Amide derivative

Patent metadata

Field	Value
Publication number	US-11040937-B2
Application number	US-201515121687-A
Country	US
Kind code	B2
Filing date	Feb 27, 2015
Priority date	Feb 28, 2014
Publication date	Jun 22, 2021
Grant date	Jun 22, 2021

Abstract

The present invention provides a useful medicament for the treatment and/or prophylaxis of a disease associated with the enhancement of OPN production including cancer, which comprises a compound of formula:wherein R1, R2, R3, R4, R5, R6, R7, m, n, p, X, and Y are as defined in the specification, a pharmaceutically acceptable salt thereof.

First claim

The invention claimed is:

1. A compound of formula:

wherein
R 1 is cyclohexyl, tetrahydropyranyl, pyridyl, thienyl, or phenyl wherein the cyclohexyl, tetrahydropyranyl, pyridyl, thienyl, and phenyl are unsubstituted or substituted with one group or the same or different two or more groups selected independently from the group consisting of halogen, hydroxy, amino, C 1-4 acylamino, C 1-6 alkyl, and C 1-6 alkoxy at any replaceable positions;
R 2 is hydrogen atom, amino, or hydroxy that is linked at the 2-position of the benzene ring;
OR 3 is linked at the 3-position of the benzene ring, and R 3 is phenyl which is unsubstituted or substituted with one group or the same or different two or more groups selected independently from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy at the 3- and/or 4-position(s);
R 4 is hydrogen atom or halogen;
R 6 and R 7 are independently hydrogen atom or C 1-4 alkyl;
n is 0 to 4, provided that when n is 1 to 4 and R 6 is C 1-4 alkyl, the terminal carbon atom of R 6 may be combined with any one carbon atom of the alkylene group in the parenthesis for n to form a 4- to 6-membered ring;
m is 0 or 1;
p is 0 or 1;
X is O, or when p is 0 and R 2 is amino or substituted amino which is linked at the 2-position of the benzene ring, X may be CH connecting the nitrogen atom in R 2 to form a pyrrole ring; and
Y is CH 2 or NH;

or a pharmaceutically acceptable salt thereof, provided that the following compound is excluded:
N-(3-(2-amino-3-(4-hydroxyphenoxy)phenyl)-3-oxopropyl)-4-hydroxybenzamide.

2. The compound according to claim 1 represented by formula (I):

wherein R 1 , R 2 , R 3 , R 4 , and X is as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is phenyl which is substituted with the group(s) selected independently from halogen, hydroxy, amino, C 1-4 acylamino, or C 1-6 alkoxy at the 3- and/or 4-position(s).

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is phenyl which is substituted with the group(s) selected independently from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy at the 3- and/or 4-position(s).

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 4 is hydrogen atom.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein m is 1, X is O, and p is 1.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein n is 1 to 4, and R 6 is C 1-4 alkyl and further the terminal carbon atom of R 6 is combined with any one carbon atom of the alkylene group in the parenthesis for n to form a 4- to 6-membered ring.

8. A compound selected from the group consisting of:
4-hydroxy-N-(2-(7-(4-hydroxyphenoxy)-1H-indol-3-yl)ethyl)benzamide;
N-(3-(2,3-dihydroxyphenyl)-3-oxopropyl)-4-(4-hydroxyphenoxy)benzamide;
N-(3-(2-amino-3-(4-hydroxyphenoxy)phenyl)-3-oxopropyl)-4-methoxybenzamide;
N-(3-(2-amino-3-(4-methoxyphenoxy)phenyl)-3-oxopropyl)-4-methoxybenzamide;
N-(3-(2-amino-3-(4-methoxyphenoxy)phenyl)-3-oxopropyl)-4-hydroxybenzamide;
N-(3-(2-amino-3-(4-hydroxyphenoxy)phenyl)-3-oxopropyl)-3-methoxybenzamide;
N-(3-(2-amino-3-(4-hydroxyphenoxy)phenyl)-3-oxopropyl)-acetamide;
N-(3-(2-amino-3-(4-hydroxyphenoxy)phenyl)-3-oxopropyl)-4-fluorobenzamide;
N-(3-(2-amino-3-(4-hydroxyphenoxy)phenyl)-3-oxopropyl)-cyclohexanecarboxamide;
N-(3-(2-amino-3-(4-hydroxyphenoxy)phenyl)-3-oxopropyl)-(tetrahydro-2H-pyran-4-yl)-carboxamide;
N-(3-(2-amino-3-methoxyphenyl)-3-oxopropyl)-4-hydroxybenzamide;
N-(3-(2-amino-3-hydroxyphenyl)-3-oxopropyl)-4-hydroxybenzamide;
N-(3-(2-amino-3-(4-methylphenoxy)phenyl)-3-oxopropyl)-4-hydroxybenzamide;
N-(3-(2-amino-3-(4-(trifluoromethyl)phenoxy)phenyl)-3-oxopropyl)-4-hydroxybenzamide;
N-(3-(2-amino-3-(3,4-dimethoxyphenoxy)phenyl)-3-oxopropyl)-4-hydroxybenzamide;
N-(3-(2-amino-3-(4-chlorophenoxy)phenyl)-3-oxopropyl)-4-hydroxybenzamide;
N-(3-(2-amino-3-(4-chlorophenoxy)phenyl)-3-oxopropyl)-4-aminobenzamide;
N-(3-(2-amino-3-(4-chlorophenoxy)phenyl)-3-oxopropyl)-4-acetylaminobenzamide;
N-(2-(3-(4-methoxyphenoxy)benzoylamino)ethyl)-4-hydroxybenzamide;
N-(2-(2-(4-methoxyphenoxy)benzoylamino)ethyl)-4-hydroxybenzamide;
N-(4-hydroxyphenyl)-4-(3-(4-chlorophenoxy)phenylamino)-4-oxobutanamide;
N-(3-(3-(4-chlorophenoxy)phenylamino)-3-oxopropyl)-4-hydroxybenzamide;
N-(2-(3-(4-methoxyphenoxy)phenylamino)-2-oxyethyl)-4-hydroxybenzamide;
N-(3-(3-(4-methoxyphenoxy)phenylamino)-3-oxopropyl)-4-hydroxybenzamide;
N-(4-(3-(4-methoxyphenoxy)phenylamino)-4-oxobuthyl)-4-hydroxybenzamide;
N-(2-(2-(4-methoxyphenoxy)phenylamino)-2-oxoethyl)-4-hydroxybenzamide;
N-(3-(2-(4-methoxyphenoxy)phenylamino)-3-oxopropyl)-4-hydroxybenzamide;
N-(3-(4-(4-methoxyphenoxy)phenylamino)-3-oxopropyl)-4-hydroxybenzamide;
N-(3-(4-chlorophenoxy)phenyl)-1-(4-hydroxyphenylcarbonyl)azetidine-3-carboxamide;
N-(3-(4-chlorophenoxy)phenyl)-1-(4-hydroxyphenylcarbonyl)pyrrolidine-3-carboxamide;
N-(3-(4-chlorophenoxy)phenyl)-1-(4-hydroxyphenylcarbonyl)piperidine-3-carboxamide;
N-(3-(4-chlorophenoxy)phenyl)-1-(4-hydroxyphenylcarbonyl)pyrrolidine-2-carboxamide;
N-(3-(3-(4-chlorophenoxy)phenylamino)-3-oxopropyl)thiophene-2-carboxamide;
N-(3-(3-(4-chlorophenoxy)phenylamino)-3-oxopropyl)thiophene-3-carboxamide;
N-(3-(3-(4-chlorophenoxy)phenylamino)-3-oxopropyl)pyridine-4-carboxamide; and
N-(3-(3-(3,4-dichlorophenoxy)phenylamino)-3-oxopropyl)-4-hydroxybenzamide;

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.

10. The pharmaceutical composition according to claim 9 , wherein the compound according to claim 1 is present in an amount effective for use in the treatment of a disease associated with the enhancement of the osteopontin production.

11. A medicament for treating a disease associated with the enhancement of the osteopontin production, comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

12. The medicament according to claim 11 wherein the compound is a compound of formula (I):

wherein R 1 , R 2 , R 3 , R 4 , and X are as defined in claim 1 .

13. The medicament according to claim 11 wherein the disease is selected from cancer, hepatitis, arteriosclerosis, multiple sclerosis, arthritis, rheumatism, pulmonary fibrosis, osteoporosis, or urolithiasis.

Assignees

• Univ Tohoku
• Univ Gunma Nat Univ Corp
• Fuso Pharmaceutical Ind

Inventors

• Kikuchi Haruhisa
• Oshima Yoshiteru
• Hattori Toshio
• Kubohara Yuzuru
• Yamada Osamu
• Zhang Jing
• Matsushita Yoshihisa
• Kida Shinya

Classifications

• A61K31/4409

  only substituted in position 4, e.g. isoniazid, iproniazid · CPC title

• A61K31/166

  having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol · CPC title

• A61K31/4045

  Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin · CPC title

• A61K31/381

  having five-membered rings · CPC title

• A61K31/165

  having aromatic rings, e.g. colchicine, atenolol, progabide · CPC title