# US 8,541,422 B2 · Methods for the treatment or prophylaxis of thrombosis or embolism > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,541,422 B2 - Document ID: US8541422B2 - Status: Granted - Kind: B2 - Application number: 13/219,030 - Filed: 2011-08-26 - Published: 2012-03-01 - Granted: 2013-09-24 - Earliest claimed: 2010-08-26 - Assignees: IPCA Laboratories Ltd. - Applicants: Ashok Kumar; Nellithanath Thankachen Byju - Inventors: Ashok Kumar; Nellithanath Thankachen Byju - Web page: https://patentgrep.com/patent/US8541422B2 ## CPC - C07D 495/04: Ortho-condensed systems - A61K 31/4365: the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine - A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings - A61K 31/519: ortho- or peri-condensed with heterocyclic rings - A61K 31/616: by carboxylic acids, e.g. acetylsalicylic acid - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to a method of ameliorating the drawbacks of anti-platelet drug named clopidogrel. The method of the present invention comprises administration of an (S)oxo-clopidogrel or its derivative of the Formula IIA in its free or pharmaceutically acceptable salt form for alleviating the symptoms of thrombosis or embolism by inhibiting blood platelet aggregation. Compositions for use in such methods are also provided. ## Claims ### Claim 1 A method for reducing or alleviating inter individual platelet response variability and metabolic loading in humans in the treatment or prophylaxis of thrombosis or embolisms observed following administration of clopidogrel comprising administering to a person in need thereof, a composition containing an effective amount of S-oxo-clopidogrel or a compound of Formula IIA or pharmaceutically acceptable salts thereof, wherein R is hydrogen or an acyl or alkyl substituted silyl group. ### Claim 2 (depends on 1) The method of claim 1, wherein the method further comprises administering one or more anti-platelet agents selected from the group consisting of aspirin, cilostazol and dipyridamole. ### Claim 3 (depends on 1) The method of claim 1, wherein the inter-individual platelet response variability is due to a CYP450 polymorphism or a failure to efficiently metabolize clopidogrel. ### Claim 4 (depends on 3) The method of claim 3, wherein the CYP450 polymorphism is CYP2C19*2 or CYP2C19*17. ### Claim 5 (depends on 1) The method of claim 1, wherein the inter-individual platelet response variability is due to P-glycoprotein efflux transports. ### Claim 6 (depends on 1) The method of claim 1, wherein said method avoids or alleviates the side effects associated with the clopidogrel acid metabolite of Formula IV ### Claim 7 (depends on 1) The method of claim 1, wherein the method achieves a therapeutic effect greater than or equivalent to that observed following the administration of a substantially higher dose of clopidogrel. ### Claim 8 (depends on 1) The method of claim 1, wherein said method results in the in vivo formation of the active metabolite of clopidogrel at a concentration greater than or equivalent to that observed following administration of a substantially higher dose of clopidogrel. ### Claim 9 (depends on 1) The method claim 1, wherein the onset of therapeutic action is at least 50% more rapid than that observed following administration of a substantially higher dose of clopidogrel. ### Claim 10 (depends on 1) The method of claim 1, wherein the amount of the S oxo-clopidogrel or the compound of Formula IIA is about 20 to about 100 mg as a loading dose. ### Claim 11 (depends on 1) The method of claim 1, wherein the amount of the S oxo-clopidogrel or the compound of Formula IIA is about 35 to about 70 mg as a loading dose. ### Claim 12 (depends on 1) The method of claim 1, wherein the amount of the S oxo-clopidogrel or the compound of Formula IIA is about 20 to about 100 mg as a loading dose. ### Claim 13 (depends on 1) The method of claim 1, wherein the amount of the S oxo-clopidogrel or the compound of Formula IIA is about 5 to about 30 mg as a maintenance dose. ### Claim 14 (depends on 1) The method of claim 1, wherein the amount of S oxo-clopidogrel or the compound of Formula IIA is about 6 to about 20 mg as a maintenance dose. ### Claim 15 (depends on 1) The method of claim 1, further comprising administering a proton inhibitor. ### Claim 16 (depends on 1) The method of claim 1, wherein the administration step comprises administering an initial loading dose of about 20-100 mg of the (S)-oxo-clopidogrel or the compound of Formula IIA to the person in need thereof, followed by administering a maintenance dose of about 5-30 mg. ### Claim 17 (depends on 1) The method of claim 1, wherein R is an acyl group having the formula R1—CO— wherein R1 is selected from the group consisting of aryl, alkyl, alkenyl and alkynyl. ### Claim 18 (depends on 17) The method of claim 17, wherein R1 is acetyl. ### Claim 19 (depends on 1) The method of claim 1, wherein R is an alkyl substituted silyl group having the formula R′3—Si— wherein R′ is a straight or branched alkyl having from one to eight carbon atoms. ### Claim 20 (depends on 19) The method of claim 19, wherein R′ is selected from the group consisting of methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, n-pentyl and 1,1-dimethylethyl. ### Claim 21 (depends on 17) The method of claim 17, wherein R1 is a straight or branched alkenyl having from two to ten carbon atoms. ### Claim 22 (depends on 21) The method of claim 21, wherein R1 is selected from the group consisting of ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. ### Claim 23 (depends on 17) The method of claim 17, wherein R1 is a straight or branched alkynyl having from two to twelve carbon atoms. ### Claim 24 (depends on 23) The method of claim 23, wherein R1 is ethynyl. ### Claim 25 (depends on 17) The method of claim 17, wherein R1 is an aryl group having six to fourteen carbon atoms. ### Claim 26 (depends on 25) The method of claim 25, wherein R1 is selected from the group consisting of phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl. ### Claim 27 (depends on 26) The method of claim 26, wherein said R1 is further substituted by a C1-C6 alkyl group or halogen atom. ### Claim 28 A method of treatment or prophylaxis of thrombosis or embolisms in a patient in need thereof comprising administering a composition a composition containing an effective amount of S-oxo-clopidogrel or a compound of Formula IIA or pharmaceutically acceptable salts thereof, wherein R is hydrogen or an acyl or alkyl substituted silyl group; wherein said administration avoids the side effects associated with the clopidogrel acid metabolite of Formula IV ### Claim 29 A method of treatment or prophylaxis of thrombosis or embolisms in a clopidogrel non-responder- or poor-responder-patient in need of such treatment, comprising administering an effective amount of a composition containing S-oxo-clopidogrel or a compound of Formula IIA or pharmaceutically acceptable salts thereof, wherein R is hydrogen oran acyl or alkyl substituted silyl group. ### Claim 30 A method of treating clopidogrel resistance in a patient in need of treatment or prophylaxis of thrombosis or embolisms, comprising administering an effective amount of a composition containing S-oxo-clopidogrel or a compound of Formula IIA or pharmaceutically acceptable salts thereof, wherein R is hydrogen or an acyl or alkyl substituted silyl group.