Methods and compositions for inhibiting cell proliferative disorders

• US 5,789,427 A
• Filed: 03/07/1995
• Issued: 08/04/1998
• Est. Priority Date: 03/07/1994
• Status: Expired due to Term

• Current Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem), Sugen Incorporated (Pharmacia Corp.)
• Original Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem), Sugen Incorporated (Pharmacia Corp.)
• Inventors: Chen, Hui, Gazit, Aviv, Tang, Peng Cho, Shawver, Laura K., Tsai, Jianming, Mann, Elaina, Hirth, Klaus Peter
• Primary Examiner(s): Jordan, Charles T.
• Assistant Examiner(s): Hardee, John R.
• Application Number:
  US08/399,967
• Time in Patent Office: 1,246 Days
• Field of Search: 546/194, 546/235, 546/237, 546/294, 546/330, 546/304, 514/352, 514/357
• US Class Current: 514/352
• CPC Class Codes: A61K 31/245 Amino benzoic acid types, e.g. procaine, novocaine salicylic acid esters A61K31/60
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: C07C 229/60 with amino and carboxyl groups bound in meta- or para- positions
• CPC Class Codes: C07C 255/36 the carbon skeleton being further substituted by hydroxy groups
• CPC Class Codes: C07C 255/37 the carbon skeleton being further substituted by etherified hydroxy groups
• CPC Class Codes: C07C 255/41 the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
• CPC Class Codes: C07C 255/42 the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
• CPC Class Codes: C07C 255/66 having cyano groups and nitrogen atoms being part of hydrazine or hydrazone groups bound to the same carbon skeleton
• CPC Class Codes: C07C 311/27 of an unsaturated carbon skeleton containing rings
• CPC Class Codes: C07C 317/46 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 327/44 to carbon atoms of an unsaturated carbon skeleton
• CPC Class Codes: C07D 241/52 Oxygen atoms

Abstract

The present invention concerns compounds and their use to inhibit the activity of a receptor tyrosine kinase. The invention is preferably used to treat cell proliferative disorders such as cancers characterized by over-activity or inappropriate activity HER2 or EGFR.

Claims

1. A compound having the chemical formula:

##STR22## or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, and R₃ are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, OH, amine, thioether, SH, halogen, hydrogen, NO₂ and NH₂ ;

Y is either nothing, --C(CN)═

C--, -alkyl- or --NH-alkyl-; and

R₅ is either CN or aryl;

provided that if R₅ is aryl and said aryl is phenyl, then a) R₁, R₂, and R₃ are not alkoxy or OH, and b) at least one of R₁, R₂, and R₃ is not hydrogen.

2. The compound of claim 1, wherein said aryl is phenyl or pyridyl.

3. The compound of claim 1, wherein at least one of R₁, R₂, and R₃ is alkyl and said alkyl is either methyl, t-butyl or isopropyl.

4. The compound of claim 1, wherein

R₁ is t-butyl or isopropyl;

R₂ is OH;

R₃ is t-butyl or isopropyl;

Y is either nothing or a lower alkyl; and

R₅ is aryl and said aryl is either phenyl or pyridyl.

9. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of any one of claims 1-8 and a pharmaceutically acceptable carrier or excipient.

10. A method of treating a patient having a cell proliferative disorder, wherein said disorder is sensitive to one of the compounds of claims 1-8, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-8.

11. The method of claim 10, wherein said disorder is characterized by inappropriate activity of EGFR.

12. The method of claim 10, wherein said cell proliferative disorder is a cancer.

13. The method of claim 12, wherein said cancer is selected from the group consisting of breast carcinomas, stomach adenocarcinomas, salivary gland adenocarcinomas, endometrial cancers, ovarian adenocarcinomas, gastric cancers, colorectal cancers, and glioblastomas.

14. The method of claim 13, wherein said cancer is a breast carcinoma.

15. A method of treating a patient having a cancer characterized by overactivity of HER2, wherein said cancer is sensitive to one of the compounds of claims 1-8, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-8.

16. A method of treating a patient having a cancer characterized by inappropriate activity of EGFR, wherein said cancer is sensitive to one of the compounds of claims 1-8, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-8.

5. A compound having the chemical formula:

##STR23## or a pharmaceutically acceptable salt thereof, wherein R₁ is t-butyl or isopropyl;

R₂ is OH;

R₃ is t-butyl or isopropyl;

Y is either nothing or a lower alkyl; and

R₅ is either phenyl or pyridyl.

6. The compound of claim 5, wherein R₅ is aryl and said aryl is phenyl.

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

(E)-3-(3,5-diisopropyl-4-hydroxyphenyl-2- (pyrid-2-yl)sulfonyl!acrylonitrile;

(E)-2-cyanomethylsulfonyl-3-(3,5-diisopropyl-4-hydroxyphenyl)acrylonitrile);

(E,E)-2- 1-cyano-2-(3,5-diisopropyl-4-hydroxyphenyl)ethenyl!sulfonyl!-3-(3,5-diisopropyl-4-hydroxyphenyl)acrylonitrile);

(E)-3-(3,5-diisopropyl-4-hydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile);

(E)-3-(3,5-dimethyl-4-hydroxyphenyl)-2- (pyrid-2-yl)sulfonyl!acrylonitrile);

(E)-3-(3,5-di-t-butyl-4-hydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile;

(E)-3-(3,5-di-t-butyl-4-hydroxyphenyl)-2- (pyrid-2-yl)sulfonyl!acrylonitrile;

(E,E)-2- 1-cyano-2-(3,5-diisopropyl-4-hydroxyphenyl)ethenyl!sulfonyl!-3-(3,5-di-t-butyl-4-hydroxyphenyl)acrylonitrile;

(E)-2-(benzylaminosulfonyl)-3-(3,5-di-t-butyl-4-hydroxyphenyl)acrylonitrile);

(E)-2-(benzylaminosulfonyl)-3-(3,5-diisopropyl-4-hydroxyphenyl)acrylonitrile);

(E)-2-(benzylaminosulfonyl)-3-(3,5-dimethyl-4-hydroxyphenyl)acrylonitrile

(E)-3-(3,5-di-t-butyl-4-hydroxyphenyl)-2- (3-phenyl-n-propyl)aminosulfonyl!acrylonitrile);

(E)-3-(3,5-diisopropyl-4-hydroxyphenyl)-2- (3-phenyl-n-propyl)aminosulfonyl!acrylonitrile; and

(E)-3-(3,5-dimethyl-4-hydroxyphenyl)-2- (3-phenyl-n-propyl)aminosulfonyl!acrylonitrile.

8. A compound selected from the group consisting of

(E)-3-(3,5-diisopropyl-4-hydroxyphenyl-2- (pyrid-2-yl)sulfonyl!acrylonitrile;

(E)-2-cyanomethylsulfonyl-3-(3,5-diisopropyl-4-hydroxyphenyl)acrylonitrile);

(E,E)-2- 1-cyano-2-(3,5-diisopropyl-4-hydroxyphenyl)ethenyl!sulfonyl!-3-(3,5-diisopropyl-4-hydroxyphenyl)acrylonitrile);

(E)-3-(3,5-diisopropyl-4-hydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile);

(E)-3-(3,5-dimethyl-4-hydroxyphenyl)-2- (pyrid-2-yl)sulfonyl!acrylonitrile);

(E)-3-(3,5-di-t-butyl-4-hydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile;

(E)-3-(3,5-di-t-butyl-4-hydroxyphenyl)-2- (pyrid-2-yl)sulfonyl!acrylonitrile;

(E,E)-2- 1-cyano-2-(3,5-diisopropyl-4-hydroxyphenyl)ethenyl!sulfonyl!-3-(3,5-di-t-butyl-4-hydroxyphenyl)acrylonitrile;

(E)-2-(benzylaminosulfonyl)-3-(3,5-di-t-butyl-4-hydroxyphenyl)acrylonitrile);

(E)-2-(benzylaminosulfonyl)-3-(3,5-diisopropyl-4-hydroxyphenyl)acrylonitrile);

(E)-2-(benzylaminosulfonyl)-3-(3,5-dimethyl-4-hydroxyphenyl)acrylonitrile

(E)-3-(3,5-di-t-butyl-4-hydroxyphenyl)-2- (3-phenyl-n-propyl)aminosulfonyl!acrylonitrile);

(E)-3-(3,5-diisopropyl-4-hydroxyphenyl)-2- (3-phenyl-n-propyl)aminosulfonyl!acrylonitrile; and

(E)-3-(3,5-dimethyl-4-hydroxyphenyl)-2- (3-phenyl-n-propyl)aminosulfonyl!acrylonitrile,

or a pharmaceutically acceptable salt thereof.