US 7,601,712 B2
Carboxylic acid compounds and medicinal compositions containing the same as the active ingredient
Atsushi Naganawa, Mishima-gun (Japan); Maki Iwahashi, Mishima-gun (Japan); Atsushi Kinoshita, Mishima-gun (Japan); Atsushi Shimabukuro, Mishima-gun (Japan); Seiji Ogawa, Mishima-gun (Japan); Koji Yano, Mishima-gun (Japan); Kaoru Kobayashi, Mishima-gun (Japan); Yutaka Okada, Mishima-gun (Japan); Yoko Kishida, Goleta, Calif. (US); Shouji Kawauchi, Neyagawa (Japan); Kohki Tsukamoto, Mishima-gun (Japan); Yoko Matsunaga, Mishima-gun (Japan); and Fumio Nambu, Mishima-gun (Japan)
Assigned to Ono Pharmaceutical Co., Ltd., Osaka (Japan)
Appl. No. 10/572,578
PCT Filed Sep. 16, 2004, PCT No. PCT/JP2004/013983
§ 371(c)(1), (2), (4) Date Mar. 17, 2006,
PCT Pub. No. WO2005/028455, PCT Pub. Date Mar. 31, 2005.
Claims priority of application No. 2003-325198 (JP), filed on Sep. 17, 2003; and application No. 2004-101863 (JP), filed on Mar. 31, 2004.
Prior Publication US 2007/0004716 A1, Jan. 04, 2007
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/535 (2006.01); A61K 31/36 (2006.01); A61K 31/34 (2006.01); A61K 31/335 (2006.01); C07D 265/36 (2006.01); C07D 317/44 (2006.01); C07D 307/00 (2006.01); C07D 319/14 (2006.01)
U.S. Cl. 514—230.5  [544/105; 549/441; 549/467; 549/366; 514/464; 514/469; 514/452] 9 Claims
 
1. A carboxylic acid compound represented by formula (I)

OG Complex Work Unit Drawing
wherein R1 represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C2-4 alkenyl, or (4) benzyl;
E represents —CO—, —SO2—, or —CH2—;
R2 represents (1) a halogen atom, (2) C1-6 alkyl, (3) C1-6 alkoxy, (4) hydroxyl, (5) trihalomethyl, (6) cyano, (7) phenyl, (8) pyridyl, (9) nitro, (10) —NR6R7, or (11) C1-4 alkyl substituted with —OR8, (12) oxidized C1-6 alkyl, (13) —SO2R11, (14) —SOR11, or (15) —SR11, or two R2's substituting for the adjacent carbon atom are taken together to represent (1) C2-5 alkylene which may be substituted by a substituent wherein one carbon atom thereof may be replaced with an oxygen atom, a nitrogen atom, or a sulfur atom which may be oxidized, or (2) C2-5 alkenylene which may be substituted by a substituent, wherein one carbon atom thereof may be replaced with an oxygen atom, a nitrogen atom, or a sulfur atom;
R3 represents (1) a halogen atom, (2) C1-6 alkyl, (3) C1-6 alkoxy, (4) hydroxyl, (5) trihalomethyl, (6) cyano, (7) phenyl, (8) pyridyl, (9) nitro, (10) —NR6R7 or (11) C1-4 alkyl substituted with —OR8, (12) oxidized C1-6 alkyl, (13) —SO2R11, (14) —SOR11, or (15) —SR11;
R6 and R7 each independently represent a hydrogen atom or C1-4 alkyl;
R8 represents C1-4 alkyl, phenyl, or pyridyl;
R4 represents (1) a hydrogen atom, (2) C1-6 alkyl, (3) benzyl, or (4) oxidized C1-6 alkyl;
R5 represents (1) C1-6 alkyl, (2) C1-10 alkoxy, (3) C1-6 alkyl substituted with C1-6 alkoxy, (4) a halogen atom, (5) hydroxyl, (6) trihalomethyl, (7) nitro, (8) —NR9R10, (9) phenyl, (10) phenoxy, (11) oxo, (12) C2-6 acyl, (13) cyano or (14) —SO2R11, (15) —SOR11, (16) —SR11, (12) oxidized C1-6 alkyl;
R9 and R10 each independently represent a hydrogen atom or C1-4 alkyl; and
R11 represents C1-6 alkyl or phenyl which may be substituted;
wherein R6's to R11's in R2's to R5's may be the same or each independently different;

OG Complex Work Unit Drawing
represents a C5-12 monocyclic or bicyclic carbocyclic ring or a 5- to 12-membered monocyclic or bicyclic heterocycle;
G represents (1) C1-6 alkylene having 0 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, (2) C2-6 alkenylene having 0 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, or (3) C2-6 alkynylene having 0 to 2 hetero atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom;

OG Complex Work Unit Drawing
represents a bicyclic heterocycle selected from the group consisting of dihydrobenzooxazin-2-yl, benzodioxan-2-yl, dihydrobenzofuran-2-yl, dihydrobenzofuran-3-yl and benzodioxol-2-yl;
m represents 0 or an integer of 1 to 4,
n represents 0 or an integer of 1 to 4, and
i represents 0 or an integer of 1 to 11,
wherein R2's may be the same or different when m is 2 or more, R3's may be the same or different when n is 2 or more, and R5's may be the same or different when i is 2 or more; and
R12 and R13 each independently represent (1) C1-4 alkyl which may be oxidized, (2) a halogen atom, (3) trihalomethyl, (4) hydroxyl which may be protected, (5) amino which may be protected, (6) phenyl which may be substituted, (7) pyridyl which may be substituted, or (8) a hydrogen atom, or R12 and R13 are taken together to represent (1) oxo, (2) C2-5 alkylene which may be substituted by a substituent, wherein one carbon atom thereof may be replaced with an oxygen atom, a nitrogen atom, or a sulfur atom, or (3) C1-6 alkylidene which may be substituted, and
wherein when R12 and R13 each simultaneously represent a hydrogen atom, the carboxylic acid compound represented by formula (I) represents a compound selected from the group consisting of the following compounds (1)-(32);
(1) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-fluorophenyl)acetic acid,
(2) (4-chloro-3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic acid,
(3) (4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic acid,
(4) (4-chloro-3-((5-chloro-2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic acid,
(5) (4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic acid,
(6) (4-chloro-3-((2-fluoro-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic acid,
(7) (4-chloro-3-((2,5-difluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic acid,
(8) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-methylphenyl)acetic acid,
(9) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-5-methylphenyl)acetic acid,
(10) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic acid,
(11) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic acid,
(12) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-5-methylphenyl)acetic acid,
(13) (5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-fluorophenyl)acetic acid,
(14) (5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-methylphenyl)acetic acid,
(15) (5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-fluorophenyl)acetic acid,
(16) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic acid,
(17) (5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-fluorophenyl)acetic acid,
(18) (5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-methylphenyl)acetic acid,
(19) (5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-methylphenyl)acetic acid,
(20) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-methylphenyl)acetic acid,
(21) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-fluorophenyl)acetic acid,
(22) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-fluorophenyl)acetic acid,
(23) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-methylphenyl)acetic acid,
(24) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-5-methylphenyl)acetic acid,
(25) (4-chloro-3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-lymethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,
(26) (2-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic acid,
(27) (2-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic acid,
(28) (2-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic acid,
(29) (4-chloro-3-((4-((3R)-2,3-dihydro-1-benzo furan-3-lymethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,
(30) (4-chloro-3-((2,6-dimethyl-4-(((3R)-5-methyl-2,3-dihydro-1-benzofuran-3-ly)methoxy)benzoyl)amino)phenyl)acetic acid,
(31) (4-chloro-3-((4-((2S)-2,3-dihydro-1-benzofuran-2-lymethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid, and
(32) (3-((4-(1,3-benzodioxo 1-2-lymethoxy)-2,6-dimethylbenzoyl)amino)-4-chlorophenyl)acetic acid, a salt thereof.