IP Library › Granted Patent US 9,340,499

Granted Patent B2

US 9,340,499 · App. 14/592,100 · Granted May 17, 2016

Phenyl derivative

Inventors: Atsushi Naganawa (Osaka, JP); Kensuke Kusumi (Osaka, JP); Kazuhiro Otsuki (Osaka, JP); Tetsuya Sekiguchi (Osaka, JP); Akito Kakuuchi (Osaka, JP); Koji Shinozaki (Osaka, JP); Hiroshi Yamamoto (Osaka, JP); Shigeyuki Nonaka (Osaka, JP)

Assignee: ONO PHARMACEUTICAL CO., LTD.

C07D205/04 C07D207/12 C07D207/16 C07D211/48 C07D211/52 C07D401/12 C07D405/12

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Quick Facts

Patent No.: US 9,340,499
App. No.: 14/592,100
Granted: May 17, 2016
Kind: B2

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Abstract

The compound represented by the formula (I-1): wherein all the symbols have the same meanings as described in the specification, has two cyclic groups, particularly phenoxy groups at specific substitution positions and thus has high human S1P 2 antagonistic activity. The compound may therefore be used as a therapeutic agent for S1P 2 -mediated diseases such as diseases resulting from vascular constriction, fibrosis and respiratory diseases.

Claims (53)

1. A compound represented by the formula (I-1):

wherein R 1 represents (1) a C1-8 alkyl group which may be substituted with 1 to 5 R 21 group(s), (2) a C2-8 alkenyl group which may be substituted with 1 to 5 R 21 group(s), (3) a C2-8 alkynyl group which may be substituted with 1 to 5 R 21 group(s), (4) a C3-7 carbocycle which may be substituted with 1 to 5 substituent(s) selected from the group consisting of a C1-4 alkyl group, a C1-4 haloalkyl group, a C1-4 alkoxy group and a halogen atom, or (5) —CONR 31 R 32 ;

R 21 represents (1) a halogen atom, (2) —OR 22 (in the group, R 22 represents (1) a hydrogen atom, (2) a C1-4 alkyl group or (3) a C1-4 haloalkyl group), (3) —NR 23 R 24 (in the group, R 23 and R 24 each independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group) or (4) an oxo group;

R 31 and R 32 each independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group;

R 2 represents (1) a hydrogen atom, (2) a C1-4 alkyl group or (3) a C1-4 haloalkyl group;

R 3 and R 4 each independently represent (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) a hydroxy group, (6) -L-CONR 6 R 7 , (7) -L-SO 2 R 8 or (8) -L-COOR 9 ;

L represents (1) a bond, (2) a group represented by the formula:

wherein A represents (1) a bond or (2) an oxygen atom; R 12 and R 13 each independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, (3) a hydroxy group or (4) NH 2 or (5) R 12 and R 13 together with the carbon atom to which they are attached may form a C3-7 carbocycle; and the arrow on the right hand side binds to —CONR 6 R 7 , —SO 2 R 8 or —COOR 9 , (3) a C2-4 alkenylene group, (4) a —O—C2-4 alkenylene group, (5) an oxygen atom or (6) a nitrogen atom which may be substituted with a C1-4 alkyl group;

R 6 and R 7 each independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a hydroxy group, (5) —CONR 15 R 16 , (6) —SO 2 NR 15 R 16 , (7) —COR 17 or (8) —SO 2 R 17 , or R 6 and R 7 together with the nitrogen atom to which they are attached may form a 4- to 7-membered nitrogen-containing saturated heterocycle that may be substituted with a hydroxy group;

R 8 represents (1) a C1-4 alkyl group, (2) a C1-4 haloalkyl group or (3) NR 10 R 11 ;

R 9 represents (1) a hydrogen atom or (2) a C1-8 alkyl group;

R 10 and R 11 each independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, (3) —CONR 15 R 16 , (4) —SO 2 NR 15 R 16 , (5) —COR 17 or (6) —SO 2 R 17 ;

the ring 1 and the ring 2 each independently represent a 5- to 7-membered cyclic group;

R 14 represents (1) a hydrogen atom or (2) a hydroxy group;

R 15 and R 16 each independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group or (3) a 5- to 7-membered cyclic group;

R 17 represents (1) a C1-4 alkyl group or (2) a 5- to 7-membered cyclic group;

M 1 and M 2 each independently represent (1) a bond, (2) —C(O)—, (3) —O—, (4) —S—, (5) —C(O)O—, (6) —CH 2 O— or (7) —C(O)NH—;

n represents an integer of 1 to 2;

m represents an integer of 1 to 2;

p represents an integer of 0 to 5;

q represents an integer of 0 to 5;

t represents an integer of 1 to 4;

when p is 2 or more, a plurality of R 3 groups may be the same or different;

when q is 2 or more, a plurality of R 4 groups may be the same or different; and

when t is 2 or more, a plurality of R 12 and R 13 groups may be respectively the same or different;

or a salt thereof.

2. The compound according to claim 1 , which is represented by the following formula:

wherein all the symbols have the same meanings defined in claim 1 .

3. The compound according to claim 2 , wherein R 1 is (1) a C1-8 alkyl group which may be substituted with 1 to 5 R 21 group(s) or (2) a C3-7 carbocycle which may be substituted with 1 to 5 substituent(s) selected from the group consisting of a C1-4 alkyl group, a C1-4 alkoxy group, a halogen atom and a trifluoromethyl group.

4. The compound according to claim 1 , which is (1) 4-(2-ethylbutyl)-N-{3-[4-(ethylcarbamoyl)phenoxy]-5-(4-fluorophenoxy)phenyl}-4-hydroxy-1-piperidine carboxamide, (2) 4-[3-(4-fluorophenoxy)-5-({[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]benzoic acid, (3) 4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-{4-[(4-hydroxy-1-piperidinyl)carbonyl]phenoxy}phenyl]-4-hydroxy-1-piperidine carboxamide, (4) 2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoic acid, (5) 1-{4-[3-(4-fluorophenoxy)-5-({[4-hydroxy-4-(3-pentanyl)-1-piperidinyl]carbonyl}amino)phenoxy]phenyl}cyclopropanecarboxylic acid, (6) 2-{4-[3-(4-fluorophenoxy)-5-{[(3-hydroxy-3-isobutyl-1-azetidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoic acid, (7) 4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]benzoic acid, (8) 2-{4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoic acid or (9) 2-(4-{[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}benzoyl]oxy}phenyl)-2-methylpropanoic acid.

5. A compound of the following formula:

wherein R 1 represents (1) a C1-8 alkyl group which may be substituted with 1 to 5 R 21 group(s), (2) a C2-8 alkenyl group which may be substituted with 1 to 5 R 21 group(s), (3)a C2-8alkynyl group which may be substituted with 1 to 5 R 21 group(s), (4) a C3-7 carbocycle which may be substituted with 1 to 5 substituent(s) selected from the group consisting of a C1-4 alkyl group, a C1-4 haloalkyl group, a C1-4 alkoxy group and a halogen atom, or (5) —CONR 31 R 32 ;

R 31 and R 32 each independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group;

R 3 and R 4 each independently represent (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) a hydroxy group, (6) -L—CONR 6 R 7 , (7) -L—SO 2 R 8 or (8) -L—COOR 9 ;

L represents (1) a bond, (2) a group of the formula:

wherein A represents (1) a bond or (2) an oxygen atom; R 12 and R 13 each independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, (3) a hydroxy group or (4) NH 2 or (5) R 12 and R 13 together with the carbon atom to which they are attached may form a C3-7 carbocycle; and the arrow on the right hand side binds to —CONR 6 R 7 , —SO 2 R 8 or —COOR S , (3) a C2-4alkenylene group, (4) a —O—C2-4 alkenylene group, (5) an oxygen atom or (6) a nitrogen atom which may be substituted with a C1-4 alkyl group;