Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors

Patent metadata

Field	Value
Publication number	US-9782407-B2
Application number	US-201514687467-A
Country	US
Kind code	B2
Filing date	Apr 15, 2015
Priority date	Dec 31, 2004
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

The present invention provides a method for treating or preventing a condition or disease in a human or an animal subject wherein the condition or disease is associated with lipoprotein metabolism, the method comprising administering to the subject a composition comprising benzylamine compounds.

First claim

We claim:

1. A method for treating a condition or disease in a human or an animal subject wherein the condition or disease is dyslipidemia, atherosclerosis, peripheral vascular disease, hypertriglyceridemia, hypercholesterolemia, hyperbetalipoproteinemia, or hypoalphalipoprotenemia, the method consisting of administering to the subject a composition comprising a therapeutically-effective amount of at least one compound of formula I, or their pharmaceutically-acceptable salts thereof wherein the compound of formula I is

or a salt, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, or any combination thereof, wherein:
A is a substituted or an unsubstituted quinoline moiety having the formula:

wherein R a , in each occurrence, is selected independently from: 1) a halogen; a hydroxyl, or a cyano; 2) an alkyl or an alkoxy, any of which having up to 12 carbon atoms; or 3) CO 2 R 6 ; and p is an integer from 0 to 3, inclusive;
R 1 and R 2 are selected independently from: 1) hydrogen; 2) a substituted or an unsubstituted alkyl, cycloalkyl, haloalkyl, aryl, heterocyclyl, heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR 10 , SO 2 , or CO; 3) CO 2 R 6 , COR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , or CONR 6 R 7 ; or 4) (CHR x ) n R 5 or (CH 2 ) n R d CO 2 R e , wherein n, in each occurrence, is 1, 2, or 3; R x , in each occurrence, is selected independently from an alkyl or an alkoxy, either of which having up to 12 carbon atoms, or hydrogen; R d , in each occurrence, is selected independently from an alkyl, a cycloalkyl, an aryl, a heterocyclyl, or a heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR 10 , SO 2 , or CO; and R e , in each occurrence, is selected independently from an alkyl or a cycloalkyl, either of which having up to 12 carbon atoms, or hydrogen;
or R 1 and R 2 together with the diradical Z to which they are attached form a substituted or an unsubstituted monocyclic or bicyclic moiety comprising up to 12 carbon atoms, and optionally comprising 1, 2, or 3 heteroatoms or heterogroups in addition to Z, selected independently from O, N, S, NR 10 , SO 2 , or CO;
R 3 is selected from: 1) cyano; 2) a substituted alkyl having up to 12 carbon atoms; 3) a substituted or an unsubstituted aryl, or a substituted or an unsubstituted 5-, 6-, or 7-membered heterocyclyl or heteroaryl, any of which having up to 12 carbon atoms, comprising 1, 2, or 3 heteroatoms or heterogroups selected independently from O, N, S, NR 10 , SO 2 , or CO; or 4) CO 2 R 6 , COR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , CONR 6 R 7 , C(S)NR 6 R 7 , C(S)NHC(O)OR 8 , or C(S)SR 8 ; or 5) a substituted or an unsubstituted group selected from 4,5-dihydro-oxazolyl, tetrazolyl, isoxazolyl, pyridyl, pyrimidinyl, oxadiazolyl, thiazolyl, or oxazolyl; wherein any optional substituents is selected independently from a) an alkyl or a haloalkyl, any of which having up to 12 carbon atoms; or b) CO 2 R 9 , wherein R 9 is an alkyl having up to 12 carbon atoms;
wherein when R 3 is an aryl, a heterocyclyl, or a heteroaryl, R 3 is optionally substituted with up to three substituents selected independently from a halide, a hydroxyl, a cyano, an alkoxy having up to 12 carbon atoms, or R 11 ;
R 4 , in each occurrence, is selected independently from: 1) halogen, cyano, or hydroxy; 2) an alkyl, a cycloalkyl, a cycloalkoxy, an alkoxy, a haloalkyl, or a haloalkoxy, any of which having up to 12 carbon atoms; 3) a substituted or an unsubstituted aryl, aralkyl, aryloxy, heteroaryl, or heteroaryloxy, any of which having up to 12 carbon atoms, wherein any heteroaryl or heteroaryloxy comprises at least one heteroatom or heterogroup selected independently from O, N, S, or NR 10 ; or 4) CO 2 R 6 , COR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , CONR 6 R 7 , or (CH 2 ) q NR 6 R 7 , wherein q is an integer from 0 to 5, inclusive;
m is an integer from 0 to 3, inclusive;
or R 4 m is a fused cyclic moiety comprising from 3 to 5 additional ring carbon atoms, inclusive, and optionally comprising at least one heteroatom or heterogroup selected independently from O, N, S, NR 10 , SO 2 , or CO;
R 5 , in each occurrence, is selected independently from: 1) an alkoxy, a haloalkoxy, or a cycloalkyl, any of which having up to 12 carbon atoms; 2) a substituted or an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR 10 , SO 2 , or CO; 3) hydroxyl, NR 6 R 7 , CO 2 R 6 , COR 8 , or SO 2 R 8 ; or 4) a substituted or an unsubstituted heterocycloalkyl comprising from 3 to 7 ring carbon atoms, and from 1 to 3 heteroatoms or heterogroups, inclusive, selected independently from O, N, S, NR 10 , SO 2 , or CO;
R 6 and R 7 , in each occurrence, are selected independently from: 1) hydrogen; 2) an alkyl, a cycloalkyl, or a haloalkyl, any of which having up to 12 carbon atoms; or 3) a substituted or an unsubstituted aryl, aralkyl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR 10 , SO 2 , or CO; or R 6 and R 7 together with the nitrogen atom to which they are attached form a substituted or an unsubstituted cyclic moiety having from 3 to 7 ring carbon atoms, and optionally comprising 1, 2, or 3 heteroatoms in addition to the nitrogen atom to which R 6 and R 7 are bonded, selected independently from O, N, S, or NR 10 ;
R 8 , in each occurrence, is selected independently from: 1) an alkyl, a cycloalkyl, or a haloalkyl, any of which having up to 12 carbon atoms; or 2) a substituted or an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms, wherein any heterocyclyl or heteroaryl comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR 10 , SO 2 , or CO;
R 10 , in each occurrence, is selected independently from: 1) hydrogen; or 2) an alkyl, a cycloalkyl, a haloalkyl, an aryl, or an aralkyl, any of which having up to 12 carbon atoms;
Z is N; or the ZR 1 moiety is S, CO, or SO 2 ;
R 11 is selected independently from:
1) an alkyl, a haloalkyl, a cycloalkyl, or an alkoxycarbonyl, any of which having up to 12 carbon atoms;
2) a substituted or an unsubstituted heteroaryl or heterocyclyl, any of which having up to 12 carbon atoms, comprises at least one heteroatom or heterogroup selected independently from O, N, S, NR 10 , SO 2 , or CO, wherein any substituted heteroaryl or heterocyclyl is substituted with up to three substituents selected independently from an alkyl having up to 12 carbon atoms or a hydroxyl; or
3) —CO—Z 2 —R 13 , —CO—R 12 , —CO—Z 2 —(CH 2 ) r —CO—Z 2 —R 13 , —NR 15 R 16 , —Z 2 —CO—(CH 2 ) r —Z 2 —R 13 , —Z 2 —CO—(CH 2 ) r —CO—Z 2 —R 13 , —O—(CH 2 ) r —CO—Z 2 —R 13 , —O—(CH 2 ) r —R 14 , —O—R 12 —(CH 2 ) r —R 13 , —O—R 14 —CO—O—R 13 , —O—(CH 2 ) r —R 12 , —O—(CH 2 ) r —NR′R″, —O—(CH 2 ) r —CO 2 —(CH 2 ) r —R 13 , —O—(CH 2 ) r —CONR′R″, —O—(CH 2 ) r —SR 8 , —O—(CH 2 ) r —CO 2 —R 13 , —O—(CH 2 ) r —O—(CH 2 ) r —OR 13 , —O—(CH 2 ) r —CONH—(CH 2 ) r —OR 13 , —O—(CH 2 ) r —SO 2 R 8 , —O—(CH 2 ) r —R 13 , —O—(CH 2 ) r —OR 13 , —S—(CH 2 ) r —CONR′R″, —SO

Assignees

• Dr Reddys Laboratories Ltd

Inventors

• Baruah Anima
• De Dibyendu
• Khanna Ish Kumar
• Pillarisetti Sivaram
• Maitra Santanu
• Alexander Christopher W
• Sreenu Jennepalli
• Dager Indu
• Alikunju Shanavas

Classifications

• C07D213/73

  Unsubstituted amino or imino radicals · CPC title

• C07D239/78

  with hetero atoms directly attached in position 2 · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D213/74

  Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title