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1. (CA2747251) METHODS FOR TREATING ACUTE MYOCARDIAL INFARCTIONS AND ASSOCIATED DISORDERS
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What is Claimed is:
1. A method of treating a patient who has suffered an acute myocardial infarction (AMI) comprising administering to the patient a therapeutically effective dose of a therapeutic having an anti-fibrotic effect, wherein optionally the treatment is initiated at a time period about 1 to 42 days after suffering the AMI, and optionally continues for up to 3 to 6 months.
2. The method of claim 1, wherein the method is to limit expansion of an infarct scar due to the AMI.
3. The method of claim 1, wherein the treatment is initiated about 5-10 days after the AMI.
4. The method of claim 3, wherein the treatment is initiated about 7 days after the AMI.
5. The method of any one of claims 1-4, wherein the treatment is for at least
weeks.
6. A method of reducing the incidence of congestive heart failure in a patient
who has suffered an acute myocardial infarction (AMI), comprising administering to the patient a therapeutically effective dose of a therapeutic having an antifibrotic effect, wherein the therapeutically effective dose reduces the incidence of congestive heart failure.
7. The method of claim 6, wherein the patient is at an increased risk of congestive heart failure due to the AMI.
8. The method of claim 6 or 7, wherein the treatment is initiated about 1 to
days after the suffering of the AMI.
9. A method of preserving viable cardiac tissue or controlling or reducing myocardial infarct size in a patient who has suffered an acute myocardial infarction (AMI) comprising administering to the patient a therapeutically effective dose of a therapeutic having an anti-fibrotic effect, wherein the administering of the therapeutic to the patient results in a relatively reduced infarct size on average compared to infarct size in a patient who has not been administered the therapeutic.
10. The method of claim 9, wherein the administering is initiated 1-42 days after suffering the AMI.
11. The method of claim 9 or 10, wherein the relative reduction in infarct size is at least 5%.
12. A method of reducing the incidence of ventricular tachycardia in a patient in need thereof, comprising administering to the patient a therapeutically effective dose of a therapeutic having an anti-fibrotic effect, wherein the administering of the therapeutic prevents or reduces the incidence of ventricular tachycardia.
13. The method of claim 12, wherein the patient has suffered an acute myocardial infarction (AMI).
14. The method of claim 13, wherein the administering is initiated about 1 to
days after the suffering of the AMI.
15. The method of claim 14, wherein the administering is initiated about 7 days after the suffering of the AMI.
16. A method of treating or preventing ventricular fibrillation in a patient in need thereof, comprising administering to the patient a therapeutic having an antifibrotic effect, wherein the administering of the therapeutic prevents ventricular fibrillation in the patient.
17. The method of claim 16, wherein the patient has suffered an acute myocardial infarction (AMI).
18. The method of claim 17, wherein the administration is initiated about 1 to
days after the suffering of the AMI.
19. The method of claim 18, wherein the administration is initiated about 7 days after the suffering of the AMI.
20. The method of any one of claims 16-19, wherein the administering reduces the incidence of sudden cardiac death.
21. The method of any one of claims 16-20, wherein the administering reduces cardiac risk of the patient.
22. A method of controlling arrhythmia in a patient in need thereof, comprising administering to the patient a therapeutic having an anti-fibrotic effect, wherein the administering of the therapeutic controls arrhythmia in the patient.
23. The method of claim 22, wherein the patient has suffered an acute myocardial infarction (AMI).
24. The method of claim 23, wherein the administration is initiated about 1 to
days after the suffering of the AMI.
25. The method of claim 24, wherein the administration is initiated about 7 days after the suffering of the AMI.
26. The method of any one of claims 22-25, wherein the administering treats ventricular remodeling.
27. The method of any one of claims 1-26, wherein the patient had not previously suffered an AMI.
28. The method of any one of claims 1-27, wherein the therapeutic having an antifibrotic effect is a therapeutic that reduces tissue remodeling or fibrosis, reduces the activity of transforming growth factor-beta (TGF-β), targets one or more
TGF-β isoforms, inhibits TGF-β receptor kinases TGFBR1 (ALK5) and/or
TGFBR2, or modulates one or more post-receptor signaling pathways; is an endothelin receptor antagonists, targets both endothelin receptor A and endothelin receptor B or selectively targets endothelin receptor A; reduces activity of connective tissue growth factor (CTGF); inhibits matrix metalloproteinase; reduces the activity of epidermal growth factor (EGF), targets the EGF receptor, or inhibits EGF receptor kinase; reduces the activity of platelet derived growth factor (PDGF), targets PDGF receptor (PDGFR), inhibits PDGFR kinase activity, or inhibits post-PDGF receptor signaling pathways; reduces the activity of vascular endothelial growth factor (VEGF), targets one or more of VEGF receptor 1 (VEGFR1, Flt-1), VEGF receptor 2 (VEGFR2, KDR), the soluble form of VEGFR1 (sFlt) and derivatives thereof which neutralize VEGF, inhibits VEGF receptor kinase activity; inhibits multiple receptor kinases such as BIRB-1120 which inhibits receptor kinases for vascular endothelial growth factor, fibroblast growth factor, and platelet derived growth factor; interferes with integrin function; interferes with pro-fibrotic activities of IL-4 and IL- 13, targets IL-4 receptor, IL- 13 receptor, the soluble form of IL-4 receptor or derivatives thereof;
modulates signaling though the JAK-STAT kinase pathway; interferes with epithelial mesenchymal transition, inhibits mTor; reduces levels of copper; reduces oxidative stress; inhibits prolyl hydrolase; inhibits phosphodiesterase 4 (PDE4) or phosphodiesterase 5 (PDE5), or modifies the arachidonic acid pathway.
29. The method of any one of claims 1-28, wherein the therapeutic is pirfenidone or compound of formula (I), (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof:
wherein
A is N or CR2 ; B is N or CR4; E is N or CX4; G is N or CX3; J is N or CX2 ; K is N or
CX1; a dashed line is a single or double bond,
R1, R2, R3, R4, X1, X2, X3, X4, X5, Y1, Y2, Y3, and Y4 are independently selected from the group consisting of H, deuterium, C1-C10 alkyl, C1-C10 deuterated alkyl, substituted C1C10 alkyl, C1-C10 alkenyl, substituted C1-C10 alkenyl, C1-C10 thioalkyl, C1C10 alkoxy, substituted C1-C10 alkoxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halogen, hydroxyl, C1-C10 alkoxyalkyl, substituted C1C10 alkoxyalkyl,
C1-C10 carboxy, substituted C1-C10 carboxy, C1-C10 alkoxycarbonyl, substituted
C1-C10 alkoxycarbonyl, CO-uronide, CO-monosaccharide, CO-oligosaccharide, and CO-
polysaccharide;
X6 and X7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylenylaryl, alkylenylheteroaryl, alkylenylheterocycloalkyl, alkylenylcycloalkyl, or X6 and X7 together form an optionally substituted 5 or 6 membered heterocyclic ring; and
Ar is pyridinyl or phenyl; and Z is O or S.
30. The method of any one of claims 1-29, wherein a therapeutically effective amount of pirfenidone or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof is administered to the patient.
31. The method of any one of claims 1-29, wherein the therapeutic administered
to the patient comprises a compound of formula (II)
wherein
X3 is H, OH, or C1-10alkoxy, Z is O, R2 is methyl, C(=O)H, C(=O)CH3, C(=O)Oglucosyl, fluoromethyl, difluoromethyl, trifluoromethyl, methylmethoxyl, methylhydroxyl, or phenyl; and R4 is H or hydroxyl, or a salt, ester, solvate, or prodrug thereof.
32. The method of claim any one of claims 1-29, wherein the therapeutic administered to the patient is selected from the group consisting of
a compound as listed in Table 1, and pharmaceutically acceptable salts, esters, solvates, and prodrugs thereof.
33. The method of any one of claims 1-28, wherein the therapeutic is a compound of formula (I), (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof:
wherein
A is N or CR2; B is N or CR4; E is N, N+X4 or CX4; G is N, N+X3 or CX3; J is
N, N+X2 or
CX2; K is N, N+X1 or CX1; a dashed line is a single or double bond,
R1, R2, R3, R4, X1, X2, X3, X4, X5, Y1, Y2, Y3, and Y4 are independently selected from the group consisting of H, deuterium, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 deuterated alkyl, optionally substituted C1-C10 alkenyl, optionally substituted C1-C10 thioalkyl, optionally substituted C1-C10 alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amido, optionally substituted sulfonyl, optionally substituted amino, optionally substituted sulfonamido, optionally substituted sulfoxyl, cyano, nitro, halogen, hydroxyl,
SO2H2, optionally substituted C1-C10 alkoxyalkyl, optionally substituted C1-C10 carboxy, optionally substituted C1-C10 alkoxycarbonyl, CO-uronide, CO-monosaccharide, COoligosaccharide, and CO-polysaccharide;
X6 and X7 are independently selected from the group consisting of hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkylenylaryl, optionally substituted alkylenylheteroaryl, optionally substituted alkylenylheterocycloalkyl, optionally substituted alkylenylcycloalkyl, or X6 and X7 together form an optionally substituted 5 or 6 membered heterocyclic ring; and
Ar is optionally substituted pyridinyl or optionally substituted phenyl; and Z is O or S.
34. The method of any one of claims 1-33, wherein the therapeutic is combined with a pharmaceutically acceptable carrier.
35. The method of any one of claims 1-34, wherein the administering is oral.
36. The method of any one of claims 1-35, wherein the therapeutically effective amount is a total daily dose of about 50 mg to about 2400 mg of the therapeutic or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof.
37. The method of claim 36, wherein the therapeutically effective amount is administered in divided doses three times a day or two times a day, or is administered in a single dose once a day.
38. The method of any one of claims 1-37, wherein the patient is human.