Claims
- 1. An inhibitor of histone deacetylase represented by formula (1):
- 2. The inhibitor of claim 1, wherein Cy is C6-C10 aryl or is a radical of a heterocyclic moiety selected from the group consisting of thiophene, benzothiophene, furan, benzofuran, pyridine, quinoline, indole, isoquinoline, thiazole, morpholine, piperidine, and piperazine, any of which groups may be optionally substituted.
- 3. The inhibitor of claim 2, wherein the aryl or heterocyclic moiety is substituted by one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C6-C10 aryl, heteroaryl, heterocyclyl, (C6-C10)ar(C1-C6)alkyl, halo, nitro, hydroxy, C1-C6 alkoxy, C6-C10 aryloxy, heteroaryloxy, C1-C6 alkoxycarbonyl, C6-C10 aryloxycarbonyl, heteroaryloxycarbonyl, carboxy, and amino.
- 4. The inhibitor of claim 1, wherein Cy has the formula —Cy1—Cy2 or —Cy1—G—Cy2, wherein Cy1 and Cy2 are independently C3-C6 cycloalkyl, C6-C10 aryl, or a radical of a heterocyclic moiety, which groups optionally may be substituted, and G is O, NR3, or S(O)n, where R3 is hydrogen, alkyl, aryl, aralkyl, sulfonyl, acyl, alkoxycarbonyl, or carbamoyl, and n is 0, 1, or 2.
- 5. The inhibitor of claim 4, wherein Cy1 and Cy2 are independently selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperidinyl, piperazinyl, which groups optionally may be substituted.
- 6. The inhibitor of claim 1, wherein X is selected from the group consisting of CH(OR1), C═N(OH), and C═N(OR1), where R1 is C1-C6 alkyl, C6-C10 aryl, or (C6-C10)ar(C1-C6)alkyl.
- 7. The inhibitor of claim 1, wherein one to about three carbon atoms of the alkylene are independently substituted with halo, oxo, oximino, nitro, haloalkyl, alkyl, aralkyl, alkoxy, aryloxy, alkoxycarbonyl, carboxy, hydroxyalkyl, acyl, acyloxy, or cyano.
- 8. The inhibitor of claim 1, wherein Y1 comprises an all-carbon linear chain connecting X and W.
- 9. The inhibitor of claim 8, wherein the linear chain connecting X and W comprises a dienyl moiety, wherein the dienyl moiety is attached to W.
- 10. The inhibitor of claim 9, wherein Y1 is selected from the group consisting of
- 11. The inhibitor of claim 8, wherein Y1 is —(CH2)m, where m is 5, 6, or 7.
- 12. The inhibitor of claim 1, wherein one carbon atom in the linear chain connecting X and W is replaced with O, NR3, or S(O)n.
- 13. The inhibitor of claim 12, wherein Y1 is —(CH2)—S(O)n—(CH2)p, where n is 0, 1, or 2, and p is 3, 4, or 5.
- 14. The inhibitor of claim 1, wherein W is —C(O)—NH—OM, M being selected from the group consisting of hydrogen, sodium, potassium, magnesium, and calcium.
- 15. The inhibitor of claim 1, wherein W is —C(O)—NH—Z or —NH—C(O)—NH—Z, Z being unsubstituted 2-anilinyl or unsubstituted 2-pyridyl.
- 16. The inhibitor of claim 1, wherein W is —C(O)—CH2—SR2, R2 being selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, (C6-C10)ar(C1-C6)alkyl, (C1-C6 alkyl)carbonyl, (C6-C10 aryl)carbonyl, and ((C6-C10)ar(C1-C6)alkyl)carbonyl, wherein the aryl portion of any such groups may be optionally substituted.
- 17. The inhibitor of claim 16, wherein R2 is selected from the group consisting of methyl, phenyl, benzyl, benzoyl, and acetyl.
- 18. An inhibitor of histone deacetylase represented by formula (2):
- 19. The inhibitor of claim 18, wherein Cy is C6-C10 aryl or is a radical of a heterocyclic moiety selected from the group consisting of thiophene, benzothiophene, furan, benzofuran, pyridine, quinoline, indole, isoquinoline, thiazole, morpholine, piperidine, piperazine, quinazolinone, benzotriazinone, phthalimide, and dioxobenzoisoquinoline, any of which groups may be optionally substituted.
- 20. The inhibitor of claim 18, wherein the aryl or heterocyclic moiety is substituted by one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C6-C10 aryl, heteroaryl, heterocyclyl, (C6-C10)ar(C1-C6)alkyl, halo, nitro, hydroxy, C1-C6 alkoxy, C6-C10 aryloxy, heteroaryloxy, C1-C6 alkoxycarbonyl, C6-C10 aryloxycarbonyl, heteroaryloxycarbonyl, carboxy, and amino.
- 21. The inhibitor of claim 20, wherein Cy has the formula —Cy1—Cy2 or —Cy1—G—Cy2, wherein Cy1 and Cy2 are independently C3-C6 cycloalkyl, C6-C10 aryl, or a radical of a heterocyclic moiety, which groups optionally may be substituted, and G is O, NR3, or S(O)n, where R3 is hydrogen, alkyl, aryl, aralkyl, sulfonyl, acyl, alkoxycarbonyl, or carbamoyl, and n is 0, 1, or 2.
- 22. The inhibitor of claim 21, wherein Cy1 and Cy2 are independently selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperidinyl, piperazinyl, which groups optionally may be substituted.
- 23. The inhibitor of claim 18, wherein one to about four carbon atoms of the alkylene are independently substituted with halo, oxo, oximino, nitro, haloalkyl, alkyl, aralkyl, alkoxy, aryloxy, alkoxycarbonyl, carboxy, hydroxyalkyl, acyl, acyloxy, or cyano.
- 24. The inhibitor of claim 18, wherein one carbon atom in the linear chain connecting Cy and W is replaced with O, NR3, or S(O)n.
- 25. The inhibitor of claim 19, wherein one carbon atom in the linear chain connecting Cy and W is replaced with NR3, where R3 is selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, (C6-C10)ar(C1-C6)alkyl, (C1-C6 alkyl)oxycarbonyl, (C6-C10 aryl)oxycarbonyl, ((C6-C10)ar(C1-C6)alkyl)oxycarbonyl, (C1-C6 alkyl)carbonyl, (C6-C10 aryl)carbonyl, and ((C6-C10)ar(C1-C6)alkyl)carbonyl.
- 26. The inhibitor of claim 18, wherein one or two carbon atoms in the linear chain connecting Cy and W are replaced by O.
- 27. The inhibitor of claim 18, wherein W is —C(O)—NH—Z or —NH—C(O)—NH—Z, Z being unsubstituted 2-anilinyl or unsubstituted 2-pyridyl.
- 28. The inhibitor of claim 18, wherein W is —C(O)—CH2—SR2, R2 being selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, (C6-C10)ar(C1-C6)alkyl, (C1-C6 alkyl)carbonyl, (C6-C10 aryl)carbonyl, and ((C6-C10)ar(C1-C6)alkyl)carbonyl, wherein the aryl portion of any such groups may be optionally substituted.
- 29. The inhibitor of claim 28, wherein R2 is selected from the group consisting of methyl, phenyl, benzyl, benzoyl, and acetyl.
- 30. An inhibitor of histone deacetylase represented by formula (3):
- 31. The inhibitor of claim 30, wherein Cy is C6-C10 aryl or is a radical of a heterocyclic moiety selected from the group consisting of thiophene, benzothiophene, furan, benzofuran, pyridine, quinoline, indole, isoquinoline, thiazole, morpholine, piperidine, and piperazine, any of which groups may be optionally substituted.
- 32. The inhibitor of claim 31, wherein the aryl or heterocyclic moiety is substituted by one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C6-C10 aryl, heteroaryl, heterocyclyl, (C6-C10)ar(C1-C6)alkyl, halo, nitro, hydroxy, C1-C6 alkoxy, C6-C10 aryloxy, heteroaryloxy, C1-C6 alkoxycarbonyl, C6-C10 aryloxycarbonyl, heteroaryloxycarbonyl, carboxy, and amino.
- 33. The inhibitor of claim 30, wherein Cy has the formula —Cy1—Cy2 or —Cy1—G—Cy2, wherein Cy1 and Cy2 are independently C3-C6 cycloalkyl, C6-C10 aryl, or a radical of a heterocyclic moiety, which groups optionally may be substituted, and G is O, NR3, or S(O)n, where R3 is hydrogen, alkyl, aryl, aralkyl, sulfonyl, acyl, alkoxycarbonyl, or carbamoyl, and n is 0, 1, or 2.
- 34. The inhibitor of claim 33, wherein Cy1 and Cy2 are independently selected from the group consisting of phenyl, pyridinyl, morpholinyl, piperidinyl, piperazinyl, which groups optionally may be substituted.
- 35. The inhibitor of claim 30, wherein Y3 is a C2-C6 alkylene optionally substituted with one or two non-hydrogen substituents independently selected from the group consisting of halo, hydroxy, oxo, nitro, (halo)1-5(C1-C3)alkyl, C1-C6 alkyl, (C6-C10)ar(C1-C6)alkyl, C1-C6 alkoxy, C6-C10 aryloxy, carboxy, hydroxy(C1-C6)alkyl, C1-C6 alkylcarbonyl, C6-C10 arylcarbonyl, C1-C6 alkylcarbonyloxy, C6-C10 arylcarbonyloxy, and cyano.
- 36. The inhibitor of claim 33, wherein Y3 is an optionally substituted saturated C4-C5 alkylene.
- 37. The inhibitor of claim 30, wherein W is —C(O)—NH—OM, M being selected from the group consisting of hydrogen, sodium, potassium, magnesium, and calcium.
- 38. The inhibitor of claim 30, wherein W is —C(O)—NH—Z or —NH—C(O)—NH—Z, Z being unsubstituted 2-anilinyl or unsubstituted 2-pyridyl.
- 39. The inhibitor of claim 30, wherein W is —C(O)—CH2—SR2, R2 being selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, (C6-C10)ar(C1-C6)alkyl, (C1-C6 alkyl)carbonyl, (C6-C10 aryl)carbonyl, and ((C6-C10)ar(C1-C6)alkyl)carbonyl, wherein the aryl portion of any such groups may be optionally substituted.
- 40. An inhibitor of histone deacetylase represented by one of formulae (4)-(5):
- 41. An inhibitor of histone deacetylase represented by one of formulae (6)-(7):
- 42. A pharmaceutical composition comprising an inhibitor of histone deacetylase represented by formula (1):
- 43. A pharmaceutical composition comprising an inhibitor of histone deacetylase represented by formula (2):
- 44. A pharmaceutical composition comprising an inhibitor of histone deacetylase represented by formula (3):
- 45. A pharmaceutical composition comprising an inhibitor of histone deacetylase represented by one of formulae (4)-(5):
- 46. A pharmaceutical composition comprising an inhibitor of histone deacetylase represented by one of formulae (6)-(7):
- 47. A method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase represented by formula (1):
- 48. A method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase represented by formula (2):
- 49. A method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase represented by formula (3):
- 50. A method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase represented by one of formulae (4)-(5):
- 51. A method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase represented by one of formulae (6)-(7):
- 52. The method of any one of claims 47-51, wherein cell proliferation is inhibited in the contacted cell.
- 53. The method of any one of claims 47-51, wherein the cell is a neoplastic cell.
- 54. The method of claim 53, wherein the neoplastic cell is in an animal.
- 55. The method of claim 54, wherein the neoplastic cell is in a neoplastic growth.
- 56. The method of any one of claims 47-51, further comprising contacting the cell with an antisense oligonucleotide that inhibits the expression of a histone deacetylase.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. Provisional Patent Application Ser. No. 60/192151, filed on Mar. 24, 2000.
Provisional Applications (1)
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Number |
Date |
Country |
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60192151 |
Mar 2000 |
US |