Combination pharmaceutical agents as rsv inhibitors

Patent metadata

Field	Value
Publication number	US-2019192535-A1
Application number	US-201816145768-A
Country	US
Kind code	A1
Filing date	Sep 28, 2018
Priority date	Sep 29, 2017
Publication date	Jun 27, 2019
Grant date	—

Abstract

The present invention relates to pharmaceutical agents administered to a subject either in combination or in series for the treatment of a Respiratory Syncytial Virus (RSV) infection, wherein treatment comprises administering a compound effective to inhibit the function of the RSV and an additional compound or combinations of compounds having anti-RSV activity.

First claim

1 . A method of treating a human respiratory syncytial virus infection in a subject in need thereof, comprising administering to the subject a compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) CN;
4) Optionally substituted —C 1 -C 8 alkyl; and
5) Optionally substituted —C 1 -C 8 alkyl —O—R 11 ;

R 2 and R 5 are each independently selected from the group consisting of:
1) Hydrogen; and
2) Optionally substituted —C 1 -C 8 alkyl;

A is selected from the group consisting of:
1) Optionally substituted —C 3 -C 12 cycloalkyl;
2) Optionally substituted —C 3 -C 12 cycloalkenyl;
3) Optionally substituted 3- to 12-membered heterocycloalkyl;
4) Optionally substituted aryl; and
5) Optionally substituted heteroaryl;

R 3 is hydrogen or R 11 ;
R 4 is selected from the group consisting of:
1) Optionally substituted —C 3 -C 12 cycloalkyl;
2) Optionally substituted —C 3 -C 12 cycloalkenyl;
3) Optionally substituted 3- to 12-membered heterocyclyl;
4) Optionally substituted aryl;
5) Optionally substituted heteroaryl;
6) Optionally substituted aryl-O—;
7) Optionally substituted heteroaryl-O;
8) Optionally substituted aryl-C 1 -C 4 -alkyl; and
9) Optionally substituted heteroaryl-C 1 -C 4 -alkyl;

each R 6 is the same or different and independently selected from hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, amino, protected amino, nitro, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 1 -C 8 alkoxy, optionally substituted —NHC 1 -C 8 alkyl, optionally substituted —S—(—C 1 -C 8 alkyl), optionally substituted —SO 2 —(—C 1 -C 8 alkyl), -optionally substituted —SO 2 —NH—(—C 1 -C 8 alkyl), optionally substituted —NH—SO 2 —(—C 1 -C 8 alkyl), —CO 2 R 12 , —NR 13 R 14 , and —CO—NR 13 R 14 ;
R 11 and R 12 are each independently is selected from the group consisting of:
1) Optionally substituted —C 1 -C 8 alkyl;
2) Optionally substituted —C 2 -C 8 alkenyl;
3) Optionally substituted —C 2 -C 8 alkynyl;
4) Optionally substituted —C 3 -C 8 cycloalkyl;
5) Optionally substituted —C 3 -C 8 cycloalkenyl;
6) Optionally substituted 3- to 8-membered heterocycloalkyl;
7) Optionally substituted aryl; and
8) Optionally substituted heteroaryl;

R 13 and R 14 are each independently selected from hydrogen, optionally substituted —C 1 -C 8 -alkyl, optionally substituted —C 2 -C 8 -alkenyl, optionally substituted —C 2 -C 8 -alkynyl; optionally substituted —C 3 -C 8 -cycloalkyl, —C(O)R 12 , —S(O) 2 R 12 , and —S(O) 2 NHR 12 , and optionally substituted —C 1 -C 8 -alkoxy; alternatively, R 13 and R 14 are taken together with the nitrogen they attached to form a heterocyclic ring; and n is 0, 1, 2, 3 or 4;
and a second anti-respiratory syncytial virus agent,
wherein the compound of Formula I and the second agent are administered in a combined amount which is therapeutically effective.

2 . The method of claim 1 , wherein the compound of Formula (I) is represented by Formula Ia or Formula Ib,

or a pharmaceutically acceptable salt thereof.

3 . The method of claim 1 , wherein A is selected from one of the following by removal of two hydrogen atoms:

wherein each of the above shown is optionally substituted when possible.

4 . The method of claim 1 , wherein R 4 is selected from one of the following by removal of one hydrogen atom:

wherein each of the above shown is optionally substituted when possible.

5 . The method of claim 1 , wherein R 4 is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, —CH 3 , —CF 3 , —OCF 3 , —CN, —NH 2 , —OH, —CH 2 N(CH 3 ) 2 , —C(O)CH 3 , optionally substituted —NH—(C 1 -C 6 )alkyl, optionally substituted —NH—(C 1 -C 6 )alkyl-(C 1 -C 6 )alkoxy, optionally substituted —SO 2 —(C 1 -C 6 )alkyl, optionally substituted —SO 2 —NH—(C 1 -C 6 )alkyl, optionally substituted —NH—SO 2 —(C 1 -C 6 )alkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C 1 -C 8 -alkyl, optionally substituted —C 1 -C 8 -alkenyl, optionally substituted —C 3 -C 8 -cycloalkyl, optionally substituted —C 3 -C 8 -cycloalkenyl, and optionally substituted —C 1 -C 8 -alkoxy.

6 . The method of claim 1 , wherein R 4 is substituted by 1 to 3 substituents independently selected from the group consisting of CH 3 , CN, fluoro, chloro, CH 3 O—, CH 3 C(O)—, CH 3 OCH 2 —, CH 3 OCH 2 CH 2 O—, —CF 3 , CF 3 O—,

7 . The method of claim 1 , wherein the compound of Formula I is represented by IIa-1, IIa-2, IIb-1, or IIb-2, or a pharmaceutically acceptable salt thereof,

wherein R 2 , R 3 , R 4 , R 5 , R 6 , n and A are as defined in claim 1 .

8 . The method of claim 1 , wherein the compound of Formula I is represented by Formula IV-1, IV-2, IV-3, or IV-4 or a pharmaceutically acceptable salt thereof,

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and n are as defined in claim 1 .

9 . The method of claim 1 , wherein the compound of Formula I is represented by Formula V-1, V-2, V-3, or V-4,

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and n are as defined in claim 1 .

10 . The method of claim 1 , wherein the compound of Formula I is selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:

Example
Structure

1

2

3

4

Assignees

• Enanta Pharm Inc

Inventors

• Shook Brian C
• Kim In Jong
• Blaisdell Thomas P
• Yu Jianming
• Panarese Joseph
• Lin Kai
• Rhodin Michael H J
• Mcallister Nicole V
• Or Yat Sun

Classifications

• C07K16/11

  Paramyxoviridae (F); Pneumoviridae (F), e.g. respiratory syncytial virus [RSV] · CPC title

• C07D217/14

  other than aralkyl radicals · CPC title

• C07D217/12

  with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring · CPC title

• A61K39/42

  viral · CPC title

• A61K31/5513 Primary

  1,4-Benzodiazepines, e.g. diazepam {or clozapine} · CPC title