Compositions and methods for therapy and prevention of pathologies including cancer, AIDS and anemia

• US 5,635,532 A
• Filed: 10/12/1993
• Issued: 06/03/1997
• Est. Priority Date: 10/21/1991
• Status: Expired due to Term

• Current Assignee: The United States of America As Represented By The Secretary of Agriculture
• Original Assignee: United States Department Of Health And Human Services
• Inventors: Samid, Dvorit
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US08/135,661
• Time in Patent Office: 1,330 Days
• Field of Search: 514/538, 514/563, 514/567, 560/19
• US Class Current: 514/538
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/015 carbocyclic
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/20 having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Compositions and methods of treating anemia, cancer, AIDS, or severe β-chain hemoglobinopathies by administering a therapeutically effective amount of phenylacetate or pharmaceutically acceptable derivatives thereof or derivatives thereof alone or in combination or in conjunction with other therapeutic agents. Pharmacologically-acceptable salts alone or in combinations and methods of preventing AIDS and malignant conditions, and inducing cell differentiation are also aspects of this invention.

Claims

1. A method of treating a neoplastic condition in a subject comprising administering a therapeutic amount of a compound of the formula:

##STR3## wherein R₀ is phenyl, naphthyl, phenoxy, substituted phenyl, substituted naphthyl, or substituted phenoxy, wherein the substitution is, independently, from 1 to 4 moieties of

halogen;

hydroxy;

or

lower straight or branched chain alkyl;

R₁ and R₂ are, independently, H, hydroxy, lower alkoxy, lower straight and branched chain alkyl or halogen;

R₃ and R₄ are, independently, H, lower alkoxy, lower straight and branched chain alkyl or halogen; and

n is an integer from 0 to 2;

or a pharmaceutically-acceptable salt or a mixture thereof.

2. The method of claim 1, wherein the neoplastic condition is a neuroblastoma.

3. The method of claim 1, wherein the neoplastic condition is an acute promyelocytic leukemia.

4. The method of claim 1, wherein the neoplastic condition is an acute myelodisplasia.

5. The method of claim 1, wherein the neoplastic condition is an acute glioma.

6. The method of claim 1, wherein the neoplastic condition is prostate cancer.

7. The method of claim 1, wherein the neoplastic condition is breast cancer.

8. The method of claim 1, wherein the neoplastic condition is a melanoma.

9. The method of claim 1, wherein the neoplastic condition is non-small cell lung cancer.

10. The method of claim 1, wherein the compound is sodium phenylacetate.

11. The method of claim 1, wherein the compound is sodium phenylbutyrate.

12. The method of claim 1, wherein n is 0.

13. The method of claim 1, wherein n is 1.

14. The method of claim 1, wherein n is 2.

15. The method of claim 12, wherein R₀ is phenyl.

16. The method of claim 12, wherein R₀ is naphthyl.

17. The method of claim 12, wherein R₀ is substituted phenyl.

18. The method of claim 12, wherein R₀ is substituted naphthyl.

19. The method of claim 17, wherein the substitution on R₀ is from 1 to 4 halogen moieties.

20. The method of claim 19, wherein the compound is 4-chlorophenylacetic acid.

21. The method of claim 19, wherein the compound is 4-iodophenylacetic acid.

22. The method of claim 19, wherein the compound is 4-fluorophenylacetic acid.

23. The method of claim 19, wherein the compound is 3-chlorophenylacetic acid.

24. The method of claim 19, wherein the compound is 2-chlorophenylacetic acid.

25. The method of claim 19, wherein the compound is 2,6-dichlorophenylacetic acid.

26. The method of claim 16, wherein the compound is 1-naphthylacetic acid.

27. The method of claim 13, wherein the compound is phenoxypropionic acid.

28. The method of claim 14, wherein R₀ is phenyl.

29. The method of claim 14, wherein R₀ is substituted phenyl.

30. The method of claim 29, wherein the substitution on R₀ is from 1 to 4 halogen moieties.

31. The method of claim 30, wherein the compound is 4-chlorophenylbutyric acid.

32. The method of claim 30, wherein the compound is 4-iodophenylbutyric acid.

33. The method of claim 30, wherein the compound is 4-fluorophenylbutyric acid.

34. The method of claim 30, wherein the compound is 3-chlorophenylbutyric acid.

35. The method of claim 30, wherein the compound is 2-chlorophenylbutyric acid.

36. The method of claim 17, wherein the substitution on R₀ is a lower straight or branched chain alkyl of from 1 to 4 carbon atoms.

37. The method of claim 36, wherein the compound is 2-methylphenylacetic acid.

38. The method of claim 36, wherein the compound is 3-methylphenylacetic acid.

39. The method of claim 36, wherein the compound is 4-methylphenylacetic acid.

40. The method of claim 15, wherein R₁ is lower straight or branched chain alkyl of from 1 to 4 carbon atoms.

41. The method of claim 40, wherein the compound is α

-methylphenylacetic acid.

42. The method of claim 40, wherein the compound is α

-ethylphenylacetic acid.

43. The method of claim 15, wherein R₁ is hydroxy or lower alkoxy of from 1 to 2 carbon atoms.

44. The method of claim 43, wherein the compound is α

-hydroxyphenylacetic acid.

45. The method of claim 43, wherein the compound is α

-methoxyphenylacetic acid.

46. The method of claim 15, wherein the compound is phenylacetic acid.

47. The method of claim 28, wherein the compound is phenylbutyric acid.

48. The method of claim 16, wherein the compound is naphthylacetic acid.

49. The method of claim 1, wherein the pharmaceutically-acceptable salt is an alkali metal salt or alkaline earth metal salt.

50. The method of claim 1, wherein the pharmaceutically-acceptable salt is an alkali metal salt.

51. The method of claim 1, wherein the pharmaceutically-acceptable salt is the sodium salt.

52. The method of claim 1, wherein the neoplastic condition is neuroblastoma, myelodysplasia, non-small cell lung cancer, prostatic carcinoma, melanoma, glial brain tumor, Kaposi'"'"'s sarcoma or lymphoma, leukemia, lung adenocarcinoma, breast cancer, osteosarcoma, fibrosarcoma, or squamous cancer.

53. The method of claim 1, wherein the therapeutic amount is from 50 to 1,000 mg/kg/day.

54. The method of claim 1, wherein the therapeutic amount is from 300 to 500 mg/kg/day.

55. The method of claim 1, wherein the therapeutic amount is from 150 to 250 mg/kg/day.

56. The method of claim 1, wherein

R₀ is phenyl, naphthyl, phenoxy, substituted phenyl, substituted naphthyl, or substituted phenoxy, wherein the substitution is, independently, from 1 to 4 moieties of

halogen;

hydroxy;

or

lower straight or branched chain alkyl of from 1 to 4 carbon atoms;

R₁ and R₂ are, independently, H, hydroxy, lower alkoxy of from 1 to 2 carbon atoms, lower straight and branched chain alkyl of from 1 to 4 carbon atoms or halogen; and

R₃ and R₄ are, independently, H, lower alkoxy of from 1 to 2 carbon atoms, lower straight and branched chain alkyl of from 1 to 4 carbons or halogen.

57. The method of claim 1, wherein

n is 0;

R₀ is phenyl, naphthyl, substituted phenyl, or substituted naphthyl, wherein the substitution is, independently, from 1 to 4 moieties of halogen or hydroxy; and

R₁ and R₂ are, independently, H, lower alkoxy, or lower straight or branched chain alkyl.

58. The method of claim 57, wherein in R₁ and R₂, the lower straight or branched chain alkyl is independently methyl, ethyl or propyl.

59. The method of claim 1, wherein

n is 0 or 2;

R₀ is phenyl or substituted phenyl, wherein the substitution is, independently, from 1 to 4 moieties of halogen or hydroxy;

R₁ and R₂ are, independently, H, lower alkoxy, or lower straight or branched chain alkyl; and

R₃ and R₄ are H.

60. The method of claim 59, wherein in R₁ and R₂, the lower straight or branched chain alkyl is independently methyl, ethyl or propyl.