Claims
- 1. A compound having the structure (I):
- 2. The compound of claim 1, having one or more of the following limitations:
a) R1 is not CH2X, if X is F or Cl; b) if 312 represents pyridyl, then RD is —SR2, —SOR2, —SO2R2, —SO2N(R2)2, —NR2SO2R2, —NR2SO2N(R2)2—; or RD is an alkyl or heteroalkyl group substituted with one or more occurrences of R2, wherein R2 is—SR3, —SOR3, —SO2R3, —SO2N(R3)2,—, —NR3SO2R3—N(R3)2, —(C═O)N(R3)2,, —NR3(C═O)R3, —O(C═O)N(R3)2,, —NR3(C═O)N(R3)2,, —NR3)(C═S)N(R3)2,, —NR3SO2N(R3)2,, wherein each occurrence of R3 is independently an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, or; or c) if 313 represents isoxazole, then RB or RD is not a group —CRXRYNHR3, wherein at least one of RX or RY is a group other than hydrogen.
- 3. The compound of claim 1, wherein
- 4. The compound of claim 1, wherein
- 5. The compound of claim 1, wherein the compound has the structure:
- 6. The compound of claim 1, wherein the compound has the structure:
- 7. The compound any one of claims 4-6, wherein one of RB or RD is
—(C0-3alkyl)NR3—SO2—(C0-3alkyl)R4; —(C0-3alkyl)SO2—NR3—(C0-3alkyl)R4; —(C0-3alkyl)NR3(C0-3alkyl)R4; —(C0-3alkyl)CONR3(C0-3alkyl)R4; —(C0-3alkyl)OCONR3(C0-3alkyl)R4; —(C0-3alkyl)NR3CONR3(C0-3alkyl)R4; —(C0-3alkyl)NR3(C═S)NR3(C0-3alkyl)R4; —(C0-3alkyl)NR3SO2NR3(C0-3alkyl)R4,
wherein each of the alkyl groups is independently substituted or unsubstituted, cyclic or acyclic, linear or branched, and wherein each occurrence of R3 and R4 is independently hydrogen or a substituted or unsubstituted alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety.
- 8. The compound any one of claims 4-6, wherein one of RB or RD is
- 9. The compound any one of claims 4-6, wherein one of RB or RD is one of the structures:
- 10. The compound any one of claims 4-6, wherein R1 is hydrogen or a substituted or unsubstituted aryl, heteroaryl, alkylaryl, heteroalkylaryl, alkylheteroaryl, or heteroalkylheteroaryl moiety.
- 11. The compound any one of claims 4-6, wherein R1 is hydrogen or
- 12. The compound any one of claims 4-6, wherein R1 is hydrogen or
- 13. The compound any one of claims 4-6, wherein R1 is hydrogen or
- 14. The compound any one of claims 4-6, wherein R1 is hydrogen or
- 15. The compound any one of claims 4-6, wherein R1 is hydrogen or
- 16. The compound any one of claims 4-6, wherein each occurrence of R3 and R4 is independently a substituted or unsubstituted aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety.
- 17. The compound any one of claims 4-6, wherein each occurrence of R3 and R4 independently comprises an aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety substituted with at least —COOH.
- 18. The compound any one of claims 4-6, wherein each occurrence of R3 and R4 is independently phenyl or —(CH2)phenyl substituted with —COOH (or an ester or bioisostere thereof) and optionally further substituted with one or more of hydroxyl, alkoxy, thio, thioalkyl, —COOH, —COO(alkyl), —CONH2, —NH(CO)alkyl, —SO2R4a, lower alkyl, lower heteroalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl, or wherein two adjacent groups taken together form an aryl, heteroaryl, cycloaliphatic, or heterocycloaliphatic group, wherein R4a is acyl, or substituted or unsubstituted alkyl or aryl.
- 19. The compound any one of claims 4-6, wherein each occurrence of R3 and R4 is independently phenyl or —(CH2)phenyl substituted with COOH or an ester or bioisostere of COOH.
- 20. The compound any one of claims 4-6, wherein each occurrence of R3 and R4 is independently phenyl or —(CH2)phenyl substituted with any one of COOH, acylsulfonamide, —CONH2, tetrazole, or 5-oxo-1,2,4-oxadiazole.
- 21. The compound any one of claims 4-6, wherein one of RB or RD is —(C0-3alkyl)NR3—SO2—(C0-3alkyl)R4; —(C0-3alkyl)SO2—NR3—(C0-3alkyl)R4; —(C0-3alkyl)NR3(C0-3alkyl)R4; —(C0-3alkyl)CONR3(C0-3alkyl)R4; —(C0-3alkyl)OCONR3(C0-3alkyl)R4; —(C0-3alkyl)NR3CONR3(C0-3alkyl)R4;.—(C0-3alkyl)NR3(C═S)NR3(C0-3alkyl)R4; —(C0-3alkyl)NR3SO2NR3(C0-3alkyl)R4, or subgroups defined generally above and herein, and the remaining groups RA, RE, RG, and one of RB or RD are each independently hydrogen, alkyl, alkoxy, halogen, hydroxyl, thio or thioalkyl.
- 22. A compound having the structure:
- 23. The compound of claim 22, wherein Q is an aryl or heteroaryl moiety having one of the structures:
- 24. The compound of claim 22 having the structure:
- 25. The compound of claim 24 having the structure:
- 26. The compound of claim 22 having the structure:
- 27. The compound of claim 26 having the structure:
- 28. The compound of claim 22 having the structure:
- 29. The compound of claim 28 having the structure:
- 30. The compound of any one of claims 22-29 wherein R1 is hydrogen or
- 31. A pharmaceutical composition comprising:
a compound of any one of claims 1-6, 22, 24, 26 or 28; and a pharmaceutically acceptable carrier or diluent.
- 32. The pharmaceutical composition of claim 31, wherein the compound is present in an amount effective to inhibit a caspase.
- 33. The pharmaceutical composition of claim 32, wherein the caspase is caspase-3 or caspase-7.
- 34. The pharmaceutical composition of claim 31, optionally further comprising an additional therapeutic agent.
- 35. A method for treating a caspase-mediated disorder comprising:
administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-6, 22, 24, 26 or 28.
- 36. The method of claim 35, optionally comprising further administering an additional therapeutic agent.
- 37. A method for treating a disorder caused by excessive apoptosis comprising:
administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-6, 22, 24, 26 or 28.
- 38. The method of claim 37, optionally comprising further administering an additional therapeutic agent.
- 39. The method of claim 35, wherein the disorder is any one of: stroke, traumatic, brain injury, spinal cord injury, meningitis, Alzheimers disease, Parkinson's disease, Huntington's disease, Kennedy's disease, prion disease, multiple sclerosis, spinal muscular atrophy, myocardial infarction, congestive heart failure and various other forms of acute and chronic heart disease, atherosclerosis, aging, burns, organ transplant rejection, graft versus host disease, hepatitis-B, -C, G, various forms of liver disease including acute alcoholic hepatitis, yellow fever, dengue fever, Japanese encephalitis, glomerulonephritis, renal disease. H. pylori-associated gastric and duodenal ulcer disease, HIV infection, tuberculosis, alopecia, diabetes, sepsis, Shigellosis, uveitis, inflammatory peritonitis, pancreatitis, erythematosus, scleroderma, chronic thyroiditis, Graves disease, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, HIV-related encephalitis, myasthenia gravis, small bowel inchemia in disease or post-surgers, psoriasis, atopic dermatitis, myelodysplatic syndrome, acute and chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, or Wiscott-Aldrich syndrome.
- 40. The method of claim 37, wherein the disorder is any one of: stroke, traumatic, brain injury, spinal cord injury, meningitis, Alzheimers disease, Parkinson's disease, Huntington's disease, Kennedy's disease, prion disease, multiple sclerosis, spinal muscular atrophy, myocardial infarction, congestive heart failure and various other forms of acute and chronic heart disease, atherosclerosis, aging, burns, organ transplant rejection, graft versus host disease, hepatitis-B, -C, G, various forms of liver disease including acute alcoholic hepatitis, yellow fever, dengue fever, Japanese encephalitis, glomerulonephritis, renal disease. H. pylori-associated gastric and duodenal ulcer disease, HIV infection, tuberculosis, alopecia, diabetes, sepsis, Shigellosis, uveitis, inflammatory peritonitis, pancreatitis, erythematosus, scleroderma, chronic thyroiditis, Graves disease, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, HIV-related encephalitis, myasthenia gravis, small bowel inchemia in disease or post-surgers, psoriasis, atopic dermatitis, myelodysplatic syndrome, acute and chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, or Wiscott-Aldrich syndrome.
- 41. A method for inhibiting an apoptotic caspase comprising:
contacting cells with an effective amount of any one of any one of the compounds of claims 1-6, 22, 24, 26 or 28.
- 42. A method for inhibiting caspase-3 or caspase-7 comprising:
contacting cells with an effective amount of any one of the compounds of claims 1-6, 22, 24, 26 or 28.
- 43. The method of claim 42, wherein the method of inhibiting comprises inhibiting caspase-3.
PRIORITY CLAIM
[0001] The present application claims priority under 35 U.S.C. §119 to U.S. Ser. No. 60/323,270, filed Sep. 18, 2001, and U.S. Ser. No. 60/371,762, filed Apr. 11, 2002, the entire contents of each of these applications are incorporated herein by reference.
Provisional Applications (2)
|
Number |
Date |
Country |
|
60323270 |
Sep 2001 |
US |
|
60371762 |
Apr 2002 |
US |