Phenyl derivative

Patent metadata

Field	Value
Publication number	US-2019030010-A1
Application number	US-201816148647-A
Country	US
Kind code	A1
Filing date	Oct 1, 2018
Priority date	Sep 29, 2011
Publication date	Jan 31, 2019
Grant date	—

Abstract

The compound of 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

1 . A method of preparing a compound of formula (I-A):

wherein
R 1 is (1) a C1-8 alkyl group which may be substituted with 1 to 5 R 21 groups, (2) a C2-8 alkenyl group which may be substituted with 1 to 5 R 21 groups, (3) a C2-8 alkynyl group which may be substituted with 1 to 5 R 21 groups, (4) a C3-7 carbocycle which may be substituted with 1 to 5 substituents 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 is (1) a halogen atom, (2) —OR 22 (wherein, R 22 is (1) a hydrogen atom, (2) a C1-4 alkyl group or (3) a C1-4 haloalkyl group), (3) —NR 23 R 24 (wherein, R 23 and R 24 each independently are (1) a hydrogen atom or (2) a C1-4 alkyl group) or (4) an oxo group;
R 31 and R 32 each independently are (1) a hydrogen atom or (2) a C1-4 alkyl group;
R 3 and R 4 each independently are (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 ;
R 5 is (1) a halogen atom, (2) a C1-4 alkyl group or (3) a C1-4 haloalkyl group;
L is (1) a bond, (2) a group represented by the formula:

wherein A is (1) a bond or (2) an oxygen atom; R 12 and R 13 each independently are (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 are (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 is (1) a C1-4 alkyl group, (2) a C1-4 haloalkyl group or (3) NR 10 R 11 ;
R 9 is (1) a hydrogen atom or (2) a C1-8 alkyl group;
R 10 and R 11 each independently are (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 are a 5- to 7-membered cyclic group;
R 15 and R 16 each independently are (1) a hydrogen atom, (2) a C1-4 alkyl group or (3) a 5- to 7-membered cyclic group;
R 17 is (1) a C1-4 alkyl group or (2) a 5- to 7-membered cyclic group;
n is an integer of 1 to 2;
m is an integer of 1 to 2;
p is an integer of 0 to 5;
q is an integer of 0 to 5;
r is an integer of 0 to 4;
t is 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;
when r is 2 or more, a plurality of R 5 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,

wherein the method comprises:
reacting a compound of formula (E):

wherein T is a protecting group of the amino group and the other symbols have the same definitions as above, in the presence of a base with a compound of formula (V)

wherein all symbols have the same definitions as above, in an organic solvent.

2 . The method according to claim 1 , wherein the ring 1 and the ring 2 each independently are (1) a benzene, (2) cyclohexane or (3) pyridine ring.

3 . The method according to claim 1 , wherein the compound of formula (I-A) is 2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoic acid or a salt thereof.

4 . The method according to claim 1 , wherein the protecting group T comprises a carbonyl group.

5 . The method according to claim 4 , wherein the protecting group T is a 2,2,2-trichloroethoxycarbonyl (Troc) group, a phenoxycarbonyl group, or a p-nitrophenoxycarbonyl group.

6 . The method according to claim 2 , wherein the compound of formula (I-A) is 2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoic acid or a salt thereof.

7 . The method according to claim 1 , wherein the ring 1 and the ring 2 each independently are a benzene.

8 . The method according to claim 2 , wherein the ring 1 and the ring 2 each independently are a benzene.

9 . The method according to claim 1 , wherein the base is selected from the group consisting of pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, or a mixture thereof.

10 . The method according to claim 1 , wherein the organic solvent is selected from N,N-dimethylacetamide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, and a mixture thereof.

11 . The method according to claim 2 , wherein the base is selected from the group consisting of pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, or a mixture thereof.

12 . The method according to claim 2 , wherein the organic solvent is selected from N,N-dimethylacetamide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, and a mixture thereof.

13 . The method according to claim 3 , wherein the base is selected from the group consisting of pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, or a mixture thereof.

14 . The method according to claim 3 , wherein the organic solvent is selected from N,N-dimethylacetamide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, and a mixture thereof.

15 . The method according to claim 7 , wherein the base is selected from the group consisting of pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, or a mixture thereof.

16 . The method according to claim 7 , wherein the organic solvent is selected from N,N-dimethylacetamide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, and a mixture thereof.

Assignees

• Ono Pharmaceutical Co

Inventors

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

Classifications

• A61P9/06

  Antiarrhythmics · 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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/08

  Vasodilators for multiple indications · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title