US2019071396A1PendingUtilityA1
Substituted 3-haloallylamine inhibitors of ssao and uses thereof
Est. expiryMay 2, 2032(~5.8 yrs left)· nominal 20-yr term from priority
Inventors:Mandar DeodharAlison Dorothy FindlayJonathan Stuart FootWolfgang JarolimekIan A. McdonaldAlan D. RobertsonCraig Ivan Turner
A61P 9/00A61P 43/00A61P 3/10A61P 9/10A61P 35/00A61P 29/00A61P 27/02A61P 31/04A61P 19/02A61P 11/00A61P 1/16A61P 1/00A61P 13/12A61P 25/00A61P 17/06A61P 11/06A61P 11/08C07C 235/46C07C 323/62A61K 31/18A61K 31/166C07C 311/37C07C 321/26C07C 311/29C07C 237/30C07C 311/16C07C 237/28C07C 271/16C07C 323/63
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Claims
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.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof; wherein:
R 1 and R 4 are independently hydrogen or optionally substituted C 1-6 alkyl; or
R 1 is selected from —C(O)alkyl, —(O)aryl, —C(O)-arylalkyl, C(O)heteroaryl, and —C(O)-heteroarylalkyl;
R 2 is hydrogen;
R 3 is fluorine;
R 5 is an unsubstituted phenylene group or a phenylene group substituted by one or more groups independently selected from alkyl, halo, alkoxy and haloalkyl;
R 6 is selected from
R 7 and R 8 are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl and optionally substituted C 3-7 cycloalkyl; and
X is CH 2 , oxygen, sulfur or SO 2 .
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen and R 4 is methyl; or R 1 is methyl and R 4 is hydrogen.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 4 are both hydrogen.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is an unsubstituted phenylene group or a phenylene group substituted by one or more groups independently selected from methyl, fluorine, chlorine, bromine, OCH 3 and CF 3 .
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 7 and R 8 are both hydrogen, R 7 and R 8 are both C 1-6 alkyl, or R 7 is hydrogen and R 8 is C 1-6 alkyl.
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is oxygen.
7 . The compound of claim 1 wherein said compound is selected from the group consisting of:
3
(E)-4-(2-(Aminomethyl)-3- fluoroallyloxy)benzamide;
5
(E)-4-(3-(Aminomethyl)-4- fluorobut-3-en-2-yloxy)-N- tert-butylbenzamide
12
(E)-N-tert-Butyl-4-(3- fluoro-2-((methylamino)- methyl)allyloxy)benzamide
13
(E)-4-(2-(Aminomethyl)-3- fluoroallyloxy)-N,N- dimethylbenzamide;
19
(E)-4-(2-(Aminomethyl)-3- fluoroallyloxy)-N-tert- butyl-3-fluorobenzamide
21
(E)-4-(2-(Aminomethyl)- 3-fluoroallyloxy)-N-tert- butyl-2-(trifluoromethyl)- benzamide
23
(E)-4-(2-(Aminomethyl)- 3-fluoroallyloxy)-N-tert- butylbenzamide;
24
(E)-4-(2-(Aminomethyl)- 3-fluoroallyloxy)-N,N- diethylbenzamide;
25
(E)-4-(2-(Aminomethyl)- 3-fluoroallyloxy)-N- methylbenzamide;
34
(Z)-4-(3-(Aminomethyl)- 4-fluorobut-3-enyl)-N-tert- butylbenzamide
39
(E)-4-(2-(Aminomethyl)- 3-fluoroallyloxy)-N- isopropylbenzamide;
or a pharmaceutically acceptable salt thereof.
8 . The compound of claim 1 selected from the group consisting of:
13
(E)-4-(2-(Aminomethyl)- 3-fluoroallyloxy)-N,N- dimethylbenzamide;
23
(E)-4-(2-(Aminomethyl)- 3-fluoroallyloxy)-N-tert- butylbenzamide;
24
(E)-4-(2-(Aminomethyl)- 3-fluoroallyloxy)-N,N- diethylbenzamide;
25
(E)-4-(2-(Aminomethyl)- 3-fluoroallyloxy)-N- methylbenzamide;
39
(E)-4-(2-(Aminomethyl)- 3-fluoroallyloxy)-N- isopropylbenzamide;
or a pharmaceutically acceptable salt thereof.
9 . The compound of claim 1 wherein said compound is (E)-4-(2-(aminomethyl)-3-fluoroallyloxy) -N-tert-butylbenzamide or a pharmaceutically acceptable salt thereof.
10 . A pharmaceutically acceptable salt of a compound according to claim 1 .
11 . The pharmaceutically acceptable salt according to claim 10 characterized in that it is an acid addition salt.
12 . The pharmaceutically acceptable salt according to claim 11 characterized in that the acid addition salt is selected from the group consisting of hydrochlorides, hydrobromides, sulfates, formates, acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, maleates, butyrates, valerates and fumarates.
13 . The pharmaceutically acceptable salt of claim 10 wherein said pharmaceutically acceptable salt is (E)-4-(2-(aminomethyl)-3-fluoroallyloxy)-N-tert-butylbenzamide hydrochloride.
14 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent.
15 . A method of inhibiting the amine oxidase activity of semicarbazide-sensitive amine oxidase/ vascular adhesion protein-1 (SSAO/VAP-1) in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to effect a positive therapeutic response.
16 . A method of therapeutically treating a disease associated with or modulated by semicarbazide-sensitive amine oxidase/ vascular adhesion protein-1 (SSAO/VAP-1), said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
17 . The method of claim 16 wherein the disease is inflammation.
18 . The method of claim 17 wherein said inflammation is associated with liver disease, respiratory disease, cystic fibrosis, asthma or chronic obstructive pulmonary disease, or ocular disease.
19 . The method of claim 16 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.
20 . The method of claim 16 wherein the disease is a neuroinflammatory disease.
21 . The method of claim 16 wherein the disease is selected from the group consisting of liver fibrosis, liver cirrhosis, non-alcoholic steatohepatitis (NASH), kidney fibrosis, idiopathic pulmonary fibrosis and radiation-induced fibrosis.
22 . The method according to claim 16 characterized in that the disease is non-alcoholic steatohepatitis (NASH).
23 . The method according to claim 16 characterized in that the disease is diabetic retinopathy.
24 . The method according to claim 16 characterized in that the disease is cancer.Join the waitlist — get patent alerts
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