Methods for treatment of disorders of cardiac contractility

• US 6,569,862 B1
• Filed: 10/06/2000
• Issued: 05/27/2003
• Est. Priority Date: 11/07/1997
• Status: Expired due to Term

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Marban, Eduardo
• Primary Examiner(s): Weddington, Kevin E.
• Application Number:
  US09/680,876
• Time in Patent Office: 963 Days
• Field of Search: 514/258, 514/222.2, 514/241, 514/315, 514/372, 514/401, 514/412
• US Class Current: 514/262.1
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/549 having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide

Abstract

The present invention relates to methods for modulating calcium sensitivity of cardiac muscle. In preferred aspects, the invention provides methods for enhancing myocardial contractility and cardiac performance, and methods for treatment of heart failure and other disorders associated with cardiac contractility by administration of one or more xanthine oxidase inhibitor compounds.

Claims

1. A method for treating heart failure in a mammal suffering from or susceptible to heart failure, comprising selecting a mammal for treatment of heart failure that is suffering from or susceptible to heart failure and administering to the selected mammal a therapeutically effective amount of a compound that provides increased cardiac contractile force as measured in a standard in vitro calcium-sensitizing assay.

3. The method of claim 1 or claim 2 wherein the compound is administered to the mammal within about 6 hours after the mammal has suffered heart failure.

4. The method of claim 1 or claim 2 wherein the compound is administered to the mammal within about 18 hours after the mammal has suffered heart failure.

5. The method of claim 1 or claim 2 wherein the compound is administered to the mammal for at least about 1 week after the mammal has suffered heart failure.

6. The method of claim 1 or claim 2 wherein the compound is administered to the mammal for at least about 4 weeks after the mammal has suffered heart failure.

7. The method of claim 1 or claim 2 wherein the mammal is suffering from or susceptible to congestive heart failure.

8. The method of claim 1 or claim 2 wherein the mammal is suffering from or susceptible to cardiogenic shock.

22. A method of claim 1, 2, 9, 10 or 17 wherein the compound induces at least about a 10 percent increase in cardiac contractile force in a standard in vitro calcium-sensitizing assay.

23. A method of claim 1, 2, 9, 10 or 17 wherein the compound induces at least about a 20 percent increase in cardiac contractile force in a standard in vitro calcium-sensitizing assay.

24. A method of claim 1, 2, 9, 10 or 17 wherein the compound induces at least about a 3 percent decrease in intracellular calcium concentration as measured in a standard in vitro calcium-sensitizing assay.

25. A method of claim 1, 2, 9, 10 or 17 wherein the compound induces at least about a 5 percent decrease in intracellular calcium concentration as measured in a standard in vitro calcium-sensitizing assay.

26. The method of any one of claims 1, 2, 9, 10 or 17 wherein the compound is administered to a human.

27. A method of claim 1, 2, 9, 10, or 17 wherein the administered compound is allopurinol or a pharmaceutically acceptable salt thereof.

28. A method of claim 1, 2, 9, 10 or 17 wherein the administered compound is oxypurinol or a pharmaceutically acceptable salt thereof.

29. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formula I

wherein R, R¹ and R⁴ are similar or dissimilar groups selected from hydrogen and lower alkyl having from 1 to about 5 carbon atoms, X is selected from halogen, trifluoromethyl, and lower alkyl, and R² is a diazine attached through one of its carbon atoms to the benzothiadiazine nucleus.

30. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae II:

wherein R, R¹ and R⁴ are similar or dissimilar groups selected from hydrogen and lower alkyl having from 1 to about 5 carbon atoms, X is selected from halogen, trifluoromethyl, and lower alkyl, and R² is a diazine attached through one of its carbon atoms to the benzothiadiazine nucleus.

31. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae III:

wherein X represents halo, C_1-3-alkyl or trifluoromethyl;

R represents hydrogen, a straight or branched chain lower alkyl having from 1 to 6 carbon atoms and phenyl-lower alkyl having from 1 to 3 carbon atoms;

R¹ represents hydrogen, lower alkyl having from 1 to 5 carbon atoms or substituted lower alkyl wherein the substituent is mono or dihalo, and phenyl, the group —

CO₂ lower alkyl having from 1 to 5 carbon atoms, an azine optionally substituted with one or more lower alkyl having 1 to 3 carbon atoms or a diazine optionally substituted with one or more lower alkyl having from 1 to 3 carbon atoms, or the group —

CONR²R³ wherein R² and R³ can be similar or dissimilar and selected from hydrogen, lower alkyl having 1 to 5 carbon atoms or hydroxy substituted lower alkyl having 1 to 5 carbon atoms.

32. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae IV:

wherein X represents halo, C_1-3-alkyl and trifluoromethyl;

R represents a straight or branched chain lower alkyl having from 1 to 6 carbon atoms and phenyl-lower alkyl having from 1 to 3 carbon atoms;

R¹ represents (1) hydrogen, (2) lower alkyl having from 1 to 5 carbon atoms or substituted lower alkyl wherein the substituent is mono, di- or trihalo, and phenyl, (3) the group —

CO₂R² wherein R-2- is hydrogen or lower alkyl having from 1 to 5 carbon atoms, (4). the group —

CONH₂ or (5) an azine optionally substituted with one or more lower alkyl having 1 to 3 carbon atoms or a diazine optionally substituted with one or more lower alkyl having from 1 to 3 carbon atoms.

33. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae V:

wherein Y₁ and Y₂ are carbon or nitrogen;

R₁ is H or an alkali metal or ammonium;

R₂ is H, CH₃, a halogen, phenylazo or NO₂;

R₃ is OR₁, H, or a halogen; and

R₄ is H, NO₂ or a halogen.

34. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae VI:

wherein R is an aromatic or substituted aromatic nucleus, R₁ is H, an alkali metal or ammonium, and R₂ is H or OR₁.

35. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae VII:

wherein R¹ is —

OH or

 

in which Y is lower alkyl or phenyl;

R² is substituted either at the 4′

-position or at the 5′

-position and is hydrogen, fluoro, bromo, chloro, hydroxy, lower alkyl or

 

in which Y is lower alkyl or phenyl;

R³ is chloro, bromo or lower alkyl;

R⁴ is hydroxy, amine, lower alkoxy or

 

in which Y is lower alkyl or phenyl;

R⁵ is hydrogen, fluoro, bromo, chloro, carboxyl, lower alkyl or

 

in which Z is lower alkyl; and

the nontoxic, pharmaceutically acceptable metal salts of said compound in which R⁵ is carboxyl.

36. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae VIII:

wherein R₁ is hydrogen or alkyl containing 1 to 3 carbon atoms;

R₂ is halogen; and

R₃ is halogen or —

CF₃;

or a pharmaceutically acceptable salt thereof.

37. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae IX:

wherein R₁ is selected from the group consisting of monohalo-phenyl, dihalo-phenyl and pyridyl, halo is Cl, Br, I or F, R₂ is selected from the group consisting of C₁-C₅ alkyl-S—

, C₁-C₅ alkyl-SO—

, C₁-C₅ alkyl-SO₂— and

R₃R₄N—

SO₂—

, and R₃ and R₄ are independently selected from H, C₁-C₅ alkyl and hydroxy substituted C₂-C₅ alkyl.

38. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae X:

wherein R₁ is selected from the group consisting of monohalo-phenyl, dihalo-phenyl and pyridyl, halo is Cl, Br, I or F;

R₂ is selected from the group consisting of C₁-C₅ alkyl-S—

, C₁-C₅ alkyl-SO—

, C₁-C₅ alkyl-SO₂— and

R₃R₄N—

SO₂—

, and R₃ and R₄ are independently selected from H, C₁-C₅ alkyl and hydroxy substituted C₂-C₅ alkyl.

39. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae XI:

wherein one of R¹ and R² is hydrogen and the other is hydrogen, hydroxy or —

OR⁴ wherein R⁴ is alkanoyl of 2 to 7 carbon atoms, tosyl or mesyl and R³is hydroxymethyl, formyl, carboxy or carbalkoxy wherein alkoxy contains 1 to 6 carbon atoms.

40. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae XII:

wherein R is 3-pyridyl or 4-pyridyl and R₁ is C₁-C₅ alkyl.

41. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae XIII:

wherein R is 3-pyridyl or 4-pyridyl, R₂ is bromo or chloro, and R₃ is hydrogen, bromo or chloro.

42. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae XIV:

wherein R is 3-pyridyl or 4-pyridyl.

43. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae XV:

wherein R is 3-pyridyl or 4-pyridyl.

44. A method of claim 1, 2, 9, 10 to 17 wherein the compound corresponds to the following Formulae XVI:

wherein Ar is pyridyl, thienyl, phenyl or

 

wherein R¹, R² and R³ are individually H, CF₃, halogen, alkyl or O-alkyl or R¹ and R² or R² and R³ when taken together are methylenedioxy;

X is NH₂, H, halogen, OH or NH-alkyl;

R is OH, OM, O-alkyl, NH₂, NH-alkyl or N(alkyl)₂;

wherein halogen is Cl, F, I, or Br; and

M is a nontoxic cation.

45. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae XVII:

wherein Ar is pyridyl, thienyl or

 

wherein R¹, R² and R³ are individually H, C_1-3 haloalkyl, F, Br, Cl, I, C_1-3 alkyloxy, R¹ and R² or R² and R³ taken together represent methylmedioxy, provided at least one of R¹, R² and R³ is H, one of R¹, R² and R³ is other than H and only one of R¹, R² and R³ can be I;

R is OH, OM, NH₂, N-alkyl, N(alkyl)₂, O-alkyl or N-alkenyl-N(alkyl)₂;

X is NH₂, OH, H, F, Cl, Br, I or C_1-3 alkyl;

alkyl is C_1-5 alkyl;

alkenyl is (CH₂)₂ or (CH₂)₃; and

M is a nontoxic cation.

46. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae XVIII:

wherein Ar is pyridyl, thienyl or

 

wherein R¹, R² and R³ are individually H, C_1-3 haloalkyl, F, Br, Cl, I, C_1-3 alkyloxy, R¹ and R² or R² and R³ taken together represent methylmedioxy, provided at least one of R¹, R² and R³ is H, one of R¹, R² and R³ is other than H and only one of R¹, R² and R³ can be I;

R is OH, OM, NH₂, N-alkyl, N(alkyl)₂, O-alkyl or N-alkenyl-N(alkyl)₂;

X is NH₂, OH, H, F, Cl, Br, I or C_1-3 alkyl;

alkyl is C_1-5 alkyl;

alkenyl is (CH₂)₂ or (CH₂)₃; and

M is a nontoxic cation.

47. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae XIX:

wherein Ar is pyridyl, thienyl or

 

wherein R¹, R² and R³ are individually H, C_1-3 haloalkyl, F, Br, Cl, I, C_1-3 alkyloxy, R¹ and R² or R² and R³ taken together represent methylmedioxy, provided at least one of R¹, R² and R³ is H, one of R¹, R² and R³ is other than H and only one of R¹, R² and R³ can be I;

R is OH, OM, NH₂, N-alkyl, N(alkyl)₂, O-alkyl or N-alkenyl-N(alkyl)₂;

X is NH₂, OH, H, F, Cl, Br, I or C_1-3 alkyl;

alkyl is C_1-5 alkyl;

alkenyl is (CH₂)₂ or (CH₂)₃; and

M is a nontoxic cation.

48. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae XX:

wherein R is 4′

-OH or 5′

-OH.

49. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae XXI:

wherein n is an integer between 2 and 6, Y is H or CO—

A, wherein A is a racemic or chiral amino acid, dipeptide, tripeptide, tetrapeptide, or pentapeptide.

50. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae XXII:

wherein R¹ is hydroxy or a lower alkanoyloxy, R² is hydrogen atom, hydroxy, or mercapto, R³ is an unsaturated heterocyclic group containing nitrogen or sulfur atom as the hetero atom;

naphthyl;

or a phenyl.

51. A method of claim 1, 2, 9, 10 or 17 wherein the compound corresponds to the following Formulae XXIII:

wherein A is a grouping of the formula

 

in which R¹ and R² each individually is hydrogen, halogen, trifluoromethyl, nitro, amino, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₃-C₆-alkenyloxy, C₁-C₆-alkylthio, C₁-C₆-alkanoylamino, aryloxy, aryl-(C₁-C₆-alkyl), aryl-(C₁-C₆-alkoxy), aryl-(C₁-C₆-alkoxy)carbonylamino or —

O—

CH₂—

R³, or R¹ and R² on adjacent carbon atoms together are —

CH═

CH—

CH═

CH—

or —

CH₂—

CH₂—

O—

, and R³ is hydroxy-(C₁-C₄-alkyl) or vicinal dihydroxy-(C₂-C5-alkyl).

2. A method for enhancing efficiency of cardiac contraction in a mammal, comprising selecting a mammal in need of enhanced efficiency of cardiac contraction and administering to the selected mammal an effective amount of a xanthine oxidase inhibitor compound.

9. A method for treatment of a disorder of cardiac contractility in a mammal suffering from or susceptible to the disorder, comprising selecting a mammal suffering from or susceptible to a disorder of cardiac contractility and administering to the selected mammal a therapeutically effective amount of a xanthine oxidase inhibitor compound.

10. A method for treating heart failure in a mammal suffering from or susceptible to heart failure, comprising selecting a mammal that is suffering from or susceptible to heart failure and administering to the selected mammal a therapeutically effective amount of a xanthine oxidase inhibitor compound.

11. The method of claim 10 wherein the compound is administered to the mammal within about 6 hours after the mammal has suffered heart failure.

12. The method of claim 10 wherein the compound is administered to the mammal within about 18 hours after the mammal has suffered heart failure.

13. The method of claim 10 wherein the compound is administered to the mammal for at least about 1 week after the mammal has suffered heart failure.

14. The method of claim 10 wherein the compound is administered to the mammal for at least about 4 weeks after the mammal has suffered heart failure.

15. The method of claim 10 wherein the mammal is suffering from or susceptible to congestive heart failure.

16. The method of claim 10 wherein the mammal is suffering from or susceptible to cardiogenic shock.

17. A method for treatment method for a disorder of cardiac contractility in a mammal suffering from or susceptible to the disorder, comprising administering to the mammal a therapeutically effective amount of a compound that inhibits xanthine oxidase.

18. The method of claim 17 wherein a mammal suffering from a disorder of cardiac contractility is selected for treatment for the disorder, and the compound is then administered to the selected mammal.

19. The method of claim 17 wherein the disorder of cardiac contractility is heart failure.

20. The method of claim 17 wherein the disorder of cardiac contractility is congestive heart failure.

21. The method of claim 17 wherein the disorder of cardiac contractility is cardiogenic shock.

52. A method for treating heart failure in a mammal suffering from or that has suffered heart failure, comprising selecting a mammal for heart failure treatment that is suffering from or has suffered heart failure and administering to the selected mammal a therapeutically effective amount of allopurinol or a pharmaceutically acceptable salt thereof.

53. The method of claim 52 wherein the mammal has suffered congestive heart failure.

54. The method of claim 52 wherein the mammal has suffered from cardiogenic shock.

55. The method of any one of claim 52 through 54 wherein the allopurinol is administered regularly to the mammal for at least two weeks.

56. The method of any one of claims 52 through 54 wherein the allopurinol is administered regularly to the mammal for at least four weeks.

57. The method of any one of claim 52 through 54 wherein the allopurinol is administered to the mammal within about 24 hours after having suffered heart failure.

58. The method of any one of claim 52 through 54 wherein the mammal is a human.

59. A method for treating heart failure in a mammal suffering from or has suffered heart failure comprising selecting a mammal for heart treatment that is suffering from or susceptible to heart failure and administering to the selected mammal a therapeutically effective amount of oxypurinol or a pharmaceutically acceptable salt thereof.

60. The method of claim 59 wherein the mammal has suffered congestive heart failure.

61. The method of claim 59 wherein the mammal has suffered from cardiogenic shock.

62. The method of any one of claims 59 through 61 wherein the oxypurinol is administered regularly to the mammal for at least two weeks.

63. The method of any one of claim 59 through 61 wherein the oxypurinol is administered regularly to the mammal for at least four weeks.

64. The method of any one of claim 59 through 61 wherein the oxypurinol is administered to the mammal within about 24 hours after having suffered heart failure.

65. The method of any one of claim 59 through 61 wherein the mammal is a human.