Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia

• US 5,972,986 A
• Filed: 10/14/1997
• Issued: 10/26/1999
• Est. Priority Date: 10/14/1997
• Status: Expired due to Term

• Current Assignee: GD Searle LLC (Pfizer Inc.)
• Original Assignee: GD Searle LLC (Pfizer Inc.)
• Inventors: Seibert, Karen, Masferrer, Jaime, Gordon, Gary B
• Primary Examiner(s): KRASS, FREDERICK F
• Application Number:
  US08/949,922
• Time in Patent Office: 742 Days
• Field of Search: 514/210, 514/247, 514/252, 514/341, 514/365, 514/372, 514/374, 514/378, 514/399, 514/400, 514/403, 514/406, 514/407
• US Class Current: 514/406
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/635 having a heterocyclic ring, e.g. sulfadiazine

Abstract

This invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in preventing and treating neoplasia. In particular, the invention describes the method of preventing and treating epithelial cell neoplasia in a subject, said method comprising treating the subject with a therapeutically-effective amount of a compound of Formula I. ##STR1## wherein A, R² and R³ are as described in the specification.

Claims

1. A method of treating a neoplasia in a subject in need thereof by inhibiting the growth associated therewith, said method comprising treating the subject with a therapeutically-effective amount of a compound of Formula II ##STR4## wherein R⁴ is C_1-6 -haloalkyl;

wherein R⁵ is hydrido; and

wherein R⁶ is phenyl optionally substituted at a substitutable position with one or more radicals selected from the group consisting of halo, C_1-6 -alkylthio, C_1-6 -alkylsulfonyl, cyano, nitro, C_1-6 -haloalkyl, C_1-6 -alkyl, hydroxyl, C_2-6 -alkenyl, C_1-6 -hydroxyalkyl, carboxyl, C_3-6 -cycloalkyl, C_1-6 -alkylamino, di-C_1-6 -alkylamino, C_1-6 -alkoxycarbonyl, aminocarbonyl, C_1-6 -alkoxy, C_1-6 -haloalkoxy, sulfamyl, five or six membered heterocyclic and amino;

or a pharmaceutically-acceptable salt or derivative thereof.

4. The method of claim 1 wherein the compound is selected from compounds, and their pharmaceutically acceptable salts, selected from the group consisting of

4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; and

4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.

5. The method of claim 4 wherein the compound is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.

6. The method of claim 4 wherein the compound is 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.

7. The method of claim 4 where the compound is 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-l-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.

8. The method of claim 1 wherein the neoplasia is selected from the group consisting of colorectal cancer, gastrointestinal cancer, liver cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer and skin cancer.

14. The method of claim 1 wherein the neoplasia is adenomatous polyps.

2. A method of inhibiting or delaying the onset of a neoplasia selected from the group consisting of adenomatous polyps, gastrointestinal cancer, liver cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer and skin cancer, in a subject in need of such inhibition or delay, the method comprising treating said subject with a therapeutically-effective amount of a compound of Formula II ##STR5## wherein R⁴ is C_1-6 -haloalkyl;

wherein R⁵ is hydrido; and

wherein R⁶ is phenyl optionally substituted at a substitutable position with one or more radicals selected from the group consisting of halo, C_1-6 -alkylthio, C_1-6 -alkylsulfonyl, cyano, nitro, C_1-6 -haloalkyl, C_1-6 -alkyl, hydroxyl, C_2-6 -alkenyl, C_1-6 -hydroxyalkyl, carboxyl, C_3-6 -cycloalkyl, C_1-6 -alkylamino, di-C_1-6 -alkylamino, C_1-6 -alkoxycarbonyl, aminocarbonyl, C_1-6 -alkoxy, C_1-6 -haloalkoxy, sulfamyl, five or six membered heterocyclic and amino;

or a pharmaceutically-acceptable salt or derivative thereof.

9. The method of claim 2 wherein the compound is selected from compounds, and their pharmaceutically acceptable salts, selected from the group consisting of

4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; and

4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.

10. The method of claim 9 wherein the compound is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.

11. The method of claim 9 wherein the compound is 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.

12. The method of claim 9 where the compound is 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.

15. The method of claim 2 wherein the neoplasia is adenomatous polyps.

3. A method of treating a subject suffering from a neoplastic disease state with a conjunctive therapy, said method comprising treating the subject with a therapeutically-effective amount of a compound of Formula II ##STR6## wherein R⁴ is C_1-6 -haloalkyl;

wherein R⁵ is hydrido; and

wherein R⁶ is phenyl optionally substituted at a substitutable position with one or more radicals selected from the group consisting of halo, C_1-6 -alkylthio, C_1-6 -alkylsulfonyl, cyano, nitro, C_1-6 -haloalkyl, C_1-6 -alkyl, hydroxyl, C_2-6 -alkenyl, C_1-6 -hydroxyalkyl, carboxyl, C_3-6 -cycloalkyl, C_1-6 -alkylamino, di -C_1-6 -alkyl amino, C_1-6 -alkoxycarbonyl, aminocarbonyl, C_1-6 -alkoxy, C_1-6 -haloalkoxy, sulfamyl, five or six membered heterocyclic and amino;

or a pharmaceutically-acceptable salt thereof;

and one or more compounds selected from the group consisting of antibiotic agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon agents, miscellaneous agents, metallomatrix proteases (MMP) inhibitors, SOD and α

_v β

₃ inhibitors.

13. The method of claim 3 wherein the compound is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.