Claims for Patent: 8,227,451

Summary for Patent: 8,227,451

Title:	Phenylacetic acid inhibitors of cyclooxygenase
Abstract:	The present invention relates to new phenylacetic acid inhibitors of cyclooxygenase activity, pharmaceutical compositions thereof, and methods of use thereof. ##STR00001##
Inventor(s):	Gant; Thomas G. (Carlsbad, CA), Shahbaz; Manouchehr M. (San Diego, CA)
Assignee:	Auspex Pharmaceuticals (La Jolla, CA)
Application Number:	12/616,242
Patent Claims:	1. A compound of structural Formula I ##STR00013## or a pharmaceutically acceptable salt thereof, wherein: R.sub.1-R.sub.13 are independently selected from the group consisting of hydrogen and deuterium; and at least one of R.sub.1-R.sub.13 is deuterium. 2. The compound as recited in claim 1 wherein at least one of R.sub.1-R.sub.13 independently has deuterium enrichment of no less than about 10%. 3. The compound as recited in claim 1 wherein at least one of R.sub.1-R.sub.13 independently has deuterium enrichment of no less than about 50%. 4. The compound as recited in claim 1 wherein at least one of R.sub.1-R.sub.13 independently has deuterium enrichment of no less than about 90%. 5. The compound as recited in claim 1 wherein at least one of R.sub.1-R.sub.13 independently has deuterium enrichment of no less than about 98%. 6. The compound as recited in claim 1 wherein said compound has a structural formula selected from the group consisting of ##STR00014## ##STR00015## ##STR00016## 7. The compound as recited in claim 1 wherein said compound has a structural formula selected from the group consisting of ##STR00017## ##STR00018## 8. The compound as recited in claim 7 wherein each position represented as D has deuterium enrichment of no less than about 10%. 9. The compound as recited in claim 7 wherein each position represented as D has deuterium enrichment of no less than about 50%. 10. The compound as recited in claim 7 wherein each position represented as D has deuterium enrichment of no less than about 90%. 11. The compound as recited in claim 7 wherein each position represented as D has deuterium enrichment of no less than about 98%. 12. The compound as recited in claim 7 wherein said compound has the structural formula: ##STR00019## 13. The compound as recited in claim 7 wherein said compound has the structural formula: ##STR00020## 14. The compound as recited in claim 7 wherein said compound has the structural formula: ##STR00021## 15. The compound as recited in claim 7 wherein said compound has the structural formula: ##STR00022## 16. A pharmaceutical composition comprising a compound as recited in claim 1 together with a pharmaceutically acceptable carrier. 17. A method of treatment of a cyclooxygenase-mediated disorder comprising the administration of a therapeutically effective amount of a compound as recited in claim 1 to a patient in need thereof. 18. The method as recited in claim 17 wherein said disorder is selected from the group consisting of pain, osteoarthritis, arthritis, dysmenorrhea, and rheumatoid arthritis. 19. The method as recited in claim 17 further comprising the administration of an additional therapeutic agent. 20. The method as recited in claim 19 wherein said additional therapeutic agent is selected from the group consisting of non-steroidal anti-inflammatory agents, anilide analgesics, disease-modifying anti-rheumatic agent, and glucocorticoids. 21. The method as recited in claim 20 wherein said non-steroidal anti-inflammatory agent is selected from the group consisting of aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoracoxib, faislamine, fenbuten, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl salicylate, sulindac, sulfinprazone, suprofen, tenoxicam, tiaprofenic acid, and tolmetin. 22. The method as recited in claim 20 wherein said anilide analgesic is selected from the group consisting of acetaminophen and phenacetin. 23. The method as recited in claim 20 wherein said disease-modifying anti-rheumatic agent is selected from the group consisting of azathioprine, cyclosporine A, D-penicillamine, gold salts, hydroxychloroquine, leflunomide, methotrexate, minocycline, sulfasalazine, cyclophosphamide, etanercept, infliximab, adalimumab, anakinra, rituximab, and abatacept. 24. The method as recited in claim 20 wherein said glucocorticoid is selected from the group consisting of beclometasone, budesonide, flunisolide, betamethasone, fluticasone, triamcinolone, mometasone, ciclesonide, hydrocortisone, cortisone acetate, prednisone, prednisolone, methylprednisolone, and dexamethasone. 25. The method as recited in claim 17, further resulting in at least one effect selected from the group consisting of: a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound; b. increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; c. decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; d. increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and e. an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound. 26. The method as recited in claim 17, further resulting in at least two effects selected from the group consisting of: a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound; b. increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; c. decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; d. increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and e. an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound. 27. The method as recited in claim 17, wherein the method effects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cytochrome P.sub.450 isoform in the subject, as compared to the corresponding non-isotopically enriched compound. 28. The method as recited in claim 27, wherein the cytochrome P.sub.450 isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6. 29. The method as recited claim 17, wherein said compound is characterized by decreased inhibition of at least one cytochrome P.sub.450 or monoamine oxidase isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound. 30. The method as recited in claim 29, wherein said cytochrome P.sub.450 or monoamine oxidase isoform is selected from the group consisting of CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO.sub.A, and MAO.sub.B. 31. The method as recited in claim 17, wherein the method reduces a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound. 32. The method as recited in claim 31, wherein the diagnostic hepatobiliary function endpoint is selected from the group consisting of alanine aminotransferase ("ALT"), serum glutamic-pyruvic transaminase ("SGPT"), aspartate aminotransferase ("AST," "SGOT"), ALT/AST ratios, serum aldolase, alkaline phosphatase ("ALP"), ammonia levels, bilirubin, gamma-glutamyl transpeptidase ("GGTP," ".gamma.-GTP," "GGT"), leucine aminopeptidase ("LAP"), liver biopsy, liver ultrasonography, liver nuclear scan, 5'-nucleotidase, and blood protein. 33. A compound as recited in claim 1 for use as a medicament. 34. A compound as recited in claim 1 for use in the manufacture of a medicament for the prevention or treatment of a disorder ameliorated by the inhibition of cyclooxygenase activity. 35. A deuterium-enriched compound of formula I or a pharmaceutically acceptable salt thereof: ##STR00023## wherein R.sub.1-R.sub.13 are independently selected from the group consisting of H and D; and the abundance of deuterium in R.sub.1-R.sub.13 is at least 8%. 36. A deuterium-enriched compound of claim 35, wherein the abundance of deuterium in R.sub.1-R.sub.13 is selected from the group consisting of: at least 8%, at least 15%, at least 23%, at least 31%, at least 38%, at least 46%, at least 54%, at least 62%, at least 69%, at least 77%, at least 85%, at least 92%, and 100%. 37. A deuterium-enriched compound of claim 35, wherein the abundance of deuterium in R.sub.1 and R.sub.10 is selected from the group consisting of: at least 50% and 100%. 38. A deuterium-enriched compound of claim 35, wherein the abundance of deuterium in R.sub.2-R.sub.3 is selected from the group consisting of: at least 50% and 100%. 39. A deuterium-enriched compound of claim 35, wherein the abundance of deuterium in R.sub.1, R.sub.10, and R.sub.2-R.sub.3 is selected from the group consisting of: at least 25%, at least 50%, at least 75%, and 100%. 40. A deuterium-enriched compound of claim 35, wherein the abundance of deuterium in R.sub.4 and R.sub.8-R.sub.9 is selected from the group consisting of: at least 33%, at least 67%, and 100%. 41. A deuterium-enriched compound of claim 35, wherein the abundance of deuterium in R.sub.5-R.sub.7 is selected from the group consisting of: at least 33%, at least 67%, and 100%. 42. A deuterium-enriched compound of claim 35, wherein the abundance of deuterium in R.sub.1-R.sub.13 is selected from the group consisting of: at least 33%, at least 67%, and 100%. 43. A deuterium-enriched compound of claim 35, wherein the compound is selected from the group consisting of compounds 1-7: ##STR00024## ##STR00025## 44. A deuterium-enriched compound of claim 35, wherein the compound is selected from the group consisting of compounds 8-14: ##STR00026## ##STR00027## 45. An isolated deuterium-enriched compound of formula I or a pharmaceutically acceptable salt thereof: ##STR00028## wherein R.sub.1-R.sub.13 are independently selected from the group consisting of H and D; and the abundance of deuterium in R.sub.1-R.sub.13 is at least 8%. 46. An isolated deuterium-enriched compound of claim 45, wherein the abundance of deuterium in R.sub.1-R.sub.13 is selected from the group consisting of: at least 8%, at least 15%, at least 23%, at least 31%, at least 38%, at least 46%, at least 54%, at least 62%, at least 69%, at least 77%, at least 85%, at least 92%, and 100%. 47. An isolated deuterium-enriched compound of claim 45, wherein the abundance of deuterium in R.sub.1 and R.sub.10 is selected from the group consisting of: at least 50% and 100%. 48. An isolated deuterium-enriched compound of claim 45, wherein the compound is selected from the group consisting of compounds 1-7: ##STR00029## ##STR00030## 49. An isolated deuterium-enriched compound of claim 45, wherein the compound is selected from the group consisting of compounds 8-14: ##STR00031## ##STR00032## 50. A mixture of deuterium-enriched compounds of formula I or a pharmaceutically acceptable salt thereof: ##STR00033## wherein R.sub.1-R.sub.13 are independently selected from the group consisting of H and D; and the abundance of deuterium in R.sub.1-R.sub.13 is at least 8%. 51. A mixture of deuterium-enriched compound of claim 50, wherein the compound is selected from the group consisting of compounds 1-7: ##STR00034## ##STR00035## 52. A mixture of deuterium-enriched compound of claim 50, wherein the compound is selected from the group consisting of compounds 8-14: ##STR00036## ##STR00037## 53. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 35 or a pharmaceutically acceptable salt form thereof. 54. A method for treating osteoarthritis comprising: administering, to a patient in need thereof, a therapeutically effective amount of a compound of claim 35 or a pharmaceutically acceptable salt form thereof.

Details for Patent 8,227,451

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2028-11-12
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2028-11-12
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Immunex Corporation	ENBREL	etanercept	For Injection	103795	05/27/1999		2028-11-12