Phenyl derivative

Patent metadata

Field	Value
Publication number	US-9340499-B2
Application number	US-201514592100-A
Country	US
Kind code	B2
Filing date	Jan 8, 2015
Priority date	Sep 29, 2011
Publication date	May 17, 2016
Grant date	May 17, 2016

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.

First claim

The invention claimed is:

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 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 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;
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

Assignees

• Ono Pharmaceutical Co

Inventors

• Naganawa Atsushi
• Kusumi Kensuke
• Otsuki Kazuhiro
• Sekiguchi Tetsuya
• Kakuuchi Akito
• Shinozaki Koji
• Yamamoto Hiroshi
• Nonaka Shigeyuki

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title