HALOALLYLAMINE INHIBITORS OF SSAO/VAP-1 AND USES THEREFOR

• US 20100298330A1
• Filed: 11/19/2008
• Published: 11/25/2010
• Est. Priority Date: 11/21/2007
• Status: Active Grant

• Current Assignee: Pharmaxis Ltd.
• Original Assignee: Pharmaxis Ltd.
• Inventors: Foot, Jonathan Stuart, McDonald, Ian A., Deodhar, Mandar, Turner, Craig Ivan
• Granted Patent: US 8,426,587 B2
• Time in Patent Office: Days
• US Class Current: 514/239.5
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 217/46 the carbon skeleton being acyclic and unsaturated
• CPC Class Codes: C07C 235/46 : having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 235/54 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 235/56 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 255/54 : containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07C 2601/08 : the ring being saturated
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 2603/74 : Adamantanes
• CPC Class Codes: C07C 311/29 : having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/22 : with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 323/27 : the carbon skeleton being acyclic and unsaturated
• CPC Class Codes: C07D 209/88 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/24 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 277/64 : with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
• CPC Class Codes: C07D 277/66 : with aromatic rings or ring systems directly attached in position 2
• CPC Class Codes: C07D 295/26 : Sulfur atoms

Abstract

The present invention is related to the preparation and pharmaceutical In use of novel haloallylamine derivatives as SSAO/VAP-1 inhibitors having the structure of Formula I, as defined in the specification:(I). The invention also relates to methods of using invention compounds, or pharmaceutically acceptable salt or derivatives thereof, for the treatment of a variety of indications, e.g., inflammatory diseases.

Claims

1. A compound of formula 1:

2. A compound of claim 1 wherein R⁶ is selected from the group consisting of:

3. A compound of claim 1 wherein B is oxygen or sulfur.

4. A compound of claim 1, wherein the compound is selected from the stereoisomer described by Formula Ia:

5. A compound of claim 4 wherein R⁶ is selected from the group consisting of:

6. A compound of claim 4, wherein R³ is fluorine;

B is oxygen.

7. A compound of claim 4, wherein R³ is chlorine;

B is oxygen.

8. A compound of claim 5, wherein R⁴ is methylene;

R⁵ is substituted aryl; and

R⁶ is selected from the group consisting of;

9. A compound of claim 5, wherein R⁴ is methylene;

R⁵ is substituted benzothiazole; and

R⁶ is selected from the group consisting of;

10. A compound of claim 1 wherein said compound is selected from the group consisting of:

(E)-3-Fluoro-4-phenoxybut-2-en-1-amine,

(E)-3-Fluoro-4-(4-(trifluoromethyl)phenoxy)but-2-en-1-amine,

(E)-4-(2,4-Dichlorophenoxy)-3-fluorobut-2-en-1-amine,

(E)-3-Fluoro-4-(4-methoxyphenoxy)but-2-en-1-amine,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)benzamide,

(E)-4-(3,4-Difluorophenoxy)-3-fluorobut-2-en-1-amine,

(E)-3-Fluoro-4-(4-nitrophenoxy)but-2-en-1-amine,

(E)-4-(4-tert-Butylphenoxy)-3-fluorobut-2-en-1-amine,

(Z)-3-Fluoro-4-(4-(trifluoromethyl)phenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(3-(trifluoromethyl)phenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(4-fluorophenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(4-(methylsulfonyl)phenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(4-(morpholinosulfonyl)phenoxy)but-2-en-1-amine,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N,N-diisopropylbenzamide,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-benzylbenzamide,

(Z)-3-Fluoro-4-phenoxybut-2-en-1-amine,

(Z)-4-(2,4-Dichlorophenoxy)-3-fluorobut-2-en-1-amine,

(E)-4-(3-Chloro-4-fluorophenoxy)-3-fluorobut-2-en-1-amine,

(E)-3-Fluoro-4-(4-phenoxyphenoxy)but-2-en-1-amine,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)benzonitrile,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-2-fluorobenzonitrile,

(E)-4-(Benzo[d][1,3]dioxol-5-yloxy)-3-fluorobut-2-en-1-amine,

(E)-3-Fluoro-4-(naphthalen-2-yloxy)but-2-en-1-amine,

(E)-(4-(4-Amino-2-fluorobut-2-enyloxy)phenyl)(phenyl)methanone,

(E)-4-(2-Chloro-4-nitrophenoxy)-3-fluorobut-2-en-1-amine,

(E)-4-(6-Chlorobenzo[d][1,3]dioxol-5-yloxy)-3-fluorobut-2-en-1-amine,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-(3-fluoro-5-(trifluoromethyl)benzyl)benzamide,

(E)-3-Fluoro-4-(4-(morpholinosulfonyl)phenoxy)but-2-en-1-amine,

(E)-4-(4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenoxy)-3-fluorobut-2-en-1-amine,

(E)-3-Fluoro-4-(4-(methylsulfonyl)phenoxy)but-2-en-1-amine,

(Z)-3-Chloro-4-(2-chloro-4-nitrophenoxy)but-2-en-1-amine,

(E)-3-Chloro-4-(2-chloro-4-nitrophenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(4-(methylthio)phenoxy)but-2-en-1-amine,

(E)-4-(4-tert-Butyl-2-chlorophenoxy)-3-fluorobut-2-en-1-amine,

(E)-3-Fluoro-4-(2-chloro-4-(methylsulfonyl)phenoxy)but-2-en-1-amine,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-cyclopentylbenzamide,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N,N-dimethylbenzenesulfonamide,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-benzyl-N-methylbenzamide,

(E)-3-Fluoro-4-(4-(trifluoromethylsulfonyl)phenoxy)but-2-en-1-amine,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N,N-dimethylbenzamide,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N,N-diethylbenzenesulfonamide,

(E)-3-Fluoro-4-(4-(methylsulfinyl)phenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(3-methyl-4-(methylsulfonyl)phenoxy)but-2-en-1-amine,

(E)-(4-(4-Amino-2-fluorobut-2-enyloxy)phenyl)(pyrrolidin-1-yl)methanone,

(E)-4-(2-Chlorophenoxy)-3-fluorobut-2-en-1-amine,

(E)-4-(3,5-Dichlorophenoxy)-3-fluorobut-2-en-1-amine,

(E)-4-(4-Bromophenoxy)-3-fluorobut-2-en-1-amine,

(E)-3-Fluoro-4-(4-iodophenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(4-(isopropylsulfonyl)phenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(4-(pyrrolidin-1-ylsulfonyl)phenoxy)but-2-en-1-amine,

(E)-4-(4-(Ethylsulfonyl)phenoxy)-3-fluorobut-2-en-1-amine,

R/S-(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-(1-phenylethyl)benzamide,

(E)-4-(4-(Benzylsulfonyl)phenoxy)-3-fluorobut-2-en-1-amine,

(E)-4-(Biphenyl-4-yloxy)-3-fluorobut-2-en-1-amine,

(E)-4-(4-amino-2-fluorobut-2-enyloxy)-N-cyclohexylbenzamide,

S-(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-(1-phenylethyl)benzamide,

R-(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-(1-phenylethyl)benzamide,

(E)-3-Fluoro-4-(phenylthio)but-2-en-1-amine,

(E)-3-Fluoro-4-(4-isopropoxyphenoxy)but-2-en-1-amine,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-tert-butylbenzamide,

(E)-4-(4-(Cyclopentylsulfonyl)phenoxy)-3-fluorobut-2-en-1-amine,

(E)-3-Fluoro-4-(4-(isobutylsulfonyl)phenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(4-(neopentylsulfonyl)phenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(4-(phenethylsulfonyl)phenoxy)but-2-en-1-amine,

(E)-4-(4-(sec-Butylsulfonyl)phenoxy)-3-fluorobut-2-en-1-amine,

(E)-3-Fluoro-4-(4-(1-phenylethylsulfonyl)phenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(4-(4-fluorobenzylsulfonyl)phenoxy)but-2-en-1-amine,

(E)-4-(9H-Carbazol-2-yloxy)-3-fluorobut-2-en-1-amine,

(E)-4-(4-(1H-Imidazol-1-yl)phenoxy)-3-fluorobut-2-en-1-amine,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-isopropylbenzamide,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-phenylbenzamide,

(E)-3-Fluoro-4-(2-methylbenzo[d]thiazol-5-yloxy)but-2-en-1-amine,

(E)-4-(Benzo[d]thiazol-2-yloxy)-3-fluorobut-2-en-1-amine,

(E)-N-(4-(4-Amino-2-fluorobut-2-enyloxy)phenyl)acetamide,

(E)-7-(4-Amino-2-fluorobut-2-enyloxy)-3-(4-hydroxyphenyl)-4H-chromen-4-one,

(E)-3-Fluoro-4-(pyridin-3-yloxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(2-p-tolylbenzo[d]thiazol-6-yloxy)but-2-en-1-amine,

(E)-2-(4-(4-Amino-2-fluorobut-2-enyloxy)phenylsulfonyl)ethanol,

(E)-3-Fluoro-4-(4-(2-morpholinoethylsulfonyl)phenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(4-(2-(pyrrolidin-1-yl)ethylsulfonyl)phenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(4-(2-(piperidin-1-yl)ethylsulfonyl)phenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(2-methylpyridin-3-yloxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(6-methylpyridin-3-yloxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(2-methylbenzo[d]thiazol-6-yloxy)but-2-en-1-amine,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-isopropylbenzenesulfonamide,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-cyclohexylbenzenesulfonamide,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-(1-phenylethyl)benzenesulfonamide,

(E)-3-Fluoro-4-(4-(4-(4-methoxyphenyl)thiazol-2-yl)phenoxy)but-2-en-1-amine,

(E)-3-Fluoro-4-(phenylsulfonyl)but-2-en-1-amine,

S-(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-(1-phenylethyl)benzenesulfonamide,

(E)-4-(2-tert-Butylbenzo[d]thiazol-5-yloxy)-3-fluorobut-2-en-1-amine,

(E)-3-Fluoro-4-(2-p-tolylbenzo[d]thiazol-5-yloxy)but-2-en-1-amine,

(E)-4-(2-Cyclohexylbenzo[d]thiazol-5-yloxy)-3-fluorobut-2-en-1-amine,

(E)-3-Fluoro-4-methoxybut-2-en-1-amine,

(Z)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-cyclohexylbenzamide,

(E)-3-Fluoro-4-(4-(trifluoromethoxy)phenoxy)but-2-en-1-amine,

S-(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-3-chloro-N-(1-phenylethyl)benzamide,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-(adamantyl)benzamide,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-(4-(trifluoromethyl)phenyl)benzamide,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-3,5-dichloro-N-cyclohexylbenzamide,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-3-chloro-N-cyclohexylbenzamide,

(E)-4-(4-Amino-2-fluorobut-2-enyloxy)-N-cyclohexyl-3-fluorobenzamide,

(E)-4-(4-Amino-2-fluoro-3-methylbut-2-enyloxy)-N-cyclohexylbenzamide, and

(Z)-4-(4-Amino-2-fluoro-3-methylbut-2-enyloxy)-N-cyclohexylbenzamide.

11. A composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable excipient, carrier or diluent therefor.

12. A method of inhibiting an amine oxidase enzyme in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound of claim 1 to effect a positive therapeutic response.

13. A method of treating a disease or condition associated with an amine oxidase enzyme, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1.

14. The method of claim 13 wherein the disease is inflammation.

15. The method of claim 14 wherein said inflammation is associated with liver disease.

16. The method of claim 14 wherein said inflammation is associated with respiratory disease.

17. The method of claim 16 wherein said respiratory disease is asthma.

18. The method of claim 16 wherein said respiratory disease is selected from the group consisting of acute lung injury and acute respiratory distress syndrome.

19. The method of claim 16 wherein said respiratory disease is bronchitis.

20. The method of claim 16 wherein said respiratory disease is chronic obstructive pulmonary disease.

21. The method of claim 14 wherein said inflammation is associated with ocular disease.

22. The method of claim 21 wherein said ocular disease is uveitis.

23. The method of claim 13 wherein the disease is diabetes.

24. The method of claim 23 wherein said diabetes is Type I diabetes.

25. The method of claim 23 wherein said diabetes is Type II diabetes.

26. The method of claim 13 wherein the disease is a neuroinflammatory disease.

27. The method of claim 13 wherein the disease is a psychiatric disorder.

28. The method of claim 13 wherein said condition is metabolic syndrome.

29. The method of claim 13 wherein said condition is organ and/or tissue transplant rejection.

30. The method of claim 13 wherein said condition is a skin disorder.

31. The method of claim 30 wherein said skin disorder is eczema.

32. The method of claim 30 wherein said skin disorder is psoriasis.

33. The method of claim 13 wherein said condition is stroke.

34. A method of treating a disease or condition modulated by SSAO/VAP-1 and/or MAO, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1.