US 9,175,000 B2Granted

Buprenorphine analogs

AssigneePurdue Pharma L.P.

InventorMark A. Youngman

Life of this patent

Estimating the term…

Abstract

The present invention is directed to Buprenorphine Analog compounds of the Formula I, Formula II, Formula III, Formula IV, and Formula V, wherein R1, R2, R3a, R3b, R15a, R15b, X, Q, G, and Y are as defined herein. Compounds of the Invention are useful for treating pain and other conditions modulated by activity of opioid receptors.

Claims47

Dependent claims

A compound of Formula I:

wherein
R1 is selected from the group consisting of hydrogen, —(C1-C10)alkyl, —(C2-C12)alkenyl, —(C2-C12)alkynyl, —(C1-C10)alkoxy, —(C3-C12)cycloalkyl, —(C4-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, -(6- to 14-membered)aryl, ((6- to14-membered)aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C1-C6)alkyl-, phenyl, and benzyl;
any of which is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of —(C1-C6)alkyl, OH, halo, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C6)alkyl-COOR7, —COOR7, NH2, —NH(C1-C6)alkyl, —NR9R10, —CN, —CONR9R10, —NR9COR10, —SR9, -(5- to 12-membered)carbocyclic ring, —(5- to 12-membered)heterocycle, phenyl, and benzyl;
R2 and R8 are each independently selected from the group consisting of hydrogen, —(C1-C10)alkyl, —(C2-C12)alkenyl, —(C2-C12)alkynyl, —CONR5R6, —COOR7, -(6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, and ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-;
each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of —OH, (═O), halo, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C6)alkyl, halo(C1-C6)alkyl-, —(C2-C6)alkenyl, —(C2-C6)alkynyl, hydroxy(C1-C6)alkyl-, dihydroxy(C1-C6)alkyl-, —(C1-C6)alkoxy, ((C1-C6)alkoxy)—CO—(C1-C6)alkoxy-, phenyl, benzyl, —NH2, —NH(C1-C6)alkyl, —(C1-C6)alkyl-NH(C1-C6)alkyl-R14, —CN, —SH, —OR4, —CONR5R6, —(C1-C6alkyl)—CO—NR5R6, —COOR7, and -(C1-C6)alkyl-CO—OR7;
R3a and R3b are each independently selected from the group consisting of hydrogen, —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —CONR5R6, and —COOR7, or together form (═O);
R4 is selected from the group consisting of —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —C(halo)3, —CH(halo)2, —CH2(halo), hydroxy(C1-C6)alkyl-, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, -(6- to 14-membered)aryl, ((6- to 14-membered)aryl) -(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, and ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-;
R5 and R6 are each independently selected from the group consisting of hydrogen, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, ((C3-C8)cycloalkyl)-(C1-C6)alkyl-, —COOR7, —(C1-C6)alkyl-CO—OR7, —CONH2, and (C1-C6)alkyl-CONH—, or R5 and R6 together with the nitrogen atom to which they are attached form a (4- to 8-membered)heterocycle;
R7 is selected from the group consisting of hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C12)cycloalkyl, —(C4-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, and ((C4-C12)cycloalkenyl) -(C1-C6)alkyl- ;
R9 and R10 are each independently selected from the group consisting of hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C10)alkoxy, —(C3-C12)cycloalkyl, —(C3-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, and ((C3-C12)cycloalkenyl)-(C1-C6)alkyl-;
R12 and R13 are each independently selected from the group consisting of hydrogen, —(C1-C10)alkyl, —(C2-C12)alkenyl, —(C2-C12)alkynyl, —(C1-C10)alkoxy, —(OCH2CH2)s—O(C1-C6)alkyl, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, —(C4-C12)cycloalkenyl, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, —(C6-C14)bicycloalkyl, ((C6-C14)bicycloalkyl)-(C1-C6)alkyl-, —(C8-C20)tricycloalkyl, ((C8-C20)tricycloalkyl)-(C1-C6)alkyl-, —(C7-C14)bicycloalkenyl, ((C7-C14)bicycloalkenyl)-(C1-C6)alkyl-, —(C8-C20)tricycloalkenyl, ((C8-C20)tricycloalkenyl)-(C1-C6)alkyl-, -(6- to 14-membered)aryl, ((6- to14-membered)aryl)-(C1-C6)alkyl-, -(7- to 12-membered)bicyclic ring system, ((7- to 12-membered)bicyclic ring system)-(C1-C6)alkyl-, -(7- to 12-membered)bicyclic aryl, ((7- to 12-membered)bicyclic aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C1-C6)alkyl-, -(7- to 12-membered)bicycloheterocycle, ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-, phenyl, benzyl and naphthyl;
each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of OH, (═O), halo, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C6)alkyl, halo(C1-C6)alkyl-, —(C2-C6)alkenyl, —(C2-C6)alkynyl, hydroxy(C1-C6)alkyl-, phenyl, benzyl, NH2, -NH(C1-C6)alkyl, CN, SH, OR4, —CONR5R6, —COOR7, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, -(6- to 14-membered)aryl, ((6- to 14-membered)aryl) -(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C1-C6)alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-;
R14 is selected from the group consisting of —COOR7, —(C1-C6)alkyl-CO—OR7, —C(═O)—(C1-C6)alkyl-COOR7, —(C1-C6)alkyl-C(═O)—(C1-C6)alkyl-COOR7, —CONH2, and (C1-C6)alkyl-CONH—;
G is NR16, or O;
X is selected from the group consisting of —(C1-C10)alkoxy, OH, hydroxy(C1-C6)alkyl-, dihydroxy(C1-C6)alkyl-, halogen, —NH2, —NR2(C═O)R12, —CONR12R13,
Q is selected from the group consisting of OH, —(C1-C10)alkoxy, —(C1-C10)alkyl, —O—(C1-C6)alkyl, -(6- to 14-membered)aryl, —O—((6- to 14-membered)aryl), ((6- to 14-membered)aryI)-(C1-C6)alkyl-, —O—((6- to 14-membered)aryI)- (C1-C6)alkyl, (5- to 12-membered)heteroaryl, —O—((5- to 12-membered)heteroaryl), ((5- to 12-membered)heteroaryI)-(C1-C6)alkyl-, and —O—((5- to 12-membered)heteroaryl-(C1-C6)alkyl;
R15a and R16b are each independently selected from the group consisting of:
a) hydrogen, OH;
b) saturated, unsaturated, or partially saturated —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((C3-C12)cycloalkyl)-(C2-C6)alkenyl-, ((C3-C12)cycloalkyl)-(C1-C6)alkoxy-;
c) -(6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C1-C6)alkyl-, ((6- to 14-membered)aryl)-(C1-C6)alkoxy-, ((6- to 14-membered)aryl) -(C2-C6)alkenyl-;
or
d) -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, ((5- to 12-membered)heteroaryl)-(C1-C6)alkoxy-, ((5- to 12-membered)heteroaryI)-(C2-C6)alkenyl-;
and
e) -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)- (C1-C6)alkyl-, ((3- to 12-membered)heterocycle)-(C1-C6)alkoxy-, -(7- to 12-membered)bicycloheterocycle, ((7- to 12-membered)bicycloheterocycle) - (C1-C6)alkyl-, and ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkoxy-;
provided that at least one of R15a and R16b is other than hydrogen;
R16 is selected from hydrogen and —(C1-C6)alkyl;
Y is —(CH2)n—CH;
n is an integer 0, 1, 2, 3, 4, 5 or 6;
s is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13;
or a pharmaceutically acceptable salt, or solvate thereof.

27 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/096,311Filed 4 Dec 2013 · us provisional application
Priority: 7 Dec 2012
Published: US 2014/0163058 A112 Jun 2014
Granted: 3 Nov 2015
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 489/12
With a bridge between positions 6 and 14: the bridge containing only two carbon atoms
A61P 1/10
Drugs for disorders of the alimentary tract or the digestive system: laxatives
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00

Family

Application61/734,828Us provisional application · filed 7 Dec 2012
US 2014/0163058 A1Pre-grant publication · published 12 Jun 2014
US 9,175,000 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula I:

wherein
R1 is selected from the group consisting of hydrogen, —(C1-C10)alkyl, —(C2-C12)alkenyl, —(C2-C12)alkynyl, —(C1-C10)alkoxy, —(C3-C12)cycloalkyl, —(C4-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, -(6- to 14-membered)aryl, ((6- to14-membered)aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C1-C6)alkyl-, phenyl, and benzyl;
any of which is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of —(C1-C6)alkyl, OH, halo, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C6)alkyl-COOR7, —COOR7, NH2, —NH(C1-C6)alkyl, —NR9R10, —CN, —CONR9R10, —NR9COR10, —SR9, -(5- to 12-membered)carbocyclic ring, —(5- to 12-membered)heterocycle, phenyl, and benzyl;
R2 and R8 are each independently selected from the group consisting of hydrogen, —(C1-C10)alkyl, —(C2-C12)alkenyl, —(C2-C12)alkynyl, —CONR5R6, —COOR7, -(6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, and ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-;
each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of —OH, (═O), halo, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C6)alkyl, halo(C1-C6)alkyl-, —(C2-C6)alkenyl, —(C2-C6)alkynyl, hydroxy(C1-C6)alkyl-, dihydroxy(C1-C6)alkyl-, —(C1-C6)alkoxy, ((C1-C6)alkoxy)—CO—(C1-C6)alkoxy-, phenyl, benzyl, —NH2, —NH(C1-C6)alkyl, —(C1-C6)alkyl-NH(C1-C6)alkyl-R14, —CN, —SH, —OR4, —CONR5R6, —(C1-C6alkyl)—CO—NR5R6, —COOR7, and -(C1-C6)alkyl-CO—OR7;
R3a and R3b are each independently selected from the group consisting of hydrogen, —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —CONR5R6, and —COOR7, or together form (═O);
R4 is selected from the group consisting of —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —C(halo)3, —CH(halo)2, —CH2(halo), hydroxy(C1-C6)alkyl-, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, -(6- to 14-membered)aryl, ((6- to 14-membered)aryl) -(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, and ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-;
R5 and R6 are each independently selected from the group consisting of hydrogen, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, ((C3-C8)cycloalkyl)-(C1-C6)alkyl-, —COOR7, —(C1-C6)alkyl-CO—OR7, —CONH2, and (C1-C6)alkyl-CONH—, or R5 and R6 together with the nitrogen atom to which they are attached form a (4- to 8-membered)heterocycle;
R7 is selected from the group consisting of hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C12)cycloalkyl, —(C4-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, and ((C4-C12)cycloalkenyl) -(C1-C6)alkyl- ;
R9 and R10 are each independently selected from the group consisting of hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C10)alkoxy, —(C3-C12)cycloalkyl, —(C3-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, and ((C3-C12)cycloalkenyl)-(C1-C6)alkyl-;
R12 and R13 are each independently selected from the group consisting of hydrogen, —(C1-C10)alkyl, —(C2-C12)alkenyl, —(C2-C12)alkynyl, —(C1-C10)alkoxy, —(OCH2CH2)s—O(C1-C6)alkyl, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, —(C4-C12)cycloalkenyl, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, —(C6-C14)bicycloalkyl, ((C6-C14)bicycloalkyl)-(C1-C6)alkyl-, —(C8-C20)tricycloalkyl, ((C8-C20)tricycloalkyl)-(C1-C6)alkyl-, —(C7-C14)bicycloalkenyl, ((C7-C14)bicycloalkenyl)-(C1-C6)alkyl-, —(C8-C20)tricycloalkenyl, ((C8-C20)tricycloalkenyl)-(C1-C6)alkyl-, -(6- to 14-membered)aryl, ((6- to14-membered)aryl)-(C1-C6)alkyl-, -(7- to 12-membered)bicyclic ring system, ((7- to 12-membered)bicyclic ring system)-(C1-C6)alkyl-, -(7- to 12-membered)bicyclic aryl, ((7- to 12-membered)bicyclic aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C1-C6)alkyl-, -(7- to 12-membered)bicycloheterocycle, ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-, phenyl, benzyl and naphthyl;
each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of OH, (═O), halo, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C6)alkyl, halo(C1-C6)alkyl-, —(C2-C6)alkenyl, —(C2-C6)alkynyl, hydroxy(C1-C6)alkyl-, phenyl, benzyl, NH2, -NH(C1-C6)alkyl, CN, SH, OR4, —CONR5R6, —COOR7, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, -(6- to 14-membered)aryl, ((6- to 14-membered)aryl) -(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C1-C6)alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-;
R14 is selected from the group consisting of —COOR7, —(C1-C6)alkyl-CO—OR7, —C(═O)—(C1-C6)alkyl-COOR7, —(C1-C6)alkyl-C(═O)—(C1-C6)alkyl-COOR7, —CONH2, and (C1-C6)alkyl-CONH—;
G is NR16, or O;
X is selected from the group consisting of —(C1-C10)alkoxy, OH, hydroxy(C1-C6)alkyl-, dihydroxy(C1-C6)alkyl-, halogen, —NH2, —NR2(C═O)R12, —CONR12R13,
Q is selected from the group consisting of OH, —(C1-C10)alkoxy, —(C1-C10)alkyl, —O—(C1-C6)alkyl, -(6- to 14-membered)aryl, —O—((6- to 14-membered)aryl), ((6- to 14-membered)aryI)-(C1-C6)alkyl-, —O—((6- to 14-membered)aryI)- (C1-C6)alkyl, (5- to 12-membered)heteroaryl, —O—((5- to 12-membered)heteroaryl), ((5- to 12-membered)heteroaryI)-(C1-C6)alkyl-, and —O—((5- to 12-membered)heteroaryl-(C1-C6)alkyl;
R15a and R16b are each independently selected from the group consisting of:
a) hydrogen, OH;
b) saturated, unsaturated, or partially saturated —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((C3-C12)cycloalkyl)-(C2-C6)alkenyl-, ((C3-C12)cycloalkyl)-(C1-C6)alkoxy-;
c) -(6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C1-C6)alkyl-, ((6- to 14-membered)aryl)-(C1-C6)alkoxy-, ((6- to 14-membered)aryl) -(C2-C6)alkenyl-;
or
d) -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, ((5- to 12-membered)heteroaryl)-(C1-C6)alkoxy-, ((5- to 12-membered)heteroaryI)-(C2-C6)alkenyl-;
and
e) -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)- (C1-C6)alkyl-, ((3- to 12-membered)heterocycle)-(C1-C6)alkoxy-, -(7- to 12-membered)bicycloheterocycle, ((7- to 12-membered)bicycloheterocycle) - (C1-C6)alkyl-, and ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkoxy-;
provided that at least one of R15a and R16b is other than hydrogen;
R16 is selected from hydrogen and —(C1-C6)alkyl;
Y is —(CH2)n—CH;
n is an integer 0, 1, 2, 3, 4, 5 or 6;
s is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13;
or a pharmaceutically acceptable salt, or solvate thereof.

27 more elements

Facts

Application

14/096,311Filed 4 Dec 2013 · us provisional application

Priority

7 Dec 2012

Published

US 2014/0163058 A112 Jun 2014

Granted

3 Nov 2015

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 489/12
With a bridge between positions 6 and 14: the bridge containing only two carbon atoms
A61P 1/10
Drugs for disorders of the alimentary tract or the digestive system: laxatives
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00