Diamine and Iminodiacetic Acid Hydroxamic Acid Derivatives

• US 20090023718A1
• Filed: 11/23/2004
• Published: 01/22/2009
• Est. Priority Date: 11/26/2003
• Status: Abandoned Application

• Current Assignee: Merck HDAC Research LLC (Merck & Co., Inc.)
• Original Assignee: Aton Pharma, Inc. (Bausch Health Cos., Inc.)
• Inventors: Miller, Thomas A., Witter, David J., Belvedere, Sandro
• Application Number:
  US10/580,480
• Publication Number:
  US 20090023718A1
• Time in Patent Office: Days
• US Class Current: 514/231.800
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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 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
• 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 2601/14 The ring being saturated
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 211/16 with acylated ring nitrogen atom
• 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 217/06 with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 277/82 Nitrogen atoms
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07D 317/66 Nitrogen atoms not forming part of a nitro radical

Abstract

The present invention relates to a novel class of hydroxamic acid derivatives having a diamine or iminodiacetic acid backbone. The hydroxamic acid compounds can be used to treat cancer. The hydroxamic acid compounds can also inhibit histone deacetylase and are suitable for use in selectively including terminal differentiation, arresting cell growth and/or apoptosis of neo-plastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compound of the invention are also useful in the prevention and treatment of 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. The present invention further provides pharmaceutical compositions comprising the hydroxamic acid derivatives, and safe, dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of the hydroxamic acid derivatives in vivo.

Claims

1. A compound represented by the following structural formula:

wherein

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

m 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 or p₂ is not 0, R₁ or R₂ or both can also represent hydrogen or alkyl;

and pharmaceutically acceptable salts, solvates, hydrates, prodrugs and polymorphs thereof.

2. The compound of claim 1, wherein p₁ and p₂ are both 0.

3. The compound of to claim 1, wherein p₁ and p₂ are both 1.

4. The compound of claim 1, wherein m is 0.

5. The compound of claim 1, wherein m is 1.

10. The compound of claim 1, wherein n is 5.

11. The compound of claim 1, wherein n is 6.

12. The compound of claim 1, wherein at least one of R₁ and R₂ is an unsubstituted or substituted phenyl, benzyl, alkylphenyl, naphthyl, biphenyl, —

CH(Ph)₂, —

CH═

CHPh, cyclohexyl, alkylcyclohexyl, quinolinyl, alkylquinolinyl, isoquinolinyl, alkylisoquinolinyl, tetrahydroquinolinyl, alkyltetrahydroquinolinyl, tetrahydroisoquinolinyl, alkyltetrahydroisoquinolinyl, indazolyl, alkylindazolyl, benzothiazolyl, alkylbenzothiazolyl, indolyl, alkylindolyl, piperazinyl, alkyklpiperazinyl, morpholinyl, alkylmorpholinyl, piperidinyl, alkylpiperidinyl, pyridyl or alkylpyridyl.

21. A composition comprising a pharmaceutically effective amount of the compound of claim 1.

22. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of claim 1, and a pharmaceutically acceptable carrier.

25. A method of treating cancer in a subject in need of treatment comprising administering to said subject a therapeutically effective amount the compound of claim 1, wherein said amount is effective to treat cancer in said subject.

26. The method of claim 25, wherein the cancer is selected from the group consisting of acute leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), Hairy Cell Leukemia, cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotrophic virus (HTLV), adult T-cell leukemia/lymphoma (ATLL), Hodgkin'"'"'s disease, non-Hodgkin'"'"'s lymphoma, large-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt'"'"'s lymphoma, primary central nervous system (CNS) lymphoma, multiple myeloma, childhood solid tumors, brain tumor, neuroblastoma, retinoblastoma, Wilm'"'"'s tumor, bone tumor, soft-tissue sarcoma, head and neck cancers, oral cancer, laryngeal cancer, esophageal cancer, genito urinary cancers, prostate cancer, bladder cancer, renal cancer, uterine cancer, ovarian cancer, testicular cancer, rectal cancer, colon cancer, lung cancer, breast cancer, pancreatic cancer, melanoma, skin cancers, stomach cancer, brain tumors, liver cancer, and thyroid cancer.

34. A method of treating a patient having a tumor characterized by proliferation of neoplastic cells, comprising the step of administering to the patient the compound of claim 1, in an amount effective to selectively induce terminal differentiation, induce cell growth arrest and/or induce apoptosis of such neoplastic cells and thereby inhibit their proliferation.

35. The method of claim 25, wherein said administering comprises administering a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier.

6. A compound represented by the following structural formula:

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;

and pharmaceutically acceptable salts, solvates, hydrates, prodrugs and polymorphs thereof.

13. The compound of claim 6 or 7, wherein at least one of R₁ and R₂ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl sec-butyl or tert-butyl.

7. A compound represented by the following structural formula:

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;

and pharmaceutically acceptable salts, solvates, hydrates, prodrugs and polymorphs thereof.

8. A compound represented by the following structural formula:

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;

and pharmaceutically acceptable salts, solvates, hydrates, prodrugs and polymorphs thereof.

14. The compound of claim 8 or 9, wherein R₁ and R₂ together with the —

CH₂—

N—

CH₂—

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

9. A compound represented by the following structural formula:

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;

and pharmaceutically acceptable salts, solvates, hydrates, prodrugs and polymorphs thereof.

15-20. -20. (canceled)

23-24. -24. (canceled)

27-33. -33. (canceled)

36-46. -46. (canceled)