Methods, Compounds, and Compositions for the Treatment of Angiotensin-Related Diseases

Patent metadata

Field	Value
Publication number	US-2016016946-A1
Application number	US-201414773041-A
Country	US
Kind code	A1
Filing date	Mar 15, 2014
Priority date	Mar 15, 2013
Publication date	Jan 21, 2016
Grant date	—

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

1 - 33 . (canceled)

34 . 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;
ring C is an optionally substituted aryl ring;
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—, or —[C(R c )(R d )] n — with n being 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 or carboxy, provided that R a and R b can also join to form a ring of up to 6 atoms;
R c and R d are independently selected from a group consisting of hydrogen, alkyl, aryl, or heteroaryl, provided that R c and R d can also join to 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, or 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.

35 . The compound of claim 34 , 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 or carboxy, provided that R 10 and R 11 can also be joined to form a carbocyclic or heterocyclic ring, and further provided that the ring can be selected from a group consisting of:

wherein
R 12 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido; and
R 13 is hydrogen, alkyl, aryl or heteroaryl;
R 14 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl,
aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; and
R f , R g , R h , and R i , are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl; and
ring B is selected from a group consisting of:

or a pharmaceutically acceptable salt thereof.

36 . The compound of claim 35 , having a general formula selected from a group consisting of:

or a pharmaceutically acceptable salt thereof.

37 . The compound of claim 35 , having a general formula 2a,b or 3a,b:

or a pharmaceutically acceptable salt thereof.

38 . The compound of claim 35 , having the general formula 4a,b, 5a,b or 6a,b:

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.

39 . The compound of claim 38 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.

40 . The compound of claim 35 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

41 . The compound of claim 35 , wherein the compound is selected from the group consisting of:

42 . A pharmaceutical composition comprising:
a compound according to claim 34 and a pharmaceutically acceptable carrier.

43 . A method to ameliorate at least one symptom associated with an angiotensin-related disease or disorder in a patient or postpone or prevent the onset of at least one symptom of the disease; or to reduce blood glucose in a patient in need thereof; or to enhance bone marrow progenitor cell proliferation in a patient in need thereof; or to reduce fat accumulation in a patient in need thereof; or to treat cancer in a patient in need thereof, comprising administering to the patient an amount effective of the compound of claim 34 to provide the needed therapeutic benefit.

44 . The method according to claim 43 , wherein the method is to ameliorate at least one symptom associated with an angiotensin-related disease or disorder, or to postpone or prevent the onset of at least one symptom of the disea

Assignees

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

Inventors

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

Classifications

• C07D213/52

  Sulfur atoms · 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

• C07D213/36

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

• A61K31/496

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