Substituted 3-haloallylamine inhibitors of SSAO and uses thereof

Patent metadata

Field	Value
Publication number	US-9815782-B2
Application number	US-201615054243-A
Country	US
Kind code	B2
Filing date	Feb 26, 2016
Priority date	May 2, 2012
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

Abstract

The present invention is related to the preparation and pharmaceutical use of substituted 3-haloallylamine derivatives as SSAO/VAP-1 inhibitors having the structure of Formula I, as defined in the specification:

The invention also relates to methods of using compounds of Formula I, or pharmaceutically acceptable salt or derivatives thereof, for the treatment of a variety of indications, e.g., inflammatory diseases, ocular diseases, fibrotic diseases, diabetes-induced diseases and cancer.

First claim

The invention claimed is:

1. A method for inhibiting the amine oxidase activity of SSAO/VAP-1 in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, or a composition comprising the foregoing, and at least one pharmaceutically acceptable excipient, carrier or diluent, to effect a positive therapeutic response.

2. A method for therapeutically treating a disease associated with or modulated by SSAO/VAP-1 protein, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, or a composition comprising the foregoing, and at least one pharmaceutically acceptable excipient, carrier or diluent.

3. The method of claim 2 wherein the disease is inflammation.

4. The method of claim 3 wherein said inflammation is associated with liver disease.

5. The method of claim 3 wherein said inflammation is associated with respiratory disease.

6. The method of claim 5 wherein said inflammation is associated with cystic fibrosis.

7. The method of claim 5 wherein said inflammation is associated with asthma or chronic obstructive pulmonary disease.

8. The method of claim 3 wherein said inflammation is associated with ocular disease.

9. The method of claim 2 wherein the disease is a diabetes-induced disease selected from the group consisting of diabetic nephropathy, glomerulosclerosis, diabetic retinopathy, non-alcoholic fatty liver disease and choroidal neovascularisation.

10. The method of claim 2 wherein the disease is a neuroinflammatory disease.

11. The method of claim 2 wherein the disease is fibrosis.

12. The method of claim 2 wherein the disease is cancer.

13. The method of claim 11 , wherein the fibrosis is selected from the group consisting of cystic fibrosis, liver fibrosis, liver cirrhosis, kidney fibrosis, scleroderma, idiopathic pulmonary fibrosis and radiation-induced fibrosis.

14. The method of claim 2 , wherein the disease is a non-alcoholic fatty liver disease.

15. The method of claim 2 , wherein the disease is a non-alcoholic steatohepatitis (NASH).

16. The method of claim 2 , wherein the disease is an alcohol induced fibrosis leading to cirrhosis of the liver.

17. The method of claim 2 , wherein the disease is diabetic retinopathy.

18. The method according to claim 1 , wherein said compound is selected from the group consisting of:
(E)-4-(2-(Aminomethyl)-3-fluoroallyloxy)benzamide;
(E)-4-(2-(Aminomethyl)-3-fluoroallyloxy)-N,N-diethylbenzamide;
(E)-4-(2-(Aminomethyl)-3-fluoroallyloxy)-N-methylbenzamide; and
(E)-4-(2-(Aminomethyl)-3-fluoroallyloxy)-N-tent-butylbenzamide,
or a pharmaceutically acceptable salt thereof.

19. The method according to claim 2 , wherein said compound is (E)-4-(2-(Aminomethyl)-3-fluoroallyloxy)benzamide, or a pharmaceutically acceptable salt thereof.

20. The method according to claim 19 , wherein said compound is (E)-4-(2-(Aminomethyl)-3-fluoroallyloxy)benzamide hydrochloride.

21. The method according to claim 2 , wherein said compound is (E)-4-(2-(Aminomethyl)-3-fluoroallyloxy)-N,N-diethylbenzamide, or a pharmaceutically acceptable salt thereof.

22. The method according to claim 21 wherein said compound is (E)-4-(2-(Aminomethyl)-3-fluoroallyloxy)-N,N-diethylbenzamide hydrochloride.

23. The method according to claim 2 , wherein said compound is (E)-4-(2-(Aminomethyl)-3-fluoroallyloxy)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

24. The method according to claim 23 , wherein said compound is (E)-4-(2-(Aminomethyl)-3-fluoroallyloxy)-N-methylbenzamide hydrochloride.

25. The method according to claim 2 , wherein said compound is (E)-4-(2-(Aminomethyl)-3-fluoroallyloxy)-N-tert-butylbenzamide, or a pharmaceutically acceptable salt thereof.

26. The method according to claim 25 , wherein said compound is (E)-4-(2-(Aminomethyl)-3-fluoroallyloxy)-N-tert-butylbenzamide hydrochloride.

Assignees

• Boehringer Ingelheim Int

Inventors

• Deodhar Mandar
• Findlay Alison Dorothy
• Foot Jonathan Stuart
• Jarolimek Wolfgang
• Mcdonald Ian Alexander
• Robertson Alan Duncan
• Turner Craig Ivan

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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

• A61P31/04

  Antibacterial agents · CPC title