Compounds and methods for treating mitochondria-associated diseases

• US 6,268,398 B1
• Filed: 04/23/1999
• Issued: 07/31/2001
• Est. Priority Date: 04/24/1998
• Status: Expired due to Fees

• Current Assignee: Mitokor
• Original Assignee: Mitokor
• Inventors: Ghosh, Soumitra, Davis, Robert E.
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US09/299,044
• Time in Patent Office: 830 Days
• Field of Search: 514/646, 514/634, 514/635
• US Class Current: 514/634
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 39/02 Antidotes
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Compounds, compositions and methods are disclosed for treating mitochondria-associated diseases, such as cancer, psoriasis, stroke, Alzheimer'"'"'s Disease and diabetes. The compounds of this invention have structure (I) below, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein Ar and L are as defined herein. The methods of this invention are directed to treating a mitochondria-associated disease by administering to a warm-blooded animal in need thereof an effective amount of a compound of structure (I), typically in the form of a pharmaceutical composition.

Claims

1. A method for treating a mitochondria-associated disease by administering to a warm-blooded animal in need thereof an effective amount of a compound having the following structure:

including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof,

wherein;

Ar is phenyl or naphthyl optionally substituted with 1 to 5 R₂ groups;

L is an optional linker moiety selected from —

(CH₂)_n—

, —

(CH₂)_nNH—

, —

(CH₂)_nN(C_1-4alkyl)—

, —

NHC(═

NH)— and

—

(CH₂)_nO(CH₂)_n—

, wherein n is 1-4 and each linker moiety is optionally substituted with 1 to 5 R₃ groups;

R₂ is hydroxy, C_1-2alkyl, C_1-2alkyloxy, halo, —

NH2, —

NHR, —

NRR, cyano, nitro, —

SR, —

COOH, C_7-12,aralkyl or heterocycle;

or C_1-12alkyl, C_1-12alkyloxy, —

NH₂, —

NHR, —

NRR, —

SR, C_7-12aralkyl or heterocycle substituted with 1 to 5 R₃ groups;

R₃ is hydroxy, halo, C_1-4alkyl, —

OR, —

NH₂, —

NHR or —

NRR; and

each occurrence of R is independently selected from C_1-4alkyl.

2. The method of claim 1 wherein Ar is phenyl optionally substituted with 1 to 5 R₂ groups.

3. The method of claim 2 wherein Ar is phenyl, 3,5-di-t-butyl-4-hydroxyphenyl, 2-methoxy-4-carboxylphenyl, 2-chloro-4-carboxyl-5-methoxyphenyl, 3,5-di-tetrafluoromethylphenyl, 3 5-difluorophenyl, 3,4,5-trimethoxyphenyl, 4-n-hexoxyphenyl, 4-fluorophenyl, 3-trifluorophenyl, 2-carbinolphenyl, 2-chloro-5-methylphenyl, 3-carboxylphenyl, 3-carboxyl-4-hydroxyphenyl, 2-methyl-4-carboxylphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 4-(N-morphinol)phenyl, 3,4-dihydroxyphenyl, 2,4-dimethylphenyl, 2-methyl-4-hydroxyphenyl, 4-n-octylphenyl, 2-hydroxy-5-n-octylphenyl, 4-chlorophenyl, or 2-methyl-4-chlorophenyl.

4. The method of claim 1 wherein Ar is naphthyl optionally substituted with 1 to 5 R₂ groups.

5. The method of claim 4 wherein Ar is naphthyl or 4-bromonaphthyl.

6. The method of claim 1 wherein the L is not present.

7. The method of claim 1 wherein L is present.

8. The method of claim 7 wherein L is —

CH₂NH—

, —

CH₂CH₂, —

CH(OH)CH₂—

, —

CH₂N(CH₃)—

or —

NHC(═

NH)—

.

9. The method of claim 1 wherein the compound is administered in the form of a pharmaceutical composition.

10. The method of claim 1 wherein the mitochondria-associated disease is a disease in which free radical mediated oxidative injury leads to tissue degeneration.

11. The method of claim 1 wherein the mitochondria-associated disease is a disease in which cells inappropriately undergo apoptosis.

12. The method of claim 1 wherein the mitochondria-associated disease is a disease in which cells fail to undergo apoptosis.

13. The method of claim 12 wherein the mitochondria-associated disease is cancer.

14. The method of claim 1 wherein the mitochondria-associated disease is stroke.

15. The method of claim 1 wherein the mitochondria-associated disease is Alzheimer'"'"'s Disease.

16. The method of claim 1 wherein the mitochondria-associated disease is diabetes.

17. The method of claim 1 wherein the mitochondria-associated disease is auto-immune disease.

18. The method of claim 1 wherein the mitochondria-associated disease is psoriasis.

19. The method of claim 1 wherein the mitochondria-associated disease is Alzheimer'"'"'s Disease.

20. The method of claim 1 wherein the mitochondria-associated disease is Parkinson'"'"'s Disease.

21. The method of claim 1 wherein the mitochondria-associated disease is Huntington'"'"'s Disease.

22. The method of claim 1 wherein the mitochondria-associated disease is auto-immune disease.

23. The method of claim 1 wherein the mitochondria-associated disease is Type I or Type II diabetes mellitus.

24. The method of claim 1 wherein the mitochondria-associated disease is congenital muscular dystrophy.

25. The method of claim 1 wherein the mitochondria-associated disease is fatal infantile myopathy or later-onset myopathy.

26. The method of claim 1 wherein the mitochondria-associated disease is MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke).

27. The method of claim 1 wherein the mitochondria-associated disease is MIDD (Mitochondrial Diabetes and Deafness).

28. The method of claim 1 wherein the mitochondria-associated disease is MERFF (Moclonic Epilepsy ragged Red Fiber Syndrome).

29. The method of claim 1 wherein the mitochondria-associated disease is arthritis.

30. The method of claim 1 wherein the mitochondria-associated disease is NARP (Neuropathy, Ataxia, Retinitis Pigmentosa).

31. The method of claim 1 wherein the mitochondria-associated disease is MNGIE (Myopathy and external ophthalmoplegia, Neuropathy, Gastro-Intestinal, Encephalopathy).

32. The method of claim 1 wherein the mitochondria-associated disease is LHON (Leber'"'"'s, Hereditary, Optic, Neuropathy).

33. The method of claim 1 wherein the mitochondria-associated disease is Kearns-Sayre disease.

34. The method of claim 1 wherein the mitochondria-associated disease is Pearson'"'"'s Syndrome.

35. The method of claim 1 wherein the mitochondria-associated disease is PEO (Progressive External Ophthalmoplegia).

36. The method of claim 1 wherein the mitochondria-associated disease is Wolfram syndrome.

37. The method of claim 1 wherein the mitochondria-associated disease is DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness).

38. The method of claim 1 wherein the mitochondria-associated disease is Leigh'"'"'s Syndrome.

39. The method of claim 1 wherein the mitochondria-associated disease is dystonia.

40. The method of claim 1 wherein the mitochondria-associated disease is schizophrenia.