndrome. Unfortunately, thus far, no optimal compound can meet this purpose. The brain-blood-barrier permeable nAChR antagonist, mecamylamine is popularly used systemically but exhibits much less nAChR subtype selectivity.
Although a variety of psychopharmacological effects contribute to drug reinforcement, actions on the mesolimbic dopaminergic pathway is the predominant hypothesis for mechanisms of nicotinic reward. The mesolimbic dopaminergic pathway originates in the ventral tegmental area (VTA) of the midbrain and projects to forebrain structures including the prefrontal cortex and to limbic areas such as the olfactory tubercle, the amygdala, the septal region, and the nucleus accumbens. Many studies have indicated that dopamine release in the nucleus accumbens of the human brain is “rewarding” or signals an encounter with a “reward” from the environment. Other substances, such as alcohol, cocaine, and opiates, operate in the same manner, resulting in a cycle of substance or alcohol abuse.
Therefore, a considerable need exists for a novel compound that can selectively block α4 subtypes of nAChRs to prevent smoking-induced “reward”, to limit increasing nicotine-induced dopamine release, and/or to diminish nicotinic withdrawal symptoms.

Patent

https://www.google.com/patents/US20040266822

Example 1

Production of N-(1-methylethyl)-2,3-dimethyl-2-butylamine (Compound 1): Method 1. The solution of 7.6 g (0.0745 mole) 2,3-dimethyl-2-butanol in 3.24 mL glacial acetic acid was cooled and maintained at −5 to −8 degree of centigrade (° C.), then was added 7.3 g (0.49 mole) of powdered potassium cyanide in several times under stirring. 32.4 mL concentrated sulfuric acid was added dropwise while keeping the temperatue below 20° C., after which, the reaction mixture was stirred for 3.5 hours below 20° C. and another 6 hours at room temperature, then stood overnight. After poured into ice colded water, the mixture was adjusted to pH10 with 20% aqueous sodium hydroxide solution, and extracted with ether (×4). The extract was dried over anhydrous sodium sulfate. After filtration on the next day, the dessicator was removed, and the filtrate was evaporated off the ether, then distilled in vacuum to give 8.8 g (yield 91.6%) N-[2-(2,3-dimethylbutyl)]-fomide; bp 105-108° C./5 mmHg.
To the mixture of 7.7 g (0.0597 mole) N-[2-(2,3-dimethylbutyl)]-formide, 6.2 mL ethanol and 51.6 mL wate, 17.4 mL concentrated hydrochloric acid was added. The reaction mixture was refluxed for 4 hours in the oil bath, then distilled off ethanol in vacuum. The residue was adjusted to above pH12 with 40% aqueous sodium hydroxide solution, and extracted with ether. The extract was dried over anhydrous potassiun carbonate. After recovering the ether, The residue was distilled at atmosphere to give 3.75 g (yield 62.2%) 2,3-dimethyl-2-butylamine, bp 97-104° C.
The mixture of 10.6 g (0.15 mole) 2,3-dimethyl-2-butylamine, 6.45 g (0.0524 mole) 2-bromopropane, 3.0 mL glycol and 22.0 mL toluene was added into an autoclave, and heated with stirring for 17 hours at temperature of 170° C., after which, the organic layer was separated and extracted with 6N hydrochloric acid (15 mL×4). The extract was combined and washed once with toluene, then adjusted to pH 12-13 with 4% aqueous sodium hydroxide in the ice bath. The mixture was extracted with ether and then dried over anhydrous potassium carbonate. After recovering the ether, The filtrate was distilled to yield the fraction of bp 135-145° C. (yield 68.8%). The hydrochloride’s Mp is 228-230° C. (1-PrOH-Et₂O). Elemental analysis for C₉H₂₂ClN(%): Calculated C, 60.14; H, 12.34; N, 7.79, Cl 19.73; Found C, 60.14; H, 12.48; N, 7.31, Cl 19.67.
¹H-NMR(D₂O, ppm) 0.98(d, J=6.75H, 6H), 1.33(s, 6H), 1.37(d, J=6.46, 6H), 2.10(m, 1H), 3.70(m, 1H). MS(m/z) 143 (M+), 100(B).
Method 2. To the mixture of 288 mL glacial acetic acid, 412 g (6.86 mole) urea and 288 g (3.43 mole) 2,3-dimethyl-2-butene, the solution of 412 mL concentrated sulfuric acid and 412 mL of glacial acetic acid was added dropwise under stirring, while maintaining the reaction temperature at the range of 45° C. to 50° C., then stirred for 5 hours at the temperature of 50-55° C. The mixture stood overnight. Next day, the mixture was reacted for another 7 hours at the temperature of 50-55° C., then poured into the solution of 1200 g (30 mole) sodium hydroxide in 8L glacial water. The resulting solid was filtered, washed with water (200 mL×5) and dried to give 404 g (yield 81.8%) N-(2,3-dimethyl-2-butyl)urea as white solid, mp 175-176° C. Elemental analysis for C₇H₁₆N₂O(%): Calculated C 58.30, H 11.18, N 19.42; Found C, 58.70; H, 11.54; N, 19.25, ¹H-NMR(CDCl₃, ppm) 0.88-0.91(d, 6H, 2×CH₃), 1.26(s, 6H, 2×CH₃), 2.20-2.26(m, 1H, CH), 4,45(br, 2H), 4.65(br, 1H). MS(m/z) 145.0, 144.0(M⁺), 143.0, 129.1, 101.0, 86.1, 69.1, 58.0(B).
To the mixture of 196 g (1.36 mole) N-(2,3-dimethyl-2-butyl)urea and 392 mL glycol or tri-(ethanol)amine, a solution of 118 g (2.95 mole) sodium hydroxide in 118 mL water was added. The reaction mixture was heated for 8 hours in an oil bath at temperature of 120° C., then distilled at atmosphere to collect the fraction of bp 95-102° C. To the fraction, 75 g anhydrous potassium carbonate and. 40 g sodium hydroxide were added. The resulting mixture was distilled to give 88.5 g (yield 64.3%) 2,3-dimethyl-2-butylamine as colorless liquid, bp 99-101° C.
¹H-NMR(CDCl₃, ppm) 0.88-0.91(d, 6H, 2×CH₃), 1.04 (s, 6H, 2×CH₃), 1.53(m, 1H, CH).
To a 50.0 ml autoclave, 10.6 g (0.15 mole) 2,3-dimethyl-2-butylamine, 6.45 g (0.0524 mol) 2-bromopropane, 3.0 ml glycol and 22.0 ml toluene were added, and heated with stirring for 17 hours at 170° C., after which the organic layer was seperated and extracted with 6N hydrochloric acid (15 ml×4). The extract was combined and washed once with toluene, then adjusted to pH 12-13 with 4% aqueous sodium hydroxide in the ice bath. The mixture was extracted with ether and then dried over anhydrous potassium carbonate the ether was recovered, and distilled to give the fraction of bp 135-145° C. (yield 68.8%). mp of the hydrochloride is 228-230° C., (i-PrOH: Et₂O). Elemental analysis for C₉H₂₂ClN(%): Calculated C, 60.14; H, 12.34; N, 7.79, Cl 19.73; Found C 60.14, H 12.48, N 7.31, Cl 19.67. ¹H-NMR(D₂O, ppm) 0.98(d, J=6.75H, 6H), 1.33(s, 6H), 1.37(d, J=6.46, 6H), 2.10(m, 1H), 3.70(m, 1H). MS(m/z) 143 (M⁺), 100(B).
Method 3. a solution of 0.10 mole enamine (prepared from the condensation of methyl iso-propyl ketone and iso-propylamine) in 20 mL hexane was filled with N₂and added dropwise to a solution containing 0.10 mole lithium methide with stirring in ice bath. After the reaction is complete, the mixture was poured into 500 g glacial water, and stirred. The aqueous layer was extracted with ether (×2). The resulting organic layer was concentrated. 3N hydrochloric acid was added to acified the organic layer to pH<1. The mixture was kept minutes and adjusted to pH>11 with 10% aqueous sodium hydroxide, then extracted with ether (×3). The extract was dried over anhydrous potassium carbonate and filtered. The filtrate was distilled at atmosphere to give a fraction of bp 140-145° C. with a yield of 80%.

REF

http://www.google.com/patents/US20060293393

//////Iptakalim Hydrochloride, 盐酸埃他卡林 , K(ir) 6.1/SUR2B activator, pulmonary arterial hypertension, nda

see……….http://apisynthesisint.blogspot.in/2015/12/iptakalim-hydrochloride.html

Tesmilifene , Antagonist of intracellular histamine

December 4, 2015 10:16 am / Leave a comment

Tesmilifene

BMS-217380; BMY-33419; DPPE

CAS No. 98774-23-3(Tesmilifene), 92981-78-7(Tesmilifene hydrochloride)

Tesmilifene

CAS 98774-23-3

N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine

DPPE

MFC19H25NO

MW 283.41

Percent Composition: C 80.52%, H 8.89%, N 4.94%, O 5.65%

Hydrochloride

CAS 92981-78-7

BMS-217380-01; BMY-33419

MF C19H25NO.HCl

MF 319.87

Percent Composition: C 71.34%, H 8.19%, N 4.38%, O 5.00%, Cl 11.08%

Properties: White crystals from isopropanol + acetone (3:1), mp 156-158°. pKa 10.9.

Melting point: mp 156-158°

pKa: pKa 10.9

Therap-Cat: Antineoplastic adjunct (chemosensitizer).

AT YM BIOSCIENCES, GILEAD

Tesmilifene is a novel potentiator of chemotherapy which, when added to doxorubicin, achieved an unexpected and very large survival advantage over doxorubicin alone in a randomized trial in advanced breast cancer.

PHASE 23 FOR An estrogen receptor antagonist potentially for the treatment of advanced breast cancer, gastric cancer

Tesmilifene is a novel agent that augments cytotoxicity of various chemotherapeutic agents both in vitro and in vivo. It binds selectively to the high-affinity microsomal antiestrogen binding site (Ki=50nm) but has no affinity for estrogen receptors. Inhibits concanavalin-A-induced histamine release in mast cells and acts as a novel antagonist of intracellular histamine.

US 4803227

The target product can be prepared by reacting para-benzylphenol (I) with 2-diethylaminoethylchloride hydrochloride (II) either by means of NaOH in H2O or with K2CO3 in DMF/acetone (at 60 C in both cases), followed by treatment with HCl to obtain the corresponding hydrochloride salt.

EP 0153160; JP 1985190742; US 4803227

US 4803227

http://www.google.com/patents/US4803227

Tesmilifene is a small molecule chemopotentiator under development by YM BioSciences, a Candian pharmaceutical company that specialises in the development of cancer treatments. It is indicated for use in combination with standard cytotoxic drugs, such as taxanes and anthracyclines, which are widely used in the treatment of metastatic disease – when cancers spread to distant sites in the body.

Tesmilifene, the company’s lead investigational compound, is currently in phase III development for patients with metastatic breast cancer. At the end of January 2007, an independent safety monitoring board advised the company that its ongoing registration trial should be stopped; it was considered unlikely that significant differences in overall survival (primary endpoint) between treatment arms would emerge over time. The company had hoped that the addition of tesmilifene to standard epirubicin/cyclophosphamide therapy would confer a survival benefit similar to that seen in its earlier phase III trial.

In light of these disappointing results, YM BioSciences plans a detailed analysis of its phase III data in advanced breast cancer to see if it can identify why tesmilifene failed to add clinical benefit in this trial.

DRUG RESISTANCE LIMITS EFFECTIVENESS OF CHEMOTHERAPY

Cytotoxic drugs have proved potent weapons in the fight against malignant tumours and are considered first-line therapy for the treatment of many cancers. However, while patients often respond well to a first course of chemotherapy over time the response to drug treatment diminishes and the tumour may eventually become drug resistant. In some cases resistance can develop across several classes of anti-cancer drugs, leading to multidrug resistance. The development of drug resistance limits the effectiveness of many anti-cancer agents and is an important contributor to cancer deaths.

The development of agents that can overcome drug resistance is seen as one of the most important areas of cancer research and for which there is significant unmet need. Various approaches are being explored to boost the use of cytotoxic agents including chemopotentiators, chemoprotectants and liposomal formulations.

Clearly any agent that can prevent or reverse drug resistance would have a major impact on treatment strategies, enhancing the benefits of standard cytotoxic drugs.

TESMILIFENE MAY BOOST CYTOTOXIC EFFECTS OF ANTHRACYCLINES

Anthracyclines are a class of cytotoxic agents with proven efficacy in the treatment of breast cancer. They include agents such as doxorubicin and epirubicin among others. Because patients with metastatic breast cancer may have received anthracycline therapy for earlier stage breast cancer (adjuvant therapy) or following disease recurrence, there is a risk that they will fail to respond to continued treatment.

A phase III trial in 305 patients with advanced breast cancer has shown that when tesmilifene is combined with doxorubicin it appears to improve survival over treatment with doxorubicin alone. In this trial approximately half the patients were treated with both tesmilifene and doxorubicin, while the other half received doxorubicin alone. Although there were no significant differences in tumour response rates, progression-free survival, or average duration of response between treatment arms at endpoint, overall survival was significantly improved in the combination arm. Among patients treated with tesmilifene and doxorubicin overall survival was 23.6 months compared with 15.6 months for those treated with doxorubicin alone.

Researchers have suggested that tesmilifene may enhance the anti-tumour effects of anthracyclines in several ways:

Reducing the cancer cell’s ability to become resistant
Decreasing the metabolism or “break-down” of doxorubicin
Disrupting the cancer cell’s energy source

TESMILIFENE REGISTRATION TRIAL

In March 2004 YM BioSciences began its pivotal international phase III trial of tesmilifene in metastatic breast cancer. By September 2005, 723 patients had been enrolled in the trial, which was designed once again to compare the efficacy and safety of tesmilifene and an antrhacycline (epirubicin) with epirubicin alone.

“At the end of January 2007, an independent safety monitoring board advised the company that its ongoing registration trial should be stopped.”

Given the survival benefit seen in the earlier trial, which was carried out by the Canadian National Cancer Institute, the company was optimistic about outcome in its pivotal registration trial. However, an interim analysis of 351 events suggested that significant differences in overall survival were unlikely to be seen between the two treatment arms as the data matured and the trial was brought to a premature end.

In addition to its work on anthracyclines, YM BioSciences has also been exploring the potential of tesmilifene to enhance the efficacy of taxanes, also standard chemotherapy for metastatic breast cancer. Other potential applications include:

Adjuvant therapy for breast cancer, i.e. immediately post-surgery and before the cancer has recurred or metastasised
Hormone-refractory prostate cancer
Lung cancer
Non-Hodgkin’s lymphoma

MARKETING COMMENTARY

Although there have been major advances in the treatment of breast cancer in the last 10 to 15 years, it remains a disease for which improved treatments are still urgently needed. Estimates from the WHO suggest that metastatic breast cancer will claim the lives of over 40,000 patients a year.

Current treatments for metastatic breast cancer are rarely curative but can nonetheless do much to improve patients’ quality of life or duration of survival. . By boosting the cytotoxic effects of standard chemotherapy agents such as anthracyclines, while protecting healthy cells, tesmilifene was thought to have potential to extend the benefits of cytotoxic therapy to more patients. This is now in doubt following premature ending of its pivotal registration trial in advanced breast cancer.

Literature References: Intracellular histamine antagonist with chemopotentiating and cytoprotective activity. Structurally similar to tamoxifen, q.v., although binds anti-estrogen binding site (AEBS) with no affinity for the estrogen receptor.

Prepn: L. J. Brandes, M. W. Hermonat, Biochem. Biophys. Res. Commun. 123, 724 (1984); and use as antineoplastic: eidem, US 4803227 (1989 to Univ. Manitoba); and study of binding affinity: M. Poirot et al., Bioorg. Med. Chem. 8, 2007 (2000). Spectral analysis of interaction with P450 isozymes: L. J. Brandes et al., Cancer Chemother. Pharmacol. 45, 298 (2000).

Clinical evaluation in combination with cyclophosphamide in prostate cancer: L. J. Brandes et al., J. Clin. Oncol. 13, 1398 (1995); in combination with doxorubicin in breast cancer: L. Reyno et al., J. Clin. Oncol. 22, 269 (2004).

Bioorg Med Chem 2000,8(8),2007

Patent	Submitted	Granted
Neoadjuvant treatment of Breast Cancer [US2008318880]	2008-12-25
Selective androgen receptor modulators for treating diabetes [US2007281906]	2007-12-06
Nuclear receptor binding agents [US8158828]	2007-11-15	2012-04-17
Treatment of hormone-refractory prostate cancer [US2004220281]	2004-11-04
METABOLITES OF SELECTIVE ANDROGEN RECEPTOR MODULATORS AND METHODS OF USE THEREOF [US8003689]	2010-01-07	2011-08-23
Treatment of metastatic breast cancer with anthracyclines, and taxanes [US2006089317]	2006-04-27
Serm reduction of lipid profiles [US2007135407]	2007-06-14
TREATMENT OF HORMONE-UNRESPONSIVE METASTATIC PROSTATE CANCER [EP0737067]	1996-10-16	2003-09-10
Use of a combination of dppe with other chemotherapeutic agents for the treatment of breast cancer [US2006142287]	2006-06-29
Neoadjuvant treatment of breast cancer [US2006160755]	2006-07-20

Product Literature References

Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene.: P. J. Ferguson, et al.; Cancer Lett. 274, 279 (2009), Abstract;

Phase III study of N,N-diethyl-2-[4-(phenylmethyl) phenoxy]ethanamine (BMS-217380-01) combined with doxorubicin versus doxorubicin alone in metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group St: L. Reyno, et al.; J. Clin. Oncol. 22, 269 (2004), Abstract;

Synergy between tamoxifen and cisplatin in human melanoma cells is dependent on the presence of antiestrogen-binding sites.: J.A. Jones, et al.; Cancer Res. 57, 2657 (1997), Abstract;

Influence of DPPE on histamine release from isolated rat mast cells.: N. Grosman; Agents Actions 41, 1 (1994), Abstract;

Histamine is an intracellular messenger mediating platelet aggregation.: S.P: Saxena, et al.; Science 243, 1596 (1989), Abstract;

///////Tesmilifene, Antineoplastic Adjunct, Chemosensitizer, PHASE 3, Tesmilifene hydrochloride, BMY-33419, BMS-217380, DPPE, N,N-DPPE, Antagonist of intracellular histamine

CCN(CC)CCOC1=CC=C(C=C1)CC2=CC=CC=C2

see……….http://apisynthesisint.blogspot.in/2015/12/tesmilifene-antagonist-of-intracellular.html

RQ 00000010 for the treatment of GERD, functional dyspepsia and chronic constipation.

December 3, 2015 11:09 am / Leave a comment

RQ 00000010

CAS 907607-22-1

Molecular Formula:	C₂₂H₂₇F₃N₂O₆
Molecular Weight:	472.45479 g/mol

HSMMHNBGQLGCBY-UHFFFAOYSA-N;

RaQualia Pharma Inc

Raqualia Pharma Inc.

PFIZER INNOVATOR

RQ-00000010; RQ-10

4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid

ΦirΦfff^fΣ^^-TrifluoroethoxyVi.a-benzisoxazol-S-vnoxylmethvπpiperidin-i-vπmethylltetrahydro-2H-pyran-4-carboxylic acid

4-[[4-[[4-(2,2,2-trifluoroethoxy)-1,2-benzoxazol-3-yl]oxymethyl]piperidin-1-yl]methyl]oxane-4-carboxylic acid

PHASE 1 for the treatment of GERD, functional dyspepsia and chronic constipation.

Useful for treating diseases mediated by 5-HT4 receptor activity eg such as gastroesophageal reflux disease (GERD), gastric motility disorder, dyspepsia, constipation, esophagitis, diabetes, CNS and cardiovascular diseases.

RaQualia, following its spin-out from Pfizer, is developing RQ-00000010, a 5-HT4 receptor partial agonist, for the treatment of gastric motility disorders, including gastroparesis associated with Parkinson’s disease.

In November 2015, the drug was reported to be in phase 1 clinical development. RaQualia and licensee CJ CheilJedang are investigating the drug for the treatment of GERD, functional dyspepsia and chronic constipation.

4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid is disclosed in PL1 as a 5-HT4 receptor agonist, which is useful in the treatment or alleviation of disease conditions mediated by 5-HT4 receptor activity; in particular 5-HT4 receptor agonistic activity, such as gastroesophageal reflux disease (GERD), gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia (FD), irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, gastritis, nausea, central nervous system disease, Alzheimer’s disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes, and apnea syndrome (See NPL 1 to 13 and PL 2 to 7).

Simply an white solid has been produced in the previously known methods of preparing 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid, described in PL 1. A generic disclosure of pharmaceutically-acceptable salts of 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid of the instant application is disclosed, and the free base of the compound of the instant invention is disclosed and claimed, in PL 1 having an international filing date of December 6, 2006, assigned to the assignee hereof. Thus any salts of the compound have been neither pacifically described nor synthesized in prior art.
It has been found that HCl-salt, HBr-salt, pTSA-salt and EDSA-salt of 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid shown below, can be isolated as a crystalline form which has advantageous properties such as ease of making a formulation, high solubility, and good stability. In addition the salts of the present invention are more easily purified than a non-crystalline form disclosed in PL 1 (WO2006/090224) and crystalline form disclosed in PL 3 (WO2012/157288).

Patent Literature
{PL 1} WO2006/090224.
{PL 2} US Patent No. 6,106,864.
{PL 3} WO2012/157288
{PL 4} WO00/35298.
{PL 5} WO91/11172.
{PL 6} WO94/02518.
{PL 7} WO98/55148.
Non Patent Literature
{NPL 1} Bockaert J. et al., TiPs 13; 141-145, 1992.
{NPL 2} Ford A. P et al., Med. Res. Rev. 13: 633-662, 1993.
{NPL 3} Gullikson G. W. et al., Drug Dev. Res. 26; 405-417, 1992.
{NPL 4} Richard M. Eglen et al., TiPs 16; 391-398, 1995.
{NPL 5} Bockaert J. et al., CNS Drugs 1; 6-15, 1994.
{NPL 6} Romanelli M. N. et al., Arzheim Forsch./Drug Res., 43; 913-918, 1993.
{NPL 7} Kaumann A. J. et al., Naunyn-Schmiedebergs Arch Pharmacol., 344; 150-159, 1991.
{NPL 8} Remington’s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).
{NPL 9} Expert Opinion in Therapeutic Patents, H (6), 981-986, by Liang and Chen (2001).
{NPL 10} Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
{NPL 11} Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al. (2001).
{NPL 12} J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
{NPL 13} Evrard, B., et al., Journal of Controlled Release 96 (3), pp. 403-410, 2004.
{NPL 14} Byrn S. R. et al., Solid-State Chemistry of Drugs 2nd ed., pp 3-43 and 461-503, 1999, SSCI, Inc.

PATENT

WO2006090224

PFIZER JAPAN INC.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006090224&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

EXAMPLE 1 :
ΦirΦfff^fΣ^^-TrifluoroethoxyVi.a-benzisoxazol-S-vnoxylmethvπpiperidin-i-vπmethylltetrahydro-2H-pyran-4-carboxylic acid

Step 1. Methyl 2-hvdroxy-6-(2,2,2-trifluoroethoxy)benzoate
A mixture of 5-hydroxy-2,2-dimethyl-4tø-1 ,3-benzodioxin-4-one (123 g, 633 mmol, Synth. Commun.

1994, 24t 1025), potassium carbonate (262 g, 1.9 mol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (95.8 mL, 665 mmol) in Λ/,Λ/-dimethylformamide (600 mL) was stirred at 50 0C for 30 min. Then methanol (300 ml_) was added to the mixture, and stirring was continued for 5 h at that temperature. After cooling to room temperature, the mixture was diluted with water (500 ml_) and neutralized with 2Λ/ hydrochloric acid. Product was extracted with a mixture of ethyl acetate-hexane (5:1 , 500 mL x 3). Combined organic layers were washed with water (500 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residual solid was recrystallized from methanol-water to afford 125 g (79%) of the desired product as colorless crystals.
1H-NMR (CDCI3) δ: 11.47 (1 H, s), 7.36 (1 H, t, J = 8.4 Hz), 6.72 (1 H, dd, J = 1.1 , 8.4 Hz), 6.38 (1 H, q, J = 8.1 Hz), 4.36 (2 H, q, J= 8.0 Hz), 3.96 (3 H, s).
MS (ESI) m/z: 251 (M+H) +, 249 (M-H) \

Step 2. 4-(2,2,2-Trifluoroethoxy)-1 ,2-benzisoxazol-3-ol
To a solution of hydroxylamine sulfate (120 g, 732 mmol) in water (360 mL) was added potassium carbonate (121 g, 875 mmol) at 0 0C. After 30 min of stirring, sodium sulfite (3.74 g, 29.7 mmol) and a methanolic solution of methyl 2-hydroxyl-6-(2,2,2-trifluoroethoxy)benzoate (36.4 g, 146 mmol, EXAMPLE 1 , step 1 , in 360 mL of methanol) were added to the mixture. Then the mixture was warmed to 50 °C and stirred for 30 h. After cooling to room temperature, reaction mixture was partially concentrated to approx. 2/3 volume and acidified with 2Λ/ hydrochloric acid. Product was extracted three times with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the desired product as a crystalline solid. Crude product (36.3 g) was used for the next step without further purification.
The described above crude product (5.56 g, 22.14 mmol) was suspended in tetrahydrofuran (22.0 mL) and heated at 50 °C. 1 ,1 ‘-carbonyldiimidazole (7.54 g, 46.48 mmol) was added to the suspension at 50 °C. After addition, the mixture was stirred at 50 0C for 14 h, the mixture was cooled to room temperature. 2Λ/ hydrochloric acid was added to the mixture and extracted with ethyl acetate. The organic layer was extracted with 10% aq. potassium carbonate (100 mL x 5). The water layers were acidified with 2Λ/ hydrochloric acid and extracted with ethyl acetate (200 mL x 2). The extracts were combined and dried over sodium sulfate and concentrated in vacuo to give brown solid. The residual solid was recrystallized from ethyl acetate/hexane to give 3.21 g (61 %) of the title compound as colorless needles.
1H-NMR (CDCl3) δ: 7.53 (1 H1 1, J = 8.5 Hz), 7.14 (1 H, d, J= 8.5 Hz), 6.73 (1 H, d, J = 7.9 Hz), 4.63 (2 H, q, J= 8.0 Hz), 3.83 (1 H, br).
MS (ESI) m/z: 234 (M+H) +, 232 (M-H) “.

Step 3. rMethoxy(tetrahydro-4H-pyran-4-ylidene)methoxyKtrimethyl)silane
To a stirred solution of diisopropylamine (5.2 mL, 37 mmol) in tetrahydrofuran (15 mL) was added dropwise n-butyllithium (1.6 M in hexane, 21 mL, 34 mmol) at 0 0C and stirred for 20 min. A mixture of methyl tetrahydro-2W-pyran-4-carboxylate (4.5 g, 31 mmol) and trimethylsilyl chloride (4.3 mL, 34 mmol) was added to the mixture at -40 0C, then trimethylsilyl chloride (0.4 mL, 0.3 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 h. The volatile components were removed by evaporation and the residual mixture was filtered through a pad of celite washing with hexane. The filtrate was evaporated to give 6.9 g (quant.) of the title compound as a clear yellow oil.
1H-NMR (CDCI3) δ: 3.64-3.59 (4 H, m), 3.52 (3 H, s), 2.24 (2 H, t, J = 5.6 Hz), 2.15 (2 H, t, J = 5.4 Hz), 0.22 (9 H, s).

Step 4. Methyl 4-{f4-(hvdroxymeth’vDpiperidin-1 -yllmethylltetrahvdro^rt-pyran^-carboxylate
To a stirred mixture of piperidin-4-ylmethanol (5.0 g, 43.4 mmol), f-butyldimethylsilylchloride (7.2 g, 47.8 mmol), and triethylamine (7.3 ml_, 52.1 mmol) in dichloromethane (50 mL) was added 4-dimethylaminopyridine (530 mg, 4.3 mmol) at 0 0C. After being stirred at 0 0C for 2 h, 50 mL of water was added to the mixture. The mixture was extracted with dichloromethane (50 mL x 3) and the extracts were combined, dried over sodium sulfate, and concentrated in vacuo to give 10.2 g of a crude oil. The residual oil was dissolved with 86 mL of ethanol, and potassium carbonate (7.2 g, 52.1 mmol) and paraformaldehyde (1.56 g, 52.1 mmol) were added to the solution. After being stirred at room temperature for 2 days, the mixture was filtered and the filtrate was concentrated in vacuo to give a yellow oil. The residual oil was dissolved with 45 mL of acetonitrile and magnesium chloride (414 mg, 4.3 mmol) was added to the solution. [methoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane (11.3 g, 52.1 mmol, EXAMPLE 1 , step 3) was added to the mixture at 0 0C. After being stirred at 0 0C for 20 h, 100 mL of 2Λ/ hydrochloric acid was added to the mixture. The mixture was stirred for 30 min and washed with diethyl ether (100 mL x 2). The water layer was neutralized with aq. ammonia and extracted with ethyl acetate (100 mL x 2). The extracts were combined and dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The residual oil was purified by silica gel column chromatography (dichloromethane/methanol/aq. ammonia 400: 10: 1 ) to give 6.8 g (41%) of the title compound as a colorless waxy solid.
1H-NMR (CDCI3) δ: 3.75-3.90 (2 H, m), 3.71 (3 H, s), 3.40-3.55 (4 H, m), 2.73 (2 H, m), 2.49 (2 H, m), 2.10-2.25 (2 H, m), 1.95-2.10 (2 H, m), 1.50-1.70 (4 H, m), 1.30-1.50 (2 H, m), 1.10-1.30 (2 H, m).
MS (ESI) m/z: 272 (M+H) +.

Step 5. Methyl 4-{r4-((r4-(2,2,2-trifluoroethoxy)-1 ,2-benzisoxazol-3-vπoxy)methyl)piperidin-1 -yllmethyll-tetrahydro-2H-pyran-4-carboxylate
A mixture of 4-(2,2,2-trifluoroethoxy)-1 ,2-benzisoxazol-3-ol (230 mg, 1 mmol, EXAMPLE 1 , step

2), methyl 4-{[4-(hydroxymethyl)piperidin-1 -yl]methyl}tetrahydro-2/-/-pyran-4-carboxylate (270 mg, 1 mmol, EXAMPLE 1 , step 4), and cyanomethyltributylphosphorane (400 mg, 1.5 mmol) in toluene (1.0 mL) was stirred at 100 0C for 16 h. After cooling, the mixture was concentrated in vacuo to give a dark brown oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 2 : 1 ) to give 250 mg (51 %) of the title compound as a white solid.
1H-NMR (CDCl3) δ: 7.44 (1 H, dd, J= 7.9, 8.4 Hz), 7.12 (1 H, d, J= 8.4 Hz), 6.61 (1 H, d, J= 7.9 Hz), 4.49 (2 H, q, J= 8.1 Hz), 4.24 (2 H, d, J= 6.4 Hz), 3.88-3.78 (2 H, m), 3.72 (3 H, s), 3.54-3.41 (2 H, m), 2.83-2.71 (2 H, m), 2.52 (2 H, s), 2.35-1.29 (11 H, m).
MS (ESI) m/z: 487 (M+H) +.

Step 6. 4-(r4-(ir4-(2,2,2-Trifluoroethoxy)-1 ,2-benzisoxazol-3-vπoxy)methyl)piperidin-1 -ylimethylltetrahydro-2H-pyran-4-carboxylic acid
A mixture of methyl 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1 ,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2/+pyran-4-carboxylate (89 mg, 0.18 mmol, EXAMPLE 1 , Step 5) in tetrahydrofuran (1 mL), methanol (1 ml_) and 2 Λ/ aq. sodium hydroxide (1 ml_) was stirred at 70 °C for 17 h. The mixture was neutralized with 2 N hydrochloric acid (1 mL) and formed precipitate was filtered.

The precipitate was triturated with diethylether to give 50 mg (58%) of the title compound as a white solid.

1H-NMR (DMSO-d6) δ: 7.59 (1 H1 dd, J= 8.1 , 8.4 Hz), 7.25 (1 H, d, J = 8.4 Hz), 6.94 (1 H, d, J = 8.1 Hz), 4.93 (2 H, q, J= 8.7 Hz), 4.19 (2 H, d, J= 5.9 Hz), 3.75-3.62 (2 H, m), 3.48-3.30 (2 H, m), 2.90-2.74 (2 H, m), 2.50 (2 H, s), 2.29-2.13 (2 H, m), 1.94-1.23 (9 H, m).
A signal due to CO2H was not observed.
MS (ESI) m/z: 473 (M+H) +, 471 (M-H) “.
m.p.: 171.7 °C.
IR (KBr) v: 2950, 1617, 1527, 1188, 1113 cm”1.
Anal. Calcd for C22H27N2O6F3: C, 55.93; H, 5.76; N, 5.93. Found: C, 55.72; H, 5.78; N, 5.80.

PATENT

WO2015174098

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015174098

PATENT

WO2014080633

http://www.google.com/patents/WO2014080633A1?cl=en

PATENT

WO 2015178020

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015178020&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

The present invention relates to novel salts of 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid. More particularly, the invention relates to salt forms (HCl-salt, HBr-salt, p-toluenesulfonate salt and ethanedisulfonate salt), and to processes for the preparation of, compositions containing and to uses of, such salt forms.

EXAMPLE 1
Preparation of
4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid according to the conventional process
A slurry of 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]-methyl}tetrahydro-2H-pyran-4-carboxylic acid (1.326 kg, 2.807 mol, a white solid) in ethyl acetate (18.564 L) is dissolved at 70 oC. The solution is cooled to 64 oC during 35 min and 200 mg of seed crystal (0.423 mmol) is seeded to the mixture. The mixture is cooled to 40 oC over 5 h period and stirred at this temperature for 14.5 h. The slurry is gradually cooled to 19 oC during 6 h period and the mixture is stirred at this temperature for 46 h. The formed precipitate is collected by filtration and the filter cake is washed with 2.0 L of ethyl acetate. The filter cake is dried under reduced pressure at 50 oC to afford 1.140 kg of the desired crystalline form of 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]-
methyl}tetrahydro-2H-pyran-4-carboxylic acid (86%).

1H-NMR (DMSO-d6) delta: 7.59 (1 H, dd, J = 8.1, 8.4 Hz), 7.25 (1 H, d, J = 8.4 Hz), 6.94 (1 H, d, J = 8.1 Hz), 4.93 (2 H, q, J = 8.7 Hz), 4.19 (2 H, d, J = 5.9 Hz), 3.75-3.62 (2 H, m), 3.48-3.30 (2 H, m), 2.90-2.74 (2 H, m), 2.50 (2 H, s), 2.29-2.13 (2 H, m), 1.94-1.23 (9 H, m).
A signal due to CO2H is not observed.
m.p. (DSC onset): 169 oC.
The temperature has a margin of error of +/- 1 oC.
Crystallinity by PXRD: Crystal (Figure 1): Main peaks at 2-Theta: 5.9, 9.3, 9.8, 11.9, 13.7, 14.3, 15.0, 17.8, 18.2-19.3, 19.7, 22.6, 23.4-24.5 and 24.9 (o ). Each peak has a margin of error of +/- 0.2.
IR nu (diffuse reflection) (Figure 6): 4389-4383, 3426, 2943-2937, 2120, 1904, 1724, 1614, 1535, 1508, 1437, 1420, 1287, 1261, 1221, 1180, 1121, 1094, 1059, 1022, 991, 974, 957, 934, 918, 868, 827, 783, 746, 731, 654, 638, 615, 588, 554, 542 and 507 cm-1. Each peak has a margin of error of +/- 2 cm-1.
Anal. Calcd for C22H27N2O6F3: C, 55.93; H, 5.76; N, 5.93. Found: C, 55.76; H, 5.74; N, 5.85.

PATENT

WO2012/157288

http://www.google.co.in/patents/WO2012157288A1?cl=pt-PT

EXAMPLE 1
Preparation of
4-{[4-({[4-(2,2,2-Trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}-tetrahydro-2H-pyran-4-carboxylic acid according to the conventional process
A mixture of methyl 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}-tetrahydro-2H-pyran-4-carboxylate (89 mg, 0.18 mmol, PCT WO2006090224 EXAMPLE 1, Step 5) in tetrahydrofuran (1 mL), methanol (1 mL) and 2 N aq. sodium hydroxide (1 mL) is stirred at 70 ^oC for 17 h. The mixture is neutralized with 2 N hydrochloric acid (1 mL) and formed precipitate is filtered. The precipitate is triturated with diethylether to give 50 mg (58%) of the title compound as a white solid.

¹H-NMR (DMSO-d₆) delta: 7.59 (1 H, dd, J = 8.1, 8.4 Hz), 7.25 (1 H, d, J = 8.4 Hz), 6.94 (1 H, d, J = 8.1 Hz), 4.93 (2 H, q, J = 8.7 Hz), 4.19 (2 H, d, J = 5.9 Hz), 3.75-3.62 (2 H, m), 3.48-3.30 (2 H, m), 2.90-2.74 (2 H, m), 2.50 (2 H, s), 2.29-2.13 (2 H, m), 1.94-1.23 (9 H, m).
A signal due to CO₂H is not observed.
MS (ESI) m/z: 473 (M+H)⁺, 471 (M-H)^–.

Anal. Calcd for C₂₂H₂₇N₂O₆F₃: C, 55.93; H, 5.76; N, 5.93. Found: C, 55.72; H, 5.78; N, 5.80.

Patent	Submitted	Granted
Benzisoxazole Derivatives [US2008207690]	2008-08-28
5-HT4 Receptor Agonist as a Prokinetic Agent [US2014051726]	2012-03-23	2014-02-20
Polymorph Form of 4-methyl)piperidin-1-yl]methyl}-tetrahydro-2H-pyran-4-carboxylic acid [US2014187583]	2012-05-18	2014-07-03

Publication Number

Publication Date

IPCR Assignee/Applicant

Structure hits

Tools

WO-2015178020-A1

2015-11-26

C07D 413/14

RAQUALIA PHARMA INC.

BENZISOXAZOLE DERIVATIVE SALT

OC(=O)C1(CN2CCC(COC3=NOC4=C3C(OCC(F)(F)F)=CC=C4)CC2)CCOCC1

WO-2015174098-A1

2015-11-19

A61K 31/454

RAQUALIA PHARMA INC

5-HT4 RECEPTOR AGONIST FOR GASTROPARESIS

US-9187463-B2

2015-11-17

C07D 413/14

NUMATA TOYOHARU

Polymorph form of 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}-tetrahydro-2H-pyran-4-carboxylic acid

US-20150322055-A1

2015-11-12

C07D 413/14

RAQUALIA PHARMA INC

POLYMORPH FORMS

EP-2922849-A1

2015-09-30

C07D 413/14

RAQUALIA PHARMA INC

POLYMORPH FORMS

EP-2710002-A4

2014-10-01

C07D 413/14

RAQUALIA PHARMA INC

POLYMORPH FORM OF 4-{[4-({[4-(2,2,2-TRIFLUOROETHOXY)-1,2-BENZISOXAZOL-3-YL]OXY}METHYL)PIPERIDIN-1-YL]METHYL}-TETRAHYDRO-2H-PYRAN-4-CARBOXYLIC ACID

US-8816090-B2

2014-08-26

C07D 261/20

NOGUCHI HIROHIDE

Benzisoxazole derivatives

EP-1856114-B1

2014-08-20

C07D 413/12

PFIZER

BENZISOXAZOLE DERIVATIVES

US-20140187583-A1

2014-07-03

C07D 413/14

NUMATA TOYOHARU

Polymorph Form of 4-methyl)piperidin-1-yl]methyl}-tetrahydro-2H-pyran-4-carboxylic acid

10.

WO-2014080633-A1

2014-05-30

C07D 413/14

RAQUALIA PHARMA INC

POLYMORPH FORMS

11.

EP-2710002-A1

2014-03-26

C07D 413/14

RAQUALIA PHARMA INC

POLYMORPH FORM OF 4-{[4-({[4-(2,2,2-TRIFLUOROETHOXY)-1,2-BENZISOXAZOL-3-YL]OXY}METHYL)PIPERIDIN-1-YL]METHYL}-TETRAHYDRO-2H-PYRAN-4-CARBOXYLIC ACID

12.

US-20140051726-A1

2014-02-20

A61K 31/435

TAKAHASHI NOBUYUKI

5-HT4 Receptor Agonist as a Prokinetic Agent

13.

EP-2688648-A1

2014-01-29

A61K 31/454

RAQUALIA PHARMA INC

A 5-HT4 RECEPTOR AGONIST AS A PROKINETIC AGENT

14.

WO-2012157288-A1

2012-11-22

C07D 413/14

RAQUALIA PHARMA INC

POLYMORPH FORM OF 4-{[4-({[4-(2,2,2-TRIFLUOROETHOXY)-1,2-BENZISOXAZOL-3-YL]OXY}METHYL)PIPERIDIN-1-YL]METHYL}-TETRAHYDRO-2H-PYRAN-4-CARBOXYLIC ACID

15.

WO-2012127878-A1

2012-09-27

A61P 25/00

RAQUALIA PHARMA INC

A 5-HT4 RECEPTOR AGONIST AS A PROKINETIC AGENT

16.

US-20080207690-A1

2008-08-28

A61K 31/454

NOGUCHI HIROHIDE

Serotonine receptor; gastrointestinal disorders; reflux disease; dyspepsia; irritable bowel disorders; nausea; central nervous system disorders; Alzheimer’ s disease; cognition activators; headaches; analgesics; antiarrhythmia agents; antidiabetic agents

17.

EP-1856114-A1

2007-11-21

C07D 413/12

PFIZER

BENZISOXAZOLE DERIVATIVES

18.

WO-2006090224-A1

2006-08-31

C07D 413/12

PFIZER JAPAN INC

BENZISOXAZOLE DERIVATIVES

see……….http://apisynthesisint.blogspot.in/2015/12/rq-00000010-for-treatment-of-gerd.html

/////c12c(cccc1onc2OCC3CCN(CC3)CC4(CCOCC4)C(=O)O)OCC(F)(F)F

C1CN(CCC1COC2=NOC3=C2C(=CC=C3)OCC(F)(F)F)CC4(CCOCC4)C(=O)O

Lefucoxib (乐福昔布)

December 3, 2015 7:26 am / Leave a comment

Lefucoxib (乐福昔布)

5-(3,4-dimethyl-phenyl)-1-methanesulfonyl-3-trifluoromethol-pyrazole

1 [4- (methylsulfonyl) phenyl] -3-trifluoromethyl-5- (3,4-dimethylphenyl) – pyrazole

CAS 849048-84-6

Molecular Formula:	C₁₉H₁₇F₃N₂O₂S
Molecular Weight:	394.41069 g/mol

IND FILED

Prostaglandin G/H Synthase 2 (PTGS2; COX-2) Inhibitors

A COX-2 inhibitor potentially for the treatment of rheumatoid arthritis.

cyclooxygenase-2 (COX-2) inhibitor

National Center of Biomedical Analysis

冉允章, 梅世昌

梅世昌, 冉允章

CHINA FLAG

PATENT

CN 1468854

http://www.google.com/patents/CN1468854A?cl=en

Example 1

1 [4- (methylsulfonyl) phenyl] -3-trifluoromethyl-5- (3,4-dimethylphenyl) – pyrazole (I1)

1- (3,4- two toluene-yl) -4,4,4-trifluoro-methyl – D-1,3-dione (IV1) of sodium metal was weighed 2.3g (0.1mol) was added 50ml of anhydrous toluene to prepare a sodium sand. After cooling, ethanol was added dropwise 12ml, and then heated at 60 ℃, complete reaction of sodium metal. After cooling to room temperature, was added 3,4-dimethylphenyl ethanone 23.8g (0.1mol) and trifluoroacetic ethyl acetate 20ml (0.2mol), reacted at 100 ℃ 5 hours. Toluene was distilled off under reduced pressure, a 10% aqueous hydrochloric acid was added, the pH was adjusted to 2-3, extracted with ethyl acetate, washed with water, dried over anhydrous MgSO4, ethyl acetate was distilled off under reduced pressure. Then under reduced pressure, distillation, collecting fractions 105-107 ℃ / 0.7mmHg, was 14.6g, 60% yield.

1- [4- (methylsulfonyl) phenyl] -3-trifluoromethyl-5- (3,4-dimethylphenyl) – pyrazole (I1) take the above-prepared substituted (IV1) 2.38g (0.01mol ), 15ml of ethanol, then added p-methanesulfonyl phenyl hydrazine salt alkoxide 2.3g (0.01ml). Was refluxed for 15 hours. Place the refrigerator overnight, the crystals were collected by filtration, recrystallized from ethanol, mp 129-31 ℃, to give 3.1 g.

Elemental analysis: C19H17F3N2O2S Calculated: C, 57.86; H, 4.34; N, 7.10 Found: C, 57.97; H, 4.29; N, 7.20MS (m / z): 395 (M + 1)

References

Cheng, Feixiong, Edited by Lee, Philip W, From Handbook of Metabolic Pathways of Xenobiotics (2014), 4, 1655-1656

Bi, X.; Meng, Z.; Chen, H.; Zhu, X.; Dou, G.
In vivo and in vitro metabolism of lefucoxib in rats, J Pharm Biomed Anal. 2008 Sep 10;48(1):134-9. doi: 10.1016/j.jpba.2008.04.024. Epub 2008 Apr 30.

Bi, X.; Meng, Z.; Dou, G. Determination of lefucoxib in rat plasma, urine, and feces by high-performance liquid chromatography with fluorescence detection: Application in pharmacokinetic studies
J Chromatogr B Anal Technol Biomed Life Sci 2007, 850(1-2): 199

Talanta (2011), 85(1), 8-27

Jiefangjun Yaoxue Xuebao (2009), 25(6), 496-498.

Yaowu Fenxi Zazhi (2006), 26(9), 1222-1224.

Zhongguo Yaolixue Yu Dulixue Zazhi (2007), 21(2), 147-151.

CN101497585B	Jan 31, 2008	Jan 12, 2011	中国科学院理化技术研究所	Method for photocatalytic synthesis of 1,3,5-trisubstituted-2-pyrazole derivative

China PLA General Hospital

//////////c1c(ccc(c1C)C)c2n(nc(c2)C(F)(F)F)c3ccc(cc3)S(=O)(=O)C

CC1=C(C=C(C=C1)C2=CC(=NN2C3=CC=C(C=C3)S(=O)(=O)C)C(F)(F)F)C

DRL 17822 from Reddy US Therapeutics/Dr Reddy’s

December 3, 2015 4:11 am / Leave a comment

CAS 920493-71-6 and CAS 898911-09-6

DRL 17822

MW 603.6045, MFC30 H31 F6 N7

Molecular Formula:	C₃₀H₃₁F₆N₇
Molecular Weight:	603.604459 g/mol

Cas 898911-09-6, 1454689-50-9

3-([[3,5-Bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino]methyl)-N,N-bis(cyclopropylmethyl)-8-methylquinolin-2-amine

3-Quinolinemethanamine, 2-[bis(cyclopropylmethyl)amino]-N-[[3,5-bis(trifluoromethyl)phenyl]methyl]-8-methyl-N-(2-methyl-2H-tetrazol-5-yl)-

3-(((3,5-bis(trifluoromethyl)benzyl)(2- methyl-2H-tetrazol-5-yl)amino)methyl)-N,N-bis(cyclopropylmethyl)-8- methylquinolin-2-amine

(3-{ [3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazoIe-5-yl)- amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine

Reddy US Therapeutics (Innovator)

Dr. Reddy’s Laboratories Ltd.

Treatment of Atherosclerosis Therapy Lipoprotein Disorders,

CETP inhibitor (dyslipidemia/atherosclerosis/cardiovascular diseases), Dr Reddy’s

Selective inhibitor of cholesteryl ester transfer protein (CETP)

30 Jun 2012Dr Reddy’s Laboratories completes a phase II trial in Hypercholesterolaemia in Italy, Poland and Ukraine (NCT01388816)
09 Mar 2012Dr Reddy’s Laboratories completes enrolment in its phase II trial for Hypercholesterolaemia in Italy, Poland, and Ukraine (NCT01388816)
02 Sep 2011Phase-II clinical trials in Hypercholesterolaemia in Ukraine (PO)

CLINICAL TRIALS…..Type II Hyperlipidemia PHASE 2…………https://clinicaltrials.gov/ct2/show/NCT01388816

Cardiovascular disease is a leading cause of death worldwide. Among cardiovascular disorders, coronary heart disease (CHD) caused by atherosclerosis is the most common cause of morbidity and mortality. Prevention, stabilization and regression of atherosclerotic plaques may have a major impact on reducing the risk of acute coronary events.

LDL-C lowering agents, primarily the statins, are the current mainstay in the pharmacologic management of dyslipidemia. However even with stain use, residual CHD risk from dyslipidemia remains. Epidemiologic and observational studies have shown that HDL-C is also a strong independent predictor of CHD, suggesting that raising HDL-C levels might afford clinical benefit in the reduction of cardiovascular risk.

Presently only niacin is approved by the FDA for HDL-C elevation and can raise HDL-C levels by 20-30%. However its use can be limited by a high incidence of flushing and, less commonly, by elevation of blood glucose and potential hepatic toxicity.

Cholesteryl ester transfer protein (CETP) inhibitors are being explored for their ability to elevate HDL-C. A small molecule CETP inhibitor, torcetrapib, has been demonstrated to elevate HDL-C by 60-100%. However, a large clinical trial (ILLUMINATE) where it increased HDL-C by a mean of 72% compared to baseline was halted as it failed to show benefit. Post-hoc analysis of this study implicated an off-target increase in blood pressure as potentially counteracting any anti-atherosclerotic benefits. Post-hoc subgroup analysis showed that patients in the highest HDL-C quartile had a 57% reduction in the risk of cardiovascular events.

Increased blood pressure appears to be specifically related to torcetrapib as two other small molecule CETP inhibitors, anacetrapib and dalcetrapib, have not shown this in clinical trials and have been well tolerated. DRL-17822 has also not shown elevation of blood pressure in either animals or in normal volunteers.

This study will investigate the efficacy and tolerability of DRL-17822 as dyslipidemia monotherapy in patients with Type II hyperlipidemia.

Hyperlipidemia or an elevation in serum lipids is associated with an increase incidence of cardiovascular disease and atherosclerosis. Primary hyperlipidemia is a term used to describe a defect in lipoprotein metabolism. The lipoproteins commonly affected are low density lipoprotein (LDL) cholesterol, which transports mainly cholesterol, and very low density lipoprotein-cholesterol (VLDL-cholesterol), which transports mainly triglycerides (TG). Most subjects with hyperlipidemia have a defect in LDL metabolism, characterized by raised cholesterol, LDL-C levels, with or without raised triglyceride levels; such subjects are termed hypercholesterolemic (Fredrickson Type II). Familial hypercholesterolemia (FH) is caused by any one of a number of genetically-determined defects in the LDL receptor, which is important for the entry of cholesterol into cells. The condition is characterized by a reduced number of functional LDL receptors, and is therefore associated with raised serum LDL-C levels due to an increase in LDL.

It is reasonably known in the art that the likelihood of cardiovascular disease can be decreased, if the serum lipids, and in particular LDL-C, can be reduced. It is further known that the progression of atherosclerosis can be retarded or the regression of atherosclerosis can be induced if serum lipids can be lowered. In such cases, individuals diagnosed with hyperlipidemia or hypercholesteremia should consider lipid-lowering therapy to retard the progression or induce the regression of atherosclerosis for purposes of reducing their risk of cardiovascular disease, and in particular coronary artery disease.

Cholesteryl ester-transfer protein (CETP) is an important player in metabolism of lipoproteins, such as, for example, a high density lipoprotein (HDL). CETP is a 70 kDa plasma glycoprotein that is physically associated with HDL particles. It facilitates the transport of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins. This transfer is accompanied by transfer of triglycerides in the opposite direction. Thus, a decrease in CETP activity can result in an increase in the level of HDL cholesterol and a decrease in the level of very low density lipoprotein (VLDL) and low density lipoprotein (LDL). CETP can therefore simultaneously affect the concentrations of pro-atherogenic (for example, LDL) and anti-atherogenic (for example, HDL) lipoproteins.

Several CETP inhibitors are currently in various clinical phases of development for treating various aforementioned disorders. In spite of having various advantages, CETP inhibitors are proven to be difficult to formulate for oral administration. CETP inhibitors are of a highly lipophilic nature and have extremely low solubility in water. Due to their poor solubility, bioavailability of conventional oral compositions is very poor. The lipophilic nature of CETP inhibitors not only leads to low solubility but also tends to poor wettability, further reducing their tendency to be absorbed from the gastrointestinal tract. In addition to the low solubility, CETP inhibitors also tend to have significant, “food effect”, where a significant difference in rate and amount of drug absorption is observed when the drug is administered with or without a meal. This “food effect”, often complicates the dosing regimen and may require high dosing to achieve the desired therapeutic effect, resulting in potentially unwanted side effects.

Several attempts have been made to improve the solubility of CETP inhibitors, but have generally ended up with limited success. At the outset, most methods aimed at enhancing aqueous concentration and bioavailability of low-solubility drugs only offer moderate improvements. References describing improving the dissolution of poorly soluble drugs include: U.S. Patent Nos. 5,456,923, 5,993,858, 6,057,289, 6,096,338, 6,267,985, 6,280,770, 6,436,430, 6,451,339, 6,531,139, 6,555,558, 6,638,522, 6,962,931 and 7,374,779.

PATENT

WO 2014128564

https://www.google.co.in/patents/WO2014128564A2?cl=en

WO-2014076568

http://www.google.com/patents/WO2014076568A2?cl=en

EXAMPLES

In the following Examples 1-17, various compositions in accordance with the present application were prepared comprising 3-(((3,5-bis(trifluoromethyl)benzyl)(2- methyl-2H-tetrazol-5-yl)amino)methyl)-N,N-bis(cyclopropylmethyl)-8- methylquinolin-2-amine as the CETP inhibitor.:

EXAMPLE 1 :

1. 3-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)- N,N-bis(cyclopropylmethyl)-8-methylquinolin-2-amineand hydroxypropyl methyl cellulose acetate succinate were mixed together in given solvent mixture to form clear solution.

2. To the solution of step I, Polyoxyl 35 castor oil and talc were added to form a homogenous suspension.

3. The suspension of step 2 was sprayed over inert sugar spheres and dried.

4. The drug layered spheres of step 3 were coated with dispersion made from given seal layer ingredients.

5. The coated spheres of step 4 were formulated further as capsule dosage form.

PATENT

WO 2013046045

https://www.google.co.in/patents/WO2013046045A1?cl=en

PATENT

WO 2013024358

PATENT

WO 2007075194

https://www.google.co.in/patents/WO2007075194A1?cl=en

Syntheis construction

Example 1

Synthesis of (3-{[3,5-bis trifluoromethyl-benzyl )-(2-cyclopropyImethyI-2H- tetrazole -5-yl)-amino]-methyl-}-8-methyI-quinolme-2-yl)-bis- cyclopropylmethyl-amine Step (i): Synthesis of 2~chloro-8-methyl-quinoline-3-carbaldehyde

DMF (1.22 g, 16.7 mmol) was taken in a flask equipped with a drying tube and POCl₃ (7.32 g, 46.7 mmol) was added dropwise with stirring at 0° C. To this solution, TV-o-Tolyl acetamide (1.00 g, 6.7 mmol) was added and the solution was refluxed for 6 h at 90° C. The excess POCl₃ was distilled off, water was added to the residue and this was stirred at room temperature for 10 min. The solid was filtered and dried under vacuum..This crude compound was purified over silica gel (100-200 mesh) using 6% ethyl acetate and petroleum ether to give the product as a yellowish solid (yield: 78%). ¹H NMR (CDCl₃, 200 MHz): δ 10.5 (s, IH)₅ 8.71 (s, IH), 7.83- 7.79 (m, IH), 7.74- 7.70 (m, IH), 7.56-7.49 (m, IH), 2.79 (s, 3H); m/z (EI-MS): 206 (M⁺, 100%). Step (ϋ): Synthesis of 2-(bis(cyclopropylmethyl)amino)-8-methylquinoline-3- carbaldehyde:

2-Chloro-8-methyl-quinoline-3-carbaldehyde (.115 g, 0.559 mmol), and potassium carbonate (0.231 g, 1.67 mmol) were put in a 25 mL two necked RB flask. To this, 3 mL of DMF was added followed by dropwise addition of bis- cyclopropylmethyl amine (0.083 g, 0.67 mmol). The reaction mixture was refluxed for 2 h and was cooled to RT. It was then poured on crushed ice (10 mL) and extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine and dried over sodium sulphate. The solvent was evaporated under vacuum to give a yellow colored oil (0.081 g, 50%).

¹H NMR (CDCl₃, 400 MHz): δ 10.5 (s, IH), 8.71 (s, IH), 7.83- 7.79 (m, IH),

7.74-7.70 (m, IH), 7.56-7.49 (m, IH), 3.55-3.47 (m, 4H), 2.79 (s, 3H), 1.73-1.72

(m, 2H), 1.70-1.46 (m, 4H), 1.20-1.11 (m, 4H); m/z (ES-MS ): 295 (M⁺H-I₅

100%); IR (neat, cm^“1): 3385, 2948, 1691.

Step (iii): Synthesis of 3-((3,5-bis(trifluoromethyl)benzylamino)methyl)-N,N- bis(cyclopropylmethyl)-8-methylquinolin-2-amine

2-(Bis(cyclopropylmethyl)amino)-8-methylquinoline-3-carbaldehyde (0.081 g, 0.39 mmol), 3,5-bis-trifluoromethylbenzylamine (0.096 g, 0.39 mmol) and acetic acid (0.047 g, 0.78 mmol) were put in a 25 mL RB flask. To this, 2 rnL of methanol was added and stirred at RT for 15 min. Sodium cyanoborohydri.de (0.075 g, 0.77 mmol) was added portionwise and stirring was continued at RT for another 1 h. Methanol was removed from the reaction mixture under vacuum, water was added to this crude and was extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with saturated NaHCO₃ solution, brine and dried over sodium sulphate. The solvent was evaporated and the crude residue was purified by column chromatography over silica gel (100-200 mesh) eluting with 4% ethyl acetate in petroleum ether to give the title amine (0.142 g, yield: 99%). ¹R NMR (CDCl₃, 400 MHz): δ 7.89-7.86 (m, IH), 7.80 (m, IH), 7.75-7.74 (m, IH), 7.60-7.40 (m, 3H), 7.30-7.26 (m,lH), 4.12 (s, 2H), 3.88 (s, 2H), 3.24-3.22 (m, 4H), 2.72 (s, 3H), 0.99-0.92 (m, 2H), 0.44-0.35 (m, 4H), 0.11-0.05 (m, 4H); m/z (EI-MS ): 522 (M⁺+l, 100%); IR (neat, cm^“1): 3357, 2929, 2851.

Step (iv): Synthesis of N-(3,5-bis(trifluoromethyl)benzyl)-N-((2- (bis(cyclopropylmethyl)amino)-8-methylqumolin-3-yl)methyl)cyanamide

To a solution of 3-((3,5~bis(trifluoromethyl)benzylamino)methyl)-N,N- bis(cyclopropylmethyl)-8-methylquinolin-2-amine (0.176 g , 0.33 mmol ), obtained in step (iii) , in MeOH (4 mL) under N₂ atmosphere was added sodium bicarbonate (0.056 g, 0.67 mmol ) followed by the addition of cyanogen bromide (0.063 g, 0.60 mmol). The reaction mixture was stirred at RT for 2 h. The solvent was removed under vacuum to give the crude residue which was dissolved in water, extracted with ethyl acetate and dried over sodium sulphate. The solvent was evaporated and concentrated in vacuo to afford N-(3,5-bis(trifluoromethyl)benzyl)- N-((2-(bis(cyclopropylmethyl)amino)-8-methylquinolin-3-yl)methyl)cyanamide (0.118 g, 64%).

¹H NMR (CDCl₃, 400 MHz ): δ 8.07 (s, IH) , 7.82 (s, IH), 7.70 (s, 2H), 7.56-7.55 (m, IH), 7.50-7.49 (m, IH), 4.49 (s, 2H), 4.23 (s, 2H), 3.17 -3.15 (m, 4H), 2.71 (s, 3H), 0.097-0.085 (m, 2H), 0.405-0.401 (m, 4H), 0.385-0.381 (m, 4H); m/z (ES- MS): 547 (M⁺+l, 100%); IR(KBr ,Cm^“1 ) : 2273, 1280.

Step (v): Synthesis of (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)- amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine

7V-(3,5-Bis(tiifluoromethyl)benzyl)-N-((2-(bis(cyclopropylmethyl)amino)- 8-methylqumolin-3-yl)methyl)cyanamide (0.118 g, 0.216 mmol), sodium azide (0.70 g 1.08 mmol) and ammonium chloride (.058 g, 1.08 mmol) were put in a RB flask under N₂atmosphere. To this reaction mixture, DMF (2 mL) was added and was refluxed for 1 h. The reaction mixture was cooled to RT and ice was added to this and extracted with ethylacetate (3×10 mL). The combined organic layer was washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford of (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)- amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine as a yellow solid (0.125 g, 99%).

¹H NMR (CDCl₃, 400 MHz ): δ 7.99 (s, IH) , 7.79 -7.74 (m, 4H ), 7.41-7.40 (m,

IH ), 7.33-7.31 (m, IH), 4.99 (s, 2H), 4.80 (s, 2H), 3.68 (s, 4H), 2.16 (s, IH) 1.56-

1.06 (m, HH); m/z (ES-MS): 578 (M⁺+l, 100%); IR (KBr , cm^“1) 3680 , 2922 ,

1660 , 1616.

METHYLATION SHOULD GIVE THE PRODUCT

Scheme 1

PATENT

WO 2006073973

http://www.google.co.in/patents/WO2006073973A2?cl=en

Example 47

Synthesis of [2-(bis-cycIopropylmethyI-amino)-8-methyl-quinolin-3-ylmethyI]-(3,5- bis-trifluoromethyl-benzyl)-carbamic acid methyl ester

Step (i): Synthesis of bis-cyclopropylmethyl-amine

(i) a. Synthesis of cyclopropanecarboxylic acid cyclopropylmethyl-amide:

Cyclopropyl carboxylic acid (1.0 g, 11.63 mmol) was added to a 50 mL two neck round bottom flask, along with DCM (25 mL). This mixture was cooled to 0° C, EDCI (4.15 g, 13.95 mmol) was added portionwise to the mixture with stirring under nitrogen atmosphere, and the temperature was maintained for 0.5 h. After this time, hydroxybenzotriazole (1.88 g, 13.95 mmol) was added to the 0° C mixture which was stirred for 10 min, then triethylamine (1.7 g, 11.63 mmol) was added, and stirring of the mixture was continued at the same temperature for another 0.5 h. Then, cyclopropylmethylamine (0.825 g, 11.63 mmol) was added, and the reaction was allowed to reach RT, and stirring was continued overnight. The solvent was then removed in vacuo, and the crude residue was purified by passing through a column over 60-120 silica gel, eluting with dichloromethane, to afford the title compound (1.6 g), yield: 87%. ¹H NMR (CDCl₃, 200 MHz): d 5.75 (br s, NH, D₂O exchangeable), 3.17-3.16 (m, 2H), 1.00-0.80 (m, 4H), 0.77-0.67 (m, 2H), 0.56-0.43 (m, 2H), 0.24-0.16 (m, 2H) m/z (CI-MS): 139 (M⁺, 100%) (i) b. Synthesis of bis-cyclopropylmethyl-amine

To a suspension of lithium aluminum hydride (1.3 g, 9.35mmol) in 10 mL dry ether, a solution of N-cyclopentenoyl-ethylamine (1.7 g, 13.3 mmol) in dry ether (10 mL) was added under a nitrogen atmosphere. This reaction was stirred at RT for 8 h and the reaction mixture was then quenched with saturated sodium sulfate solution, filtered, and the precipitate was washed with diethyl ether. The filtrate was concentrated to afford the title amine (0.8 g), yield: 69%.

¹H NMR (CDCl₃, 200 MHz): d 5.75 (br s, NH, D₂O exchangeable), 3.16-3.09 (m, 2H), 2.50-2.4 (m, 2H), 0.56-0.43 (m, 4H), 0.24-0.21 (m, 3H), 0.21-0.13 (m, 3H) m/z (ES-MS): 139 (M^+14, 100%)

Step (ii): Synthesis of [2-(bis-cyclopropylmethyl-amino)-8-methyl-quinolin-3-ylmethyl]- (S^-bis-trifluoromethyl-benzy^-carbamicacid methyl ester

The title compound was synthesized by using the same procedure as in Example 35, except using o-tolyl acetanilide in step (i) instead of acetanilide and bis- cyclopropylmethyl amine in step (iii), which yielded the desired product as a light yellow, viscous liquid (0.05 g), yield:40%, of purity 98.8% (HPLC: Symmetry Shield RP8, [0.01M KH₂PO₄: CH₃CN], 217 nM, R_t12.719 min).

¹H NMR (CDCl₃, 400 MHz): d 7.7 (s, IH), 7.68-7.44 (m, 3H), 7.27-7.24 (m, 2H), 4.78- 4.65 (m, 2H), 4.47-4.4 (m, 2H), 3.8 (s, 3H), 3.16-3.14 (d, J=7Hz, 2H), 2.7 (s, 3H), 1.55 (s, 3H), 1.01-0.9(m, IH), 0.38-0.34 (m, 4H), 0.07-0.05 (m, 4H); m/z (CI-MS): 579 (M⁺, 100%)

Example 57

Synthesis of (3-{ [3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazoIe-5-yl)- amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine

The title compound was prepared as an oil by following the same synthetic procedures as in Example 52, except using {3-[(3,5-bis-trifluoromethyl-benzylamino)- methyl]-8-methyl-quinolin-2-yl}-bis-cyclopropylmethyl-amine in step (i) instead of {3- [(3,5-bis-trifluoromethyl-benzylamino)-methyl]-quinolin-2-yl}-cyclopentylmethyl-ethyl- amine (0.07 g), yield: 52%.

Purity: 95.53% (HPLC: Symmetry Shield RP8, [0.01M KH₂PO₄: CH₃CN], 217 nM, R_t 9.538 min).

IR (neat, cm⁴) 3079, 2925, 1582;

¹H NMR (CDCl₃, 400 MHz): d 7.82 (s, IH), 7.69-7.67 (m, 2H), 7.44-7.41 (m, IH), 7.23- 7.2 (m, 3H), 4.91 (s, 2H), 4.65 (s, 2H), 4.21 (s, 3H), 3.29 -3.19 (m, 4H)₅ 2.71 (s, 3H), 1.01-1.00 (m, 2H), 0.99-0.83 (m, 2H), 0.39-0.34 (m, 3H), 0.08-0.07 (m, 3H). m/z (ES-MS): 604 (M⁺+!, 100%)

Dr. Reddy’s announces start of Phase II study with the CETP inhibitor, DRL-17822 in dyslipidemia patients

Hyderabad, India, September 02, 2011: Dr Reddy’s Laboratories (NYSE: RDY) announced the initiation of dosing with DRL-17822 in patients with diagnosis of type II dyslipidaemia. DRL-17822, is a selective, orally bioavailable inhibitor of cholesteryl ester transfer protein (CETP), for the treatment and/or prevention of dyslipidaemia, atherosclerosis and associated cardiovascular disease.

The current study is being conducted under a CTA in a number of countries in Europe. The objective of the study is to evaluate the efficacy and safety of DRL-17822 in patients with Type-II dyslipidemia. This is a randomized, double blind, placebo controlled, parallel group study in 160 subjects. The primary outcome measure is to assess the elevation in HDL cholesterol and reduction in LDL cholesterol from baseline to end of treatment compared to placebo. Three doses (50, 150 & 300 mg) of DRL-17822 given once daily for 4 weeks will be evaluated during this study.

Three human Phase I studies with DRL-17822 had already been conducted in Europe, where DRL-17822 was shown to be safe and well tolerated. In these studies, the proof of mechanism had been demonstrated by dose-dependent inhibition of plasma CETP activity as well as by significant increase in HDL cholesterol & decrease in LDL cholesterol levels.

Cardiovascular disease is a leading cause of death among men and women worldwide. Among cardiovascular disorders, coronary heart disease (CHD), caused by atherosclerosis is the most common cause of morbidity and mortality. Stabilization and/or regression of atherosclerotic plaques may have a major impact on reducing the risk of acute coronary events. Low-density lipoprotein cholesterol lowering agents, primarily the statins, are the current mainstay in the pharmacological management of dyslipidaemia. However, significant residual cardiovascular risk remains despite use of statins.

Epidemiological and observational studies demonstrate that reduced high density lipoprotein cholesterol levels are a strong, independent predictor of CHD, suggesting that raising HDL cholesterol levels might afford clinical benefit in the reduction of cardiovascular risk. One approach to raise HDL level has been inhibition of CETP activity. Currently it is believed that, raising HDL cholesterol and lowering LDL cholesterol through CETP inhibition would lead to a significant benefit in terms of CHD risk reduction.

Dr. K. Anji Reddy, Founder Chairman, Dr. Reddy’s Laboratories added, “We are committed to delivering products of differentiated value in this area of high global clinical unmet need. We are excited to continue to advance our CETP program and look forward to the data from our Phase II study. This class of therapy could transform the treatment of CHD and DRL 17822 is in a position to be one of the front-running products in the class”.

Disclaimer
This press release includes forward-looking statements, as defined in the U.S. Private Securities Litigation Reform Act of 1995. We have based these forward-looking statements on our current expectations and projections about future events. Such statements involve known and unknown risks, uncertainties and other factors that may cause actual results to differ materially. Such factors include, but are not limited to, changes in local and global economic conditions, our ability to successfully implement our strategy, the market acceptance of and demand for our products, our growth and expansion, technological change and our exposure to market risks. By their nature, these expectations and projections are only estimates and could be materially different from actual results in the future.

About Dr. Reddy’s
Dr. Reddy’s Laboratories Ltd. (NYSE: RDY) is an integrated global pharmaceutical company, committed to providing affordable and innovative medicines for healthier lives. Through its three businesses – Pharmaceutical Services and Active Ingredients, Global Generics and Proprietary Products – Dr. Reddy’s offers a portfolio of products and services including APIs, custom pharmaceutical services, generics, biosimilars, differentiated formulations and NCEs. Therapeutic focus is on gastro-intestinal, cardiovascular, diabetology, oncology, pain management, anti-infective and pediatrics. Major markets include India, USA, Russia and CIS, Germany, UK, Venezuela, S. Africa, Romania, and New Zealand. For more information, log on to: www.drreddys.com

For more information please contact:

Investors and Financial Analysts:
Kedar Upadhye at kedaru@drreddys.com / +91-40-66834297
Raghavender R at raghavenderr@drreddys.com / +91-40-49002135
Milan Kalawadia (USA) at mkalawadia@drreddys.com / +1 908-203-4931

Media:
S Rajan at rajans@drreddys.com / +91-40- 49002445

WO2005011634A1 *	Jul 21, 2004	Feb 10, 2005	William John Curatolo	Dosage forms providing controlled release of cholesteryl ester transfer protein inhibitors and immediate release of hmg-coa reductase inhibitors
WO2006073973A2 *	Dec 28, 2005	Jul 13, 2006	Reddy Us Therapeutics Inc	Novel benzylamine derivatives as cetp inhibitors
WO2006129167A1 *	May 22, 2006	Dec 7, 2006	Pfizer Prod Inc	PHARMACEUTICAL COMPOSITIONS OF CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITORS AND HMG-CoA REDUCTASE INHIBITORS
WO2007128568A1 *	May 8, 2007	Nov 15, 2007	Novartis Ag	Bicyclic derivatives as cetp inhibitors
EP0298666A2 *	Jul 1, 1988	Jan 11, 1989	American Home Products Corporation	Spray dried ibuprofen compositions
EP1741424A2 *	Jul 27, 1998	Jan 10, 2007	Pfizer Products Inc.	Solid pharmaceutical dispersions with enhanced bioavailabilty
US5456923	Dec 23, 1993	Oct 10, 1995	Nippon Shinyaku Company, Limited	Method of manufacturing solid dispersion
US5474989	Mar 1, 1994	Dec 12, 1995	Kurita Water Industries, Ltd.	Drug composition
US5985326	May 30, 1996	Nov 16, 1999	Icos Corporation	Method of producing a solid dispersion of a poorly water soluble drug
US6350786	Sep 7, 1999	Feb 26, 2002	Hoffmann-La Roche Inc.	Stable complexes of poorly soluble compounds in ionic polymers
US6548555	Jan 31, 2000	Apr 15, 2003	Pfizer Inc	Basic drug compositions with enhanced bioavailability
US6638522	Dec 10, 1999	Oct 28, 2003	Pharmasolutions, Inc.	Microemulsion concentrate composition of cyclosporin
US6730679	Mar 20, 1997	May 4, 2004	Smithkline Beecham Corporation	Pharmaceutical formulations
US7008640	Jul 16, 2001	Mar 7, 2006	Yamanouchi Pharmaceutical Co., Ltd.	Pharmaceutical composition for oral use with improved absorption
US7034013	Mar 19, 2002	Apr 25, 2006	Cydex, Inc.	Formulations containing propofol and a sulfoalkyl ether cyclodextrin
US7037528	Jun 5, 2001	May 2, 2006	Baxter International Inc.	Microprecipitation method for preparing submicron suspensions
US7078057	Dec 19, 2000	Jul 18, 2006	Kerkhof Nicholas J	Process for producing nanometer particles by fluid bed spray-drying
US7081255	Aug 14, 2002	Jul 25, 2006	Janssen Pharmaceutica, N.V.	Antifungal compositions with improved bioavailability
US8030359	Feb 9, 2007	Oct 4, 2011	Merck Sharp & Dohme Corp.	Polymer formulations of CETP inhibitors
US20060178514	Dec 28, 2005	Aug 10, 2006	Anima Baruah	Novel benzylamine derivatives as CETP inhibitors

Reference
1	*	EINFAL T ET AL: “Methods of amorphization and investigation of the amorphous state“, ACTA PHARMACEUTICA 20130901 CROATIAN PHARMACEUTICAL SOCIETY DEU, vol. 63, no. 3, 1 September 2013 (2013-09-01), pages 305-334, XP002721717, ISSN: 1330-0075
2	*	KAI TOSHIYA ET AL: “Oral absorption improvement of poorly soluble drug using solid dispersion technique“, CHEMICAL AND PHARMACEUTICAL BULLETIN (TOKYO), vol. 44, no. 3, 1996, pages 568-571, XP002721716, ISSN: 0009-2363
3	*	KIM TAE-WAN ET AL: “Characterization of dual layered pellets for sustained release of poorly water-soluble drug“, CHEMICAL & PHARMACEUTICAL BULLETIN (TOKYO), vol. 55, no. 7, July 2007 (2007-07), pages 975-979, XP002721715, ISSN: 0009-2363
4	*	KIM TAE-WAN ET AL: “Modified release of coated sugar spheres using drug-containing polymeric dispersions.“, ARCHIVES OF PHARMACAL RESEARCH JAN 2007, vol. 30, no. 1, January 2007 (2007-01), pages 124-130, XP002721714, ISSN: 0253-6269

Citing Patent	Filing date	Publication date	Applicant	Title
WO2014128564A2 *	Feb 21, 2014	Aug 28, 2014	Dr. Reddy’s Laboratories Ltd.	Pharmaceutical compositions of cetp inhibitors

Patent	Submitted	Granted
Novel benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors [US2007015758]	2007-01-18
Novel benzylamine derivatives as CETP inhibitors [US2006178514]	2006-08-10

Publication Number

Publication Date

IPCR Assignee/Applicant

Structure hits

Tools

EP-2919765-A2

2015-09-23

A61K 9/16

REDDYS LAB LTD DR

PHARMACEUTICAL COMPOSITIONS OF CETP INHIBITORS

CN1N=NC(=N1)N(CC1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)CC1=CC2=CC=CC(C)=C2N=C1N(CC1CC1)CC1CC1

US-20150216866-A1

2015-08-06

A61K 31/506

REDDYS LAB LTD DR

SUBSTITUTED BENZYLAMINO QUINOLINES AS CHOLESTEROL ESTER-TRANSFER PROTEIN INHIBITORS

US-9040558-B2

2015-05-26

C07D 239/78

BARUAH ANIMA

Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors

WO-2014128564-A2

2014-08-28

A61K 9/16

REDDYS LAB LTD DR

PHARMACEUTICAL COMPOSITIONS OF CETP INHIBITORS

WO-2014076568-A2

2014-05-22

A61K 9/16

REDDYS LAB LTD DR

PHARMACEUTICAL COMPOSITIONS OF CETP INHIBITORS

US-20140134235-A1

2014-05-15

C07D 471/04

REDDYS LAB LTD DR

NOVEL BENZYLAMINE DERIVATIVES AND THEIR UTILITY AS CHOLESTEROL ESTER-TRANSFER PROTEIN INHIBITORS

US-20070015758-A1

2007-01-18

A61K 31/55

BARUAH ANIMA

Novel benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors

SEE

http://circ.ahajournals.org/cgi/content/meeting_abstract/122/21_MeetingAbstracts/A13981

////////

Cn1nc(nn1)N(Cc2cc5cccc(C)c5nc2N(CC3CC3)CC4CC4)Cc6cc(cc(c6)C(F)(F)F)C(F)(F)F

CC1=CC=CC2=CC(=C(N=C12)N(CC3CC3)CC4CC4)CN(CC5=CC(=CC(=C5)C(F)(F)F)C(F)(F)F)C6=NN(N=N6)C

WO 2015177807, New patent on AVANAFIL by Wanbury

November 30, 2015 4:11 am / Leave a comment

WO 2015177807

Suryakant Shivaji Pol; Nitin Sharadchandra Pradhan; Shashikant Balu Padwal; Vihar Raghunath Telange; Nitn Shankar Bondre

Wanbury ltd

The present invention relates to a novel compound of Formula (II), and its use in preparation of Avanafil, [Formula should be inserted here] wherein R is -OH, -CI or -OR¹ and R¹ is C₁ to C₃ alkyl group

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015177807&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

It having been developed and launched by VIVUS and JW Pharmaceutical, under license from Mitsubishi Tanabe Pharma, and Auxilium Pharmaceuticals, for treating ED.

A process for preparation of Avanafil was first disclosed in US 6,797,709 (depicted in Scheme I), wherein 4-chloro-5-ethoxycarbonyl-2-methylthio-pyrimidine is coupled with 3-chloro-4-methoxybenzylamine in presence of triethylamine to provide compound of Formula (A), which on oxidization provides a sulfonyl compound of Formula (B). Said compound of Formula (B) is reacted with L-prolinol and exert compound of Formula (C). The resulting compound of Formula (C) undergoes column chromatographic purification and crystallization, while further subjected to hydrolysis to obtain compound of Formula (D). The compound of Formula (D) is coupled with 2-aminomethylpyrimidine to obtain Avanafil of Formula (I). The final product obtained is purified by column chromatography. The need to purify the intermediate compound of Formula (C) and final product, by column chromatography makes this process cumbersome, time consuming and unviable for large scale production thereby contributing to main disadvantages of the process.

Scheme I

Formula (A)

m-CPBA/chloroform

Formula (C) Formula (B)

NaOH/DMSO

Formula (D) Formula (I)

CN 103254179, discloses a process for preparation of Avanafi, wherein 3-chloro-4-methoxybenzylhalide is coupled with cytosine to result compound of Formula (E), later on condensation with L-prolinol yields 4-[(3-chloro-4-methoxy benzyl)amino-2-(2-hydroxymethyl)-l -pyrrolinyl]pyrimidine of Formula (F). The compound of Formula (F) is then condensed with N-(2-pyrimidylmethyl)formamide to obtain Avanafil of Formula (I). Process is depicted in Scheme II

Scheme II

Formula (F) Formula (I)

CN 103254180 describes an alternate process for preparation of Avanafil of Formula (I), wherein a substitution reaction on 6-amino-l ,2-dihydropyrimidine-2-keto-5-carboxylic acid, ethyl ester and 3-chloro-4-methoxybenzylchloride provides 6-(3-chloro-4-methoxybenzylamino)-l ,2-dihydropyrimidine-2-keto-5-carboxylic acid, ethyl ester of Formula (G) which on condensation with L-prolinoI generates 6-(3-chloro-4-methoxybenzylamino)-l ,2-dihydropyrimidine-2-keto-5-carboxylic acid ethyl ester of Formula (H). The compound of Formula (H) is then hydrolysed and coupled with N-(2-pyrimidylmethyI)formamide to obtain Avanafil of Formula (I). Process is depicted in Scheme III

Scheme III

Formula (H) Formula (Γ)

In all the prior art discussed above, chiral compound L-prolinol is coupled in molecule in earlier steps of synthesis. This approach seems to be less feasible for large scale production; the insertion of L-prolinol in early stage may need to exert number of purifications for intermediates. Further the main shortcoming in such process is that the chirality of molecule is disturbed by inserting L-prolinol in early stages because there are number of operations in line in process to obtain the target compound.

CN 103483323, discloses a synthetic method for preparation of avanafil, wherein amidation of pyrimidine-5-carbonyl chlorides with 2-(aminomethyl)pyrimidine at temperature ranging from -10 to 5°C resulted an amide (intermediates A); which underwent condensation with 3-chloro-4-methoxybenzylamine at the temperature ranging from 0 -3°C to give 4-[(3-chloro-4-methoxybenzyl)amino]-5-

pyrimidinecarboxamides (intermediates B), which further on condensation with L-prolinol gave avanafil. The disadvantage of this process is the need to maintain the reaction temperature in range of – 10 to 5°C which adds up to cost of process and makes the process complicated. The process is depicted in Scheme IV.

Scheme IV

Intermediate (A)

wherein, R’ & R² are independently, hydrogen, halogen, alkoxy, alkoxyalkyl, cyno group, amino group

Hence, to overcome shortcomings of prior art the inventors of present invention have skillfully designed a process with novel intermediate which concomitantly result Avanafil compound of Formula (I), substantially free from impurities. Further this invention encompass L-proline in last stage of molecule in order to avoid the number of purifications of intermediate which relent the economic significances by taking into account yield of each stage.

Object of the invention

1. The main object of the invention is to provide a novel compound of Formula

(ID-

2. Another object of present invention is to provide a process for preparation of a novel compound of Formula (II).

3. Yet another object of present invention is to provide a process for preparation of Avanafil of Formula (I), in high yield and purity using a novel compound of Formula (II).

4. Yet another object of the present invention to provide simple, economic and industrially scalable process for the preparation of Avanafil o Formula (I).

Summary of the invention

According to an aspect of present invention, there is provided a novel compound of Formula (II).

Formula (II)

wherein R is -OH, -CI or -OR and R is Q to C₃ alkyl group

The invention will be specifically described below with reference to Examples but it should not be construed that the scope of the invention is limited thereto. Since the starting compound was produced by a modified method from that described in prior art, it will be described as Referential Example 1 to 3. Here synthesis routes of Referential Example 1 to 3 and Example 1 to 10 are illustrated below in Scheme (V).

Scheme (V)

Formula (I) Referential Examples

Referential Example 1 – Preparation of ethyl 4-[(3-chloro-4-methoxybenzyl)amino]-2-(methyl sulfanyl)pyrimidine-5-carboxylate

To 600ml of methylene dichloride was added l OOg of ethyl 4-chloro-2-(methylsulfanyl) pyrimidine-5-carboxylate and 91.2g of 3-chloro-4-methoxybenzylamine. The reaction mixture was stirred and 500ml of water, 48g of sodium carbonate and Ig of tetra-butylammonium bromide were added to it. The reaction mixture was then maintained overnight at 25-30°C. After completion of reaction, methylene dichloride layer was separated, washed with water and evaporated to obtain 145g of ethyl 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylate having 95% of HPLC purity.

Above reaction can also be carried out using ammonia or triethylamine in same reaction conditions and parameters, in place of sodium carbonate.

Referential Example 2 – Preparation of 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylic acid

To 600ml of methanol was added l OOg of ethyl 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylate (Referential Example 1) and an aqueous solution of sodium hydroxide (15g of NaOH in 140ml of water). The reaction mixture was heated to reflux temperature. After completion of reaction, the pH of mixture was adjusted to 1 -2 using concentrated hydrochloric acid followed by stirring the mixture for 1 hour at 10-15°C. The solid product obtained was filtered, washed sequentially with water and methanol, and dried overnight at 70-75°C to get 87g of 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylic acid.

Referential Example 3 – Preparation of 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfinyl)-N-(pyrimidin-2-ylmethyl) pyrimidine-5-carboxiamide of Formula (III)

To a mixture of 400ml of toluene and 0.5ml of dimethyl formamide was added 50g of 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylic acid (Referential Example 2) and 70g of thionyl chloride, and the reaction mixture was refluxed for 2.5 hours. After completion of reaction, solvent was distilled under vacuum and the residue was stripped with toluene to obtain yellow solid mass. The solid mass thus obtained, was cooled to 15-20°C followed by addition of 1 75ml of methylene dichloride, 36. l g of 2-amino methyl pyrimidine mesylate and 35.55g of triaethylamine. The reaction mixture was stirred overnight at 25-30°C. After completion of reaction, methylene dichloride was distilled out to get residue. The residue was washed sequentially with 2.5% sodium carbonate solution and water. The residue was then treated with methanol to obtain 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfinyl)-N-(pyrimidin-2-ylmethyl) pyrimidine-5-carboxiamide of Formula (III) having HPLC purity of more than 95% (yield: 80%)

Referential Example 4 – Preparation of 4-[(3-Chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)-l -pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide (Avanafil)

Step i)

To 200ml of dichloromethane was added lOg of 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfinyI)-N-(pyrimidin-2-ylmethyl) pyrimidine-5-carboxiamide and 6.5g of m-chloro per benzoic acid and the mixture was stirred for 1 hour at 25-30°C. After completion of reaction, the reaction mixture was washed with aqueous solution of sodium carbonate and water. The resulting dichloromethane layer comprising compound of Formula (IV) was taken to next step.

Step ii)

To the dichloromethane layer obtained in step i), was added 2.57g of triethylamine followed by slow addition of 125ml solution of L-prolinol in dichloromethane (2.46g of L-prolinol in 125ml of dichlromethane). The reaction mixture was maintained overnight. After completion of reaction, the reaction mixture was washed with water followed by evaporation of dichloromethane to obtain an oily mass. The oily mass thus obtained was treated with methanol to yield 8g of Avanafil.

Examples

Example 1 : Preparation of Compound of Formula (II) (wherein R is -OH)

Step i)

To 200ml of methylene dichloride was added lOg of 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfinyl)-N-(pyrimidin-2-ylmethyl) pyrimidine-5-carboxiamide of Formula (III) and 6.5g of m-chloro per benzoic acid and the mixture was stirred for 1 hour at 25-30°C. After completion of reaction, the reaction mixture was washed with aqueous solution of sodium carbonate and water. The resulting methylene dichloride layer comprising compound of Formula (IV) was taken to next step.

Step ii)

To the methylene dichloride layer comprising compound of Formula (IV) obtained in step i), was added 5g of triethylamine followed by slow addition of 125ml solution of L-proline in methylene dichloride (2.8g of L-proline in 125ml of methylene dichloride). The reaction mixture was maintained overnight. After completion of reaction, the reaction mixture was washed with water and 5% sodium carbonate solution, followed by evaporation of methylene dichloride to obtain an oily mass. The oily mass obtained was stripped with 50ml acetone to yield 9g of compound of Formula (II) having HPLC purity 98%.

Example 2: Preparation of Compound of Formula (II) (wherein R is -OC₂H₅)

Example 3 : Preparation of Compound of Formula (II) (wherein R is -CI)

To a mixture of 400ml of toluene and 0.5ml of dimethylformamide was added 50g of compound of Formula (II) obtained in example 1 , and 70g of thionyl chloride. The reaction mixture was refluxed for 2.5 hours. After completion of reaction, solvent was distilled under vacuum and the residue was stripped with toluene to obtain 50.5g of oily carboxylic acid chloride compound of Formula (II).

Example 4: Preparation of Avanafil of Formula (I)

In an inert atmosphere, a solution of 30g of compound of Formula (II) obtained in example 1 or 2, in 150 ml of tetrahydrofuran was dropwise added to 180ml of suspension of 1.0M lithium aluminium hydride solution in tetrahydrofuran, The reaction mixture was refluxed for 5 hours. After completion of reaction, the mixture was cooled in ice-bath and saturated aqueous solution of sodium sulfate was added to decompose excess of lithium aluminium hydride. The mixture was then diluted with 200ml of methylene dichloride and thus formed organic layer was separated. The organic layer was washed with water (3 ^χ 100 ml), dried over MgS04 and concentrated to collect crude Avanafil of Formula (I) which was subjected to purification using methanol as solvent to yield 22.8g of Avanafil of Formula (I) having HPLC purity of 99.20%.

Example 5 : Preparation of Avanafil of Formula (I)

To a mixture of 1.3g sodium borohydride, 1 ml methanesulfonic acid and 50ml ethanol was added l Og of compound of Formula (II) obtained in example 1 or 2, and the mixture was stirred at 25-30°C for 5 hours. After completion of reaction, 100ml water was added and the mixture was extracted with 1 00ml methylene dichloride (50ml X 2). The methylene dichloride layer obtained was evaporated under reduced pressure to get an oily mass. The oily mass was stripped with ethyl acetate at 45- 50°C. To the oily residue formed was added 50ml of ethyl acetate and the mixture was cooled to 0-5°C. The solid obtained was filtered, washed with ethyl acetate and dried to yield crude Avanafil of Formula (I) which was subjected to purification using methanol as solvent to yield 7g of Avanafil of Formula (I) having HPLC purity of 99%.

Example 6 to Example 8

The procedure is carried out as in example 5 except for instead of methanesulfonic acid other reducing agents are used in combination with sodium borohydride. The results are given in Table I

Table I

Example 9: Preparation of Avanafil of Formula (I)

To 100ml of ethanol was added 0.5ml of sulphuric acid and l Og of compound of Formula (II) obtained in example 1 , and the reaction mixture was maintained at reflux temperature till completion of reaction. The reaction mixture was then cooled to 25-30°C and the pH of reaction mixture was adjusted to 7-8 using sodium carbonate. Filter the reaction mixture and collect filterate containing product. To the fi Iterate was added 1.2g of sodium borohydride and 2.6g of lithium bromide, and the mixture was stirred for 5 hours. After complete conversion of ester to final product, l OOml water was added and the mixture was extracted with 100ml methylene dichloride (50ml X 2). The methylene dichloride layer obtained was evaporated under reduced pressure to get an oily mass. The oily mass was stripped with 25ml ethyl acetate at 45-50°C. To the oily residue formed was added 50ml of ethyl acetate and the mixture was cooled to 0-5°C. The solid obtained was filtered, washed with ethyl acetate and dried to yield crude Avanafil of Formula (I) which was subjected to purification using methanol as solvent to yield 7.5g of Avanafil of Formula (I) having HPLC purity of 99%.

Example 10: Preparation of Avanafil of Formula (I) from Compound of Formula (II) (wherein R is -CI)

To a mixture of 400ml of tetrahydrofuran and 50g of carboxylic acid chloride compound of Formula (II) obtained in example 3, was added 12g sodium borohydride at 0-5°C. After completion of reaction, water was added to reaction mixture to decompose excess of sodium borohydride present. The reaction mixture was then concentrated and a solution of 30g of potassium hydroxide in 200 ml of water was added. The mixture was heated to 60-70°C and maintained for 15-18 hours. The mixture was then cooled to 25-30°C and 500 ml of methylene dichloride was added. The organic layer thus formed, was separated and evaporated to yield crude Avanafil

of Formula (I) which was then subjected to purification using methanol as solvent to obtain 40g of Avanafil of Formula (I) having HPLC purity of 99.01%.

Mr. K. Chandran

		Wholetime Director & Vice Chairman

Tarapur plant

MR K. CHANDRAN (left), Director, Wanbury, and Mr Asok Shinkar, Director-Corporate Finance, at a press conference held in Mumbai on Monday. Paul Noronha

MR K. CHANDRAN (left), Director, Wanbury, and Mr Asok Shinkar, Director-Corporate Finance, at a press conference held in Mumbai on Monday.

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

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

Pfizer’s PF 04991532 a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus

November 27, 2015 7:05 am / 2 Comments on Pfizer’s PF 04991532 a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus

PF 04991532

GKA PF-04991532

(S)-6-{3-cyclopentyl-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]propanamido}nicotinic acid

(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid

(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid

MW 396.36, MF C₁₈ H₁₉ F₃ N₄ O₃

CAS 1215197-37-7

3-Pyridinecarboxylic acid, 6-[[(2S)-3-cyclopentyl-1-oxo-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]propyl]amino]-

http://www.biochemj.org/content/441/3/881

Type 2 diabetes mellitus (T2DM) is a rapidly expanding public epidemic affecting over 300 million people worldwide. This disease is characterized by elevated fasting plasma glucose (FPG), insulin resistance, abnormally elevated hepatic glucose production (HGP), and reduced glucose-stimulated insulin secretion (GSIS). Moreover, long-term lack of glycemic control increases risk of complications from neuropathic, microvascular, and macrovascular diseases.

The standard of care for T2DM is metformin followed by sulfonylureas, dipeptidyl peptidase-4 (DPP-IV) inhibitors, and thiazolidinediones (TZD) as second line oral therapies. As disease progression continues, patients typically require injectable agents such as glucagon-like peptide-1 (GLP-1) analogues and, ultimately, insulin to help maintain glycemic control. Despite these current therapies, many patients still remain unable to safely achieve and maintain tight glycemic control, placing them at risk of diabetic complications and highlighting the need for novel therapeutic options.

Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia.

While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index.

As blood glucose increases, it is transported into pancreatic beta cells via a glucose transporter. Intracellular mammalian glucokinase (GK) senses the rise in glucose and activates cellular glycolysis, i.e. the conversion of glucose to glucose-6-phosphate, and subsequent insulin release. Glucokinase is found principally in pancreatic β-cells and liver parenchymal cells. Because transfer of glucose from the blood into muscle and fatty tissue is insulin dependent, diabetics lack the ability to utilize glucose adequately which leads to undesired accumulation of blood glucose (hyperglycemia). Chronic hyperglycemia leads to decreases in insulin secretion and contributes to increased insulin resistance. Glucokinase also acts as a sensor in hepatic parenchymal cells which induces glycogen synthesis, thus preventing the release of glucose into the blood. The GK processes are thus critical for the maintenance of whole body glucose homeostasis.

Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, NIDDM (Moller, D. E., “New drug targets for Type II diabetes and the metabolic syndrome” Nature 414; 821-827, (2001)): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents.

Ideally, an effective new treatment for NIDDM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are independent from the actions of insulin; (d) it would desirably be metabolically stable to allow less frequent usage; and (e) it would be usable in combination with tolerable amounts of any of the categories of drugs listed herein.

Substituted heteroaryls, particularly pyridones, have been implicated in mediating GK and may play a significant role in the treatment of NIDDM. For example, U.S. Patent publication No. 2006/0058353 and PCT publication Nos. WO2007/043638, WO2007/043638, and WO2007/117995 recite certain heterocyclic derivatives with utility for the treatment of diabetes. Although investigations are on-going, there still exists a need for a more effective and safe therapeutic treatment for diabetes, particularly NIDDM.

PATENT

US 20100063063

http://www.google.com/patents/US20100063063

SYNTHESIS CONSTRUCTION

6-aminonicotinic acid

BENZYL BROMIDE

FIRST KEY INTERMEDIATE

SECOND SERIES FOR NEXT INTERMEDIATE

(R)-2-amino-3-cyclopentylpropanoic acid

(R)-methyl 3-cyclopentyl-2-hydroxypropanoic acid (I-1a)

(R)-methyl 3-cyclopentyl-2-hydroxypropanoate (I-1b)

Trifluoromethanesulfonic acid anhydride

(R)-methyl 3-cyclopentyl-2-(trifluoromethylsulfonyloxy)propanoate (I-1c)

CONDENSED WITH

4-Trifluoromethyl-1H-imidazole

TO GIVE PRODUCT SHOWN BELOW

(S)-methyl 3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate (I-8a)

(S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoic acid (I-8b)

CONVERTED TO ACID CHLORIDE, (S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoyl chloride (I-8c)

AND CONDENSED WITH

WILL GIVE BENZYL DERIVATIVE AS BELOW

THEN DEBENZYLATION TO FINAL PRODUCT

Intermediate: (R)-methyl 3-cyclopentyl-2-hydroxypropanoic acid (I-1a)

To a stirred solution of (R)-2-amino-3-cyclopentylpropanoic acid (5.0 grams; Chem-Impex International, Inc., Wood Dale, Ill.) and 1 M H₂SO₄(45.1 mL) at 0° C., was added a solution of NaNO₂(3.12 g) in H₂O (15.6 mL) drop wise over 10 minutes. The reaction mixture was stirred for 3 hours at 0° C., then for 2 hours at room temperature. The solution was then extracted (3 times) with diethyl ether. The combined organic extracts were dried over MgSO₄, filtered, and the filtrate concentrated to afford 2.36 g of (I-1a). ¹H NMR (400 MHz, CDCl₃) δ 4.26-4.28 (1H), 1.99-2.07 (1H), 1.76-1.81 (4H), 1.60-1.62 (4H), 1.12-1.16 (2H); LCMS for C₈H₁₄O₃m/z 157.1 (M−H)⁻.

Intermediate: (R)-methyl 3-cyclopentyl-2-hydroxypropanoate (I-1b)

To a stirred solution of 2.36 g of (I-1a) in anhydrous methanol (15 mL) at room temperature was added SOCl₂(1.64 mL). The resulting mixture was heated at reflux for 2 hours. It was then cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous saturated NaHCO₃solution. The biphasic mixture was separated and the aqueous portion was extracted with ethyl acetate. The combined extracts were dried over MgSO₄, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, heptanes/ethyl acetate) to afford 1.5 g of (I-1b) as a clear oil.¹H NMR (400 MHz, CDCl₃) δ 4.15-4.20 (1H), 3.77 (3H), 2.62-2.63 (1H), 1.97-2.05 (1H), 1.49-1.86 (8H), 1.06-1.17 (2H); LCMS for C₉H₁₆O₃m/z 171.6 (M)⁺. Intermediate (I-1b) can alternatively be prepared by the method described below.

A 0.2M solution of Li₂CuCl₄was prepared as follows: Anhydrous CUCl₂(26.9 g, 200 mol) and anhydrous LiCl (17.0 g, 400 mmol) were dissolved in THF (1000 mL). The mixture required gentle heating to completely dissolve the solids. After cooling the solution is ready for use.

A solution of Li₂CuCl₄(0.2 M in THF, 125 mL, 25.0 mmol) was added slowly to a suspension of cyclopentylmagnesium bromide (2 M in diethyl ether, 135 mL, 270 mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) and THF (500 mL) at −50° C. over 2-3 mins. The pale grey/brown suspension was then allowed to warm slowly to −10° C. over 30 mins, by which time the color had developed to a dark grey. The mixture was re-cooled to −78° C. and (R)-methyl oxirane-2-carboxylate (25.0 g, 245 mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) was added neat via syringe over 90 seconds. The reaction was then stirred at −78° C. for 20 mins, before removing the ice-bath and allowing to warm to approximately −50° C. over 30 mins. Saturated NH₄Cl (aq, 700 mL) was then added and the mixture stirred for 30 mins. The organic layer was collected and the aqueous layer extracted with diethyl ether (2×250 mL). The combined organics were washed with saturated NH₄Cl (aq, 350 mL), dried over MgSO₄, and evaporated. Distillation of the crude residue (68-70° C. at 0.8 mbar) yielded 65-70% of (I-1b) as a pale yellow oil. A small amount of less volatile material remained in the still pot. ¹H NMR (400 MHz; CDCl₃): δ 4.17(1H), 3.76 (3H), 2.67 (1H), 2.01 (1H), 1.48-1.88 (8H), 1.11 (2H).

Intermediate: (R)-methyl 3-cyclopentyl-2-(trifluoromethylsulfonyloxy)propanoate (I-1c)

Intermediate: (R)-methyl 3-cyclopentyl-2-(trifluoromethylsulfonyloxy)propanoate (I-1c

Intermediate (I-1b) (6.37 g, 37.0 mmol) was dissolved in dry dichloromethane (260 mL) and stirred under nitrogen in an ice bath. 2,6-Lutidine (9.0 mL, 77 mmol) was added. Trifluoromethanesulfonic acid anhydride (11 mL, 65 mmol) in dry dichloromethane (75 mL) was added dropwise. The reaction was stirred in the ice bath for 60 minutes, concentrated under reduced pressure, and taken up in 1N HCl and methyl t-butyl ether. The aqueous layer was separated, and the organic layer was washed with additional 1N HCl to insure the removal of all the lutidine. The combined organic layer was then washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried under high vacuum to afford (I-1c) (11.3 g, 37 mmol, 100%), which was used immediately without further purification; ¹H NMR (400 MHz, CDCl₃) δ 5.10-5.14 (1H), 3.82 (3H), 2.02-2.12 (1H), 1.79-1.98 (4H), 1.51-1.66 (4H), 1.08-1.18 (2H).

Intermediate: (S)-methyl 3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate (I-8a)

4-Trifluoromethyl-1H-imidazole (5.0 g, 37.0 mmol; Apollo Scientific Ltd., Bredbury, Cheshire, UK) was stirred in dry THF (180 mL) under nitrogen at room temperature. Lithium hexamethyldisilazide (1M in THF, 33.4 mL, 33.4 mmol) was added dropwise via addition funnel. The mixture was stirred at room temperature for 50 minutes and then chilled in an ice bath. A solution of (I-1c) (11.3 g, 37 mmol) in dry THF (45 mL), which had been chilled in an ice bath, was added in one portion. The reaction was allowed to warm to room temperature, stirred for 2 hours, quenched with saturated aqueous ammonium chloride solution (20 mL) and allowed to stir overnight. The aqueous layer was separated, and the organic layer was concentrated and then diluted with water and ethyl acetate. The organic layer was washed in series with dilute aqueous phosphoric acid, aqueous 10% potassium carbonate, and brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to a brown oil. The crude material, containing the undesired regioisomer as a small impurity, was purified by chromatography on a 330 g pre-packed silica gel column, eluting with 10% ethyl acetate/heptane, linear gradient to 70% ethyl acetate/heptane. The product fractions were located by spotting on a silica TLC plate and visualizing with KMnO₄stain. TLC (1:1 ethyl acetate/heptane, developed in potassium permanganate) located the pure and mixed fractions. The clean product fractions were combined, evaporated, and dried under high vacuum to afford (I-8a) as a clear oil (6.61 g, 22.4 mmol, 67%). ¹H NMR (400 MHz, CDCl₃) δ 7.57 (1H), 7.38 (1H), 4.71-4.74 (1H), 3.76 (3H), 2.01-2.14 (2H), 1.45-1.79 (7H), 1.03-1.18 (2H); m/z 291.4 (M+H)⁺.

Intermediate: (S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoic acid (I-8b

6N HCl (140 mL) was added to (I-8a) (6.61 g, 22.4 mmol) and the mixture was warmed to 95° C. for 16 hours and then allowed to cool. Solid potassium carbonate (58 g) was added in portions to bring the pH to about 4. A precipitate crashed out. Ethyl acetate was added, and the mixture was stirred until everything dissolved. The aqueous layer was extracted once with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried under high vacuum to afford (I-8b) as a clear glass (6.15 g, 21.9 mmol, 98%). ¹H NMR (400 MHz, CDCl₃) δ 7.73 (1H), 7.34 (1H), 6.85-7.15 (1H), 4.66-4.70 (1H), 1.98-2.17 (2H), 1.41-1.75 (7H), 1.01-1.19 (2H); m/z 277.4 (M+H)⁺.

Intermediate: (S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoyl chloride (I-8c)

To a suspension of intermediate (I-8b) (0.25 g, 0.9 mmol) in dichloromethane (5 mL) was added oxalyl chloride (0.35 g, 2.7 mmol) and N,N-dimethylformamide (1 drop) at room temperature. The mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo, and the residue was chased with dichloromethane two times and concentrated in vacuo to afford (I-8c) (0.27 g, 100%) as an oil, which was used in the next step directly.

Intermediate: (S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido) nicotinoyl chloride (I-21a)

Thionyl chloride (225 mg, 1.89 mmol) was added to a solution of the compound of Example 48 (150 mg, 0.387 mmol) in dichloromethane (1.5 mL) and the reaction stirred at room temperature for 1 hour. LCMS of an aliquot in methanol showed ˜67% methyl ester. To the reaction mixture was added another 25 uL of thionyl chloride and this was stirred at room temp for another 30 minutes. Solvents were evaporated to afford 157 mg (100%) of (I-21a) as a grayish-white solid. LCMS in methanol to generate the methyl ester gave m/z 395.9 (M+H)⁺.

(I-8b

Intermediate: (S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoic acid (I-8b)

(I-28a

Intermediate: benzyl 6-aminonicotinate (I-28a)

To a stirred suspension of 6-aminonicotinic acid (100 g, 0.72 mol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) in N,N-dimethylformamide (700 mL) with brisk mechanical stirring was added potassium carbonate (150 g, 1.08 mol) and the reaction was stirred for 10 min before the portionwise addition of benzyl bromide (95 mL, 0.80 mol). The reaction was stirred at room temperature overnight, then the solids were filtered off and washed thoroughly with ethyl acetate, and the solvent was removed under vacuum. The filter cake was dissolved in water and extracted with ethyl acetate. The residue after evaporation of N,N-dimethylformamide was combined with the ethyl acetate extracts (total volume 2 L of ethyl acetate) and the combined organic extracts washed with brine (5×500 mL), dried (MgSO₄) and the solvent removed under reduced pressure. The crude product was refluxed with 1:1 diethyl ether:hexane for 30 min then the solids filtered off (warm), washed with diethyl ether:hexane (1:1), and dried. This solid was precipitated from hot toluene (hot filtration required to remove dibenzylated material) and dried to afford (I-28a) (107.2 g, 65%) as an off-white solid; ¹H NMR (DMSO-d₆): δ 8.50 (1H), 7.82 (1H), 7.34-7.29 (5H), 6.84 (2H), 6.43 (1H), 5.23 (2H); m/z 229.4 (M+H)⁺.

Example 47

(S)-benzyl 6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinate

Formula (1A-4) wherein R⁴is

To Intermediate (I-8b) (16.28 g, 59.8 mmol) stirring in dry dichloromethane (400 mL) at room temperature under nitrogen was added 2 drops of DMF. Oxalyl chloride (11 mL, 130 mmol) was added dropwise. After the bubbling subsided the reaction was left stirring for 90 minutes and then concentrated under reduced pressure. Two successive portions of 1,2-dichloroethane were added and evaporated to remove all excess oxalyl chloride. The crude acid chloride was taken up in dichloromethane (150 mL) and stirred at room temperature. Intermediate (I-28a) (14.3 g, 62.5 mmol) and pyridine (10 mL, 130 mmol) were stirred in 400 mL dry dichloromethane. This was added to the acid chloride solution, using another 50 mL dry dichloromethane to complete the transfer. The mixture was left stirring at room temperature under nitrogen for 18 hours. The reaction was diluted with dichloromethane and water, and 1M aqueous phosphoric acid was added. The organic layer was separated and washed sequentially with dilute aqueous potassium carbonate, and brine. This was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to a glass, which was taken up in hot ethyl acetate and stirred at room temperature. A precipitate appeared at about 30 minutes. The mixture was stirred for 16 hours and then filtered. The precipitate was washed with ethyl acetate and then diethyl ether and dried under high vacuum at 60° C. to afford the title compound as a white solid (17.8 g, 36.6 mmol, 61%). The mother liquor was evaporated and purified by silica gel chromatography on a 120 g pre-packed column, eluting with 40% ethyl acetate/heptane. The product fractions were combined, concentrated under reduced pressure, dried under high vacuum to a glass, and converted as previously described to additional product (3.5 g, 7.2 mmol, 12%, total yield 73%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.50 (1H), 8.87-8.88 (1H), 8.29-8.32 (1H), 8.12-8.14 (1H), 7.93-7.94 (2H), 7.39-7.46 (2H), 7.30-7.37 (3H), 5.32 (2H), 5.21-5.25 (1H), 2.06-2.19 (2H), 1.26-1.63 (8H), 1.01-1.06 (1H); m/z 487.5 (M+H)⁺.

Example 48

(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid

Formula (1A-4) wherein R⁴is

The compound of Example 47 (4.07 g, 8.35 mmol) was added to a 500 mL Parr bottle, followed by ethyl acetate (50 mL) and ethanol (100 mL). The mixture was warmed until all of the solid dissolved, and then cooled to room temperature. 10% Pd/C (450 mg) was added, and the mixture was shaken under 50 psi hydrogen for 90 minutes. The reaction was filtered through a microfiber filter. The filtrate was concentrated under reduced pressure and dried under high vacuum at 50° C. to afford product as a glassy solid (3.0 g, 7.75 mmol, 90.6%). The glassy solid was stirred overnight in diethyl ether. The white solid precipitate was filtered, washed with diethyl ether, suction dried, and dried under high vacuum at 50° C. to afford the title compound as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.10-13.25 (1H), 11.44 (1H), 8.83 (1H), 8.23-8.26 (1H), 8.09-8.12 (1H), 7.94-7.95 (2H), 5.22-5.26 (1H), 2.06-2.17 (2H), 1.29-1.64 (8H), 1.04-1.07 (1H);

m/z 397.3 (M+H)⁺.

THIS NMR IS FROM SUPPORTING INFO OF A JOURNAL

PAPER

Organic Process Research & Development (2012), 16(10), 1635-1645

http://pubs.acs.org/doi/abs/10.1021/op300194c

This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis of intermediates and API bearing a particularly racemization-prone α-aryl carboxylate functionality. In particular, a T3P-mediated amidation process was optimized for the coupling of a racemization-prone acid substrate and a relatively non-nucleophilic amine. Furthermore, an unusually hydrolytically-labile amide in the API also complicated the synthesis and isolation of drug substance. The evolution of the process over multiple campaigns is presented, resulting in the preparation of over 110 kg of glucokinase activator.

(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid (1)

Pressure Hydrogenation

1 (89% yield) as a white solid:

mp 187–189 °C;

¹H NMR (400 MHz, d₆-DMSO) δ 13.23 (s, 1H), 11.49 (s, 1H), 8.86 (dd, J = 0.4, 2.4 Hz, 1H), 8.27 (dd, J = 2.4, 8.8 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.97–7.99 (m, 2H), 5.27 (dd, J = 5.6, 10.0 Hz, 1H), 2.20 (ddd, J = 6.0, 10.0, 14.0, 1H), 2.10 (ddd, J = 5.6, 8.4, 14.0, 1H), 1.27–1.69 (m, 8H), 1.03–1.12 (m, 1H);

¹³C NMR (100 MHz, d₆-DMSO) δ 168.8, 165.7, 154.3, 149.7, 139.6, 138.8, 129.9 (q, J_CF = 38 Hz), 122.6, 122.0 (q, J_CF = 265 Hz), 120.0 (q, J_CF = 4 Hz), 112.8, 60.0, 37.6, 36.2, 32.0, 30.8, 24.6, 24.4;

¹⁹F NMR (376 MHz, d₆-DMSO) δ −60.7.

HRMS-ESI m/z: [M + H]⁺ calcd for C₁₈H₁₉F₃N₄O₃, 397.1482; found, 397.1481.

Achiral HPLC: rt 4.6 min. Chiral SFC: rt 4.1 min (1), 3.1 min (ent-1).

NMR……..http://pubs.acs.org/doi/suppl/10.1021/op300194c/suppl_file/op300194c_si_001.pdf

PAPER

Journal of Medicinal Chemistry (2012), 55(3), 1318-1333

http://pubs.acs.org/doi/abs/10.1021/jm2014887

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure–activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.

(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid (19)

afford 19 as a white solid (3.22 g, 71%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.47 (s, 1H), 8.86 (d, J = 1.95 Hz, 1H), 8.27 (dd, J = 2.24, 8.68 Hz, 1H), 8.13 (d, J = 8.78 Hz, 1H), 7.97 (d, J = 4.88 Hz, 2H), 5.27 (dd, J = 5.37, 9.66 Hz, 1H), 2.04–2.26 (m, 2H), 1.38–1.72 (m, 7H), 1.26–1.37 (m, 1H), 1.08 (td, J = 7.88, 11.75 Hz, 1H);

LCMS m/z 397.5 (M + H)⁺.

HPLC purity (method A): t_R = 7.690 min, 100%.

PAPER

Bioorganic & Medicinal Chemistry Letters (2013), 23(24), 6588-6592

http://www.sciencedirect.com/science/article/pii/S0960894X13012638

Figure 1.

Structure of Hepatoselective GKA PF-04991532 (1).

References

Drug Metabolism & Disposition (2015), 43(2), 190-198

PLoS One (2014), 9(5), e97139/1-e97139/9,

Journal of Biological Chemistry (2012), 287(17), 13598-13610

Drug Discovery Today (2012), 17(9-10), 528-529

Biochemical Journal (2012), 441(3), 881-887.

///////////

Figure 1. Representative structures of glucokinase activators.

Pfizer’s PF 04937319 glucokinase activators for the treatment of Type 2 diabetes

November 27, 2015 4:24 am / 1 Comment on Pfizer’s PF 04937319 glucokinase activators for the treatment of Type 2 diabetes

Graphical abstract: Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

PF 04937319

N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide

MW 432.43

MF C₂₂ H₂₀ N₆ O₄

CAS 1245603-92-2

2-Pyrimidinecarboxamide, N,N-dimethyl-5-[[2-methyl-6-[[(5-methyl-2-pyrazinyl)amino]carbonyl]-4-benzofuranyl]oxy]-

N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4- yloxy)pyrimidine-2-carboxamide

Pfizer Inc. clinical candidate currently in Phase 2 development.

CLINICAL TRIALS

A trial to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of PF-04937319 in subjects with type 2 diabetes mellitus (NCT01044537)

Multiple dose study of PF-04937319 in patients with type 2 diabetes (NCT01272804)

Phase 2 study to evaluate safety and efficacy of investigational drug – PF04937319 in patients with type 2 diabetes (NCT01475461)

SYNTHESIS

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.

Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood glucose levels. Two major forms of diabetes are recognized. Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin. Type Il diabetes, or non-insulin dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues and cells to respond appropriately to insulin. Aggressive control of NIDDM with medication is essential; otherwise it can progress into IDDM. As blood glucose increases, it is transported into pancreatic beta cells via a glucose transporter. Intracellular mammalian glucokinase (GK) senses the rise in glucose and activates cellular glycolysis, i.e. the conversion of glucose to glucose-6-phosphate, and subsequent insulin release. Glucokinase is found principally in pancreatic β-cells and liver parenchymal cells. Because transfer of glucose from the blood into muscle and fatty tissue is insulin dependent, diabetics lack the ability to utilize glucose adequately which leads to undesired accumulation of blood glucose (hyperglycemia). Chronic hyperglycemia leads to decreases in insulin secretion and contributes to increased insulin resistance. Glucokinase also acts as a sensor in hepatic parenchymal cells which induces glycogen synthesis, thus preventing the release of glucose into the blood. The GK processes are thus critical for the maintenance of whole body glucose homeostasis.

It is expected that an agent that activates cellular GK will facilitate glucose-dependent secretion from pancreatic beta cells, correct postprandial hyperglycemia, increase hepatic glucose utilization and potentially inhibit hepatic glucose release. Consequently, a GK activator may provide therapeutic treatment for NIDDM and associated complications, inter alia, hyperglycemia, dyslipidemia, insulin resistance syndrome, hyperinsulinemia, hypertension, and obesity. Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, NIDDM (Moller, D. E., “New drug targets for Type 2 diabetes and the metabolic syndrome” Nature 414; 821 -827, (2001 )): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents. Ideally, an effective new treatment for NIDDM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are independent from the actions of insulin; (d) it would desirably be metabolically stable to allow less frequent usage; and (e) it would be usable in combination with tolerable amounts of any of the categories of drugs listed herein.

Substituted heteroaryls, particularly pyridones, have been implicated in mediating GK and may play a significant role in the treatment of NIDDM. For example, U.S. Patent publication No. 2006/0058353 and PCT publication No’s. WO2007/043638, WO2007/043638, and WO2007/117995 recite certain heterocyclic derivatives with utility for the treatment of diabetes. Although investigations are on-going, there still exists a need for a more effective and safe therapeutic treatment for diabetes, particularly NIDDM.

Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

Jeffrey A. Pfefferkorn,*^a et al

*Corresponding authors

^aPfizer Worldwide Research & Development, Eastern Point Road, Groton
E-mail: jeffrey.a.pfefferkorn@pfizer.com
Tel: +860 686 3421

Med. Chem. Commun., 2011,2, 828-839

DOI: 10.1039/C1MD00116G

http://pubs.rsc.org/en/content/articlelanding/2011/md/c1md00116g/unauth#!divAbstract

http://www.rsc.org/suppdata/md/c1/c1md00116g/c1md00116g.pdf

N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4- yloxy)pyrimidine-2-carboxamide (28). To a solution of the 5-methyl-2-aminopyrazine (38.9 g, 356 mmol) in dimethoxyethane (315 mL) in a 3-neck flask equipped with overhead stirring and a condenser at 0 o C was added Me2AlCl (1 M solution in hexanes) (715 mL). The mixture was warmed to room temperature and stirred for 1.5 h. In a separate flask, 26 (52.6 g, 142.5 mmol) was dissolved in dimethoxyethane (210 mL). This mixture was then added to the amine mixture. A gum precipitated and upon scratching the flask it dissipated into a solid. The reaction was refluxed for 3.5 h. Aq. Rochelle’s salt (5 L) and 2-MeTHF (2 L) was added to the mixture and this was allowed to stir with overhead stirring for 14 h, after which time, a yellow solid precipitated. The solid was collected by filtration, washing with 2-MeTHF. The resulting solid was dried in a vacuum oven overnight to afford the desired material (50.0g) in 81% yield.

1 H NMR (400MHz, CDCl3) δ 9.54 (d, J = 1.56 Hz, 1H), 8.50 (s, 2H), 8.37 (s, 1H), 8.14 (d, J = 0.78 Hz, 1H), 7.88 – 7.92 (m, 1H), 7.52 (d, J = 1.37 Hz, 1H), 6.28 (t, J = 0.98 Hz, 1H), 3.14 (s, 3H), 2.98 (s, 3H), 2.55 (s, 3H), 2.49 (d, J = 1.17 Hz, 3H);

MS(ES+ ): m/z 433.4 (M+1), MS(ES- ): m/z 431.3 (M-1).

PAPER

http://pubs.rsc.org/en/content/articlelanding/2013/md/c2md20317k#!divAbstract

PAPER

Bioorganic & Medicinal Chemistry Letters (2013), 23(16), 4571-4578

http://www.sciencedirect.com/science/article/pii/S0960894X13007452

Figure 1.

Glucokinase activators 1 and 2.

PATENT

Pfizer Inc.

WO 2010103437

https://www.google.co.in/patents/WO2010103437A1?cl=en

Scheme I outlines the general procedures one could use to provide compounds of the present invention having Formula (I).

Preparations of Starting Materials and Key Intermediates

Preparation of Intermediate (E)-3-(ethoxycarbonyl)-4-(5-methylfuran-2-yl)but- 3-enoic acid (I- 1a):

(Ma) To a vigorously stirred solution of 5-methyl-2-furaldehyde (264 ml_, 2650 mmol) and diethyl succinate (840 ml_, 5050 mmol) in ethanol (1.820 L) at room temperature was added sodium ethoxide (0.93 L of a 21 weight % solution in ethanol) in one portion. The reaction mixture was then heated at reflux for 13 hours. After cooling to room temperature, the mixture was concentrated in vacuo (all batches were combined at this point). The resulting residue was partitioned between ethyl acetate (1 L) and hydrochloric acid (1 L of a 2M aqueous solution). After separation, the aqueous layer was extracted with ethyl acetate (2 x 1 L). The combined organic extracts were then extracted with sodium hydrogen carbonate (2 x 1 L of a saturated aqueous solution). These aqueous extracts were combined and adjusted to pH 2 with hydrochloric acid (2M aqueous solution) then extracted with ethyl acetate (2 x 1 L). These organic extracts were combined and concentrated in vacuo to give desired (E)-3-(ethoxycarbonyl)-4-(5-methylfuran-2-yl)but-3-enoic acid (J₁ Ia: 34.34 g, 5%). The original organic extract was extracted with sodium hydroxide (2 L of a 2M aqueous solution). This aqueous extract was adjusted to pH 2 with hydrochloric acid (2M aqueous solution) then extracted with ethyl acetate (2 x 1 L). These organic extracts were combined and concentrated in vacuo to give additional desired materials (395.2 gram, 63%) as red liquid. ¹H NMR (CDCI₃, 300 MHz) δ ppm 7.48 (s, 1 H), 6.57 (d, 1 H), 6.09 (d, 1 H), 4.24 (q, 2H), 3.87 (s, 2H), 2.32 (s, 3H), 1.31 (t, 3H).

Preparation of Intermediate ethyl 4-acetoxy-2-methylbenzofuran-6- carboxylate (1-1 b):

(M b) To a vigorously stirred solution of (E)-3-(ethoxycarbonyl)-4-(5- methylfuran-2-yl)but-3-enoic acid (1-1 a: 326.6 g, 1 .371 mol) in acetic anhydride (1 .77 L, 18.72 mol) at room temperature was added sodium acetate (193 g, 2350 mmol) in one portion. The reaction mixture was then heated at reflux for 2.5 hours. After cooling to room temperature, the mixture was concentrated in vacuo (all batches were combined at this point). The resulting residue was suspended in dichloromethane (1 .5 L) and filtered, washing the solids with dichloromethane (3 x 500 ml_). The combined filtrate and washings were then washed with sodium hydrogencarbonate (2 x 1 L of a saturated aqueous solution) and brine (2 L), then concentrated in vacuo to give desired ethyl 4-acetoxy-2-methylbenzofuran-6-carboxylate (H b: 549.03 g, quantitative). ¹H NMR (CDCI₃, 300 MHz) δ ppm 8.00-7.99 (m, 1 H), 7.64 (d, 1 H), 6.32-6.32 (m, 1 H), 4.38 (q, 2H), 2.47 (d, 3H), 2.37 (s, 3H), 1 .39 (t, 3H).

Preparation of Intermediate ethyl 4-hydroxy-2-methylbenzofuran-6- carboxylate (1- 1 c):

(He) To a stirred solution of ethyl 4-acetoxy-2-methylbenzofuran-6- carboxylate (Hb: 549.03 g, 1 .37 mol) in ethanol (4.00 L) at room temperature was added potassium carbonate (266 g, 1 .92 mol) in one portion. The reaction mixture was then heated at 60⁰C for 3 hours. Potassium carbonate (100 g, 0.720 mol) was then added in one portion and the reaction mixture was heated at 60⁰C for a further 3 hours. After cooling to room temperature the mixture was diluted with dichloromethane (2 L) and the suspension filtered, washing the solids with dichloromethane (2 x 1 L) (all batches were combined at this point). The combined filtrate and washings were then washed with citric acid (2.5 L of a 1 M aqueous solution), then concentrated in vacuo and the resulting residue purified by dry flash chromatography (hexane then 2:1 hexane:ethyl acetate). All fractions containing the desired product were combined and concentrated in vacuo. The resulting residue, which solidified on standing, was slurried with cold toluene and filtered. The solids were then stirred with hot toluene and decolourising charcoal for 1 hour, followed by filtration of the hot mixture through a pad of celite. The filtrate was allowed to cool and the resulting precipitate isolated by filtration to give desired ethyl 4-hydroxy-2- methylbenzofuran-6-carboxylate (1-1 c: 360 g, 90%) as orange powder.

¹H NMR (CDCI₃, 300 MHz) δ ppm 7.73-7.73 (m, 1 H), 7.45 (d, 1 H), 6.51 -6.50 (m, 1 H), 5.85 (s, 1 H), 4.39 (q, 2H), 2.48 (d, 3H), 1.40 (t, 3H). LCMS (liquid chromatography mass spectrometry): m/z 221.06 (96.39 % purity).

Preparation of SM-25-bromo-N,N-dimethylpyrimidine-2-carboxamide (SM-

£1:

(SM-2) Oxalyl chloride (47.4g, 369mmol) was added to a suspension of 5-

Bromo-pyrimidine-2-carboxylic acid (5Og, 250mmol) in dichloromethane (821 ml) at room temperature followed by 1 -2 drop of dimethylformamide. The reaction mixture was stirred under nitrogen for 2 hours LCMS in methanol indicated the presence of the methyl ester and some acid. Dimethylformamide (0.2ml) was added to the reaction mixture. The acid dissolved after 30 minutess. LCMS showed corresponding methyl ester and no starting material peak was observed. The solvent was removed and dried in vacuo to afford the crude 5-Bromo-pyrimidine-2-carbonyl chloride (55g, 100%). The 5-Bromo-pyrimidine-2-carbonyl chloride (55g, 250mmol) was dissolved in tetrahydrofuran (828ml) and dimethyl-amine (2M solution in tetrahydrofuran) (373ml, 745mmol) was added portionwise at room temperature. The reaction was stirred at room temperature under nitrogen for 16 hours, after which time, LCMS indicated completion. The mixture was diluted with ethyl acetate (500ml) and washed with H₂O (500ml). The water layer was further extracted with CH₂CI₂ (5x500ml), all organics combined, and dried over magnesium sulfate. The filtrate was concentrated in vacuo and then suspended in methyl-/-butylether (650ml). The solution was then heated to reflux. The hot solution was allowed to cool overnight to afford pink crystals. The crystals were filtered and washed with cold methyl-t-butylether (100ml) the solid was dried in a vacuum oven at 55⁰C for 12 hourrs to afford the title compound 5-bromo-N,N-dimethylpyhmidine-2-carboxamide (SM-2: 44g, 77%) as a pink solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.94 (s, 3 H) 3.13 (s, 3 H) 8.85 (s, 2 H) m/z (M+1 ) = 232.

Preparation of Intermediate Ethyl 4-(2-(dimethylcarbamoyl)Dyrimidin-5- yloxy)-2-methylbenzofuran-6-carboxylate (l-2a):

A mixture of Cs₂CO₃ (62.1 g, 191 mmol), 5-bromo-N,N- dimethylpyrimidine-2-carboxamide (SM-2: 24g, 104mmol) and ethyl 4- hydroxy-2-methylbenzofuran-6-carboxylate (1-1 c: 2Og, 91 mmol); 1 ,10- phenanthroline (1.64g, 9.07mmol) and copper iodide (864mg, 4.54mmol) in dimethylformamide (200ml) was purged with N₂ gas and then heated to 90°C using a mechanical stirrer. The heterogeneous reaction mixture was stirred at this temperature for 18 hours. HPLC indicated near completion. The reaction mixture was cooled to 35⁰C and diluted with ethyl acetate (300ml). The mixture was filtered to remove any cesium carbonate. The filtrate was then partitioned between water (500ml) and ethyl acetate (500ml); however, no separation was observed. Concentrated HCL (20ml) was added to the mixture. When the aqueous phase was about pH1 , the phases separated. The organics were separated and the aqueous layer reextracted with ethyl acetate (2x500ml). All organics were combined and back extracted with water (200ml) and brine (500ml). The organics were separated and treated with activated charcoal (10g) and magnesium sulfate. The mixture was allowed to stir for 10 minutes and then filtered through a plug of celite to afford a crude yellow solution. The filter cake was washed with ethyl acetate (100 ml_). The organics were concentrated in vacuo to afford a crude solid this was dried under high vacuum for 4 days. The dry crude solid was triturated using methanol (80 ml_). The solids were dispersed into a fine light orange crystalline powder with a red liquor. The solids were isolated by filtration and rinsed with methanol (20 ml_). The solid was dried in the vacuum oven at 55⁰C for 12 hours to afford ethyl 4-(2- (dimethylcarbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (J₁ 2a) as a yellow solid (18.2g, 54%)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (t, J=7.12 Hz, 3 H) 2.50 (d, J=0.98 Hz, 3 H) 3.00 (s, 3 H) 3.17 (s, 3 H) 4.41 (d, J=7.22 Hz, 2 H) 6.29 (s, 1 H) 7.62 (d, J=1.17 Hz, 1 H) 8.06 (s, 1 H) 8.50 (s, 2 H). m/z (M+1 ) = 370.5

Preparation of Starting material 5-bromo-N-ethyl-N-methylpyrimidine-2- carboxamide (SM-3):

(SM-3) Oxalyl chloride (1 .45g, 1 1 .1 mmol) was added to a suspension of 5-

Bromo-pyrimidine-2-carboxylic acid (1 .5g, 7.4mmol) in dichloromethane (50ml) at room temperature followed by 1 -2 drop of dimethylformamide. The reaction mixture was stirred under nitrogen for 2 hours LCMS in methanol indicated the presence of the methyl ester and some acid. Dimethylformamide (0.2ml) was added to the reaction mixture and all of the acid dissolved after 30 minutes. LCMS showed corresponding methyl ester and no starting material peak was observed. The solvent was removed and dried in vacuo to afford the crude 5-Bromo-pyrimidine-2-carbonyl chloride (1 -6g). 5-Bromo-pyrinnidine-2-carbonyl chloride (1600mg, 7.225mnnol) was dissolved in dichloromethane (25ml) and triethylamine (4.03ml, 28.9mmol) was added followed by ethyl-methyl-amine (0.68 mL, 7.92 mmol). The reaction was stirred at room temperature under nitrogen for 16 ours, after which time, LCMS indicated completion. The mixture was diluted with dichloromethane (50ml) and washed with water (50ml) followed by 10% citric acid (50ml) and brine (50ml). The organic layer was separated and dried over MgSO4, the residue was filtered and the solvent was removed in vacuo to afford the title compound 5-bromo-N-ethyl-N-methylpyrimidine-2- carboxamide (SM-3): (1.4g, 79.4%) as a brown oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.08 – 1.31 (m, 3 H) 2.99 (d, J=79.05 Hz, 3 H) 3.19 (q, J=7.22 Hz, 1 H) 3.59 (q, J=7.22 Hz, 1 H) 8.84 (d, J=3.12 Hz, 2 H)

Example 2

Preparation of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2- yl)carbamoyl)-benzofuran-4-yloxy)Dyrimidine-2-carboxamide (2):

(2)

To a solution of the 5-methyl-2-aminopyrazine (38.9 g, 356 mmol) in dimethylether (315 ml_) in a 3-neck flask equipped with overhead stirring and a condensor at O⁰C was added Me2AICI (1 M solution in hexanes) (715 ml_). The mixture was warmed at room temperature and stirred for 1.5 hours. In a separate flask, ethyl 4-(2-(dimethylcarbamoyl)pyrimidin-5-yloxy)-2- methylbenzofuran-6-carboxylate (l-2a: 52.6g, 142.5mmol) was dissolved in dimethylether (210 ml_). This mixture was then added to the complexed amine. A gum precipitated upon scratching the flask and dissipated into a solid. The resultant reaction was refluxed for 3.5 hours HPLC indicated 93% complete. Five liters of Rochelles salt made up in water and 2 liters of 2- methyltetrahydrofuran was added to the mixture. The reaction mixture was then poured into the biphasic system. The mixture was allowed to stir with overhead stirring for 14 hours, after which time, a yellow solid precipitated. The solid was collected through filteration. The solid retained was washed with 2-methyltetrahydrofuran. The resultant solid was dried in vacuo oven overnight to afford the title compound N,N-dimethyl-5-(2-methyl-6-((5- methylpyrazin-2-yl)carbamoyl)benzofuran-4-yloxy)pyhmidine-2-carboxamide (2): (49.98g, 81 %)

1H NMR (400 MHz, CHLOROFORM-d) d ppm 2.49 (d, J=1 .17 Hz, 3H) 2.55 (s, 3H) 2.98 (s, 3 H) 3.14 (s, 3 H) 6.28 (t, J=0.98 Hz, 1 H) 7.52 (d, J=1 .37 Hz, 1 H) 7.88 – 7.92 (m, 1 H) 8.14 (d, J=0.78 Hz, 1 H) 8.37 (s, 1 H) 8.50 (s, 2 H) 9.54 (d, J=1 .56 Hz, 1 H).

m/z (M+1 ) = 433.4, m/z (M-1 )= 431 .5

REFERENCES

Beebe, D.A.; Ross, T.T.; Rolph, T.P.; Pfefferkorn, J.A.; Esler, W.P.
The glucokinase activator PF-04937319 improves glycemic control in combination with exercise without causing hypoglycemia in diabetic rats
74th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 13-17, San Francisco) 2014, Abst 1113-P

Amin, N.B.; Aggarwal, N.; Pall, D.; Paragh, G.; Denney, W.S.; Le, V.; Riggs, M.; Calle, R.A.
Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes
Diabetes Obes Metab 2015, 17(8): 751

Study to compare single dose of three modified release formulations of PF-04937319 with immediate release material-sparing-tablet (IR MST) formulation previously studied in adults with type 2 diabetes mellitus (NCT02206607)

OTHERS

///////////Pfizer , PF 04937319, glucokinase activators, Type 2 diabetes

TARANABANT

November 26, 2015 8:45 am / Leave a comment

Taranabant ( MK-0364)

701977-09-5

N-[3-(4-Chlorophenyl)-2(S)-(3-cyanophenyl)-1(S)-methylpropyl]-2-methyl-2-[5-(trifluoromethyl)pyridin-2-yloxy]propionamide

N-[(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)butan-2-yl]-2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]oxypropanamide

Taranabant (codenamed MK-0364) is a cannabinoid receptor type 1 inverse agonist being investigated as a potential treatment forobesity due to its anorectic effects.^[1]^[2] It was discovered by Merck & Co.

In October 2008, Merck has stopped its phase III clinical trials with the drugs due to high level of central side effects, mainlydepression and anxiety.^[3]^[4]^[5]^[6]

The compound had also been in clinical evaluation in chronic cigarette smokers as an aid for smoking cessation.

Paper

http://pubs.rsc.org/en/content/articlelanding/2013/cs/c2cs35410a#!divAbstract

PATENT

WO 2003077847

http://www.google.co.in/patents/WO2003077847A2?cl=en

PAPERS

Convenient total synthesis of taranabant (MK-0364), a novel cannabinoid-1 receptor inverse agonist as an anti-obesity agent
Tetrahedron 2007, 63(52): 12845

Wallace, D.J.; Campos, K.R.; Shultz, S.; Klapars, A.; et al.
New efficient asymmetric synthesis of taranabant, a CB1R inverse agonist for the treatment of obesity
Org Process Res Dev 2009, 13(1): 84

Lin, L.S.; Lanza, T.J. Jr.; Jewell, J.P.; Liu, P.; Shah, S.K.; Qi, H.; Tong, X.; Wang, J.; Xu, S.S.; Fong, T.M.; Shen, C.P.; Lao, J.; Xiao, J.C.; Shearman, L.P.; Stribling, D.S.; Rosko, K.; Strack, A.; Marsh, D.J.; Feng, Y.; Kumar, S.; Samuel, K.; Yin, W.; Ploeg, L.H.; Goulet, M.T.; Hagmann, W.K.
Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- [[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity
J Med Chem 2006, 49(26): 7584

Cole, P.; Serradell, N.; Rosa, E.; Bolos, J. Taranabant Drugs Fut 2008, 33(3): 206

PAPER

Chen, C.-Y.; Frey, L.F.; Shultz, S.; et al. Catalytic, enantioselective synthesis of taranabant, a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity
Org Process Res Dev 2007, 11(3): 616

http://pubs.acs.org/doi/abs/10.1021/op700026n

Chiral amide 1 (MK-0364, taranabant) is a potent, selective, and orally bioavailable cannabinoid-1 receptor (CB-1R) inverse agonist indicated for the treatment of obesity. An asymmetric synthesis featuring a dynamic kinetic resolution via hydrogenation for the preparation of the bromo alcohol 5 is disclosed. Conversion of the alcohol intermediate to the chiral amide 1 is accomplished in good overall yield.

N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (1, MK-0364). hemisolvate (approximately 94 wt %, 94% isolated yield from amine salt).

¹H NMR (CDCl₃): δ 8.35 (s, 1H), 7.83 (dd, J = 2.38, 8.70 Hz, 1H), 7.45 (d, J = 7.57 Hz, 1H), 7.31 (t, J = 7.99 Hz, 1H), 7.24 (m, 2H), 7.07 (d, J = 8.34 Hz, 2H), 6.88 (d, J = 8.63 Hz, 1H), 6.72 (d, J = 8.33 Hz, 2H), 5.88 (d, J = 8.95 Hz, 1H), 4.34 (m, 1H), 3.13 (dd, J = 3.04, 12.72 Hz, 1H), 2.82 (m, 2H), 1.76 (s, 3H), 1.72 (s, 3H), 0.87 (d, J = 6.72 Hz, 3H).

¹³C NMR (CDCl₃): δ 173.4, 163.9, 144.5 (q, J = 4.30 Hz), 142.4, 137.5, 136.3 (q, J = 3.02 Hz), 133.0, 132.2, 132.0, 130.7, 130.0, 129.3, 128.5, 123.7 (q, J = 271.45 Hz), 121.1 (q, J = 33.32 Hz), 118.6, 112.7, 112.6, 82.1, 53.6, 48.6, 38.2, 25.4, 25.1, 18.4.

Anal. Calcd for C₂₇H₂₅ClF₃N₃O₂: C 62.85; H 4.88; N 8.14. Found: C 62.95; H 4.74; N 8.00.

References

Armstrong HE, Galka A, Lin LS, Lanza TJ Jr, Jewell JP, Shah SK, et al. “Substituted acyclic sulfonamides as human cannabinoid-1 receptor inverse agonists.” Bioorganic & Medicinal Chemistry Letters. 2007 Apr 15;17(8):2184-7. PMID 17293109. doi:10.1016/j.bmcl.2007.01.087
Fong TM, Guan XM, Marsh DJ, Shen CP, Stribling DS, Rosko KM, et al. “Antiobesity efficacy of a novel cannabinoid-1 receptor inverse agonist, N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), in rodents.” Journal of Pharmacology and Experimental Therapeutics. 2007 Jun;321(3):1013-22. PMID 17327489.doi:10.1124/jpet.106.118737
“Press release by Merck”. Retrieved October 2008.
Aronne LJ, Tonstad S, Moreno M, Gantz I, Erondu N, Suryawanshi S, Molony C, Sieberts S, Nayee J, Meehan AG, Shapiro D, Heymsfield SB, Kaufman KD, Amatruda JM (May 2010). “A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study”. International Journal of Obesity (2005) 34 (5): 919–35. doi:10.1038/ijo.2010.21.PMID 20157323.
Kipnes MS, Hollander P, Fujioka K, Gantz I, Seck T, Erondu N, Shentu Y, Lu K, Suryawanshi S, Chou M, Johnson-Levonas AO, Heymsfield SB, Shapiro D, Kaufman KD, Amatruda JM (June 2010). “A one-year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes”. Diabetes, Obesity & Metabolism 12 (6): 517–31. doi:10.1111/j.1463-1326.2009.01188.x. PMID 20518807.
Proietto J, Rissanen A, Harp JB, Erondu N, Yu Q, Suryawanshi S, Jones ME, Johnson-Levonas AO, Heymsfield SB, Kaufman KD, Amatruda JM (August 2010). “A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study”. International Journal of Obesity (2005) 34 (8): 1243–54. doi:10.1038/ijo.2010.38. PMID 20212496.

Radiolabeled cannabinoid-1 receptor modulators [US7754188]	2006-06-01	2010-07-13
Combination therapy for the treatment of obesity [US2006270650]	2006-11-30
CERTAIN CRYSTALLINE DIPHENYLAZETIDINONE HYDRATES, PHARMACEUTICAL COMPOSITIONS THEREOF AND METHODS FOR THEIR USE [US8003636]	2009-08-13	2011-08-23
NOVEL DIPHENYLAZETIDINONE SUBSTITUTED BY PIPERAZINE-1-SULFONIC ACID AND HAVING IMPROVED PHARMACOLOGICAL PROPERTIES [US2009264402]	2009-10-22
Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, process for preparing them, medicaments comprising these compounds, and their use [US7759366]	2009-08-27	2010-07-20
COMPOUNDS WITH A COMBINATION OF CANNABINOID CB1 ANTAGONISM AND SEROTONIN REUPTAKE INHIBITION [US8138174]	2008-09-04	2012-03-20
Substituted imidazoline-2,4-diones, process for preparation thereof, medicaments comprising these compounds and use thereof [US2011112097]	2011-05-12
Novel phenyl-substituted imidazolidines, process for preparation thereof, medicaments comprising said compounds and use thereof [US2011178134]	2011-07-21
HETEROCYCLIC COMPOUNDS, PROCESSES FOR THEIR PREPARATION, MEDICAMENTS COMPRISING THESE COMPOUNDS, AND THE USE THEREOF [US2011183998]	2011-07-28
Cyclic pyridyl-N-[1,3,4]-thiadiazol-2-yl-benzene sulfonamides, processes for their preparation and their use as pharmaceuticals [US2011224263]	2011-09-15

Taranabant
Systematic (IUPAC) name


N-[(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)-2-butanyl]-2-methyl-2-{[5-(trifluoromethyl)-2-pyridinyl]oxy}propanamide
Clinical data
Routes of administration	Oral
Identifiers
CAS Number	701977-09-5
ATC code	A08AX
PubChem	CID: 11226090
UNII	X9U622S114
Chemical data
Formula	C₂₇H₂₅Cl F₃N₃O₂
Molecular mass	515.95 g/mol

///////////CC(C(CC1=CC=C(C=C1)Cl)C2=CC=CC(=C2)C#N)NC(=O)C(C)(C)OC3=NC=C(C=C3)C(F)(F)F

C[C@@H]([C@@H](CC1=CC=C(C=C1)Cl)C2=CC=CC(=C2)C#N)NC(=O)C(C)(C)OC3=NC=C(C=C3)C(F)(F)F

Revised USP Chapter on Visual Inspection published

November 26, 2015 3:46 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

After the long-awaited Chapter <1790> on visual inspection of injections was first published in the PF 41(1) as a draft the USP has now submitted a revised draft in the PF41 (6). Read more about the revised draft of the USP Chapter <1790>.

http://www.gmp-compliance.org/enews_05091_Revised-USP-Chapter–1790–on-Visual-Inspection-published_15154,Z-PEM_n.html

After the long-awaited Chapter <1790> Visual Inspection of Injections was first published in the Pharmacopeial Forum 41(1) as a draft the USP has now submitted a revised draft in the PF41 (6). Through its number >1000, the monograph <1790> is not binding but rather offers an explanation to Chapter <790> Visible Particulates in Injections.

With regard to the content, several comments recommended by the industry have been included. The new Chapter 9 represents the biggest change and describes the evaluation of marketed products where anomalies had been observed regarding particles. The test procedure for it is described in Chapter <790>. Yet, this topic was missing…

View original post 149 more words

Latest Posts

Amogammadex
Amogammadex CAS 1309580-40-2 MF C88H136N8O56S8 MW2458.56 (2R)-2-acetamido-3-[[(1S,3S,5S,6S,8S,10S,11S,13S,15S,16S,18S,20S,21S,23S,25S,26S,28S,30S,31S,33S,35S,36S,38S,40S,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,54R,55R,56R)-10,15,20,25,30,35,40-heptakis[[(2R)-2-acetamido-2-carboxyethyl]sulfanylmethyl]-41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56-hexadecahydroxy-2,4,7,9,12,14,17,19,22,24,27,29,32,34,37,39-hexadecaoxanonacyclo[36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36]hexapentacontan-5-yl]methylsulfanyl]propanoic acid L-CYSTEINE, S,S’,S”,S”’,S””,S”””,S”””,S”””’-(6A,6B,6C,6D,6E,6F,6G,6H-OCTADEOXY-.GAMMA.-CYCLODEXTRIN-6A,6B,6C,6D,6E,6F,6G,6H-OCTAYL)OCTAKIS(N-ACETYL-AMOGAMMADEX [INN]CYCLOOCTAKIS-(1->4)-(6-S-((2R)-2-ACETAMIDO-2-CARBOXYETHYL)-6-THIO-.ALPHA.-D-GLUCOPYRANOSYL) cyclooctakis-(1→4)-{6-S-[(2R)-2-acetamido-2-carboxyethyl]-6-thio-α-Dglucopyranosyl}rocuronium and vecuronium reversal agent, L-CYSTEINE, S,S’,S”,S”’,S””,S”””,S”””,S”””’-(6A,6B,6C,6D,6E,6F,6G,6H-OCTADEOXY-.GAMMA.-CYCLODEXTRIN-6A,6B,6C,6D,6E,6F,6G,6H-OCTAYL)OCTAKIS(N-ACETYL-AMOGAMMADEX [INN]CYCLOOCTAKIS-(1->4)-(6-S-((2R)-2-ACETAMIDO-2-CARBOXYETHYL)-6-THIO-.ALPHA.-D-GLUCOPYRANOSYL) Pat WO2012068981 https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012068981&_cid=P21-MJW9RG-10499-1 CD-8 Weigh 23.7…
Alizulatide vixocianine
Alizulatide vixocianine CAS 2924859-51-6 MF C115H145N17O25S, 2,197.55 L-Serine, N-[6-[2-[7-[1,3-dihydro-1,1-dimethyl-3-(4-sulfobutyl)-2H-benz[e]indol-2-ylidene]-1,3,5-heptatrien-1-yl]-1,1-dimethyl-1H-benz[e]indolio]-1-oxohexyl]-L-α-glutamyl-L-α-glutamyl-L-α-aspartyl-3-cyclohexyl-L-alanyl-L-phenylalanyl-D-seryl-D-arginyl-L-tyrosyl-L-leucyl-L-tryptophyl-, inner salt 4-[2-[7-[3-[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2R)-5-carbamimidamido-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxy-2-hydroxyethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-6-oxohexyl]-1,1-dimethylbenzo[e]indol-3-ium-2-yl]hepta-2,4,6-trienylidene]-1,1-dimethylbenzo[e]indol-3-yl]butane-1-sulfonate diagnostic imaging agent, 8M3Q8XZ6MJ Alizulatide vixocianine is a polypeptide that can be discovered…
Aleniglipron
Aleniglipron CAS 2685823-26-9 MF C49H55FN9O6P MW916.0 g/mol 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-diethylphosphoryl-3-(methylamino)phenyl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one glucagon-like peptide 1 (GLP-1) receptor agonist, GSBR-1290, GSBR 1290, Z6XCL6R9SX Aleniglipron (development code GSBR-1290) is a small-molecule GLP-1 agonist developed by Structure Therapeutics.[1] It…
Limnetrelvir
Limnetrelvir CAS 2923500-04-1 MF C27H23F4N5O4 MW 557.50 N-[(3R)-1-[4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl]pyrrolidin-3-yl]-8-fluoro-2-oxo-1H-quinoline-4-carboxamide N-{(3R)-1-[4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl]pyrrolidin-3-yl}-8-fluoro-2-oxo1,2-dihydroquinoline-4-carboxamideantiviral, ABBV-903, ABBV 903, 4TPS988XGG Limnetrelvir (ABBV-903) is a MPro inhibitor. Limnetrelvir could be used in antiviral research. SYN https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=4D458E543A941751578F87216FA39801.wapp1nA?docId=WO2024081351&_cid=P10-MJQJMM-46773-1#detailMainForm:MyTabViewId:PCTDESCRIPTION Example…
Aficamten
Aficamten C18H19N5O2, 337.4 g/mol FDA 2025, APPROVALS 2025, Myqorzo, 12/19/2025, To treat symptomatic obstructive hypertrophic cardiomyopathy CK-3773274, B1I77MH6K1, BAY-3723113; CK 3773274; CK 274; MYQORZO N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]-1-methylpyrazole-4-carboxamide Aficamten,…
Zoliflodacin
Zoliflodacin MF C22H22FN5O7 MW 487.4 g/mol FDA 2025, APPROVALS 2025, 12/12/2025, Nuzolvence (4′R,6′S,7′S)-17′-fluoro-4′,6′-dimethyl-13′-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]spiro[1,3-diazinane-5,8′-5,15-dioxa-2,14-diazatetracyclo[8.7.0.02,7.012,16]heptadeca-1(17),10,12(16),13-tetraene]-2,4,6-trione Spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione, 11-fluoro-1,2,4,4a-tetrahydro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-3-oxazolidinyl]-, (2R,4S,4aS)- (2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione To treat uncomplicated urogenital gonorrhea due to Neisseria gonorrhoeae…
Iscartrelvir
Iscartrelvir CAS 2921711-74-0 MF 2921711-74-0, 526.4 g/mol N-{(1S,2R)-2-[4-bromo-2-(methylcarbamoyl)-6-nitroanilino]cyclohexyl}isoquinoline-4-carboxamideantiviral, WU-04, WU 04, W2LTV65R5E Iscartrelvir is an investigational new drug developed by the Westlake University for the treatment of COVID-19. It targets the SARS-CoV-2 3CL…
Zoracopan
Zoracopan CAS 2243483-63-6 MF C31H31BrN6O3 MW 615.52 2-Azabicyclo[3.1.0]hexane-3-carboxamide, 2-[2-[3-acetyl-7-methyl-5-(2-methyl-5-pyrimidinyl)-1H-indol-1-yl]acetyl]-N-(6-bromo-3-methyl-2-pyridinyl)-5-methyl-, (1R,3S,5R)- (1R,3S,5R)-2-{[3-acetyl-7-methyl-5-(2-methylpyrimidin5-yl)-1H-indol-1-yl]acetyl}-N-(6-bromo-3-methylpyridin2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamidecomplement factor D inhibitor, ALXN-2080, ALXN 2080, E7799Y8LXY Zoracopan is a selective complement factor D (CFD) inhibitor.…
Zopocianine
Zopocianine CAS 2206660-94-6, NA SALT 2206660-95-7 MF C74H93N7O27S4, 1,640.83 L-Tyrosine, N-[[[(1S)-1,3-dicarboxypropyl]amino]carbonyl]-L-g-glutamyl-3-[2-(2-aminoethoxy)ethoxy]propanoyl-L-phenylalanyl-O-[6-[2-[1,3-dihydro-3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-2H-indol-2-ylidene]ethylidene]-2-[2-[3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-3H-indolium-2-yl]ethenyl]-1-cyclohexen-1-yl]-, inner salt N-{[(1S)-1,3-dicarboxypropyl]carbamoyl}-L-γ-glutamyl3-[2-(2-aminoethoxy)ethoxy]propanoyl-L-phenylalanylO-[(6Ξ)-2-{(1Ξ)-2-[3,3-dimethyl-1-(4-sulfobutyl)-5-sulfonato-3H-indol-1-ium-2-yl]ethen-1-yl}-6-{(2Ξ)-2-[3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-1,3-dihydro-2Hindol-2-ylidene]ethylidene}cyclohex-1-en-1-yl]-Ltyrosinediagnostic imaging agent, UD9V5S9M7A, OTL 0078, OTL 78 AS ON OCT2025 4.511…
Zomiradomide
Zomiradomide CAS 2655656-99-6 MF C45H48F3N7O6S MW871.97 antineoplastic, IRAK degrader-1, AQ5UXV5646 Zomiradomide is an orally active PROTAC degrader for IRAK4 (DC50=6 nM), thereby inhibiting the NF-κB signaling pathway. Zomiradomide acts also as…

DISCLAIMER

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

Blog at WordPress.com.

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel
	VÍDEOS – A Pfizer ac… on Temanogrel
	Pfizer Bought Arena… on Temanogrel
	Pfizer va profita de… on Temanogrel
	Pfizer to Cash In on… on Temanogrel
	Pfizer tocmai a achi… on Temanogrel
	Pfizer just purchase… on Temanogrel
	Pfizer just purchase… on Temanogrel
	Tanya A on Dasotraline, ダソトラリン
	Julia Chernus on RIDINILAZOLE
	Adv.Siji Antony Kera… on Myself Anthony Crasto up for g…

SEARCH THIS BLOG

FLAGS AND HITS

Meta

Pages

Archives

Categories

MYSELF

Follow Blog via Email

Verified Services

Recent Posts

SEARCH THIS BLOG

Share this:

DRUG RESISTANCE LIMITS EFFECTIVENESS OF CHEMOTHERAPY

TESMILIFENE MAY BOOST CYTOTOXIC EFFECTS OF ANTHRACYCLINES

TESMILIFENE REGISTRATION TRIAL

Product Literature References

Share this:

PATENT

PATENT

PATENT

PATENT

PATENT

Share this:

Share this:

DRL 17822

Share this:

amcrasto@gmail.com

Share this:

PATENT

PAPER

PAPER

References

Share this:

CLINICAL TRIALS

SYNTHESIS

Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

PAPER

PATENT

REFERENCES

Share this:

Paper

PATENT

PAPERS

PAPER

References

Share this:

Share this:

Post navigation

SEARCH THIS BLOG

DR ANTHONY MELVIN CRASTO

Meta

Follow Blog via Email

ORGANIC SPECTROSCOPY

Latest Posts

Pages

feedjit

Recent Comments

DISCLAIMER

SEARCH THIS BLOG

SEARCH THIS BLOG

FLAGS AND HITS

Follow Blog via Email