Anti-thrombotic compounds

a technology of antithrombotic compounds and compounds, applied in the field of antithrombotic compounds, can solve the problems of reducing blood flow, affecting the treatment effect, affecting the survival rate of patients, etc., and achieves the effects of preventing side effects, preventing bleeding, and avoiding side effects

Inactive Publication Date: 2012-12-27
IPCA LAB LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0023]The invention also provides a method of treatment and / or prophylaxis of thrombosis and / or embolisms in a patient in need of such treatment, comprising administering an amount of isolated (7aS,2′S)-2-oxo-clopidogrel or a pharmaceutically acceptable salt thereof, while avoiding and / or alleviating the side effects associated with the clopidogrel acid metabolite of Formula IV, Formula VI, or VII which otherwise was impossible without the advent of the compound of the present invention.
[0024]In preferred embodiments of this aspect of the present invention, the method achieves a therapeutic effect substantially greater to that observed following the administration of a substantially higher dose of clopidogrel due to the elimination of unwanted metabolic products and other isomers in the administration of clopidogrel.
[0025]In preferred embodiments of this aspect of the present invention, the method results in the in vivo formation of the active metabolite of clopidogrel at a concentration greater than or equivalent that observed following administration of a substantially higher dose of clopidogrel.

Problems solved by technology

Conditions resulting from thrombotic or thromboembolic events are the leading causes of illness and death in adults in western civilization.
Unregulated activation of the hemostatic system has the potential to cause thrombosis and embolism, which can reduce blood flow to critical organs like the brain and myocardium.
These thrombi often form in leg veins and can break off and embolize to the pulmonary circulation.
These arterial thrombi may readily dislodge from the arterial wall and embolize to distant sites to cause temporary or permanent ischemia.
This is particularly common in the cerebral and retinal circulation and may lead to transient neurologic dysfunction (transient ischemic attacks) including temporary monocular blindness (amaurosis fugax) or strokes.
However, clopidogrel has several potential limitations.
Third, almost all clinical trials involving clopidogrel reveal that therapeutic levels of platelet inhibition are not achieved in a majority of patients because of large inter-individual variability in response to clopidogrel treatment.
Treatment of patients with a recently approved drug, namely, prasugrel rendered them susceptible to bleeding episodes, which may be life threatening, restricting its application in patients having a body weight of less than 60 kg and age of more than 75 years.
Therefore there are unmet medical needs, which are not being offered by the current therapy options such as clopidogrel and prasugrel.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of mixture of (7aS,2′S) / (7aR,2′S)-isomers of 2-oxoclopidogrel

a) Methyl-(R)-2-hydroxy-2-(2-chlorophenyl)acetate

[0082]In a four necked round bottomed flask, 500 gm of (R)-2-chloromandelic acid was taken in 2000 ml methanol. Then 18.8 gm of sulfuric acid was added and heated to reflux, till completion of reaction. Then excess of methanol was distilled off under reduced pressure. Residue was taken in dichloromethane and washed with aqueous sodium bicarbonate solution. Dichloromethane was distilled under reduced pressure to obtain 522 gm of Methyl-(R)-2-hydroxy-2-(2-chlorophenyl)acetate as an oil. Yield: 94%. Purity:98.5%

b) Methyl(R)-2-(4-nitrophenylsulfonyloxy)-2(2-chlorophenyl)acetate

[0083]

[0084]In a four necked round bottomed flask, under nitrogen atmosphere, 640 ml of dichloromethane, 221 gm of 4-Nitro benzene sulfonyl chloride, 12.1 gm of 4-dimethylaminopyridine, and 200 gm of Methyl(R)-2-hydroxy-2(2-chlorophenyl)acetate were added. It was cooled to around 0° C., and 101...

example 2

Methyl (7aS,2′S)-2-(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydro thieno[3,2-c]-5-pyridin-2-one)acetate

[0089]In a four necked round bottomed flask, under nitrogen atmosphere, 150 ml of ethyl acetate-methanol and 70 gm of mixture of isomers (Ratio of (7aS,2′S) / (7aR,2′S)-isomers=53.62:46.38) was taken and warmed to dissolve, and stirred for 20 hours under room temperature, crystals obtained were filtered and the solid was dried to obtain 52 gm Methyl (S)-2(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate. Yield=60%; Ratio of (7aS,2′S) / (7aR,2′S)-isomers as per chiral HPLC: 99.5:0.5.

[0090]1H-NMR (DMSO-d6) spectra collected on a BRUKER 400 MHz instrument has shown values given in table 2 corresponding to structure of formula IIA free base below:

TABLE 2Chemical shiftAssignmentvalue (δ / ppm)(Multiplicity#, Number of protons, Position*)1.54-1.64(m, 1H, a)2.36-2.41(m, 1H, b)2.56-2.62(m, 1H, c)2.92-2.96(d, 1H, d)3.21-3.24(dd, 1H, e)3.66(s, 3H, f)3.86-3.89(dd, 1H, g)4....

example 3

Preparation of Methyl (7aS,2′S)-2-(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate hydrogen sulfate

[0091]In a four necked round bottomed flask, under nitrogen atmosphere, 1750 ml of acetone and 70 gm of Methyl(S)-2(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate isomeric mixture (Ratio of (7aS,2′S) / (7aR,2′S)-isomers=51.42:47.48) were added. It was cooled to around 5° C. and 20.8 gm of sulfuric acid was added slowly. After sulfuric acid addition, stirred at about 20-30° C. temperature. Filtered and dried under reduced pressure to obtain 84 gm of Methyl (7aS,2′S)-2(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate hydrogen sulfate. Yield=93%; Purity by HPLC=99.5%, Ratio of isomers by Chiral HPLC=99.8:0.2.

[0092]1H-NMR (DMSO-d6) spectra collected on a BRUKER 400 MHz instrument has shown values given in table 3 corresponding to structure of formula IIA hydrogen sulphate below:

TABLE 3Chemical shiftA...

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Abstract

New compounds, namely, (7aS,2′S)-2-oxoclopidogrel and its pharmaceutically acceptable salts thereof are disclosed for treatment or prophylaxis of thrombo-embolism and/or cardiovascular diseases.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims priority to Indian Patent Application No. 1848 / MUM / 2011, filed Jun. 27, 2011, the entire disclosure of which is incorporated by reference herein.TECHNICAL FIELD OF INVENTION[0002]The present invention relates to anti-thrombotic compounds, specifically substantially pure isomer of an intermediate metabolite of clopidogrel, namely, (7aS,2′S)-2-oxoclopidogrel and its pharmaceutically acceptable salts thereof. The present invention also relates to a method of ameliorating the drawbacks of the anti-platelet drug, clopidogrel, said method comprises administration of isolated substantially pure isomer of (7aS,2′S)-2-oxoclopidogrel in its free or pharmaceutically acceptable salt form for alleviating the symptoms of thrombosis and / or embolism by inhibiting blood platelet aggregation.BACKGROUND OF THE INVENTION[0003]Conditions resulting from thrombotic or thromboembolic events are the leading causes of illness and dea...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4365A61K31/616A61P1/00A61P7/02A61P9/00A61K31/4709C07D495/04A61K31/519
CPCC07D513/04C07D495/04A61K45/06A61K31/4365A61P1/00A61P7/02A61P9/00A61P43/00
Inventor KUMAR, ASHOKSOUDAGAR, SATISH RAJANIKANTBYJU, NELLITHANATH THANKACHENSAHAL, GAURAVMATHUR, ARPANA PRASHANTGAWADE, SANJAY PANDURANGBHADRA, DINESH KANJIMOJE, DEVKI
Owner IPCA LAB LTD
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