Histone Deacetylase Inhibitor Prodrugs

• US 20090023786A1
• Filed: 04/05/2005
• Published: 01/22/2009
• Est. Priority Date: 04/05/2004
• Status: Active Grant

• Current Assignee: Merck HDAC Research LLC (Merck & Co., Inc.)
• Original Assignee: Altana Pharma AG (Takeda Pharmaceutical Company Limited)
• Inventors: Miller, Thomas A., Witter, David J., Belvedere, Sandro
• Granted Patent: US 8,227,636 B2
• Time in Patent Office: Days
• US Class Current: 514/356
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 259/06 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07D 213/80 in position 3
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 215/38 Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 215/40 attached in position 8
• CPC Class Codes: C07D 215/42 attached in position 4

Abstract

The present invention is directed to prodrugs of hydroxamic acid based histone deacetylase (HDAC) inhibitors, e.g., suberoylanilide hydroxamic acid (SAHA). The prodrugs are acylated derivatives having increased aqueous solubility and cellular permeability as compared with the free hydroxamic acid, and are useful for inhibiting HDACs, and for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the prodrugs of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The prodrugs of the invention are also useful in the prevention and treatment of thioredoxin (TRX)-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases.

Claims

1. A prodrug of a hydroxamic acid derivative histone deacetylase (HDAC) inhibitor, represented by the structure of formula 1:

wherein R is a residue of a hydroxamic acid derivative histone deacetylase inhibitor; and

R_a is represented by the structure;

wherein R_b and R_c are independently of each other a hydrogen or an unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclyl, alkylheteroaryl or an amino acid residue; and

R_d is hydrogen or an amino protecting group;

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or any combination thereof.

2. The prodrug according to claim 1, wherein R_b and R_c are independently of each other a hydrogen, methyl, ethyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, phenyl, benzyl, alkylphenyl, napththyl or pyridyl.

3. The prodrug according to claim 1, wherein R_a is selected from the group consisting of:

and wherein m is an integer of 1 to 10.

4. The prodrug according to claim 1, represented by the structure:

wherein each of R₁ and R₂ are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylcycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyloxy, aryloxy, or pyridine group, or R₁ and R₂ are bonded together to form a nitrogen containing heterocyclic ring optionally containing one or more additional heteroatoms, and n is an integer of 4 to 8.

5. The prodrug according to claim 1, represented by the structure:

wherein n is an integer of 4 to 8.

6. The prodrug according to claim 1, represented by the structure:

7. The prodrug according to claim 1, represented by the structure:

wherein n is an integer from about 4 to about 8.

8. The prodrug according to claim 1, represented by the structure:

9. The prodrug according to claim 1, represented by the structure:

10. The prodrug according to claim 1, represented by the structure:

wherein R₁ is a substituted or unsubstituted phenyl, piperidino, thiazolyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl and n is an integer of 4 to 8.

11. The prodrug according to claim 1, represented by the structure:

wherein R₁ is a substituted or unsubstituted phenyl, piperidino, thiazolyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl and n is an integer of 4 to 8.

12. The prodrug according to claim 1, represented by the structure:

wherein A is an amide moiety, R₁ and R₂ are each selected from substituted or unsubstituted aryl, arylalkyl, naphthyl, cycloalkyl, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amino, thiazoleamino, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; and

n is an integer of 3 to 10.

13. The prodrug according to claim 12, represented by the structure:

14. The prodrug according to claim 12, represented by the structure:

15. The prodrug according to claim 1, represented by the structure:

wherein A is an amide moiety, R₁ and R₂ are each selected from substituted or unsubstituted aryl, arylalkyl, naphthyl, cycloalkyl, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amino, thiazoleamino, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl;

R₃ is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer of 3 to 10.

16. The prodrug according to claim 15, represented by the structure:

17. The prodrug according to claim 15, represented by the structure:

wherein n is an integer from about 3 to 10.

18. The prodrug according to claim 1, represented by the structure:

wherein L is a linker selected from the group consisting of an amide moiety, O—

, —

S—

, —

NH—

, NR, —

CH₂—

, —

(CH₂)_p—

, —

(CH═

CH)—

, phenylene, cycloalkylene, or any combination thereof wherein R is a substituted or unsubstituted C₁-C₅ alkyl; and

wherein each of R₁ and R₂ are independently a substituted or unsubstituted aryl, arylalkyl, naphthyl, cycloalkyl, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amino, thiazoleamino, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl;

p is an integer of 0 to 10.

19. The prodrug according to claim 18, represented by the structure:

20. The prodrug according to claim 18, represented by the structure:

21. The prodrug according to claim 1, represented by the structure:

wherein

n is 2, 3, 4, 5, 6, 7 or 8;

q is 0 or 1;

p₁ and p₂ are independently of each other 0 or 1;

R₁ and R₂ are independently of each other an unsubstituted or substituted aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylaryl, alkylheteroaryl, alkylcycloalkyl or alkylheterocyclyl;

or when p₁ and p₂ are both 0, R₁ and R₂ together with the —

CH₂—

N—

CH₂—

group to which they are attached can also represent a nitrogen-containing heterocyclic ring;

or when at least one of p₁ and p₂ is not 0, R₁ or R₂ or both can also represent hydrogen or alkyl.

22. The prodrug according to claim 1, represented by the structure:

wherein

n is 2, 3, 4, 5, 6, 7 or 8;

R₁ and R₂ are independently of each other a hydrogen or an unsubstituted or substituted alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylaryl, alkylheteroaryl, alkylcycloalkyl or alkylheterocyclyl.

23. The prodrug according to claim 1, represented by the structure:

wherein

n is 2, 3, 4, 5, 6, 7 or 8;

R₁ and R₂ are independently of each other a hydrogen or an unsubstituted or substituted alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylaryl, alkylheteroaryl, alkylcycloalkyl or alkylheterocyclyl.

24. The prodrug according to claim 1, represented by the structure:

wherein

n is 2, 3, 4, 5, 6, 7 or 8;

R₁ and R₂ are independently of each other an unsubstituted or substituted aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylaryl, alkylheteroaryl, alkylcycloalkyl or alkylheterocyclyl;

or R₁ and R₂ together with the —

CH₂—

N—

CH₂—

group to which they are attached can also represent a nitrogen-containing heterocyclic ring.

25. The prodrug according to claim 1, represented by the structure:

wherein

n is 2, 3, 4, 5, 6, 7 or 8;

R₁ and R₂ are independently of each other an unsubstituted or substituted aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylaryl, alkylheteroaryl, alkylcycloalkyl or alkylheterocyclyl;

or R₁ and R₂ together with the —

CH₂—

N—

CH₂—

group to which they are attached can also represent a nitrogen-containing heterocyclic ring.

26. The prodrug according to claim 1, represented by the structure:

wherein A is alkyl, aryl or a group selected from

wherein R₁-R₁₆ are independently of each other a hydrogen or an unsubstituted or substituted alkyl, aryl, cycloalkyl, heterocyclyl, alkylaryl, alkylcycloalkyl or alkylheterocyclyl;

or one or more of R₁ and R₂, R₆ and R₇, and R₁₁ and R₁₂, together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocyclic ring; and

l, p and q are independently of each other 0, 1 or 2.

27. The prodrug according to claim 1, represented by the structure:

wherein

A is alkyl, aryl or a group selected from;

wherein R₁-R₁₆ are independently of each other a hydrogen or an unsubstituted or substituted alkyl, aryl, cycloalkyl, heterocyclyl, alkylaryl, alkylcycloalkyl or alkylheterocyclyl;

or one or more of R₁ and R₂, R₆ and R₇, and R₁ and R₁₂, together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocyclic ring;

B is

n is 0 or 1; and

l, p and q are independently of each other 0, 1 or 2.

28. A pharmaceutical composition comprising the prodrug of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

29. Use of the prodrug of claim 1 in the manufacture of a medicament for the treatment of cancer.

30. Use of the prodrug of claim 1 in the manufacture of a medicament for the treatment of a thioredoxin (TRX)-mediated disease.

31. Use of the prodrug of claim 1 in the manufacture of a medicament for the treatment of a disease of the central nervous system.

32. Use of the prodrug of claim 1 in the manufacture of a medicament for the treatment of a tumor characterized by proliferation of neoplastic cells.