Methods for treatment of disorders of cardiac contractility

• US 6,191,136 B1
• Filed: 11/05/1998
• Issued: 02/20/2001
• Est. Priority Date: 11/07/1997
• Status: Expired due to Fees

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Marban, Eduardo
• Primary Examiner(s): Weddington, Kevin E.
• Application Number:
  US09/186,755
• Time in Patent Office: 838 Days
• Field of Search: 514/258, 514/222.2, 514/241, 514/315, 514/372, 514/401, 514/412
• US Class Current: 514/259.3
• 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 of increasing calcium sensitivity of cardiac muscle, comprising selecting a mammal in need of increased cardiac sensitivity and administering to mammalian cardiac muscle of the maimnal an effective amount of a xanthine oxidase compound.

2. A method of claim 1 wherein the compound is allopurinol.

3. A method of claim 1 wherein the compound is oxypurinol.

4. A method of claim 1 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.

5. A method of claim 1 or 4 wherein the compound induces at least about a 10 percent increase n cardiac contractile force in a standard in vitro calcium-sensitizing assay.

6. A method of claim 1 or 4 wherein the compound induces at least about a 20 percent increase in cardiac contractile force in a standard in vitro calcium-sensitizing assay.

7. A method of claim 1 or 4 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.

8. A method of claim 1 or 4 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.

9. The method of any one of claims 1 or 2 through 4 wherein the compound is administered to a primate.

10. The method of any one of claims 1 or 2 through 4 wherein the compound is administered to a human.

11. The method of any one of claims 1 or 2 through 4 wherein a mammal that is suffering from heart failure is selected for treatment for heart failure, and the compound is then administered to the selected mammal.

12. The method of claim 1 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.

13. A method of claim 1 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.

14. A method of claim 1 wherein the compound corresponds to the following Fornulae 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.

15. A method of claim 1 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 alkvl 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.

16. A method of claim 1 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.

17. A method of claim 1 wherein the compound corresponds to the following Formulae VI:

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

18. A method of claim 1 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.

19. A method of claim 1 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.

20. A method of claim 1 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 R₃ and R₄ are independently selected from H, C₁-C₅ alkyl and hydroxy substituted C₂-C₅ alkyl.

21. A method of claim 1 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.

22. A method of claim 1 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 R³ is hydroxymethyl, formyl, carboxy or carbalkoxy wherein alkoxy contains 1 to 6 carbon atoms.

23. A method of claim 1 wherein the compound corresponds to the following Formulae XII;

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

24. A method of claim 1 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.

25. A method of claim 1 wherein the compound corresponds to the following Formulae XIV:

whrein R is 3-pyridyl or 4-pyridyl.

26. A method of claim 1 wherein the compound corresponds to the following Formulae XV:

wherein R is 3-pyridyl or 4-pyridyl.

27. A method of claim 11 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.

28. A method of claim 1 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, l, 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;

is C_1-5 alkyl;

alkenyl is (CH₂)₂ or (CH₂)₃; and

M is a nontoxic cation.

29. A method of claim 1 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 methylmedioxyy, 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.

30. A method of claim 1 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.

31. A method of claim 1 wherein the compound corresponds to the following Formulae XX:

wherein R is 4′

-OH or 5′

-OH.

32. A method of claim 1 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.

33. A method of claim 1 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.

34. A method of claim 1 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).