6-aminoisoquinoline compounds

Patent metadata

Field	Value
Publication number	US-9365518-B2
Application number	US-201414583439-A
Country	US
Kind code	B2
Filing date	Dec 26, 2014
Priority date	Jan 10, 2007
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

6-Amino isoquinoline compounds are provided that influence, inhibit or reduce the action of a kinase. Pharmaceutical compositions including therapeutically effective amounts of the 6-aminoisoquinoline compounds and pharmaceutically acceptable carriers are also provided. Various methods using the compounds and/or compositions to affect disease states or conditions such as cancer, obesity and glaucoma are also provided.

First claim

What is claimed is:

1. A compound according to Formula II:

wherein R 1 and R 2 are, independently, hydrogen, hydroxyl, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, amino, nitro, cyano, C 1 -C 4 carbonyl, C 1 -C 4 carbonylamino, C 1 -C 4 alkoxy, C 1 -C 4 sulfonyl, C 1 -C 4 sulfonylamino, C 1 -C 4 thioalkyl or C 1 -C 4 carboxyl;
wherein R 4 is hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, amino, cyano, cycloalkyl, heterocycloalkyl, aryl, C 1 -C 4 alkyl aryl, heteroaryl, C 1 -C 4 alkyl heteroaryl, carbonyl, carbonylamino, thioalkyl, sulfonyl, sulfonylamino, acyl, or carboxyl; and
wherein B is a chain containing from 0 to 3 member atoms, X represents n independently chosen member atoms which together form a ring structure and n is an integer from about 1 to about 5.

2. The compound of claim 1 , wherein B is a chain containing either 0 or 1 member atoms, X represents n independently chosen member atoms which together form a ring structure and n is an integer of from 1 to 4.

3. The compound according to claim 2 , wherein R 1 , and R 2 are, independently, hydrogen, hydroxyl, halogen, methyl, ethyl, amino, nitro or cyano.

4. The compound according to claim 3 , wherein R 4 is alkyl, alkenyl, alkynyl, alkoxy, amino, cycloalkyl, heterocycloalkyl, aryl, C 1 -C 4 alkyl aryl, heteroaryl, C 1 -C 4 alkyl heteroaryl, acyl, or carboxyl.

5. The compound of claim 1 , wherein n is 1.

6. The compound according to claim 1 , wherein n is 1 and X is —CR′R′—, —NH—, or —O—; and wherein each R′ is, independently, hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, amino, cyano, C 1 -C 4 carbonyl, C 1 -C 4 carbonylamino, C 1 -C 4 alkoxy, C 1 -C 4 sulfonyl, C 1 -C 4 sulfonylamino, C 1 -C 4 thioalkyl or C 1 -C 4 carboxyl.

7. The compound according to claim 1 , wherein X is —CR′R′— and B is zero, wherein each R′ is, independently, hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, amino, cyano, C 1 -C 4 carbonyl, C 1 -C 4 carbonylamino, C 1 -C 4 alkoxy, C 1 -C 4 sulfonyl, C 1 -C 4 sulfonylamino, C 1 -C 4 thioalkyl or C 1 -C 4 carboxyl.

8. The compound according to claim 7 , wherein X is —CR′R′— wherein each R′ is, independently, hydrogen, halogen, C 1 -C 4 alkyl, amino, or cyano.

9. The compound according to claim 1 , wherein R 4 is cycloalkyl, heterocycloalkyl, aryl, C 1 -C 4 alkyl aryl, heteroaryl, or C 1 -C 4 alkyl heteroaryl.

10. The compound according to claim 9 , wherein R 4 is aryl and X is —CR′R′—; and wherein each R′ is, independently, hydrogen, halogen, C 1 -C 4 alkyl, amino or cyano.

11. The compound according to claim 1 , wherein the compound is selected from the following:

12. A compound selected from the following:

13. A method for influencing the action of a kinase in a cell, a tissue, or a living mammal comprising administering to or contacting with the cell, tissue, or mammal at least one compound according to claim 1 , or increasing the effectiveness of another therapeutic agent in a cell, tissue or living mammal comprising administering to or contacting with the cell, tissue or mammal a therapeutically effective amount of at least one compound according to claim 1 .

14. The method according to claim 13 , wherein the kinase affected is tyrosine kinase.

15. The method according to claim 13 , wherein the kinase affected is ROK-I, ROK-II, PKA, PKC, CAM Kinases, GRK-2, GRK-3, GRK-5 or GRK-6.

16. A method of treating a condition comprising administering to a subject in need of treatment a safe and effective amount of a 6-aminoisoquinoline derivative according to claim 1 , wherein the condition is selected from the group consisting of eye disease, bone disorder, obesity, heart disease, hepatic disease, renal disease, pancreatitis, cancer, myocardial infarct, gastric disturbance, hypertension, fertility control, nasal congestion, neurogenic bladder disorder, gastrointestinal disorder, and dermatological disorder.

17. The method of claim 16 , wherein the condition comprises eye disease.

18. The method of claim 17 , wherein the condition comprises glaucoma or a neurodegenerative eye disease.

19. A pharmaceutical composition comprising:
a) a 6-aminoisoquinoline derivative having the structure

wherein R 1 , and R 2 are, independently, hydrogen, hydroxyl, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, amino, nitro, cyano; C 1 -C 4 carbonyl, C 1 -C 4 carbonylamino, C 1 -C 4 alkoxy, C 1 -C 4 sulfonyl, C 1 -C 4 sulfonylamino, C 1 -C 4 thioalkyl or C 1 -C 4 carboxyl; and
wherein R 4 is hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, amino, cyano, cycloalkyl, heterocycloalkyl, aryl, C 1 -C 4 alkyl aryl, heteroaryl, C 1 -C 4 alkyl heteroaryl, carbonyl, carbonylamino, thioalkyl, sulfonyl, sulfonylamino, acyl, or carboxyl; and
b) a carrier.

20. The composition of claim 19 , wherein the carrier is selected from the group consisting of systemic and topical carriers.

21. The composition of claim 19 , wherein the composition comprises about 0.001% to 10% of the 6-aminoisoquinoline derivative and 90 to 99.999% of the systemic carrier.

Assignees

• Aerie Pharmaceuticals Inc

Inventors

• Delong Mitchell A
• Royalty Susan M
• Sturdivant Jill Marie
• Heintzelman Geoffrey Richard

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title