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AVOSENTAN

N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(4-pyridyl)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide

5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidin-4-yl]-amide,

5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide,

Endothelin ETA Receptor Antagonists

M.Wt: 479.51
Formula: C23H21N5O5S

Roche (Originator)

CAS No.: 290815-26-8

  • RO 67-0565
  • SPP 301
  • UNII-L94KSX715K

PHASE 3

CLINICAL TRIALS

http://clinicaltrials.gov/search/intervention=spp301+OR+Avosentan

SPP-301 is an oral, once-daily, second-generation endothelin ETA receptor antagonist which had been in phase III clinical development at Speedel for the treatment of diabetic nephropathy. In December 2006, the company reported that the phase III trial had been stopped based on the recommendation from the trial’s Data Safety Monitoring Board (DSMB) to stop the trial following incidence of a significant imbalance in fluid retention in patients in the study arms. Speedel reported that the compound will be evaluated for potential new clinical development for the treatment of diabetic kidney disease and other indications.

Originally developed by Roche and specifically optimized for improved liver safety, SPP-301 was licensed to Speedel in October 2000. In 2003, Speedel exercised its option to license from Roche all rights to SPP-301, including exclusive worldwide rights for the full development and commercialization of the ETA antagonist. SPP-301 has fast track designation and has undergone a special protocol assessment (SPA) by the FDA. Speedel had been studying the drug for the treatment of hypertension.

AVOSENTAN

290815-26-8 CAS

PATENTS

1. WO2000052007A1

2. WO 2004078104

3. WO 2005113543

4. WO 2007031501

5. WO 2008077916

6. Channels and transporters. Mini-symposium of the Division of Medicinal Chemistry (DMC) of the Swiss Chemical Society (SCS) at the Department of Chemistry, University of Basel, May 27, 2010.

Dutzler R, Ernstb B, Hediger MA, Keppler D, Mohr P, Neidhart W, Märki HP.Chimia (Aarau). 2010;64(9):662-6.

………………………

INTRODUCTION

  • 5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide corresponding to the formula

    Figure 00010001

    is an inhibitor of endothelin receptors. WO00/52007 describes the preparation of said compound which is crystallized from Me2Cl2.

  • Own investigations have shown that there exist two distinct crystalline forms, hereinafter referred to as form A and form B, as well as a number of further solvates, in particular the methanol, ethanol, isopropanol, dichloromethane, acetone, methyl ethyl ketone and tetrahydrofuran solvates.
  • It was further surprisingly found that the thermodynamically stable crystalline form – form B – can be prepared under controlled conditions and that said form B can be prepared with a reliable method in an industrial scale, which is easy to handle and to process in the manufacture and preparation of formulations.

………………..

US20020137933

Figure US20020137933A1-20020926-C00003

4,6-Dichloro-5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine (described in EP 0 799 209) can be transformed to the intermediate of formula (III)—according to scheme 1—on reaction with an appropriate sulfonamide of formula (II), wherein Ris as defined in claim 1, in a suited solvent such as DMSO or DMF at room temperature or at elevated temperature and in the presence of a suited base such as potassium carbonate.

Figure US20020137933A1-20020926-C00004

Figure US20020137933A1-20020926-C00005

EXAMPLE 1

[0064] a) To a solution of 6.9 g sodium in MeOH (300 ml) were added 14.52 g of 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide at RT and the mixture was refluxed for 5 days until completion of the reaction according to TLC analysis. The reaction mixture was concentrated in vacuo to half its volume upon which the crude reaction product precipitated as a sodium salt. It was filtered off by suction and dried in a high vacuum. The solid was dissolved in water, which was then made acidic by addition of acetic acid. The precipitating free sulfonamide was extracted into Me2Cl2. The organic layer was dried over Mg2SO4, concentrated on a rotary evaporator, and the crystalline solid that had formed was filtered off. It was then dried in a high vacuum for 12 h at 120° C. to give the desired 5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as white crystals. Melting point 225-226° C. ISN mass spectrum, m/e 478.2 (M-1 calculated for C23H21N5O5S1: 478).

[0065] C23H21N5O5S1: Calc: C 57.61; H 4.41; N 14.61; S 6.69. Found: C 57.56; H 4.38; N 14.61; S 6.83

[0066] Preparation of the starting material:

[0067] b) 11.3 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine and 19.66 g of 5-methylpyridyl-2-sulfonamide potassium salt (preparations described in EP 0 799 209) were dissolved in DMF (255 ml) under argon. The solution was stirred for 2 h at 40° C. until completion of the reaction according to TLC analysis. The reaction mixture was cooled to RT and the solvent removed in a high vacuum. The residue was suspended in water (850 ml), acetic acid (85 ml) was added and the mixture was stirred for 30 minutes at RT. The solid that precipitated was collected by filtration and dried in a high vacuum at 60° C. for 16 h to give 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide ( CHLORO STARTING MATERIAL) as yellow crystals. Melting point 177-179° C. ISN mass spectrum, m/e 482.2 (M-1 calculated for C22H18ClN5O5S1: 482).

……………………………….

http://www.google.com/patents/US6417360

EXAMPLE 1

a) To a solution of 6.9 g sodium in MeOH (300 ml) were added 14.52 g of 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide at RT and the mixture was refluxed for 5 days until completion of the reaction according to TLC analysis. The reaction mixture was concentrated in vacuo to half its volume upon which the crude reaction product precipitated as a sodium salt. It was filtered off by suction and dried in a high vacuum. The solid was dissolved in water, which was then made acidic by addition of acetic acid. The precipitating free sulfonamide was extracted into Me2Cl2. The organic layer was dried over Mg2SO4, concentrated on a rotary evaporator, and the crystalline solid that had formed was filtered off. It was then dried in a high vacuum for 12 h at 120° C. to give the desired 5-methyl-pyridine-2-sulfonic acid [6-methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as white crystals. Melting point 225-226° C. ISN mass spectrum, m/e 478.2 (M-1 calculated for C23H21N5O5S1: 478).

C23H21N5O5S1: Calc: C 57.61; H 4.41; N 14.61; S 6.69. Found: C 57.56; H 4.38; N 14.61; S 6.83

Preparation of the starting material:

b) 11.3 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine and 19.66 g of 5-methylpyridyl-2-sulfonamide potassium salt (preparations described in EP 0 799 209) were dissolved in DMF (255 ml) under argon. The solution was stirred for 2 h at 40° C. until completion of the reaction according to TLC analysis. The reaction mixture was cooled to RT and the solvent removed in a high vacuum. The residue was suspended in water (850 ml), acetic acid (85 ml) was added and the mixture was stirred for 30 minutes at RT. The solid that precipitated was collected by filtration and dried in a high vacuum at 60° C. for 16 h to give 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as yellow crystals. Melting point 177-179° C. ISN mass spectrum, m/e 482.2 (M-1 calculated for C22H18ClN5O5S1: 482).

…………………….

http://www.google.com/patents/EP0799209B1

SYNTHESIS OF

4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine

A  BASIC STARTING MATERIAL FOR AVOSENTAN

    Preparation of the starting material

    • b) 53.1 g of 4-cyano-pyridine (98%) are added all at once to a solution of 1.15 g of sodium in 200 ml of abs. MeOH. After 6 hours 29.5 g of NH4Cl are added while stirring vigorously. The mixture is stirred at room temperature overnight. 600 ml of ether are added thereto, whereupon the precipitate is filtered off under suction and thereafter dried at 50°C under reduced pressure. There is thus obtained 4-amidino-pyridine hydrochloride (decomposition point 245-247°C).
    • c) 112.9 g of diethyl (2-methoxyphenoxy)malonate are added dropwise within 30 minutes to a solution of 27.60 g of sodium in 400 ml of MeOH. Thereafter, 74.86 g of the amidine hydrochloride obtained in b) are added all at once. The mixture is stirred at room temperature overnight and evaporated at 50°C under reduced pressure. The residue is treated with 500 ml of ether and filtered off under suction. The filter cake is dissolved in 1000 ml of H2O and treated little by little with 50 ml of CH3COOH. The precipitate is filtered off under suction, washed with 400 ml of H2O and dried at 80°C under reduced pressure. There is thus obtained 5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine-4,6-diol (or tautomer), melting point above 250°C.
    • d) A suspension of 154.6 g of 5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine-4,6-diol (or tautomer) in 280 ml of POCl3 is heated at 120°C in an oil bath for 24 hours while stirring vigorously. The reaction mixture changes gradually into a dark brown liquid which is evaporated under reduced pressure and thereafter taken up three times with 500 ml of toluene and evaporated. The residue is dissolved in 1000 ml of CH2Cl2, treated with ice and H2O and thereafter adjusted with 3N NaOH until the aqueous phase has pH 8. The organic phase is separated and the aqueous phase is extracted twice with CH2Cl2. The combined CH2Cl2 extracts are dried with MgSO4, evaporated to half of the volume, treated with 1000 ml of acetone and the CH2Cl2remaining is distilled off at normal pressure. After standing in a refrigerator for 2 hours the crystals are filtered off under suction and dried at 50°C overnight. There is thus obtained 4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine, melting point 178-180°C.

…………………………

http://www.google.com/patents/WO2000052007A1

Preparation of the starting material:

5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2- methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl] -amide  IE THE 6 CHLORO COMPD

b) 11.3 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine and 1 .66 g of 5-methylpyridyl-2-sulfonamide potassium salt (preparations described in EP 0 799 209) were dissolved in DMF (255 ml) under argon. The solution was stirred for 2 h at 40°C until completion of the reaction according to TLC analysis. The reaction mixture was cooled to RT and the solvent removed in a high vacuum. The residue was suspended in water (850 ml), acetic acid (85 ml) was added and the mixture was stirred for 30 minutes at RT. The solid that precipitated was collected by filtration and dried in a high vacuum at 60 °C for 16 h to give 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2- methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl] -amide as yellow crystals. Melting point 177-179 °C. ISN mass spectrum, m/e 482.2 (M-l calculated for C22Hi8ClN5O5Sι: 482).

Figure US06417360-20020709-C00004

………………………………………………………………………………………….

NEXT

Figure imgf000007_0001

Example 1AVOSENTAN

a) To a solution of 6.9 g sodium in MeOH (300 ml) were added 14.52 g of

5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl- pyrimidin-4-yl] -amide at RT and the mixture was refluxed for 5 days until completion of the reaction according to TLC analysis. The reaction mixture was concentrated in vacuo to half its volume upon which the crude reaction product precipitated as a sodium salt. It was filtered off by suction and dried in a high vacuum. The solid was dissolved in water, which was then made acidic by addition of acetic acid. The precipitating free sulfonamide was extracted into Me2Cl2. The organic layer was dried over Mg SO , concentrated on a rotary evaporator, and the crystalline solid that had formed was filtered off. It was then dried in a high vacuum for 12 h at 120 °C to give the desired 5-methyl-pyridine-2-sulfonic acid [6- methoxy-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl] -amide as white crystals. Melting point 225-226 °C. ISN mass spectrum, m/e 478.2 (M-l calculated for

Figure imgf000013_0001

C23H21N5O5S1: Calc: C 57.61; H 4.41; N 14.61; S 6.69. Found: C 57.56; H 4.38; N 14.61; S 6.83

…………………………………………….

IS DESCRIBED IN

http://www.google.com/patents/EP2331513A1?cl=en

ALSO

 

  • Diabetic nephropathy is the principle cause of end stage renal disease in the western world. It is a major cause of morbidity and mortality in Type-I Diabetes, but is an increasing problem in Type-II Diabetes and because the incidence of this is five times that of Type-I Diabetes, it contributes at least 50% of diabetics with end stage renal disease.
  • The initial stage of subtle morphologic changes in the renal glomeruli is followed by microalbuminuria. This is associated with a modestly rising blood pressure and an increased incidence of cardiovascular disease. There follows a continued increase in urinary protein excretion and declining glomerular filtration rate. Diabetic nephropathy has many possible underlying pathophysiological causes including metabolic, glycosylation of proteins, haemodynamics, altered flow/pressure in glomeruli, the development of hypertension and cytokine production; all of these are associated with the development of extracellular matrix and increased vascular permeability leading to glomerular damage and proteinuria.
WO2005113543A1 * May 12, 2005 Dec 1, 2005 Alexander Bilz Crystalline forms of a pyridinyl-sulfonamide and their use as endothelin receptor antagonists
WO2007031501A2 * Sep 11, 2006 Mar 22, 2007 Speedel Pharma Ag Pyridylsulfonamidyl-pyrimidines for the prevention of blood vessel graft failure
WO2008077916A1 * Dec 21, 2007 Jul 3, 2008 Ovidiu Baltatu Pharmaceutical composition using aliskiren and avosentan
EP1454625A1 * Mar 6, 2003 Sep 8, 2004 Speedel Development AG Pyridylsulfonamidyl-pyrimidines for the treatment of diabetic nephropathies
EP1595880A1 * May 13, 2004 Nov 16, 2005 Speedel Pharma AG Crystalline forms of a pyridinyl-sulfonamide and their use as endothelin receptor antagonists
EP1938812A1 * Dec 22, 2006 Jul 2, 2008 Speedel Pharma AG Pharmaceutical composition using aliskiren and avosentan
US6951856 Jul 10, 2001 Oct 4, 2005 Actelion Pharmaceuticals Ltd. Arylethene-sulfonamides
US7402587 May 12, 2005 Jul 22, 2008 Speedel Pharma Ag Crystalline forms of a pyridinyl-sulfonamide and their use as endothelin receptor antagonists
WO1996019459A1 * Dec 8, 1995 Jun 27, 1996 Volker Breu Novel sulfonamides
EP0713875A1 * Nov 13, 1995 May 29, 1996 F. Hoffmann-La Roche AG Sulfonamides
EP0897914A1 * Aug 10, 1998 Feb 24, 1999 F. Hoffmann-La Roche Ag Process for the preparation of 2,5-disubstitued pyridines

READ MORE ON SNTAN SERIES……http://medcheminternational.blogspot.in/p/sentan-series.html

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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