3,5-disubstituted-[1,2,4]-oxadiazoles and analogs as activators of caspases and inducers of apoptosis and the use thereof

• US 7,317,029 B2
• Filed: 11/06/2006
• Issued: 01/08/2008
• Est. Priority Date: 12/18/2002
• Status: Expired due to Fees

• Current Assignee: Cytovia Incorporated (Immune Pharmaceuticals Inc.)
• Original Assignee: Cytovia Incorporated (Immune Pharmaceuticals Inc.)
• Inventors: Kuemmerle, Jared D., Zhang, Hong, Cai, Sui Xiong, Zhang, Han-Zhong, Kemnitzer, William E.
• Primary Examiner(s): Anderson; Rebecca
• Assistant Examiner(s): CHUNG, SUSANNAH LEE
• Application Number:
  US11/593,030
• Publication Number:
  US 20070112003A1
• Time in Patent Office: 428 Days
• Field of Search: 514/364, 548/131
• US Class Current: 514/364
• CPC Class Codes: A61K 31/4245 Oxadiazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators

Abstract

Disclosed are 3,5-disubstituted-[1,2,4]-oxadiazoles and analogs thereof, represented by the Formula I:

wherein Ar₁, R₂, A, B and D are defined herein. The present invention relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention may be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

Claims

1. A method of treating cancer, wherein the cancer is selected from the group consisting of breast carcinoma, ovarian carcinoma, and lung carcinoma in a human suffering therefrom, comprising administering to a human in need of such treatment an effective amount of a compound having the Formula IV:

2. The method of claim 1, wherein Q is O or S.

3. The method of claim 1, wherein R₃ is not hydrogen.

4. The method of claim 1, wherein ring A is optionally substituted morpholinyl, piperazinyl, piperidinyl or cyclohexyl.

5. The method of claim 1, wherein said compound is selected from the group consisting of:

5-(3-Chlorothiophen-2-yl)-3-(1-piperidinyl)-[1,2,4]-oxadiazole; and

5-(3-Chlorothiophen-2-yl)-3-(4-morpholinyl)-[1,2,4]-oxadiazole,

or a pharmaceutically acceptable salt or prodrug thereof.

7. The method of claim 1 or 6, wherein said cancer is drug resistant cancer.

8. The method of claim 1 or 6, further comprising administering at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent.

9. The method according to claim 1 or 6, wherein said compound is administered together with at least one compound selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2′

-deoxy-uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, arsenic trioxide, gamcitabine, doxazosin, terazosin, tamsulosin, CB-64D, CB-184, haloperidol, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, amprenavir, abacavir, CGP-73547, CGP-61755, DMP-450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, BMS-232,632, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α

-difluoromethylornithine, ILX23-7553, fenretinide, N-4-carboxyphenyl retinamide, lactacystin, MG-132, PS-341, imatinib mesilate ZD1839 (Iressa), SH268, genistein, CEP2563, SU6668, SU11248, EMD121974, R115777, SCH66336, L-778,123, BAL9611, TAN-1813, flavopiridol, UCN-01, roscovitine, olomoucine, celecoxib, valecoxib, rofecoxib and alanosine.

10. The method of claim 1 or 6, further comprising treating said human with radiation-therapy.

11. The method of claim 1 or 6, wherein said compound is administered after surgical treatment of said human for said cancer.

12. The method of claim 1 or 6, wherein said cancer is breast carcinoma.

6. A method of treating cancer, wherein the cancer is selected from the group consisting of breast carcinoma, ovarian carcinoma, and lung carcinoma in a human suffering therefrom, comprising administering to a human in need of such treatment an effective amount of a compound selected from the group consisting of:

3-(3-Amino-4-chloro-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]-oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(3-dimethylamino-4-chloro-phenyl)-[1,2,4]-oxadiazole;

3-(3-Amino-4-chloro-phenyl)-5-(3-bromofuran-2-yl)-[1,2,4]-oxadiazole;

5-(3-Bromofuran-2-yl)-3-(3-dimethylamino-4-chloro-phenyl)-[1,2,4]-oxadiazole;

N-{2-Chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]-oxadiazol-3-yl]-phenyl}-2-(4-methyl-piperazin-1-yl)-acetamide;

N-{2-Chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]-oxadiazol-3-yl]-phenyl}-succinamic acid ethyl ester;

5-(3-Chlorothiophen-2-yl)-3-(4-chloro-3-cyano-phenyl)-[1,2,4]-oxadiazole;

3-(4-Chloro-benzyloxy)-5-(3-chlorothiophen-2-yl)-[1,2,4]-oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(4-chloro-3-fluoro-phenyl)-[1,2,4]-oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(4-chloro-3-nitro-phenyl)-[1,2,4]-oxadiazole;

3-(5-Chloro-pyridin-2-yl)-5-(3-methoxy-thiophen-2-yl)-[1,2,4]-oxadiazole;

3-(5-Chloro-pyridin-2-yl)-5-(3-methyl-3H-imidazol-4-yl)-[1,2,4]-oxadiazole;

3-[2-(4-Chloro-phenyl)-vinyl]-5-(3-chlorothiophen-2-yl)-[1,2,4]-oxadiazole;

5-(3-Chloro-1H-pyrrol-2-yl)-3-(5-chloro-pyridin-2-yl)-[1,2,4]-oxadiazole;

3-(4-Chloro-phenyl)-5-(3-chloro-1H-pyrrol-2-yl)-[1,2,4]-oxadiazole;

5-(3-Chloro-1-methyl-1H-pyrrol-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole; and

5-[3-Chloro-1-(2-dimethylaminoethyl)-1H-pyrrol-2-yl]-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(morpholin-4-yl)-[1,2,4]oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(pyrrolidin-1-yl)-[1,2,4]oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(4-methylpiperidin-1-yl)-[1,2,4]oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(2-methylpiperidin-1-yl)-[1,2,4]oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(4-trifluoromethylpiperidin-1-yl)-[1,2,4]oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(4-methylpiperazin-1-yl)-[1,2,4]oxadiazole;

4-[5-(3-Chlorothiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-piperazine-1-carboxylic acid benzyl ester;

4-[5-(3-Chlorothiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-piperazine-1-carboxylic acid tert-butyl ester;

{1-[5-(3-Chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidin-4-yl}-carbamic acid tert butyl ester;

{1-[5-(3-Chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidin-4-yl}-acetic acid ethyl ester;

{1-[5-(3-Chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidin-3-yl}-acetic acid ethyl ester;

5-(3-Chlorothiophen-2-yl)-2-(piperidine-1-yl)-[1,3,4]oxadiazole;

5-(3-Chlorothiophen-2-yl)-2-(morpholin-4-yl)-[1,3,4]oxadiazole;

5-(3-Chlorothiophen-2-yl)-2-(4-methylpiperazin-1-yl)-[1,3,4]oxadiazole;

4-[5-(3-Bromofuran-2-yl)-[1,2,4]oxadiazol-3-yl]-piperazine-1-carboxylic acid benzyl ester;

4-[5-(3-Bromofuran-2-yl)-[1,2,4]oxadiazol-3-yl]-piperazine-1-carboxylic acid tert-butyl ester;

5-(3-Chlorothiophen-2-yl)-2-(piperazin-1-yl)-[1,3,4]oxadiazole trifluoroacetic acid salt;

5-(3-Bromofuran-2-yl)-2-(piperazin-1-yl)-[1,3,4]oxadiazole trifluoroacetic acid salt;

5-(3-Chlorothiophen-2-yl)-3-(4-aminopiperidin-1-yl)-[1,2,4]oxadiazole trifluoroacetic acid salt;

5-(3-Chlorothiophen-2-yl)-3-(thiophen-2-yl)-[1,2,4]oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(1H-pyrrol-2-yl)-[1,2,4]oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(furan-2-yl)-[1,2,4]oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(furan-3-yl)-[1,2,4]oxadiazole;

3-(4-Chloro-2-methyl-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(5-methylfuran-2-yl)-[1,2,4]oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(5-nitrofuran-2-yl)-[1,2,4]oxadiazole;

3-(4-Chloro-2-fluoro-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazole;

5-(3-Chlorothiophen-2-yl)-3-(3-methyl-pyridin-2-yl)-[1,2,4]oxadiazole;

3-(4-Chloro-3-methyl-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazole;

5-(3-Bromofuran-2-yl)-3-(4-chloro-2-methyl-phenyl)-[1,2,4]oxadiazole;

5-(3-Bromofuran-2-yl)-3-(5-chloro-3-methyl-pyridin-2-yl)-[1,2,4]oxadiazole;

{2-Chloro-5-[5-(3-chlorothiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-phenylamino}-acetic acid ethyl ester;

N′

-{2-Chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-N,N-diethyl-ethane-1,2-diamine;

{2-Chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-(2-morpholin-4-yl-ethyl)-amine;

({2-Chloro-5-[5-(3-chlorothiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methylamino)-acetic acid ethyl ester;

({2-Chloro-5-[5-(3-chlorothiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methylamino)-acetic acid;

({2-Chloro-5-[5-(3-chlorothiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methylamino)-acetic acid N-hydroxysuccinimidyl ester;

5-(3-Bromofuran-2-yl)-3-(3-methyl-pyridin-2-yl)-[1,2,4]oxadiazole;

4-({2-Chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methyl-amino)-butyric acid methyl ester;

4-({2-Chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methyl-amino)-butyric acid;

4-({2-Chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methyl-amino)-butyric acid N-hydroxysuccinimidyl ester;

4-({2-Chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methyl-amino)-1-(4-methyl-piperazin-1-yl)-butan-1-one;

N-Butyl-4({2-Chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methyl-amino)-butyramide;

4-({2-Chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methyl-amino)-butyric acid octyl ester;

{2-Chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl-amine;

N-{2-Chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetamide;

3-(3-Bromomethyl-4-chloro-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazole;

3-(2-Bromomethyl-4-chloro-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazole;

3-(4-Chloro-3-pyrrolidin-1-ylmethyl-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazole;

3-(4-Chloro-3-dimethylaminomethyl-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazole;

3-(4-Chloro-2-pyrrolidin-1-ylmethyl-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazole; and

3-(4-Chloro-2-dimethylaminomethyl-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazole;

or a pharmaceutically acceptable salt or prodrug thereof.