US 2014/0275117 A1Published application

Buprenorphine analogs

AssigneePurdue Pharma L.P.

InventorsRichard Goehring, Laykea Tafesse, Jiangchao Yao

Life of this patent

Estimating the term…

Abstract

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.

Claims35

Dependent claims

A compound of Formula I:

wherein
G is selected from carbonyl C(═O), sulfonyl S(═O)2, or sulfinyl S(═O);
Q is selected from OH, —(C1-C10)alkoxy, —(C1-C10)alkyl, —(C3-C12)cycloalkyl, -(5- to 12-membered)aryl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((5- 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 or R14;
any of which may optionally be substituted with 1, 2, or 3 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;
X is selected from OH, hydroxy(C1-C6)alkyl-, dihydroxy(C1-C6)alkyl-, halogen, —NH2, —NR20(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, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, ((5- 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-, or ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkoxy-;
any of which may optionally be substituted with 1, 2, or 3 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;
Z is —(CH2)m—, optionally substituted with 1 or 2-(C1-C6)alkyl;
m is an integer 1, 2, 3, 4, 5, or 6;
p is an integer 0, 1 or 2;
s is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13;
R1 is selected from 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-, -(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-, phenyl, and benzyl;
any of which is optionally substituted with 1, 2, or 3 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;
R3a and R3b are each independently selected from 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-, -(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-, ((3- to 12 membered)heterocycle)-(C1-C6)alkoxy-(C1-C6)alkyl-, or together form (═O);
R4 is selected from —(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-, -(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, or ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-;
R5 and R6 are each independently hydrogen, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, ((C3-C8)cycloalkyl)-(C1-C6)alkyl-, —COOR7, —(C1-C6)alkyl-CO—OR7, —CONH2, or (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 hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C12)cycloalkyl, —(C4-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, or ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-;
R9 and R10 are each independently selected from 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-;
each R11 is independently selected from 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, or ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-;
R12 and R13 are each independently selected from 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-, -(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 or 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-, phenyl, benzyl, NH2, —NH(C1-C6)alkyl, CN, SH, OR4, —CONR5R6, —COOR7, —(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, ((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 —COOR7, —(C1-C6)alkyl-CO—OR7, —C(═O)—(C1-C6)alkyl-COOR7, —(C1-C6)alkyl-C(═O)—(C1-C6)alkyl-COOR7, —CONH2, or (C1-C6)alkyl-CONH—;
R15 is selected from R20 or R21;
R16 is selected from hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C10)alkoxy, —C(═O)—(C1-C6)alkyl, —(C3-C12)cycloalkyl, —(C3-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((C3-C12)cycloalkenyl)-(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;
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;
R20 is selected from hydrogen, —(C1-C10)alkyl, —(C2-C12)alkenyl, —(C2-C12)alkynyl, —(C1-C10)alkoxy, —(OCH2CH2)s—O(C1-C6)alkyl, —(CH2CH2O), —(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-, -(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 or 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-;
R21 is selected from R20 or an alpha-amino compound of structure:
wherein
each R17 is independently selected from 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-CON R9R10, —(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-, ((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 may form 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 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;
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 may optionally be a peptide-forming moiety having the structure
where t is an integer 1, 2 or 3;
provided that when R1 is cyclopropylmethyl, G is C═O, Q and X are both —OCH3, Z is —CH2—, R15 is —C(NH2)CH3, and R16 is hydrogen, then either:
a) at least one of R3a and R3b is a substituent other than hydrogen;
or
b) at least one of R18 and R19 is a substituent other than hydrogen;
and further provided that when R1 is cyclopropylmethyl, G is S(═O)2, X and Q are both —OCH3, Z is —CH2—, R15 is —CH3, and R16 is benzyl, then at least one of R3a and R3b is a substituent other than hydrogen;
or a pharmaceutically acceptable salt or solvate thereof.

40 more elements

A compound having the general formula II:

wherein
Q and X are OH or (C1-C6)alkoxy;
R1 is selected from hydrogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, and ((C3-C6)cycloalkyl)-(C1-C6)alkyl;
R15 is selected from an alpha-amino compound of structure:
wherein
wherein each R17 is independently selected from 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-CON R9R10, —(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-, ((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 may form 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 wherein
R18 and R19 are each independently selected from 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;
or R19 may optionally be a peptide-forming moiety having the structure
where t is an integer 1 or 2;
provided that when R1 is cyclopropylmethyl, Q and X are both —OCH3, and R15 is —C(NH2)CH3, then either:
a) at least one of R3a and R3b is a substituent other than hydrogen;
or
b) at least one of R18 and R19 is a substituent other than hydrogen;
or a pharmaceutically acceptable salt or solvate thereof.

14 more elements

A compound having the general formula III:

wherein
Q and X are OH or (C1-C6)alkoxy;
R1 is selected from hydrogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, and ((C3-C6)cycloalkyl)-(C1-C6)alkyl;
R15 is R20 selected from 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-, -(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 or 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-;
or a pharmaceutically acceptable salt or solvate thereof.

3 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/206,295Filed 12 Mar 2014
Priority: 15 Mar 2013
Published: 18 Sep 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 489/02
Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4,…
A61K 31/439
Having six-membered rings with one nitrogen as the only ring hetero atom: the ring forming part of a bridged ring system, e.g. quinuclidine
A61K 31/497
Non-condensed pyrazines: containing further heterocyclic rings
A61P 1/10
Drugs for disorders of the alimentary tract or the digestive system: laxatives

Family

Application61/786,997Us provisional application · filed 15 Mar 2013
US 8,969,358 B2Related patent
US 2014/0275117 A1This patent

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

Timeline

Citations

Open elsewhere

Building an agent or pulling many patents? Use the API or MCP server instead of scraping pages. Get an API key

patentgrep

Loading patent…

Abstract

A compound of Formula I:

wherein
G is selected from carbonyl C(═O), sulfonyl S(═O)2, or sulfinyl S(═O);
Q is selected from OH, —(C1-C10)alkoxy, —(C1-C10)alkyl, —(C3-C12)cycloalkyl, -(5- to 12-membered)aryl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((5- 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 or R14;
any of which may optionally be substituted with 1, 2, or 3 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;
X is selected from OH, hydroxy(C1-C6)alkyl-, dihydroxy(C1-C6)alkyl-, halogen, —NH2, —NR20(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, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, ((5- 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-, or ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkoxy-;
any of which may optionally be substituted with 1, 2, or 3 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;
Z is —(CH2)m—, optionally substituted with 1 or 2-(C1-C6)alkyl;
m is an integer 1, 2, 3, 4, 5, or 6;
p is an integer 0, 1 or 2;
s is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13;
R1 is selected from 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-, -(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-, phenyl, and benzyl;
any of which is optionally substituted with 1, 2, or 3 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;
R3a and R3b are each independently selected from 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-, -(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-, ((3- to 12 membered)heterocycle)-(C1-C6)alkoxy-(C1-C6)alkyl-, or together form (═O);
R4 is selected from —(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-, -(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, or ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-;
R5 and R6 are each independently hydrogen, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, ((C3-C8)cycloalkyl)-(C1-C6)alkyl-, —COOR7, —(C1-C6)alkyl-CO—OR7, —CONH2, or (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 hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C12)cycloalkyl, —(C4-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, or ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-;
R9 and R10 are each independently selected from 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-;
each R11 is independently selected from 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, or ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-;
R12 and R13 are each independently selected from 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-, -(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 or 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-, phenyl, benzyl, NH2, —NH(C1-C6)alkyl, CN, SH, OR4, —CONR5R6, —COOR7, —(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, ((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 —COOR7, —(C1-C6)alkyl-CO—OR7, —C(═O)—(C1-C6)alkyl-COOR7, —(C1-C6)alkyl-C(═O)—(C1-C6)alkyl-COOR7, —CONH2, or (C1-C6)alkyl-CONH—;
R15 is selected from R20 or R21;
R16 is selected from hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C10)alkoxy, —C(═O)—(C1-C6)alkyl, —(C3-C12)cycloalkyl, —(C3-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((C3-C12)cycloalkenyl)-(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;
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;
R20 is selected from hydrogen, —(C1-C10)alkyl, —(C2-C12)alkenyl, —(C2-C12)alkynyl, —(C1-C10)alkoxy, —(OCH2CH2)s—O(C1-C6)alkyl, —(CH2CH2O), —(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-, -(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 or 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-;
R21 is selected from R20 or an alpha-amino compound of structure:
wherein
each R17 is independently selected from 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-CON R9R10, —(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-, ((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 may form 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 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;
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 may optionally be a peptide-forming moiety having the structure
where t is an integer 1, 2 or 3;
provided that when R1 is cyclopropylmethyl, G is C═O, Q and X are both —OCH3, Z is —CH2—, R15 is —C(NH2)CH3, and R16 is hydrogen, then either:
a) at least one of R3a and R3b is a substituent other than hydrogen;
or
b) at least one of R18 and R19 is a substituent other than hydrogen;
and further provided that when R1 is cyclopropylmethyl, G is S(═O)2, X and Q are both —OCH3, Z is —CH2—, R15 is —CH3, and R16 is benzyl, then at least one of R3a and R3b is a substituent other than hydrogen;
or a pharmaceutically acceptable salt or solvate thereof.

40 more elements

Facts

Application

14/206,295Filed 12 Mar 2014

Priority

15 Mar 2013

Published

18 Sep 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 489/02
Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4,…
A61K 31/439
Having six-membered rings with one nitrogen as the only ring hetero atom: the ring forming part of a bridged ring system, e.g. quinuclidine
A61K 31/497
Non-condensed pyrazines: containing further heterocyclic rings
A61P 1/10
Drugs for disorders of the alimentary tract or the digestive system: laxatives