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Last Updated: March 28, 2024

Claims for Patent: 8,252,933


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Summary for Patent: 8,252,933
Title:2-oxo-1,2-dihydro-quinoline modulators of immune function
Abstract: The present invention relates to new 2-oxo-1,2-dihydro-quinoline modulators of immune function, pharmaceutical compositions thereof, and methods of use thereof. ##STR00001##
Inventor(s): Gant; Thomas G. (Carlsbad, CA), Shahbaz; Manouchehr M. (Vista, CA)
Assignee: Teva Pharmaceuticals Industries, Ltd. (Petach-Tikva, IL)
Application Number:12/552,663
Patent Claims:1. A compound of structural Formula I ##STR00029## or a salt thereof, wherein: R.sub.1-R.sub.17 are independently selected from the group consisting of hydrogen and deuterium; and at least one of R1-R17 is deuterium.

2. The compound as recited in claim 1 wherein at least one of R.sub.1-R.sub.17 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.17 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.17 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.17 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: ##STR00030## ##STR00031## ##STR00032## ##STR00033##

7. The compound as recited in claim 1 wherein said compound has a structural formula selected from the group consisting of ##STR00034##

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: ##STR00035##

13. The compound as recited in claim 7 wherein said compound has the structural formula: ##STR00036##

14. The compound as recited in claim 7 wherein said compound has the structural formula: ##STR00037##

15. A pharmaceutical composition comprising a compound as recited in claim 1 together with a pharmaceutically acceptable carrier.

16. A method of treatment of a immune function-mediated disorder comprising the administration of a therapeutically effective amount of a compound as recited in claim 1 to a patient in need thereof.

17. The method as recited in claim 16 wherein said disorder is multiple sclerosis and autoimmune disorders.

18. The method as recited in claim 16 further comprising the administration of an additional therapeutic agent.

19. The method as recited in claim 18 wherein said additional therapeutic agent is selected from the group consisting of immunomodulators and cyclosporins.

20. The method as recited in claim 19 wherein said immunomodulator is selected from the group consisting of filgrastim, molgramostim, sargramostim, lenograstim, ancestim, pegfilgrastim, interferon gamma, interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon beta-1a, interferon beta-1b, interferon alphacon-1, peginterferon alpha-2b, peginterferon alpha-2a, interferon omega, aldesleukin, oprelvekin, lentinan, roquinimex, BCG vaccine, pegademase, pidotimod, Poly I:C, Poly ICLC, thymopentin, immunocyanin, tasonermin, melanoma vaccine, glatiramer acetate, histamine dihydrochloride, mifamurtide, plerixefor, muromonab-CD3, antilymphocyte immunoglobulin (horse), antithymocyte immunoglobulin (rabbit), mycophenolic acid, sirolimus, leflunomide, alefacept, everolimus, gusperimus, efalizumab, abetimus, natalizumab, abatacept, eculizumab, etanercept, infliximab, afelimomab, adalimumab, certolizumab pegol, daclizumab, basiliximab, anakinra, ciclosporin, tacrolimus, azathioprine, thalidomide, methotrexate, and lenalidomide.

21. The method as recited in claim 16, further resulting in 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.

22. The method as recited in claim 16, 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.

23. The method as recited in claim 16, wherein the method effects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cytochrome P450 isoform in the subject, as compared to the corresponding non-isotopically enriched compound.

24. The method as recited in claim 23, wherein the cytochrome P450 isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

25. The method as recited claim 16, wherein said compound is characterized by decreased inhibition of at least one cytochrome P 450 or monoamine oxidase isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

26. The method as recited in claim 25, wherein said cytochrome P450 or monoamine oxidase isoform is selected from the group consisting of CYPIAI, CYPIA2, CYPIBI, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2CI8, CYP2CI9, CYP2D6, CYP2EI, CYP2GI, CYP2J2, CYP2RI, CYP2SI, CYP3A4, CYP3A5, CYP3A5PI, CYP3A5P2, CYP3A7, CYP4AII, CYP4BI, CYP4F2, CYP4F3, CYP4F8, CYP4Fll, CYP4FI2, CYP4XI, CYP4ZI, CYP5AI, CYP7AI, CYP7BI, CYP8AI, CYP8BI, CYPIIAI, CYPIIBI, CYPIIB2, CYPI7, CYPI9, CYP21, CYP24, CYP26AI, CYP26BI, CYP27AI, CYP27BI, CYP39, CYP46, CYP51, MAOA, and MAOB.

27. The method as recited in claim 16, wherein the method reduces a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound.

28. The method as recited in claim 27, 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.

Details for Patent 8,252,933

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Merck Teknika Llc N/A bcg vaccine For Injection 103050 06/21/1989 ⤷  Try a Trial 2028-09-03
Clinigen, Inc. PROLEUKIN aldesleukin For Injection 103293 05/05/1992 ⤷  Try a Trial 2028-09-03
Amgen, Inc. NEUPOGEN filgrastim Injection 103353 02/20/1991 ⤷  Try a Trial 2028-09-03
Amgen, Inc. NEUPOGEN filgrastim Injection 103353 06/28/2000 ⤷  Try a Trial 2028-09-03
Partner Therapeutics, Inc. LEUKINE sargramostim For Injection 103362 03/05/1991 ⤷  Try a Trial 2028-09-03
Partner Therapeutics, Inc. LEUKINE sargramostim Injection 103362 03/05/1991 ⤷  Try a Trial 2028-09-03
Centocor Ortho Biotech Products, L.p. ORTHOCLONE OKT3 muromanab-cd3 Injection 103463 09/14/1992 ⤷  Try a Trial 2028-09-03
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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