Sunday 8 March 2015

Saroglitazar magnesium....New patent WO 2015029066 Cadila Healthcare Ltd

SAROGLITAZAR
Saroglitazar skeletal.svg





New patent WO  2015029066
Dwivedi, Shri Prakash Dhar; Singh, Ramesh Chandra; Patel, Vikas; Desai, Amar Rajendra
Cadila Healthcare Ltd
Polymorphic form of pyrrole derivative and intermediate thereof
The present invention relates to Saroglitazar free acid of Formula (IA) or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable esters, stereoisomers, tautomers, analogs and derivs. thereof. The present invention also provides an amorphous form of saroglitazar free acid and processes of prepn. thereof. The present invention also provides pharmaceutical compn. comprising an amorphous form saroglitazar magnesium.
Amorphous forms of saroglitazar free acid and its salt form are claimed. Also claims the process for the synthesis the same compound. Useful for treating obesity, hyperlipidemia and hypercholesteremia. Picks up from WO2015011730, claiming the stable composition comprising saroglitazar magnesium or its derivatives. Zydus-Cadila has developed and launched saroglitazar for treating diabetic dyslipidemia and hypertriglyceridemia.
In September 2013, saroglitazar was launched for treating dyslipidemia and hypertriglyceridemia.
As of March 2015, Zydus-Cadila is developing saroglitazar for treating nonalcoholic steatohepatitis and type II diabetes (both in phase III clainical trials).
Pyrrole derivative of present invention is chemically 2-ethoxy-3-(4-(2-(2-methyl- 5-(4-(methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy)ph’enyl)propanoate, which may be optically active or racemic and its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof. The INN name for pyrrole derivative is Saroglitazar® which is magnesium salt of pyrrole compound o f saroglitazar,

the process comprising: 5WO 2015/029066 PCT/IN2014/000551 (a) dissolving saroglitazar magnesium of Formula (I) in one or more organic solvents to obtain a solution, (b) adding the solution in one or more o f anti-solvent at temperature from about -80°C to about 150°C to obtain saroglitazar magnesium o f Formula (I); and (c) obtaining the amorphous saroglitazar magnesium by removal of anti-solvent.

Example-1: Preparation of saroglitazar magnesium (Ί) In a 5 Liter three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 2-ethoxy-3-(4-hydroxy-phenyl)- propionic acid ethyl ester (A) (100.0 g) and cyclohexane (1300.0 ml) were charged and reaction mixture was heated to 45° to 55°C. Potassium carbonate (58.0 g) was added and stirred for 30 min. methanesulfonic acid 2-[2-methyl-5-(4-methyIsulfanyl-phenyl)-pyrroll-yl]-ethyl ester (A l) (150.24 g) and THF (200.0 ml) were added and heated to 75°C to 85°C for 36 hour. The reaction mixture was cooled to 25° to 35°C and water (1000.0 ml) was added and stirred for 15 min. The separated aqueous layer was treated with cyclohexane (200.0 ml) and stirred for 15 min. The organic layers were combined and washed with caustic solution (600.0 ml). The separated organic layer was washed with water (600.0 ml) and characoalized with (5.0 g) charcoal and stirred for 30 min and filtered. The filtrate was distilled to remove cyclohexane and the residue was collected (residue-A). The residue-A as obtained was treated with ethanol (400.0 ml) and stirred for 15 min. Sodium hydroxide 20.14 g solution in water (200.0 ml) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with water (1800.0 ml) and stirred for 15 min. The separated aqueous layer was washed with n-butyl acetate. The separated aqueous layer was added magnesium acetate tetrahydrate solution (90.0 g) in water (100.0 ml) and stirred for I hour. The aqueous layer was extracted with methylene dichloride (200 ml). The separated organic layer was washed with sodium chloride solution and charcoalized. The charcoalized solution was filtered and filtrate was distilled to remove methylene dichloride completely. The residue was diluted with methylene dichloride (1000 ml) and stirred for 30 min. The organic solution was added into n-heptane (1500 mL) and stirred for 3 hours. The product was filtered and washed with n-heptane and dried in vacuum tray dryer at 25°C to 30°C for 3 hours. The product was sieved through 0.5 mm sieve and milled through jet-milled. The product was further dried in vacuum tray drier at 40°C to 50°C for 6 hours followed by drying at 55°C to 65°C for 40 hours to obtain substantially amorphous saroglitazar magnesium (I). The compound is characterized by x-ray power diffraction (FIG.I).
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WO/2015/011730
The present invention relates to the stable pharmaceutical composition of a suitable hypolipidemic agent. Preferably, the present invention discloses novel formulations of the compound of formula (I), or pharmaceutically acceptable salts of compounds of formula (I). More particularly the present invention relates to the stable pharmaceutical composition of compounds of formula (I) comprising compounds of formula (I) or its pharmaceutically acceptable salts, wherein the pH of the formulation is maintained above 7. formula (I)


front page image
The compounds of formula (I) are new synthetic compounds having hypolipidemic activity. The compounds of formula (I) are used primarily for triglyceride lowering, with concomitant beneficial effect on glucose lowering and cholesterol lowering.
The structural formula of compounds of formula (I) is shown below.
wherein ‘R’ is selected from hydroxy, hydroxyalkyl, acyl, alkoxy, alkylthio, thioalkyl, aryloxy, arylthio and M+ represents suitable metal cations such as Na+, K+, Ca+2, Mg+2 and the like. Preferably, R is selected from alkylthio or thioalkyl groups; most preferably R represents -SCH3.The Mg+2 salt is preferred. The compounds of formula (I) are generally insoluble in water, but freely soluble in dimethyl sulfoxide, dichloromethane & slightly soluble in methanol and IPA.
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see also my full fledged article on its synthesis

see also my full fledged article on its synthesis

see also my full fledged article on its synthesis

see also my full fledged article on its synthesis

Tuesday 3 March 2015

US 20150011782 New patent .....Amprenavir

Amprenavir skeletal.svg
Amprenavir
KVX-478, 141W94, VX-478,
DrugSyn.org
US5585397
(3S)-Tetrahydro-3-furanyl ((1S,2R)-3-(((4-aminophenyl)sulfonyl)(2-methylpropyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)carbamate
(3S)-tetrahydro-3-furyl N-[(1S,2R)-3-(4-amino-N-isobutylbenzenesulphonamido)-1-benzyl-2-hydroxypropyl] carbamate
CAS NO. 161814-49-9, [(3S)-oxolan-3-yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate
161814-49-9
Weight 505.224656557
Chemical Formula C25H35N3O6S

Amprenavir is a protease inhibitor used to treat HIV infection.
Amprenavir (Agenerase, GlaxoSmithKline) is a protease inhibitor used to treat HIV infection. It was approved by the Food and Drug Administration on April 15, 1999, for twice-a-day dosing instead of needing to be taken every eight hours. The convenient dosing came at a price, as the dose required is 1,200 mg, delivered in eight very large gel capsules.
Production of amprenavir was discontinued by the manufacturer December 31, 2004; a prodrug version (fosamprenavir) is available.

Amprenavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Amprenavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.
HIV-1 Protease dimer with Amprenavir (sticks) bound in the active site. PDB entry 3nu3 [1]

PATENT
Example 11Synthesis of Amprenavir (1)To a solution of carbamate nitro derivative 15 (0.05 g, 0.09 mmol) in 2 mL of EtOAc was added SnCl2.2H2O (0.1 g, 0.5 mmol) at 70° C. The reaction mixture was heated for 1 h until starting material disappeared and the solution cooled to room temperature. It was then poured into saturated aq. NaHCO3 solution and extracted with EtOAc. The organic extract was dried over anhyd. Na2SO4 and concentrated under reduced pressure. It was purified over chromatography using petroleum ether:EtOAc (3:2) to give amprenavir 1 (0.04 g, 90%).IR: (CHCl3, cm−1): υmax 757, 1090, 1149, 1316, 1504, 1597, 1633, 1705, 2960, 3371; 1H NMR (200 MHz, CDC3): δ 0.86 (d, J=5.7 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H), 1.78-2.21 (m, 3H), 235-3.11 (m, 6H), 3.58-4.11 (m, 7H), 4.25 (s, 2H), 5.01 (br s, 1H), 5.07 (br s, 1H), 6.65 (d, J=8.4 Hz, 2H), 7.20-7.28 (m, 5H), 7.51 (d, J=8.4 Hz, 2H); 13C NMR (50 MHz, CDC3): δ 19.9, 20.2, 27.3, 32.8, 35.4, 35.7, 53.8, 55.0, 58.6, 66.8, 72.6, 73.2, 75.3, 114.0, 125.9, 126.5, 1280.4, 129.5, 137.7, 150.9, 155.9; Anal. Calcd for C25H35N3O6S: C, 59.39; H, 6.98; N, 8.31; S, 6.34. Found: C, 59.36; H, 6.81; N, 8.25; S, 6.29%.


Process for synthesis of syn azido epoxide and its use as intermediate for the synthesis of amprenavir & saquinavir
US 20150011782 A1
Publication numberUS20150011782 A1
Publication typeApplication
Application numberUS 14/371,466
PCT numberPCT/IN2013/000021
Publication dateJan 8, 2015
Filing dateJan 10, 2013
Priority dateJan 10, 2012
Also published asWO2013105118A1, WO2013105118A8
InventorsSunita Khanderao Gadakh, Reddy Santhosh Rekula, Arumugam Sudalai
Original AssigneeCouncil Of Scientific & Industrial Research