Phosphorus-substituted quinoxaline-type piperidine compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-9598447-B2
Application number	US-201113996440-A
Country	US
Kind code	B2
Filing date	Dec 21, 2011
Priority date	Dec 22, 2010
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

The disclosure relates to Phosphorus-Substituted Quinoxaline-Type Piperidine Compounds of Formula (I):

and pharmaceutically acceptable derivatives thereof wherein the dashed line, A, B, Q, R 1 , R 2 , R 3 , R 4 , Y 1 , Z, and a are as defined herein, compositions comprising an effective amount of a Phosphorus-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 Phosphorus-Substituted Quinoxaline-Type Piperidine Compound.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof wherein:
Y 1 is O or S;
Q is benzo or (5- or 6-membered)heteroaryl;
each R 2 is independently selected from:
(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 OT 3 , —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 , and —N(T 3 )S(═O) 2 N(T 1 )(T 2 ); and
(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, and -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R 8 groups; and
(c) -phenyl, -naphthalenyl, —(C 14 )aryl, and -(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 is present as a bond to provide one bond of a double bond then one R 4 group is absent, one R 4 group is present, and optionally R 3 is absent;
R 3 is selected from:
(a) —H; and
(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 ; and
(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 group is independently selected from —H and —U 1 —U 2 —U 3 —U 4 —U 5 —U 6 —U 7 —U, wherein said compound of Formula (I) contains at least one R 4 group that is not hydrogen;
U is —P(═O)(OR 9 )([O] x R 9 );
U 1 , U 3 , U 5 , and U 7 are independently selected from:
(a) a single bond; and
(b) —(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl-, —(C 6 -C 12 )cycloalkyl-, —(C 6 -C 14 )bicycloalkyl-, —(C 5 -C 14 )cycloalkenyl-, —(C 7 -C 14 )bicycloalkenyl-, -phenyl-, and -(5- or 6-membered)heterocycle-, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R 7 groups; and
(c) absent;

U 2 , U 4 , and U 6 are independently —Y—, —N(R 9 )—, —C(═Y)—, a single bond, or absent;
each Y is independently O or S;
A and B are independently selected from:
(a) —H, —CN, —C(═O)OT 3 , and —C(═O)N(T 1 )(T 2 ); and
(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, and —(C 1 -C 6 )alkoxy, each of which is unsubstituted or substituted with:
(1′) 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
(2′) 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 selected from:
(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 2 )cycloalkyl, and —N(R c )-(3- to 7-membered)heterocycle; and
(b) -phenyl, -naphthalenyl, and -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R 7 groups; and
(c) —N(R c )-phenyl, —N(R c )-naphthalenyl, —N(R c )—(C 14 )aryl, and —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; —(C 2 -C 10 )alkenyl- optionally substituted by R 1 ; or —(C 1 -C 10 )alkyl-N(R 6 )C(═Y)—;
each R 1 is independently selected from:
(a) —H, -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 , and —C(═O)CN; and
(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, -(3- to 7-membered)heterocycle, and -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R 8 groups; and
(c)

 and
(d) -phenyl, -naphthalenyl, —(C 14 )aryl, and -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with a 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 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(R 12 );
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 , —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)N(T 1 )(T 2 ), —N(R 9 )C(═O)OR 12 , —C(═O)N(T 1 )(T 2 ), —C(═O)OR 9 , —OC(═O)R 9 , —OC(═O)N(T 1 )(T 2 ), —OC(═O)OR 9 , —S(═O)R 9 , or —S(═O) 2 R 9 ;
each R 8 is independently —(C 1 -C 6 )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, -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)N(R 12 )(R 12 ), —N(R 9 )C(═O)OR 12 , —C(═O)R 9 , —C(═O)N(R 12 )(R 12 ), —C(═O)OR 9 , —OC(═O)R 9 , —OC(═O)N(R 12 )(R 12 ), —OC(═O)OR 9 , —S(═O)R 9 , or —S(═O) 2 R 9 ;
each R 9 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -benzyl, —CH 2 —O—C(O)-phenyl, —CH 2 —C(O)—O-phenyl, —CH 2 —O—

Assignees

• Tadesse Dawit
• Tafesse Laykea
• Zhou Xiaoming
• Purdue Pharma Lp

Inventors

• Tadesse Dawit
• Tafesse Laykea
• Zhou Xiaoming

Classifications

• A61P43/00

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

• A61P9/12

  Antihypertensives · CPC title

• A61P7/00

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

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title