7-BETA ANALOGS OF ORVINOLS

摘要

The application is directed to compounds of Formula I (I) and pharmaceutically acceptable salts and solvates thereof, wherein R1, R1a, R1b, X, Y, Z, G, Q, W1 and W2 are defined as set forth in the specification. The invention is also directed to use of the compounds of Formula I and the pharmaceutically acceptable salts and solvates thereof to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain compounds of the present invention are especially useful for treating pain.;

主权项

1. A compound of Formula I:or a pharmaceutically acceptable salt or solvate thereof, wherein
the 7β-epimer compound of Formula I is present in an enantiomeric excess relative to any 7α-epimer compound, 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 12-membered)aryl, ((6- 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, and ((3- to 12 membered)heterocycle)-(C1-C6)alkyl-; 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, —SR11, (5- to 12-membered)carbocyclic ring, (5- to 12-membered)heterocycle, phenyl, and benzyl; Z is —(CH2)m—, optionally substituted with 1 or 2 (C1-C6)alkyl; Y is —(CH2)n—CH or a direct bond, provided that when Y is a direct bond then W2 is absent and W1 is attached to G; G is selected from the group consisting of —O—, —OC(═O)—, —C(═O)—, —NR3—, —S—, —SO—, and SO2—; W1 and W2 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, —(CH2CH2O)s—(C1-C6)alkyl, NH2, —NH(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-, (6- to 12-membered)aryl, ((6- 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, and ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-; any of which is optionally substituted with one or two substituents each 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-, —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)-(6- to 12-membered)aryl, —NH—C(═O)—(C1-C6)alkyl-(6- 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-, (6- to 12-membered)aryl, (6- to 12-membered)aryloxy, —(C1-C6)alkoxyC(O)NR5R6, —NH—(C1-C6)alkylC(O)—NR5R6, —C(O)NH—(C1-C6)alkyl-COOR7, ((6- 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-, provided that W1 is other than hydrogen when Y is direct bond and G is O; Q is selected from the group consisting of OH, (C1-C10)alkoxy, (C1-C10)alkyl, (C3-C12)cycloalkyl, (6- to 12-membered)aryl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((6- to 12-membered)aryl)-(C1-C6)alkyl-, —(OCH2CH2)s—O(C1-C6)alkyl, —(CH2CH2O)s—(C1-C6)alkyl, —(OCH2CH2)s—OH, —O(C═O)R9, —O—(C1-C6)alkyl-COOR7, —NH—(C1-C6)alkyl-COOR7, —O—C(O)—(C1-C6)alkyl-C(O)OR7, —NH—C(O)—(C1-C6)alkyl-C(O)OR7, —O—(C1-C6)alkyl-C(O)NR9R10, —NH—(C1-C6)alkyl-C(O)NR9R10, —O—C(O)—(C1-C6)alkyl-C(O)NR9R10, —NH—C(O)—(C1-C6)alkyl-C(O)NR9R10, and R14; R1a and R1b are each 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)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-, (6- to 12-membered)aryl, ((6- to 12-membered)aryl)-(C1-C6)alkyl-, ((6- to 12-membered)aryl)-(C1-C6)alkoxy-, ((6- 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 R1a and R1b together form (═O); X is selected from the group consisting of OH, hydroxy(C1-C6)alkyl-, dihydroxy(C1-C6)alkyl-, halogen, NH2, —NR2(C═O)R12, —CONR12R13, —(C1-C6)alkyl-CONH2, —(C1-C6)alkyl-COOH, COOH, —O—(C1-C6)alkyl-COOH, —O—(C1-C6)alkyl-CONH2, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)alkoxy, —(OCH2CH2)s—O(C1-C6)alkyl, —(OCH2CH2)s—OH, —(CH2)pCHOHCH2OH, CN, —NH—SO2R9, (C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((C3-C12)cycloalkyl)-(C1-C6)alkoxy-, (5- to 12-membered)aryl, ((6- to 12-membered)aryl)-(C1-C6)alkyl-, ((6- to 12-membered)aryl)-(C1-C6)alkoxy-, (5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, ((5- to 12-membered)heteroaryl)-(C1-C6)alkoxy-, (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-; or X is —O-PG, wherein PG is a hydroxyl protecting group; R2 is selected from the group consisting of hydrogen, (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)tricycloalkenyl)-(C1-C6)alkyl-, (6- to 12-membered)aryl, ((6- 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-; R3 is 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-, —C(═O)(C1-C6)alkyl, and —SO2(C1-C6)alkyl; 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-, (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)tricycloalkenyl)-(C1-C6)alkyl-, (6- to 12-membered)aryl, ((6- 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 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 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-, and ((C3-C12)cycloalkenyl)-(C1-C6)alkyl-; R11 is 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-; 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 12-membered)aryl, ((6- 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, and ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-; any of which is optionally substituted with one or two substituents each 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-, NH2, —NH(C1-C6)alkyl, CN, SH, OR4, —CONR5R6, —COOR7, (C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, (6- to 12-membered)aryl, ((6- 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-; 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—; m is an integer 1, 2, 3, 4, 5, or 6; n is an integer 0, 1, 2, 3, 4, 5 or 6; p is an integer 0, 1 or 2; and s is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13.