Substituted-quinoxaline-type piperidine compounds and the uses thereof

Patent metadata

Field	Value
Publication number	US-9278967-B2
Application number	US-201414331034-A
Country	US
Kind code	B2
Filing date	Jul 14, 2014
Priority date	Aug 31, 2007
Publication date	Mar 8, 2016
Grant date	Mar 8, 2016

Abstract

The invention relates to Substituted-Quinoxaline-Type Piperidine Compounds, compositions comprising an effective amount of a Substituted-Quinoxaline-Type Piperidine Compound and methods to treat or prevent a condition, such as pain, comprising administering to an animal in need thereof an effective amount of a Substituted-Quinoxaline-Type Piperidine Compound.

First claim

What is claimed:

1. A method for treating pain in an animal in need thereof, comprising administering to the animal an effective amount of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt of the compound of Formula (I) or (II):

wherein:
Y 1 is O or S;
Q is fused benzo or fused (5- or 6-membered)heteroaryl;
each R 2 is independently:
(a) -halo, —CN, —NO 2 , —OT 3 , —C(═O)T 3 , —C(═O)OT 3 , —C(═O)N(T 1 )(T 2 ), —S(═O) 2 OH, —S(═O)T 3 , —S(═O) 2 T 3 , —S(═O) 2 N(T 1 )(T 2 ), —N(T 1 )(T 2 ), —N(T 3 )C(═O)T 3 , —N(T 3 )C(═O)N(T 1 )(T 2 ), —N(T 3 )S(═O) 2 T 3 , or —N(T 3 )S(═O) 2 N(T 1 )(T 2 ); or
(b) —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkoxy, —(C 3 -C 7 )cycloalkyl, —(C 6 -C 14 )bicycloalkyl, —(C 8 -C 20 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 7 -C 14 )bicycloalkenyl, —(C 8 -C 20 )tricycloalkenyl, —(5- or 6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups; or
(c) -phenyl, -naphthalenyl, —(C 14 )aryl, or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R 7 groups;

a is an integer selected from 0, 1, and 2;
the dashed line in the 6-membered, nitrogen-containing ring that is fused to the Q group denotes the presence or absence of a bond, and when that dashed line denotes the presence of a bond then R 3 and one R 4 are absent;
R 3 is:
(a) —H; or
(b) —(C 1 -C 4 )alkyl which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from —OH, —(C 1 -C 4 )alkoxy, —N(R 6 ) 2 , —C(═O)OR 9 , and —C(═O)N(R 6 ) 2 ; or
(c) —(C 3 -C 7 )cycloalkyl which is unsubstituted or substituted with 1, 2 or 3 groups independently selected from —OH, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkoxy, —N(R 6 ) 2 , —C(═O)OR 9 , and —C(═O)N(R 6 ) 2 ;

each R 4 is independently:
(a) —H; or
(b) -halo, —CN, or —NO 2 ; or
(c) —X, —(C 1 -C 6 )alkyl-X, -(5- or 6-membered)heterocycle-X, or -(5- or 6-membered)heterocycle-(C 1 -C 6 )alkyl-X; or
(d) —C(═Y)CN, —C(═Y)X, —C(═Y)T 3 , —C(═Y)YX, —C(═Y)YT 3 , —C(═Y)N(T 1 )(T 2 ), —C(═Y)N(R 9 )CN, —C(═Y)N(R 9 )X, —C(═Y)N(R 9 )YH, —C(═Y)N(R 9 )YX, —C(═Y)N(R 9 )YCH 2 X, —C(═Y)N(R 9 )YCH 2 CH 2 X, or —C(═Y)N(R 9 )S(═O) 2 T 3 ; or
(e) —N(R 9 )X, —N(R 9 )—CH 2 X, —N(R 9 )—CH 2 CH 2 X, —N(R 9 )CH 2 N(R 9 )C(═N(R 12 ))N(R 12 ) 2 , —N(R 9 )—CH 2 CH 2 N(R 9 )C(═N(R 12 ))N(R 12 ) 2 , —N(T 1 )(T 2 ), —N(T 3 )C(═Y)T 3 , —N(T 3 )C(═Y)YT 3 , —N(T 3 )C(═Y)N(T 1 )(T 2 ), —N(T 3 )S(═O) 2 T 3 , or —N(T 3 )S(═O) 2 N(T 1 )(T 2 ); or
(f) —YH, —CH 2 YH, —CH 2 CH 2 YH, —YX, or —YT 3 ; or
(g) —S(═O)T 3 , —S(═O) 2 T 3 , —S(═O)N(T 1 )(T 2 ), —S(═O) 2 N(T 1 )(T 2 ), —S(═O)X, or —S(═O) 2 X;

X is:
(a) —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkoxy, —(C 3 -C 7 )cycloalkyl, —(C 6 -C 14 )bicycloalkyl, —(C 8 -C 20 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 7 -C 14 )bicycloalkenyl, —(C 8 -C 20 )tricycloalkenyl, -(5- or 6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups; or
(b) -phenyl, -naphthalenyl, —(C 14 )aryl, or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R 7 groups;

each Y is independently O or S;
A and B are independently:
(a) —H, —CN, —C(═O)OT 3 , or —C(═O)N(T 1 )(T 2 ); or
(b) —(C 3 -C 12 )cycloalkyl, —(C 3 -C 12 )cycloalkoxy, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, or —(C 1 -C 6 )alkoxy, each of which is unsubstituted or substituted with 1 or 2 substituents independently selected from —OH, —S(═O) 2 NH 2 , —N(R 6 ) 2 , ═NR 6 , —C(═O)OT 3 , —C(═O)N(R 6 ) 2 , —N(R 6 )C(═O)R 9 , and -(5- or 6-membered)heterocycle, or 1, 2 or 3 independently selected -halo; or
(c) A-B can together form a (C 2 -C 6 )bridge, which is unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7 or 8 substituents independently selected from —OH, —(C 1 -C 4 )alkyl, -halo, and —C(halo) 3 , and which bridge optionally contains —HC═CH— or —O— within the (C 2 -C 6 )bridge; wherein the 6-membered, nitrogen-containing ring that is fused to the Q group can be in the endo- or exo-configuration with respect to the A-B bridge; or
(d) A-B can together form a —CH 2 —N(R a )—CH 2 — bridge, a

bridge, or a

bridge;
wherein the 6-membered, nitrogen-containing ring that is fused to the Q group can be in the endo- or exo-configuration with respect to the A-B bridge;
R a is —H, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl, —CH 2 —C(═O)—R c , —(CH 2 )—C(═O)—OR c , —(CH 2 )—C(═O)—N(R c ) 2 , —(CH 2 ) 2 —O—R c , —(CH 2 ) 2 —S(═O) 2 —N(R c ) 2 , R c , or —(CH 2 ) 2 —N(R c )S(═O) 2 —R c ;
R b is:
(a) —H, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl, -(3- to 7-membered)heterocycle, —N(R c ) 2 , —N(R c )—(C 3 -C 7 )cycloalkyl, or —N(R c )-(3- to 7-membered)heterocycle; or
(b) -phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R 7 groups; or
(c) —N(R c )-phenyl, —N(R c )-naphthalenyl, —N(R c )—(C 14 )aryl, or —N(R c )-(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R 7 groups;

each R c is independently —H or —(C 1 -C 4 )alkyl;
Z is —[(C 1 -C 10 )alkyl optionally substituted by R 1 ] h —, wherein h is 0 or 1; or —(C 1 -C 10 )alkyl-NR 6 C(═Y)—;
each R 1 is independently:
(a) -halo, —CN, —OH, —CH 2 OH, —CH 2 CH 2 OH, —NO 2 , —N(R 6 ) 2 , —S(═O)NH 2 , —S(═O) 2 NH 2 , —C(═O)OV 1 , or —C(═O)CN; or
(b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —O(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkoxy, —(C 6 -C 14 )bicycloalkyl, —(C 8 -C 20 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 7 -C 14 )bicycloalkenyl, —(C 8 -C 20 )tricycloalkenyl, or -(3- to 7-membered)heterocycle, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups; or
(c)

or
(d) -phenyl, -naphthalenyl, or —(C 14 )aryl, each of which is unsubstituted or substituted with an R 7 group; or

—Z—R 1 is 3,3-diphenylpropyl- optionally substituted at the 3 carbon of the propyl with —CN, —C(═O)N(R 6 ) 2 , —C(═O)OV 1 , or -tetrazolyl; or
—Z—R 1 is —(C 1 -C 4 )alkyl substituted with tetrazolyl;
each R 5 is independently —(C 1 -C 4 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -(5- or 6-membered)heteroaryl, —(C 1 -C 6 )alkyl-C(═O)OR 9 , —OR 9 , —SR 9 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, ═O, ═S, -halo, —N 3 , —NO 2 , —CH═N(R 9 ), —N(R 9 )(C 1 -C 6 )alkyl-C(═O)OR 9 , —N(R 9 ) 2 , —N(R 9 )OH, —N(R 9 )S(═O)R 12 , —N(R 9 )S(═O) 2 R 12 , —N(R 9 )C(═O)R 12 , —N(R 9 )C(═O)OR 12 , —C(═O)R 9 , —C(═O)OR 9 , —OC(═O)R 9 , —OC(═O)OR 9 , —S(═O)R 9 , or —S(═O) 2 R 9 ;
each R 6 is independently —H, —(C 1 -C 6 )alkyl, or —(C 3 -C 7 )cycloalkyl, or two R 6 groups attached to the same nitrogen atom can together form a 5- to 8-membered ring, wherein the number of atoms in the ring includes the nitrogen atom, and in which one of the 5- to 8-membered ring carbon atoms is optionally replaced by O, S, or N(T 3 );
each R 7 is independently —(C 1 -C 4 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —OR 9 , —SR 9 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, -halo, —N 3 , —NO 2 , —CH═N(R 9 ), —N(R 9 ) 2 ,

Assignees

• Purdue Pharma Lp
• Shionogi & Co
• Shionogi & Co

Inventors

• Fuchino Kouki
• Goehring R Richard
• Matsumura Akira
• Shao Bin
• Taoda Yoshiyuki
• Tsuno Naoki
• Whitehead John William Frank
• Yao Jiangchao

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title