Inhibitors of paxillin function and related compositions and methods

Patent metadata

Field	Value
Publication number	US-9834525-B2
Application number	US-201515116764-A
Country	US
Kind code	B2
Filing date	Feb 4, 2015
Priority date	Feb 4, 2014
Publication date	Dec 5, 2017
Grant date	Dec 5, 2017

Abstract

This disclosure relates to small molecule inhibitors of paxillin and paxillin binding, and related compositions and methods of treatment.

First claim

The invention claimed is:

1. A compound having the structure of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
X is O or S;
Z is O or NH;
R 1 is selected from the group consisting of hydrogen, alkyl and arylalkyl;
R 2 is 3,4,5-trimethoxyphenyl;
R 3 , independently for each occurrence, is selected from the group consisting of alkyl, alkenyl, alkoxy, trifluoromethoxy, acetyl, aryl, hydroxy, halogen, cyano, nitro, amino, alkylamino, diakylamino, amido, alkylamido and arylamido; or
wherein any two adjacent R 3 may combine to form a fused aromatic ring, wherein said fused aromatic ring can be substituted one or more times with R 4 ;
R 4 , independently for each occurrence, are selected from the group consisting of alkyl, alkenyl, alkoxy, trifluoromethoxy, acetyl, aryl, hydroxy, halogen, cyano, nitro, amino, alkylamino, diakylamino, amido, alkylamido and arylamido; and
m is 0, 1, 2, 3 or 4.

2. The compound of claim 1 , wherein R 3 , independently for each occurrence, is selected from the group consisting of alkyl, alkenyl, alkoxy, trifluoromethoxy, acetyl, aryl, hydroxy, halogen, cyano, nitro, amino, alkylamino, diakylamino, amido, alkylamido and arylamido.

3. The compound of claim 1 having the structure of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
R 3 and R 4 , independently for each occurrence, are selected from the group consisting of alkyl, alkenyl, alkoxy, trifluoromethoxy, acetyl, aryl, hydroxy, halogen, cyano, nitro, amino, alkylamino, diakylamino, amido, alkylamido and arylamido;
m is 0, 1 or 2; and
n is 0, 1, 2, 3 or 4.

4. The compound of claim 1 wherein R 1 is hydrogen.

5. The compound of claim 2 , wherein:
R 1 is hydrogen;
R 2 is 3,4,5-trimethoxyphenyl;
R 3 , independently for each occurrence, is selected from the group consisting of alkoxy and hydroxy; and
m is 0, 1 or 2.

6. The compound of claim 3 , wherein:
R 3 , independently for each occurrence, is selected from the group consisting of alkoxy and halide; and
R 4 is hydrogen.

7. The compound of claim 1 , wherein X is O and Z is O.

8. The compound of claim 1 , wherein X is O and Z is NH.

9. The compound of claim 1 , wherein X is S and Z is O.

10. The compound of claim 1 , wherein X is S and Z is NH.

11. The compound of claim 2 , selected from the group consisting of:

or pharmaceutically acceptable salts thereof.

12. The compound of claim 3 , selected from the group consisting of:

or pharmaceutically acceptable salts thereof.

13. The compound:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein the compound has (R) stereochemistry.

15. The compound of claim 1 , wherein the compound has (S) stereochemistry.

16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

17. A method for the treatment of a disorder selected from the group consisting of metastatic cancer, retinal neovascularization, radiation retinopathy, diabetic retinopathy and polycystic kidney disease in a mammal, comprising administering to the mammal an effective amount of a compound of claim 1 .

18. A method of inhibiting paxillin function in a mammal, comprising administering to the mammal an effective amount of a compound of claim 1 .

Assignees

• Univ Tennessee Res Found
• Aleiwi Bilal Abou

Inventors

• Yates Charles Ryan
• Miller Duane D
• Park Frank
• Toutounchian Jordan J
• Morales-Tirado Vanessa
• Patil Shivaputra
• Pagadala Jayaprakash
• Aleiwi Bilal Abou

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P27/00

  Drugs for disorders of the senses · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61K9/1075

  Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence) · CPC title