Buprenorphine analogs

摘要

The present invention is directed to Buprenorphine Analog compounds of Formula I, II, III, IV or V and including various stereoisomers (such as Formula IA shown below), wherein R1, R3a, R3b, R16, R15, G, Q, X, A and Z are as defined herein.;
Compounds of the Invention may be useful for preparing medicaments useful for treating pain, constipation, and other conditions modulated by activity of opioid and ORL-1 receptors. Compounds of the Invention may be useful for treating Conditions such as pain, constipation, and others modulated by activity of opioid and ORL-1 receptors.

主权项

1. A compound of Formula IV:or a pharmaceutically acceptable salt or solvate thereof,wherein
Z is —CH—; all of R3a, R3b and R16 are hydrogen; G is C(═O); Q is OH or —(C1-C10)alkoxy; X is OH, hydroxy(C1-C6)alkyl-, or dihydroxy(C1-C6)alkyl-; s is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; R1 is ((C3-C12)cycloalkyl)-(C1-C6)alkyl-; R4 are each independently 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-, —(C6-C14)bicycloalkyl, ((C6-C14)bicycloalkyl)-(C1-C6)alkyl-, —(C8-C20)tricycloalkyl, ((C8-C20)tricycloalkyl)-(C1-C6)alkyl-, —(C4-C12)cycloalkenyl, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, —(C7-C14)bicycloalkenyl, (C7-C14)bicycloalkenyl)-(C1-C6)alkyl-, —(C8-C20)tricycloalkenyl, ((C8-C20)tricyloalkenyl)-(C1-C6)alkyl-, -(5- to 12-membered)aryl, ((5- to 12-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-; R5 and R6 are each independently 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; any of which is optionally substituted with 1 or 2 substituents 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, —OR4, —CONR9R10, —NR9COR10, —SR11, -(3- to 12-membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, and benzyl; 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-; each R11 is independently selected from the group consisting of hydrogen, —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C1-C10)alkoxy, ((C1-C6)alkyl)sulfonyl(C1-C6)alkyl-, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, —(C4-C12)cycloalkenyl, and ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-; R14 is selected from the group consisting of —COOR, —(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—; R15 is selected from the group consisting of R20, R21 and R22; R20 is selected from the group consisting of hydrogen, —(C1-C10)alkyl, —(C2-C12)alkynyl, —(C1-C10)alkoxy, —(OCH2CH2)s—O(C1-C6)alkyl, —(CH2CH2O)s—(C1-C6)alkyl, CN, —CONR5R6, (C1-C6)alkyl-CO—NR5R6, —COOR7, —(C1-C6)alkyl-CO—OR7, —(C1-C6)alkoxy-COOR7, —(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-, -(5- to 12-membered)aryl, ((5- to 12-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 one or two 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, —(C1-C6)alkyl-CO—OR7, —(C1-C6)alkoxy-COOR7, —(OCH2CH2)s—O(C1-C6)alkyl, —(CH2CH2O)s—(C1-C6)alkyl, ((C1-C6)alkyl)sulfonyl(C1-C6)alkyl-, —NH—SO2(C1-C6)alkyl, —N(SO2(C1-C6)alkyl)2, —C(═NH)NH2, —NH—CO—(C1-C6)alkyl, —NH—CO—NH2, —NH—C(═O)—NH—(C1-C6)alkyl, —NH—C(═O)-(5- to 12-membered)aryl, —NH—C(═O)—(C1-C6)alkyl-(5- to 12-membered)aryl, —NH—(C1-C6)alkyl-CO—OR7, —NH—C(═O)—(C1-C6)alkyl-CO—OR7, —NH—C(═O)—CH(NH2)—(C1-C6)alkyl-CO—OR7, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, -(5- to 12-membered)aryl, -(5- to 12-membered)aryloxy, —(C1-C6)alkoxyC(O)NR5R6, —NH—(C1-C6)alkylC(O)—NR5R6, —C(O)NH—(C1-C6)alkyl-COOR7, ((5- to 12-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-; R22 is an amino group unsubstituted or substituted one or two times with substituents independently selected from the group consisting of —(C1-C10)alkyl, —(C2-C12)alkenyl, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, -(5- to 12-membered)aryl, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, or ((3- to 12 membered)heterocycle)-(C1-C6)alkyl-; each of which is optionally substituted with 1 or 2 substituents 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, —OR4, —CONR9R10, —NR9COR10, —SR11, -(3- to 12-membered)carbocyclic ring, and -(5- to 12-membered) heterocycle; R21 is R20 or an alpha-amino compound of structure:wherein
each R17 is independently selected from the group consisting of hydrogen, —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C1-C10)alkoxy, OH, hydroxy(C1-C6)alkyl-, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C6)alkyl-C(═O)—(C1-C6)alkoxy, —(C1-C6)alkoxy-C(═O)—(C1-C6)alkyl, —(C1-C6)alkyl-CN, —(C1-C6)alkyl-COOR7, —(C1-C6)alkyl-CN, —(C1-C6)alkyl-CONR9R10, —(C1-C6)alkoxy-COOR7, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((C3-C12)cycloalkyl)-(C1-C6)alkoxy-, ((C3-C12)cycloalkyl)-(C1-C6)alkoxy-(C1-C6)alkyl-, —(C4-C12)cycloalkenyl, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, ((C4-C12)cycloalkenyl)-(C1-C6)alkoxy-, ((C4-C12)cycloalkenyl)-(C1-C6)alkoxy-(C1-C6)alkyl-, -(5- to 12-membered)aryl, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, ((5- to 12-membered)aryl)-(C1-C6)alkoxy-, ((5- to 12-membered)aryl)-(C1-C6)alkoxy-(C1-C6)alkyl-, -(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)heteroaryl)-(C1-C6)alkoxy-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C1-C6)alkyl-, ((3- to 12 membered)heterocycle)-(C1-C6)alkoxy-, and ((3- to 12 membered)heterocycle)-(C1-C6)alkoxy-(C1-C6)alkyl-; or R17 together with R18 or R19 and the N to which they are attached forms a 3- to 12-membered heterocycle; any of which is optionally substituted with 1 or 2 substituents 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, —OR4, —CONR9R10, —NR9COR10, —SR11, -(3- to 12-membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, and benzyl; and R18 and R19 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-, ((C3-C12)cycloalkenyl)-(C1-C6)alkyl-, and —C(═O)—(C1-C6)alkyl; any of which is optionally substituted with 1 or 2 substituents 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, —OR4, —CONR9R10, —NR9COR10, —SR11, -(3- to 12-membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, and benzyl; or R19 is optionally be a peptide-forming moiety having the structurewhere t is an integer 1, 2 or 3;provided that
1) when R1 is cyclopropylmethyl, G is C═O, Q and X are both —OCH3, Z is —CH2—, R15 is —CH(NH2)CH3, and R16 is hydrogen, then
at least one of R18 and R19 is a substituent other than hydrogen; and 2) when R1 is cyclopropylmethyl, G is C═O, Q and X are both —OCH3, Z is —CH2—, R15 is R20, and R20 is unsubstituted —(C1-C10)alkyl, then R16 is hydrogen.