Heterobicyclic compounds and their use for the treatment of tuberculosis

Patent metadata

Field	Value
Publication number	US-10464926-B2
Application number	US-201816029850-A
Country	US
Kind code	B2
Filing date	Jul 9, 2018
Priority date	Aug 28, 2014
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

Abstract

It is an object of the present invention to provide a compound having an excellent antibacterial activity against tuberculosis bacteria, multidrug-resistant tuberculosis bacteria and/or non-tuberculous mycobacteria. Disclosed is a compound of the general formula (1):

wherein each symbol is defined as described in the attached specification, or a salt thereof.

First claim

The invention claimed is:

1. A method for treating tuberculosis, comprising administering to a patient an effective amount of a compound of the general formula (1):

or a salt thereof,
wherein R 1 is
(1) hydrogen,
(2) amino which may have one or two of the same or different lower alkyl or
(3) lower alkyl;

R 2 is
(1) halogen,
(2) amino which may have one or two of the same or different lower alkyl,
(3) lower alkyl,
(4) lower alkoxy or
(5) hydroxy;

m is an integer of 0 to 3;
provided that when m is 2 or 3, R 2 may be different from each other;

a partial structure (Y) of formula (1) is represented by the following partial structure:

wherein *1 is a binding point to a partial structure (X) of formula (1) and *2 is a binding point to Ring A, and the partial structure (X) of formula (1) is represented by the following partial structure:

wherein * is a binding point to X 1 ,

the partial structure (Y) is any one of the structures selected from the group consisting of the following formulae (Y1) to (Y8):

wherein R 3a is
(1) hydrogen,
(2) carboxy,
(3) halogen,
(4) lower alkyl, which may have one or more hydroxy, or
(5) cyano;

R 3b and R 3c are each independently
(1) hydrogen,
(2) lower alkyl, or
(3) —C(═O)—R 6 ;

R G11 and R G12 are each independently hydrogen or lower alkyl;
the total number of carbon atoms in R G11 and R G12 is 0 to 5;

R 5 is
(1) hydrogen,
(2) lower alkyl or
(3) lower alkanoyl;

R 6 is
(1) lower alkoxy or
(2) lower alkyl, wherein the lower alkyl may have amino which may have one
or two of the same or different lower alkyl;

R 7 is
(1) hydrogen,
(2) amino,
(3) lower alkanoyl or
(4) lower alkyl;

R 4 is
(1) amino which may have one or two of the same or different lower alkyl,
(2) halogen,
(3) cyano,
(4) lower alkyl,
(5) oxo,
(6) —O—R 8 or
(7) —O—C(═O)—R 9 ;
R 8 is
(1) hydrogen,
(2) lower alkyl,
(3) —PH(═O)OH or
(4) benzyl which may have one or more of the same or different lower alkoxy;

R 9 is
(1) lower alkyl,
(2) -G 2 -COOH,
(3) amino which may have one or two of the same or different lower alkyl,
(4) lower alkoxy or
(5) pyrazinyl;
 G 2 is lower alkylene;

n is an integer of 0 to 8;
provided that when n is 2 or more, each of R 4 , R 8 , R 9 , and G 2 may be different from each other and may be substituted on the same carbon atom;

X 2 is N or CH;
provided that when X 2 is CH, H of the group may be replaced with R 4 which is defined as above, wherein multiple R 4 s in formula (1) may be the same or different from each other;

Ring A is
(1) aryl which may have one or more substituents, or
(2) heterocyclyl which may have one or more substituents; and

a moiety of formula:

represents single bond or double bond.

2. The method of claim 1 , wherein the partial structure (X) is any one of the structures selected from the group consisting of the following formulae (X1) to (X6):

wherein the symbols are as defined in the above and claim 1 .

3. The method of claim 1 , wherein Ring A is aryl or heterocyclyl which may have 1 to 5 substituents independently selected from:
(a) halogen;
(b) cyano;
(c) nitro;
(d) hydroxy;
(e) lower alkyl which may have one or more substituents independently selected from:
(i) halogen,
(ii) hydroxy,
(iii) lower alkoxy, and
(iv) aryloxy which may have one or more of the same or different halogen;

(f) lower alkoxy which may have one or more substituents independently selected from:
(i) halogen,
(ii) lower alkoxy which may have one or more of the same or different lower alkoxy,
(iii) aryloxy which may have one or more of the same or different halogen,
(iv) heterocyclyl which may have one or more of the same or different lower alkyl which may have one or more of the same or different halogen, and
(v) amino which may have one or two of the same or different lower alkyl;

(g) lower alkoxycarbonyl;
(h) lower alkylsulfanyl;
(i) aryl which may have one or more of the same or different halogen;
(j) aryloxy; and
(k) aralkyloxy which may have one or more substituents independently selected from:
(i) halogen,
(ii) lower alkyl which may have one or more of the same or different halogen, and
(iii) lower alkoxy which may have one or more of the same or different halogen.

4. The method of claim 1 , wherein R 1 is hydrogen.

5. The method of claim 1 , wherein R 2 is halogen.

6. The method of claim 1 , wherein m is 0, 1 or 2.

7. The method of claim 1 , wherein n is 0, 1 or 2.

8. The method of claim 1 , wherein the partial structure (X) is a structure of a formula selected from the group consisting of the formulae (X1-1), (X1-2), (X1-3), (X1-4), (X1-6), and (X1-7):

wherein * is binding point to X 1 ;
R 1 is hydrogen;
R 2 is substituent selected from (1) halogen or (2) lower alkyl;
provided that when R 2 may be multiple, each of them may be different from each other;
the partial structure (Y) is a structure of a formula selected from the group consisting of the formulae (Y1-1), (Y2-1), (Y3-1), (Y4-1), (Y5-1), and (Y6-1):

wherein *1 is binding point to the partial structure (X);
*2 is binding point to Ring A;
R 5 is hydrogen;
R 3a is (1) hydrogen or (2) halogen;
R 3b and R 3c are each hydrogen;
R 7 is hydrogen;
R 4 is substituent selected from (1) halogen, (2) —O—R 8 , (3) —O—C(═O)—R 9 , or (4) cyano;
R 8 is (1) hydrogen or (2) lower alkyl;
R 9 is (1) lower alkyl or (2) lower alkoxy;
n is an integer of 0 to 2;
provided that when n is 2, each of R 4 , R 8 , and R 9 may be different from each other and may be substituted on the same carbon atom;
X 2 is N or CH;
provided that when X 2 is CH, H of the group may be substituted with R 4 which is defined as above or may be different from the other R 4 ; and
Ring A is phenyl or pyridyl which may have 1 to 3 groups independently selected from:
(a) halogen;
(b) lower alkoxy which may have (i) halogen and (ii) lower alkoxy; or
(c) aralkyloxy which may have one or more of the same or different lower alkoxy which may have one or more of the same or different halogen; or
quinolyl which may have 1 to 2 halogen.

9. The method of claim 1 , wherein a compound of the general formula (1) or a salt thereof is selected from the group consisting of the following compounds:
5-{[4-amino-1-(3,5-dichloropyridin-2-yl)piperidin-4-yl]methoxy}-8-fluoro-3,4-dihydroquinolin-2(1H)-one;
5-{[4-amino-1-(4-chloro-2-fluorophenyl)piperidin-4-yl]methoxy}-8-chloro-3,4-dihydroquinolin-2(1H)-one;
5-{[4-amino-1-(4-chloro-2-fluorophenyl)piperidin-4-yl]methoxy}-8-chloroquinolin-2(1H)-one;
5-{[1-(4-chlorophenyl)-4-hydroxypiperidin-4-y

Assignees

• Otsuka Pharma Co Ltd

Inventors

• Shimizu Hiroshi
• Kawano Yoshikazu
• Ishikawa Shunpei
• Uematsu Yukitaka
• Shinohara Toshio
• Itotani Motohiro
• Haraguchi Yoshikazu
• Takemura Isao
• Kaneshige Atsunori
• Nakai Yuya
• Hariguchi Norimitsu
• Hayashi Yohei
• Matsumoto Makoto

Classifications

• A61P31/06

  for tuberculosis · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07D215/227 Primary

  only one oxygen atom which is attached in position 2 · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title