IP Library › Granted Patent US 9,856,246
Granted Patent B2
US 9,856,246 · App. 15/414,803 · Granted Jan 2, 2018

TRPM8 antagonists

Inventors: Alessio Moriconi (L'Aquila, IT); Gianluca Bianchini (L'Aquila, IT); Sandro Colagioia (L'Aquila, IT); Laura Brandolini (L'Aquila, IT); Andrea Aramini (L'Aquila, IT); Chiara Liberati (Milan, IT); Silvia Bovolenta (Milan, IT)
Assignee: Dompé farmaceutici S.p.A.
C07D417/12C07D263/40C07D277/56C07D413/04C07D417/04C07D417/10
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Quick Facts
Patent No.
US 9,856,246
App. No.
15/414,803
Granted
Jan 2, 2018
Kind
B2
Abstract

The invention relates to compounds acting as selective antagonists of Transient Receptor Potential cation channel subfamily M member 8 (TRPM8), and having formula: Said compounds are useful in the treatment of diseases associated with activity of TRPM8 such as pain, inflammation, ischaemia, neurodegeneration, stroke, psychiatric disorders, itch, irritable bowel diseases, cold induced and/or exacerbated respiratory disorders and urological disorders.

Claims (110)

1. A compound selected from:

2-(4-chlorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylic acid (1)

4-hydroxy-2-(4-methylphenyl)-1,3-thiazole-5-carboxylic acid (2)

2-(3-fluorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylic acid (3)

2-(4-fluorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylic acid (4)

methyl 2-(2,4-difluorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylate (6)

ethyl 2-(3-fluorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylate (10)

ethyl 2-(4-fluorophenyl)-4-hydroxy-1,3-thiazole-5-carboxylate (11)

ethyl-4-hydroxy-2-(4-pyridin-4-yl)phenyl-1,3-thiazole-5-carboxylate (12)

ethyl 2-[4-(dimethylamino)phenyl]-4-hydroxy-1,3-thiazole-5-carboxylate (13)

ethyl 4-hydroxy-2-[2′-(trifluoromethyl)biphenyl-3-yl]-1,3-thiazole-5-carboxylate (15)

ethyl 2-(2′-fluorobiphenyl-3-yl)-4-hydroxy-1,3-thiazole-5-carboxylate (16)

ethyl 4-hydroxy-2-[2′-(trifluoromethyl)biphenyl-4-yl]-1,3-thiazole-5-carboxylate (17)

ethyl 2-(2′-fluorobiphenyl-4-yl)-4-hydroxy-1,3-thiazole-5-carboxylate (18)

ethyl 2-{4-[(2-fluorobenzyl)oxy]phenyl}-4-hydroxy-1,3-thiazole-5-carboxylate (19)

ethyl 2-{4-[(4-fluorobenzyl)oxy]phenyl}-4-hydroxy-1,3-thiazole-5-carboxylate (20)

ethyl 2-(4-fluorophenyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (21)

ethyl 4-methoxy-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (22)

ethyl 2-(4-methylphenyl)-4-(2-methylpropoxy)-1,3-thiazole-5-carboxylate (23)

ethyl 4-(benzyloxy)-2-phenyl-1,3-thiazole-5-carboxylate (24)

ethyl 4-[(3-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylate (25)

ethyl 4-[(3-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylate (26)

ethyl 4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (29)

ethyl 4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylate (30)

ethyl 4-[(2-chlorobenzyl)oxy]-2-(4-fluorophenyl)-1,3-thiazole-5-carboxylate (32)

ethyl 4-[(2-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylate (33)

ethyl 4-[(2-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1,3-thiazole-5-carboxylate (34)

ethyl 4-[(2-chlorobenzyl)oxy]-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (35)

ethyl 2-(3-fluorophenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1,3-thiazole-5-carboxylate (37)

ethyl 2-(4-methylphenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1,3-thiazole-5-carboxylate (38)

ethyl4-(2-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)acetoyloxy)-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (39)

ethyl 4-[(benzylcarbamoyl)oxy]-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylate (40)

ethyl 4-(2-aminoethoxy)-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylate (41)

ethyl 2-(4-chlorophenyl)-4-{2-[(furan-2-ylmethyl)amino]ethoxy}-1,3-thiazole-5-carboxylate (42)

4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1,3-thiazole-5-carboxylic acid (43)

4-[(4-chlorobenzyl)oxy]-2-phenyl-1,3-thiazole-5-carboxylic acid (44)

4-[(4-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylic acid (45)

4-[(4-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1,3-thiazole-5-carboxylic acid (46)

4-(benzyloxy)-2-phenyl-1,3-thiazole-5-carboxylic acid (47)

4-[(3-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylic acid (48)

4-[(2-chlorobenzyl)oxy]-2-phenyl-1,3-thiazole-5-carboxylic acid (49)

4-[(2-chlorobenzyl)oxy]-2-(4-fluorophenyl)-1,3-thiazole-5-carboxylic acid (50)

4-[(2-chlorobenzyl)oxy]-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylic acid (51)

4-[(2-chlorobenzyl)oxy]-2-(3-chlorophenyl)-1,3-thiazole-5-carboxylic acid (52)

4-[(2-chlorobenzyl)oxy]-2-(4-methylphenyl)-1,3-thiazole-5-carboxylic acid (53)

4-[(2-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylic acid (54)

2-phenyl-4-{[4-(trifluoromethyl)benzyl]oxy}-1,3-thiazole-5-carboxylic acid (55)

2-(3-fluorophenyl)-4-{[4-(trifluoromethyl)benzyl]oxy}-1,3-thiazole-5-carboxylic acid (56)

2-phenyl-4-{[4-(trifluoromethyl)benzoyl]oxy}-1,3-thiazole-5-carboxylic acid (57)

2-(3-fluorophenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1,3-thiazole-5-carboxylic acid (58)

2-(4-methylphenyl)-4-{[4-(trifluoromethyl)benzoyl]oxy}-1,3-thiazole-5-carboxylic acid (59)

4-methoxy-2-(4-methylphenyl)-1,3-thiazole-5-carboxylic acid (60)

2-(4-methylphenyl)-4-(2-methylpropoxy)-1,3-thiazole-5-carboxylic acid (61)

ethyl 4-[(tert-butoxycarbonyl)amino]-2-(4-fluorophenyl)-1,3-thiazole-5-carboxylate (62)

ethyl 4-amino-2-(4-fluorophenyl)-1,3-thiazole-5-carboxylate hydrochloride (63)

ethyl 4-(acetylamino)-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (64)

ethyl 2-(4-methylphenyl)-4-{[4-(trifluoromethyl)benzoyl]amino}-1,3-thiazole-5-carboxylate (65)

ethyl 2-(4-methylphenyl)-4-[(phenylcarbamoyl)amino]-1,3-thiazole-5-carboxylate (66)

ethyl 4-[(2-aminoethyl)amino]-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (67)

ethyl 2-(4-chlorophenyl)-4-{[2-(methylamino)ethyl]amino}-1,3-thiazole-5-carboxylate (68)

ethyl 2-(4-chlorophenyl)-4-{[2-(propylamino)ethyl]amino}-1,3-thiazole-5-carboxylate (69)

ethyl 4-[(2-aminoethyl)amino]-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylate (70)

ethyl 4-{[2-(methylamino)ethyl]amino}-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (71)

ethyl 4-[(2-aminoethyl)amino]-2-[2′-(trifluoromethyl)biphenyl-4-yl]-1,3-thiazole-5-carboxylate (72)

ethyl 4-[(2-aminoethyl)amino]-2-[2′-(trifluoromethyl)biphenyl-3-yl]-1,3-thiazole-5-carboxylate (73)

ethyl 2-(4-chlorophenyl)-4-{[2-(cyclopentylamino)ethyl]amino}-1,3-thiazole-5-carboxylate (74)

ethyl 2-phenyl-4-{[2-(pyrrolidin-1-yl)ethyl]amino}-1,3-thiazole-5-carboxylate (75)

ethyl 4-(benzylamino)-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylate (76)

ethyl 4-[(1,3-benzodioxol-5-ylmethyl)amino]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylate (77)

ethyl 2-(3-fluorophenyl)-4-[(pyridin-3-ylmethyl)amino]-1,3-thiazole-5-carboxylate (78)

4-[(2-aminoethyl)amino]-2-(4-methylphenyl)-1,3-thiazole-5-carboxylic acid (79)

4-{[2-(methylamino)ethyl]amino}-2-(4-methylphenyl)-1,3-thiazole-5-carboxylic acid (80)

4-[(2-aminoethyl)amino]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylic acid (81)

sodium 4-[(3-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylate (82)

sodium 4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (83)

sodium 4-(4-chlorobenzyloxy)-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylate (84)

sodium 4-(2-chlorobenzyloxy)-2-(4-chlorophenyl)-1,3-thiazole-5-carboxylate (85)

sodium 4-(2-chlorobenzyloxy)-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (86)

sodium 4-(2-chlorobenzyloxy)-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylate (87)

sodium 4-(4-chlorobenzyloxy)-2-(3-fluorophenyl)-1,3-thiazole-5-carboxylate (88)

(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-4-(benzyloxy)-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (89)

(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-4-hydroxy-2-(4-methylphenyl)-1,3-thiazole-5-carboxylate (90)

ethyl 2-(4-chlorophenyl)-4-(methoxymethoxy)-1,3-thiazole-5-carboxylate (91)

2-(4-chlorophenyl)-4-(methoxymethoxy)-1,3-thiazole-5-carboxylic acid (92)

2-(4-chlorophenyl)-4-(methoxymethoxy)-1,3-thiazole-5-carboxamide (93)

2-(4-chlorophenyl)-4-(methoxymethoxy)-1,3-thiazole-5-carbonitrile (94)

2-(4-chlorophenyl)-5-(1H-tetrazol-5-yl)-1,3-thiazol-4-ol (95)

2-(4-chlorophenyl)-5-(1-methyl-1H-tetrazol-5-yl)-1,3-thiazol-4-ol (96)

2-(3-fluorophenyl)-5-(1-methyl-1H-tetrazol-5-yl)-1,3-thiazol-4-ol (97)

2-(4-chlorophenyl)-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1,3-thiazol-4-ol (98)

2-(3-fluorophenyl)-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1,3-thiazol-4-ol (99)

2-(4-chlorophenyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)-1,3-thiazol-4-01 (100)

2-(3-fluorophenyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)-1,3-thiazol-4-ol (101)

3-{4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-thiazol-5-yl}-5-methyl-1,2,4-oxadiazole (102)

2-(4-chlorophenyl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-thiazol-4-ol (103)

2-(3-fluorophenyl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-thiazol-4-ol (104)

ethyl 2-(3-fluorophenyl)-4-hydroxy-1,3-oxazole-5-carboxylate (106)

ethyl 4-hydroxy-2-(4-methylphenyl)-1,3-oxazole-5-carboxylate (107)

ethyl 4-[(4-chlorobenzyl)oxy]-2-phenyl-1,3-oxazole-5-carboxylate (108)

ethyl 4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-oxazole-5-carboxylate (109)

ethyl 4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1,3-oxazole-5-carboxylate (110)

ethyl 2-phenyl-4-{[4-(trifluoromethyl)benzoyl]oxy}-1,3-oxazole-5-carboxylate (111)

4-[(4-chlorobenzyl)oxy]-2-phenyl-1,3-oxazole-5-carboxylic acid (112)

4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-oxazole-5-carboxylic acid (113)

4-[(4-chlorobenzyl)oxy]-2-(4-methylphenyl)-1,3-oxazole-5-carboxylic acid (114)

2-(3-fluorophenyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)-1,3-oxazol-4-ol (115)

3-{4-[(4-chlorobenzyl)oxy]-2-(3-fluorophenyl)-1,3-oxazol-5-yl}-5-methyl-1,2,4-oxadiazole (116)

ethyl 2-(3-fluorophenyl)-5-hydroxy-1,3-thiazole-4-carboxylate (117)

2-(3-fluorophenyl)-5-(2-ethyl-2H-tetrazol-5-yl)-1,3-thiazol-4-ol (118).

2. A pharmaceutical composition comprising as the active ingredient at least one compound of claim 1 , in combination with pharmaceutically acceptable excipients and/or diluents.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 8, 2017
From: MORICONI, ALESSIO; BIANCHINI, GIANLUCA; COLAGIOIA, SANDRO; BRANDOLINI, LAURA; ARAMINI, ANDREA; LIBERATI, CHIARA; BOVOLENTA, SILVIA
To: DOMPE' S.P.A.
Reel/Frame 041199/0461 →
MERGER Recorded Feb 8, 2017
From: DOMPÉ S.P.A.
To: DOMPÉ FARMACEUTICI S.P.A.
Reel/Frame 041199/0581 →
Priority Claims (2)
EP 11194365 · Dec 19, 2011 · regional
EP 12178327 · Jul 27, 2012 · regional
Continuity (2)
Division 14366796
Related Publication 20170129881A1 · May 11, 2017