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1. WO2004098583 - COMBINAISON COMPRENANT DU S-[2-([[1-(2-ETHYLBUTYL)CYCLOHEXYL]CARBONYL]AMINO)PHENYL]2-METHYLPROPANETHIOATE ET UN INHIBITEUR DE HMG COA REDUCTASE

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

WHAT IS CLAIMED IS:

1. A combination comprising (a) S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] 2-methylpropanethioate or a prodrug that forms S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] thiol in vivo, and (b) at least one HMG CoA reductase inhibitor.

2. The combination of claim 1, comprising (a) S-[2-([[l-(2-ethylbutyl)cyclohexyl] carbonyl] amino)phenyl] 2-methylpropanethioate and (b) at least one HMG CoA reductase inhibitor.

3. The combination of claim 1, comprising (a) a prodrug that forms S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] thiol in vivo, and (b) at least one HMG CoA reductase inhibitor.

4. The combination of any of claims 1-3, wherein the HMG CoA reductase inhibitor is selected from the group consisting of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin, and phamiaceutically acceptable salts and hydrates thereof.

5. The combination of claim 4, wherein the HMG CoA reductase inhibitor is atorvastatin calcium, pravastatin sodium, fluvastatin sodium, simvastatin, lovastatin, or rosuvastatin calcium.

6. The combination of any of claims 1 -3, wherein the HMG CoA reductase inhibitor is pitavastatin or a pharmaceutically acceptable salt and/or hydrate thereof.

7. A pharmaceutical composition comprising (a) S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] 2-methylpropanethioate or a prodrug that forms S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] thiol in vivo, (b) at least one HMG CoA reductase inhibitor, and (c) one or more pharmaceutically acceptable carriers.

8. The pharmaceutical composition of claim 7, comprising (a) S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] 2-methylpropanethioate (b) at least one HMG CoA reductase inhibitor, and (c) one or more pharmaceutically acceptable carriers.

9. The pharmaceutical composition of claim 7, comprising (a) a prodrug that forms S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] thiol in vivo, (b) at least one HMG CoA reductase inhibitor, and (c) one or more pharmaceutically acceptable carriers.

10. The pharmaceutical composition of any of claims 7-9, wherein the HMG CoA reductase inhibitor is selected from the group consisting of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin, and pharmaceutically acceptable salts and hydrates thereof.

11. The pharmaceutical composition of claim 10, wherein the HMG CoA reductase inhibitor is atorvastatin or a pharmaceutically acceptable salt and/or hydrate thereof.

12. The pharmaceutical composition of claim 10, wherein atorvastatin or a pharmaceutically acceptable salt and/or hydrate thereof is present in an amount of about 10 mg to about 80 mg.

13. The pharmaceutical composition of claim 10, wherein the HMG CoA reductase inhibitor is pravastatin or a pharmaceutically acceptable salt and/or hydrate thereof.

14. The pharmaceutical composition of claim 13, wherein pravastatin or a pharmaceutically acceptable salt and/or hydrate thereof is present in an amount of about 10 mg to about 40 mg.

15. The pharmaceutical composition of claim 14, wherein pravastatin or a phamiaceutically acceptable salt and/or hydrate thereof is present in an amount of about 40 mg.

16. The pharmaceutical composition of claim 10, wherein the HMG CoA reductase inhibitor is fluvastatin or a pharmaceutically acceptable salt and/or hydrate thereof.

17. The pharmaceutical composition of claim 16, wherein fluvastatin or a pharmaceutically acceptable salt and/or hydrate thereof is present in an amount of about 20 mg to about 80 mg.

18. The pharmaceutical composition of claim 10, wherein the HMG CoA reductase inhibitor is simvastatin or a pharmaceutically acceptable salt and/or hydrate thereof.

19. The pharmaceutical composition of claim 18, wherein simvastatin or a pharmaceutically acceptable salt and/or hydrate thereof is present in an amount of about 5 mg to about 80 mg.

20. The pharmaceutical composition of claim 10, wherein the HMG CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt and/or hydrate thereof.

21. The pharmaceutical composition of claim 20, wherein lovastatin or a pharmaceutically acceptable salt and/or hydrate thereof is present in an amount of about 10 mg to about 60 mg.

22. The pharmaceutical composition of claim 10, wherein the HMG CoA reductase inhibitor is rosuvastatin or a pharmaceutically acceptable salt and/or hydrate thereof.

23. The pharmaceutical composition of claim 22, wherein rosuvastatin or a pharmaceutically acceptable salt and/or hydrate thereof is present in an amount of about 10 mg to about 40 mg.

24. The pharmaceutical composition of any of claims 7-9, wherein the HMG CoA reductase inhibitor is pitavastatin or a pharmaceutically acceptable salt and/or hydrate thereof.

25. The pharmaceutical composition of claim 24, wherein pitavastatin or a pharmaceutically acceptable salt and/or hydrate thereof is present in an amount of about 1 mg to about 80 mg.

26. The pharmaceutical composition of any of claims 7, 8, and 10-25, wherein the S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] 2-methylpropanethioate is present in an amount of about 100 mg to about 300 mg.

27. A package comprising separate dosage units, of which (a) at least one dosage unit comprises S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] 2-methylpropanethioate or aprodrug that forms S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] thiol in vivo, and (b) at least one other dosage unit comprises an HMG CoA reductase inhibitor.

28. The package of claim 27, of which (a) at least one dosage unit comprises S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] 2-methylpropanethioate and (b) at least one other dosage unit comprises an HMG CoA reductase inhibitor.

29. The package of claim 27, of which (a) at least one dosage unit comprises a prodrug that forms S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] thiol in vivo and (b) at least one other dosage unit comprises an HMG CoA reductase inhibitor.

30. The package of any of claims 27-29, wherein the HMG CoA reductase inhibitor is selected from the group consisting of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin, and pharmaceutically acceptable salts and hydrates thereof.

31. The package of claim 30, wherein the HMG CoA reductase inhibitor is atorvastatin calcium, pravastatin sodium, fluvastatin sodium, simvastatin, lovastatin, or rosuvastatin calcium.

32. The package of any of claims 27-31 , wherein the HMG CoA reductase inhibitor is present in its dosage unit in an amount of about 5 mg to about 80 mg.

33. The package of any of claims 27-29, wherein the HMG CoA reductase inhibitor is pitavastatin or a pharmaceutically acceptable salt and/or hydrate thereof.

34. The package of claim 33, wherein the pitavastatin is present in its dosage unit in an amount of about 1 mg to about 80 mg.

35. The package of any of claims 27, 28 and 30-34, wherein the S-[2-([[l-(2- /
ethylbutyl)cyclohexyl] carbonyl] amino)phenyl] 2-methylpropanethioate is present in its dosage unit in amount of about 100 mg to about 300 mg.

36. A kit comprising (a) a first pharmaceutical composition comprising a therapeutically effective amount of (i) S-[2-([[l-(2-ethylbutyl)cyclohexyl] carbonyl] amino)phenyl] 2-methylpropanethioate or a prodrug that forms S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] thiol in vivo, and (ii) a pharmaceutically acceptable carrier, (b) a second pharmaceutical composition comprising (i) at least one HMG CoA reductase inhibitor, and (ii) a pharmaceutically acceptable carrier, (c) prescribing information, and (d) a container, wherein the first and second phannaceutical compositions can be the same or different, and wherein the prescribing information includes advice to a patient regarding co-administration of S-[2-([[l-(2-ethylbutyl)cyclohexyl] carbonyl] amino)phenyl] 2-methylpropanethioate or aprodrug that forms S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] thiol in vivo, and the HMG CoA reductase inhibitor.

37. The kit of claim 36, comprising (a) a first pharmaceutical composition comprising a therapeutically effective amount of (i) S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] 2-methylpropanethioate and (ii) a pharmaceutically acceptable carrier, (b) a second pharmaceutical composition comprising (i) at least one HMG CoA reductase inhibitor, and (ii) a pharmaceutically acceptable carrier, (c) prescribing information, and (d) a container, wherein the first and second pharmaceutical compositions can be the same or different, and wherein the prescribing infonnation includes advice to a patient regarding administration of S-[2-([[l-(2-ethylbutyl)cyclohexyl] carbonyl] amino)phenyl] 2-methylpropanethioate and the HMG CoA reductase inhibitor.

38. The kit of claim 36, comprising (a) a first pharmaceutical composition comprising a therapeutically effective amount of (i) a prodrug that forms S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] thiol in vivo and (ii) a pharmaceutically acceptable carrier, (b) a second phannaceutical composition comprising (i) at least one HMG CoA reductase inhibitor, and (ii) a phamiaceutically acceptable carrier, (c) prescribing information, and (d) a container, wherein the first and second phannaceutical compositions can be the same or different, and wherein the prescribing information includes advice to a patient regarding co-administration of the prodrug that forms S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] thiol in vivo, and the HMG CoA reductase inhibitor.

39. The kit of any of claims 36-38, wherein the first and second pharmaceutical compositions are different.

40. The kit of any of claims 36, 37, and 39, wherein the therapeutically effective amount of the S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] 2-methylpropanethioate is about 100 mg to about 300 mg.

41. The kit of any of claims 36-40, wherein the first and second pharmaceutical compositions are in the form of tablets.

42. The kit of claim 41, wherein at least one of the tablets comprises about 100 mg to about 300 mg of the S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] 2-methylpropanethioate.

43. The kit of claim 41 or 42, wherein at least one of the tablets comprises about 1 mg to about 80 mg of an HMG CoA reductase inhibitor.

44. The kit of claim 43, wherein at least one of the tablets comprises about 5 mg to about 80 mg of an HMG CoA reductase inhibitor.

45. A method for the treatment or prophylaxis of a cardiovascular disorder in a patient, which comprises treating the patient with a therapeutically effective amount of a combination of (a) S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] 2-methylpropanethioate or aprodrug that forms S-[2-([[l-(2-ethylbutyl)cyclohexyl] carbonyl] amino)phenyl] thiol in vivo, and (b) at least one HMG CoA reductase inhibitor.

46. The method of claim 45, which comprises treating the patient with a therapeutically effective amount of a combination of (a) S-[2-([[l-(2-ethylbutyl)cyclohexyl] carbonyl] amino)phenyl] 2-methylpropanethioate and (b) at least one HMG CoA reductase inhibitor.

47. The method of claim 45, which comprises treating the patient with a therapeutically effective amount of a combination of (a) aprodrug that forms S-[2-([[l-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] thiol in vivo and (b) at least one HMG CoA reductase inhibitor.

48. The method of any of claims 45-47, wherein the HMG CoA reductase inhibitor selected from the group consisting of the group consisting of atorvastatin, pravastatin, fluvastatin, simvastatin, lovastatin, rosuvastatin, and pharmaceutically acceptable salts and hydrates thereof.

49. The method of claim 48, wherein the HMG CoA 'reductase inhibitor is atorvastatin calcium, pravastatin sodium, fluvastatin sodium, simvastatin, lovastatin, or rosuvastatin calcium.

50. The method of any of claims 45-49, wherein the HMG CoA reductase inhibitor is administered to the patient in an amount of about 5 mg to about 80 mg per day.

1 51. The method of any of claims 45-47, wherein the HMG CoA reductase inhibitor is pitavastatin or a pharmaceutically acceptable salt and/or hydrate thereof.

52. The method of claim 51 , wherein the HMG CoA reductase inhibitor is administered to the patient in an amount of about 1 mg to about 80 mg per day.

53. The method of any of claims 45, 46, and 48-52, wherein S-[2-([[l-(2-ethylbutyl)cyclohexyl] carbonyl] amino)phenyl] 2-methylpropanethioate is administered to ' the patient in an amount of about 300 mg to about 900 mg per day.

54. The method of any of claims 46-53, wherein the cardiovascular disorder is selected from the group consisting of cardiovascular disease, coronary heart disease, coronary artery disease, hypertriglyceridemia, and hypercholesterolemia.

55. The method of any of claims 46-53, wherein the cardiovascular disorder is atherosclerosis.

56. The method of any of claims 46-53, wherein the cardiovascular disorder is hypoalphalipoproteinemia or hyperbetalipoproteinemia.

57. The method of any of claims 46-53, wherein the cardiovascular disorder is hyperlipidemia.

58. The method of any of claims 46-53, wherein the cardiovascular disorder is primary hypercholesterolemia and/or mixed dylipidemia.

59. The method of any of claims 46-58, wherein cholesteryl ester transfer protein (CETP) activity is inhibited post-treatment relative to CETP activity pretreatment.

60? The method of any of claims 46-59, wherein the high density lipoprotein cholesterol (HDL-C) level is increased post-treatment relative to pretreatment HDL-C level.

61. The method of any of claims 46-60, wherein the low density lipoprotein cholesterol (LDL-C) level is decreased post-treatment relative to pretreatment LDL-C level.

62. The method of any of claims 46-61, wherein the ratio of total cholesterol to
I HDL-C level (TC/HDL-C) is decreased post-treatment relative to pretreatment TC/HDL-C.

63. The method of any of claims 46-62, wherein the ratio of LDL-C level to HDL-C level (LDL-C/HDL-C) is decreased post-treatment relative to pretreatment LDL-C/HDL-C.

64. The method of any of claims 45-63, wherein the HDL-C level of the patient is about 60 mg/dL or less prior to initiating the treatment or prophylaxis.

65. The method of claim 64, wherein the HDL-C level of the patient is about 50 mg/dL or less prior to initiating the treatment or prophylaxis.

66. The method of claim 65, wherein the HDL-C level of the patient is about 40 mg/dL or less prior to initiating the treatment or prophylaxis.

67. The method of any of claims 45-66, wherein the patient has a medical history of, or is currently diagnosed with, coronary heart disease or coronary heart disease risk equivalent as defined by at least one of the following: atherosclerotic disease; type II diabetes wherein the patient exhibits hyperocholesterolemia and/or
hyperbetalipoproteinemia; and Framingham 10-years coronary heart disease risk of about 20% or more.

68. The method of any of claims 45-66, wherein the patient has at least one of the following risk factors: cigarette smoking; hypertension with a blood pressure of greater than or equal to 140/90 mm Hg or the patient is receiving hypertension medication; family history of premature coronary heart disease; and age of greater than or equal to 45 for men or greater than or equal to 55 for women.

69. The method of claim 68, wherein the patient has a Framingham 10-years coronary heart disease risk of about 20%o or more.

70. The method of claim 68, wherein the patient has a Framingham 10-years coronary heart disease risk from about 10%> to about 20%>.

71. The method of claim 68, wherein the patient has a Framingham 10-years coronary heart disease risk of about 10% or less.

72. The method of any of claims 45, 46, and 48-71 , wherein S-[2-([[ 1 -(2-ethylbutyl)cyclohexyl] carbonyl] amino)phenyl] 2-methylpropanethioate is administered with food.