INHIBITORS OF HISTONE DEACETYLASE FOR THE TREATMENT OF DISEASE

• US 20070135438A1
• Filed: 12/08/2006
• Published: 06/14/2007
• Est. Priority Date: 12/09/2005
• Status: Abandoned Application

• Current Assignee: Kalypsys Inc
• Original Assignee: Kalypsys Inc
• Inventors: Smith, Nicholas, Payne, Joseph, Hassig, Christian, Scranton, Shawn
• Application Number:
  US11/608,736
• Publication Number:
  US 20070135438A1
• Time in Patent Office: Days
• US Class Current: 514/242
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 213/76 to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

Abstract

Disclosed herein are carbonyl compounds of having the structural formula: or a pharmaceutically acceptable salt, ester, or prodrug thereof, Methods and compositions are disclosed for treating disease states including, but not limited to cancers, autoimmune diseases, tissue damage, central nervous system disorders, neurodegenerative disorders, fibrosis, bone disorders, polyglutamine-repeat disorders, anemias, thalassemias, inflammatory conditions, cardiovascular conditions, and disorders in which angiogenesis play a role in pathogenesis, using the compounds of the invention. In addition, methods of modulating the activity of histone deacetylase (HDAC) are also disclosed.

Claims

1. A compound having structural Formula (I)

or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:

G₁ is optionally substituted 5 or 6 membered heteroaryl;

G₂ is an N-sulfonamide moiety having structure (II), an S-sulfonamide moiety having structure (III), or an amide of the form —

NR₃C(O)—

or —

C(O)NR₃—

;

G₃ is optionally substituted phenyl, optionally substituted 5 or 6 membered aryl, or optionally substituted 5 or 6 membered heteroaryl;

R₁ and R₂ are each independently selected from the group consisting of hydrogen, lower alkyl, halogen and perhaloalkyl, or R₁ and R₂ taken together may form an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

R₃ and R₄ are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, and optionally substituted aryl;

G₄ is selected from the group consisting of —

(X₁)_n1O(X₂)_n2—

, —

(X₁)_n1S(X₂)_n2— and

—

(X₁)_n1NR₇(X₂)_n2—

, wherein each may be optionally substituted with one or more R₉ moieties attached to any carbon atom, and each is drawn with its left end attached to G₃ and its right end attached to —

NR₅R₆;

R₅ and R₆ are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, optionally substituted cycloaklenyl, optionally substituted fused aryl, optionally substituted fused heteroaryl, optionally substituted fused heterocycloalkyl, and optionally substituted fused cycloalkyl;

R₇ is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted heteroalkyl, and optionally substituted lower alkoxy;

R₉ is selected from the group consisting of lower alkyl, lower alkylene, lower alkynylene, lower alkoxy, lower amine, halogen, lower perhaloalkyl, and hydroxyl;

X₁ and X₂ are each independently selected from the group consisting of optionally substituted lower alkylene, optionally substituted alkenylene, and optionally substituted alkynylene;

n1 is 0-5;

n2 is 1-5;

G₅ is selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted aryl, optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted alkylthio, optionally substituted arylthio and optionally substituted heteroarylthio or G₅ may have the structural Formula (IV);

thereby forming a homodisulfide or heterodisulfide dimer of a compound of the present invention, wherein;

R₁₁ and R₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, halogen and perhaloalkyl, or R₁₁ and R₁₂ taken together may form an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

R₁₃ and R₁₄ are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, optionally substituted cycloaklenyl, optionally substituted fused aryl, optionally substituted fused heteroaryl, optionally substituted fused heterocycloalkyl, and optionally substituted fused cycloalkyl;

G₆ is optionally substituted 5 or 6 membered heteroaryl;

G₇ is an N-sulfonamide moiety having structure (V), an S-sulfonamide moiety having structure (VI), or an amide of the form —

NR₁₅C(O)—

or —

C(O)NR₁₅—

;

R₁₅ and R₁₆ are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, and optionally substituted aryl;

G₈ is optionally substituted phenyl, optionally substituted 5 or 6 membered aryl, or optionally substituted 5 or 6 membered heteroaryl;

G₉ is selected from the group consisting of —

(X₃)_n3O(X₄)_n4—

, —

(X₃)_n3S(X₄)_n4— and

—

(X₃)_n3NR₂₀(X₄)_n4—

, wherein each may be optionally substituted with one or more R₂₁s attached to any carbon atom, and each group is drawn with its left end attached to G₈ and its right end attached to —

NR₁₃R₁₄;

X₃ and X are each independently selected from the group consisting of optionally substituted lower alkylene, optionally substituted alkenylene, and optionally substituted alkynylene;

n3 is 0-5;

n4 is 1-5;

R₂₀ is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted heteroalkyl, and optionally substituted lower alkoxy; and

R₂₁ is selected from the group consisting of lower alkyl, lower alkylene, lower alkynylene, lower alkoxy, lower amine, halogen, lower perhaloalkyl, and hydroxyl.

2. The compound as recited in claim 1 wherein G₄ is —

(X₁)_n1O(X₂)_n2— and

n1 is 0.

3. The compound as recited in claim 2 wherein G₂ is N-sulfonamide.

4. The compound as recited in claim 3 wherein G₅ is selected from the group consisting of optionally substituted acyl and hydrogen.

5. The compound as recited in claim 4 wherein G₁ is pyridinyl.

6. The compound as recited in claim 5 wherein G₃ is phenyl.

9. The compound as recited in claim 1 wherein G₄ is (X₁)_n1S(X₂)_n2—

and n1 is 0.

10. The compound as recited in claim 9 wherein:

G₁ is pyridinyl;

G₃ is phenyl; and

R₅ and R₆ are each independently selected from the group consisting of hydrogen and optionally substituted lower alkyl.

11. The compound as recited in claim 1 wherein G₄ is —

(X₁)_n1NR₇(X₂)_n2— and

n1 is 0.

12. The compound as recited in claim 11 wherein:

G₁ is pyridinyl;

G₃ is phenyl; and

R₅ and R₆ are each independently selected from the group consisting of hydrogen and optionally substituted lower alkyl.

17. The compound as recited in claim 1 wherein said compound is selected from the group consisting of Examples 1-4.

18. A pharmaceutical composition comprising a compound as recited in claim 1 together with at least one pharmaceutically acceptable carrier, diluent or excipient.

19. The compound as recited in claim 1 wherein the compound or pharmaceutically acceptable salt, ester or prodrug thereof inhibits the catalytic activity of histone deacetylase (HDAC).

20. A method of treatment of a HDAC-related disease in a patient in need thereof comprising the administration of the following in any order:

a) a therapeutically effective amount of a compound as recited in claim 1;

and

b) null or another chemotherapeutic agent.

21. The method as recited in claim 20 wherein said chemotherapeutic agent is one selected from the group consisting of aromatase inhibitors, antiestrogen, anti-androgen, or a gonadorelin agonists, topoisomerase 1 and 2 inhibitors, microtubule active agents, alkylating agents, antineoplastic antimetabolite, or platin containing compound, lipid or protein kinase targeting agents, protein or lipid phosphatase targeting agents, anti-angiogentic agents, agents that induce cell differentiation, bradykinin 1 receptor and angiotensin II antagonists, cyclooxygenase inhibitors, heparanase inhibitors, lymphokines or cytokine inhibitors, bisphosphanates, rapamycin derivatives, anti-apoptotic pathway inhibitors, apoptotic pathway agonists, PPAR agonists, inhibitors of Ras isoforms, telomerase inhibitors, protease inhibitors, metalloproteinase inhibitors, and aminopeptidase inhibitors.

22. The method as recited in claim 21 wherein said chemotherapeutic agent is useful for the treatment of multiple myeloma and is selected from the group consisting of alkylating agents, anthracyclines, corticosteroids, IMiDs, protease inhibitors, IGF-1 inhibitors, CD40 antibody, Smac mimetics, FGF3 modulator, mTOR inhibitor, HDAC inhibitors, IKK inhibitors, P38MAPK inhibitors, HSP90 inhibitor, and akt inhibitor.

23. The method as recited in claim 22 wherein said chemotherapeutic agent is selected from the group consisting of melphalan, doxorubicin, dexamethasone, prednisone, thalidomide, lenalidomide, bortezomib, and NPI0052.

24. The method as recited in either claim 20, wherein said disease is selected from the group consisting of a hyperproliferative condition, a neurological disorder, a cardiovascular condition, an autoimmune disease, a dermatologic disorder, and an ophthalmologic disorder.

25. The method as recited in claim 24 wherein said hyperproliferative condition is selected from the group consisting of hematologic and nonhematologic cancers.

26. The method as recited in claim 25 wherein said hematologic cancer is selected from the group consisting of multiple myeloma, leukemias, and lymphomas.

27. The method as recited in claim 26 wherein said hematologic cancer is multiple myeloma.

28. The method as recited in claim 26 wherein said lymophoma is selected from the group consisting of cutaneous t-cell lymphoma (CTCL) and mantle cell lymphoma (MCL).

29. A method of inhibition of HDAC comprising contacting HDAC with a compound as recited in claim 1.

30. The compound as recited in claim 1 for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the modulation of histone deacetylase (HDAC).

7. The compound as recited in claim 7 wherein R₅ and R₆ is lower alkyl.

8. The compound as recited in claim 8 wherein R₅ and R₆ is methyl.

13. A compound of structural Formula (VII)

or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:

W, Y and Z are each independently selected from the group consisting of N and CR₈, provided at least one of W, Y or Z is N;

P₈ and R₂₅ are each indepedently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted lower heteroalkyl, optionally substituted lower heterocycloalkyl, optionally substituted lower haloalkyl, optionally substituted lower haloalkenyl, optionally substituted lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, optionally substituted lower alkoxy, nitro, cyano, and NH₂;

X₂ is selected from the group consisting of optionally substituted lower alkylene, optionally substituted alkenylene, and optionally substituted alkynylene;

n2 is 1-5;

R₅ and R₆ are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, optionally substituted cycloaklenyl, optionally substituted fused aryl, optionally substituted fused heteroaryl, optionally substituted fused heterocycloalkyl, and optionally substituted fused cycloalkyl;

G₅ is selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted aryl, optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted alkylthio, optionally substituted arylthio and optionally substituted heteroarylthio or G₅ may have the structural Formula (IV);

thereby forming a homodisulfide or heterodisulfide dimer of a compound of the present invention, wherein;

R₁₁ and R₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, halogen and perhaloalkyl, or R₁₁ and R₁₂ taken together may form an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

R₁₃ and R₁₄ are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, optionally substituted cycloaklenyl, optionally substituted fused aryl, optionally substituted fused heteroaryl, optionally substituted fused heterocycloalkyl, and optionally substituted fused cycloalkyl;

G₆ is optionally substituted 5 or 6 membered heteroaryl;

G₇ is an N-sulfonamide moiety having structure (V), an S-sulfonamide moiety having structure (VI), or an amide of the form —

NR₁₅C(O)—

or —

C(O)NR₁₅—

;

R₁₅ and R₁₆ are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, and optionally substituted aryl;

G₈ is optionally substituted phenyl, optionally substituted 5 or 6 membered aryl, or optionally substituted 5 or 6 membered heteroaryl;

G₉ is selected from the group consisting of (X₃)_n3O(X₄)_n4—

, —

(X₃)_n3S(X₄)_n4— and

—

(X₃)_n3NR₂₀(X₄)_n4—

, wherein each may be optionally substituted with one or more R₂₁s attached to any carbon atom, and each group is drawn with its left end attached to G₈ and its right end attached to NR₁₃R₁₄;

X₃ and X₄ are each independently selected from the group consisting of optionally substituted lower alkylene, optionally substituted alkenylene, and optionally substituted alkynylene;

n3 is 0-5;

n4 is 1-5;

R₂₀ is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted heteroalkyl, and optionally substituted lower alkoxy; and

R₂₁ is selected from the group consisting of lower alkyl, lower alkylene, lower alkynylene, lower alkoxy, lower amine, halogen, lower perhaloalkyl, and hydroxyl.

14. The compound as recited in claim 13 wherein:

Y═

N;

Z=CR₈; and

G₅ is selected from the group consisting of hydrogen and optionally substituted acyl.

15. The compound as recited in claim 14 wherein:

R₅ and R₆ are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl; and

X₂ is optionally substituted lower alkylene.

16. The compound as recited in claim 15 wherein R₈ and R₂₅ are each indepedently selected from the group consisting of hydrogen, and lower alkyl.