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

• US 7,041,685 B2
• Filed: 06/10/2002
• Issued: 05/09/2006
• Est. Priority Date: 06/08/2001
• Status: Expired due to Fees

• Current Assignee: Cytovia Incorporated (Immune Pharmaceuticals Inc.)
• Original Assignee: Cytovia Incorporated (Immune Pharmaceuticals Inc.)
• Inventors: Cai, Sui Xiong, Kasibhatla, Shailaja, Drewe, John A., Zhang, Han-Zhong, Reddy, P. Sanjeeva, Kuemmerle, Jared Daniel, Ollis, Kristin P.
• Primary Examiner(s): Shameem, Golam M M
• Application Number:
  US10/164,705
• Publication Number:
  US 20030045546A1
• Time in Patent Office: 1,429 Days
• Field of Search: 548/131, 546/269.4, 546/135, 546/139, 514/340, 514/364, 544/242, 544/138, 544/336
• US Class Current: 514/340
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/38 having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention is directed to substituted 3-aryl-5-aryl-[1,2,4]-oxadiazoles and analogs thereof, represented by the Formula I:
wherein Ar₁, Ar₃, A, B and D are defined herein. The present invention also 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 compound having the Formula II

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

Ar₁ is substituted aryl or substituted heteroaryl, wherein said substituents are selected from the group consisting of halo, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₄-C₇ cycloalkyl, C₂-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl(C₁-C₆)alkyl, C₆-C₁₀ aryl(C₂-C₆)alkenyl, C₆-C₁₀ aryl(C₂-C₆)alkynyl, C₁-C₆ hydroxyalkyl, amino, ureido, cyano, C₁-C₆ acylamino, hydroxy, thiol, C₁-C₆ acyloxy, azido, C₁-C₆ alkoxy and carboxy;

Ar₃ is optionally substituted arylalkyl, aryloxy, phenoxymethyl, anilino, benzylamino, benzylideneamino, benzoylamino or Ar₂, wherein Ar₂ is optionally substituted aryl or optionally substituted heteroaryl, wherein said substituents are selected from the group consisting of halo, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₄-C₇ cycloalkyl, C₂-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl(C₁-C₆)alkyl, C₆-C₁₀ aryl(C₂-C₆)alkenyl, C₆-C₁₀ aryl(C₂-C₆)alkynyl, C₁-C₆ hydroxyalkyl, amino, ureido, cyano, C₁-C₆ acylamino, hydroxy, thiol, C₁-C₆ acyloxy, azido, C₁-C₆ alkoxy and carboxy;

with the provisos that;

(a) when Ar₁ is substituted thienyl, then Ar₃ is other than phenyl substituted by chloro or trifluoromethyl;

(b) when Ar₁ is substituted isoxazolyl, then Ar₃ is other than unsubstituted phenyl;

(c) when Ar₁ is substituted pyrazolyl, then Ar₃ is other than pyridinyl substituted by trifluoromethyl and other than phenyl substituted by trifluoromethyl; and

(d) when Ar₁ is substituted pyrrolyl, then Ar₃ is other than unsubstituted pyridinyl.

2. The compound of claim 1, wherein Ar₃ is optionally substituted phenyl.

3. The compound of claim 2, having the Formula III:

or a pharmaceutically acceptable salt or prodrug thereof, wherein;

R₁-R₈ are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteoraryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, amino, cyano, acylamino, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol, each of which is optionally substituted; and

Q is S, O or NR₉, wherein R₉ is hydrogen, Optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl;

wherein R₃ is not a hydrogen.

4. The compound of claim 3, wherein Q is S or O.

5. The compound of claim 3, wherein said compound is selected from the group consisting of:

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

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

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

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

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

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

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

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

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

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

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

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

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

5-(3-Bromo-furan-2-yl)-3-(4-trifluoromethyl-phenyl)-[1,2,4]-oxadiazole;

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

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

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

5-(3-Bromo-5-formyl-furan-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole;

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

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

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

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

5-(3-Bromo-5-morpholinomethyl-furan-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole;

5-(3-Bromo-5-hydroxymethyl-furan-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole;

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

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

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

4-(2-{4-[5-(3-Chloro-thiophen-2-yl)-[1,2,4]-oxadiazol-3-yl]-phenoxy}-ethyl)-morpholine;

(2-{4-[5-(3-Chloro-thiophen-2-yl)-[1,2,4]-oxadiazol-3-yl]-phenoxy}-ethyl)-dimethyl-amine;

{4-[5-(3-Chloro-thiophen-2-yl)-[1,2,4]-oxadiazol-3-yl]-phenoxy}-acetic acid methyl ester;

3-(4-Butoxy-phenyl)-5-(3-chloro-thiophen-2-yl)-[1,2,4]-oxadiazole; and

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

or a pharmaceutically acceptable salt or prodrug thereof.

6. The compound of claim 2, wherein said compound is:

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

or a pharmaceutically acceptable salt or prodrug thereof.

7. The compound of claim 1, wherein Ar₃ is optionally substituted pyridinyl.

8. The compound of claim 7, wherein said compound is selected from the group consisting of:

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

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

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

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

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

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

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

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

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

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

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

5-(3-Chloro-thiophen-2-yl)-3-(6-chloro-pyridin-3-yl)-[1,2,4]-oxadiazole;

5-(3-Chloro-thiophen-2-yl)-3-(6-trifluoromethyl-pyridin-3-yl)-[1,2,4]-oxadiazole;

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

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

5-(3-Chloro-thiophen-2-yl)-3-(5,6-dichloro-pyridin-3-yl)-[1,2,4]-oxadiazole;

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

5-(3-Bromo-furan-2-yl)-3-(6-trifluoromethyl-pyridin-3-yl)-[1,2,4]-oxadiazole;

5-(3-Bromo-furan-2-yl)-3-(5-trifluoromethyl-pyridin-2-yl)-[1,2,4]-oxadiazole;

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

5-(3-Bromo-furan-2-yl)-3-(5-trifluoromethyl-pyridin-2-yl)-[1,2,4]-oxadiazole; and

5-(3-Chloro-thiophen-2-yl)-3-(6-methoxy-pyridin-3-yl)-[1,2,4]-oxadiazole;

or a pharmaceutically acceptable salt or prodrug thereof.

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

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

(4-Chloro-benzylidene)-[5-(3-chloro-thiophen-2-yl)-[1,2,4]-oxadiazol-3-yl]-amine;

[5-(3-Chloro-thiophen-2-yl)-[1,2,4]-oxadiazol-3-yl]-(3-trifluoromethyl-benzylidene)-amine;

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

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

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

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

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

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

5-(3-Chloro-thiophen-2-yl)-3-(8-hydroxy-quinolin-2-yl)-[1,2,4]-oxadiazole;

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

5-(3-Chloro-thiophen-2-yl)-3-(7-methyl-5-trifluoromethyl-pyrazolo[1,5-α

]pyrimidin-3-yl)-[1,2,4]-oxadiazole;

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

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

4-Chloro-N-[5-(3-chloro-thiophen-2-yl)-[1,2,4]-oxadiazol-3-yl]-benzamide;

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

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

or a pharmaceutically acceptable salt or prodrug thereof.

10. A compound having the Formula II:

or a pharmaceutically acceptable salt or prodrug thereof, wherein;

Ar₁ is substituted heteroaryl, wherein said substituents are selected from the group consisting of halo, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₄-C₇ cycloalkyl, C₂-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl(C₁-C₆)alkyl, C₆-C₁₀ aryl(C₂-C₆)alkenyl, C₆-C₁₀ aryl(C₂-C₆)alkynyl, C₁-C₆ hydroxyalkyl, amino, ureido, cyano, C₁-C₆ acylamino, hydroxy, thiol, C₁-C₆ acyloxy, azido, C₁-C₆ alkoxy and carboxy; and

Ar₃ is optionally substituted heteroaryl, wherein said substituents are selected from the group consisting of halo, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₄-C₇cycloalkyl, C₂-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl(C₁-C₆)alkyl, C₆-C₁₀ aryl(C₂-C₆)alkenyl, C₆-C₁₀ aryl(C₂-C₆ )alkynl, C₁-C₆ hydroxyalkyl, amino, ureido, cyano, C₁-C₆ acylamino, hydroxy, thiol, C₁-C₆ acyloxy, azido, C₁-C₆ alkoxy and carboxy;

with the provisos that;

(a) when Ar₁ is substituted pyrazolyl, then Ar₃ is other than pyridinyl substituted by trifluoromethyl; and

(b) when Ar₁ is substituted pyrrolyl, then Ar₃ is other than unsubstituted pyridinyl.

11. The compound of claim 10, wherein Ar₃ is optionally substituted pyridinyl.

12. The compound of claim 10, wherein said compound is selected from the group consisting of:

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

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

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

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

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

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

5-(3-Chloro-thiophen-2-yl)-3-(8-hydroxy-quinolin-2-yl)-[1,2,4]-oxadiazole;

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

5-(3-Chloro-thiophen-2-yl)-3-(7-methyl-5-triflouromethyl-pyrazolo[1,5-α

]pyrimidin-3-yl)-[1,2,4]-oxadiazole; and

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

or a pharmaceutically acceptable salt or prodrug thereof.