Methods, compounds, and compositions for the treatment of angiotensin-related diseases

Patent metadata

Field	Value
Publication number	US-9732074-B2
Application number	US-201414773041-A
Country	US
Kind code	B2
Filing date	Mar 15, 2014
Priority date	Mar 15, 2013
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

Disclosed are small molecule non-peptidic compounds, as well as methods and compositions for the treatment of angiotensin-related diseases and disorders, including cardiovascular diseases, metabolic diseases, gastrointestinal diseases, renal diseases, inflammatory/autoimmune diseases, neurological diseases, bone marrow diseases and cancer.

First claim

What is claimed is:

1. A compound having the general formula 1:

wherein:
ring A is a five-membered or six-membered heteroaryl or heterocyclyl ring containing either a combination of two non-adjacent nitrogen or oxygen atoms, or a combination of three or four nitrogen or oxygen atoms;
ring B is a five-membered or six-membered heteroaryl ring that contains at least one nitrogen atom;
A 1 , A 2 , A 3 , A 4 are independently selected from a group consisting of ═N—, —C(═O)—, —C(R a )═, ═C(R b )—, —C(R c )(R d )—N(R e )—, —C(R c )(R d )—O—, and —[C(R c )(R d )] n —, wherein n is 1 or 2;
X 1 —X 2 is —(R 6 )C—N—, —N—C(R 6 )—, —N—N—,—N—O—, —O—N—,—N—S—or —S—N—;
X 3 is —(R 7 )C═C(R 8 )—, —O—, —S—, or —N(R 9 )—;
Z is —O—, —NH— or a bond to R 5 ;
R a and R b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy,
or R a and R b , together with the atoms to which they are attached, form a ring of up to 6 atoms;
R c and R d are independently selected from a group consisting of hydrogen, alkyl, aryl, and heteroaryl,
or R c and R d , together with the atoms to which they are attached, form a ring of up to 6 atoms;
R e is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl;
R 1 , R 3 , R 4 , R 6 , R 7 , and R 8 are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo, cyano, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, and aryloxyalkyl;
R 2 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, alkoxy, trifluoromethoxy, perfluoroalkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl;
R 5 is alkyl, aryl, heteroaryl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, or aryloxyalkyl; and
R 9 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein:
ring A is selected from a group consisting of:

wherein:
R 10 and R 11 are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy,
or R 10 and R 11 , together with ring A to which they are attached, form:

wherein
R f , R g , R h , and R i ,are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, and aryloxyalkyl;

R 12 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido;
R 13 is hydrogen, alkyl, aryl or heteroaryl;
R 14 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; and

ring B is selected from a group consisting of:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , having a general formula selected from a group consisting of:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 , having a general formula of 2a, 2b, 3a or 3b:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2 , having the general formula of 4a, 4b, 5a, 5b, 6a or 6b:

wherein
R 15 is alkyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, trifluoromethyl or pentafluoroethyl; and
R 16 is hydrogen, hydroxy, methoxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, amino, alkylamino, or dialkylamino;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , wherein R 10 , R 11 and R 12 are hydrogen, or R 15 is trifluoromethyl, or R 16 is ethyl, or Z is selected from the group consisting of —O— and —NH—.

7. The compound of claim 2 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 2 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 2 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 2 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 2 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 2 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound accordi

Assignees

• Univ Southern California
• Petasis Nicos A
• Rodgers Kathleen E
• Louie Stan G
• Dizerega Gere S
• Gaffney Kevin J

Inventors

• Petasis Nicos A
• Rodgers Kathleen E
• Louie Stan G
• Dizerega Gere S
• Gaffney Kevin J

Classifications

• C07D213/36

  Radicals substituted by singly-bound nitrogen atoms (nitro radicals C07D213/26) · CPC title

• C07D401/06 Primary

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

• C07D417/06 Primary

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

• C07D213/52

  Sulfur atoms · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title