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US 2006/0223840 A1Published application
Substituted piperidine compounds and methods of their use
AssigneeAdolor Corporation
InventorsRoland Dolle, Bertrand Le Bourdonnec
Life of this patent
Estimating the term…
Abstract
Certain 4-aryl-piperidine compounds, including N-substituted 9β-substituted-5-(3-substituted-phenyl)morphans and N-substituted octahydro-4a-(3-hydroxyphenyl)-10a-methyl-benzo[g]isoquinolines, pharmaceutical compositions, and methods of their use, inter alia, as opioid antagonists are disclosed.
Claims60
A compound of formula I:
- wherein:
- R1 is —OR7, —NR7R8, —COOR7, —CONR7R8, or —CH2OH;
- each R7 is independently H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;
- each R8 is independently H, alkyl, aralkyl, or aryl;
- R2, R3, R4, and R5 are selected such that:
- R2 and R5 together form —(CH2)q—, where q is 2 or 4, R3 is alkyl, and R4 is H;
- or
- R2 and R3 together with the carbon atoms to which they are attached form a fused carbocycle, R4 is alkyl, and R5 is H;
- R6 is H or —(CHR9)mW;
- each R9 is independently H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl or heteroaryl;
- W is H, alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, —CH2OH, —CH2OR7, or —C(═O)R10;
- R10 is —OR7 or NR7R11;
- R11 is H, alkyl, aralkyl, aryl or —(CHR9)nC(═O)R12;
- R12 is —OR7 or NR7R8;
- m is an integer from 1 to 4;
- and
- n is an integer from 1 to 4;
- provided that:
- (1) when R1 is —OCH3, R4 is CH3, R5 is H, and R2 and R3 together with the carbon atoms to which they are attached form unsubstituted tetrahydronaphthalene, then W is other than H, alkyl, or phenyl;
- (2) when R1 is —OH, then W is heterocycloalkyl, alkylheterocycloalkyl, —CH2OH, or —C(═O)R10;
- and
- (3) when R1 is —OH and W is heterocycloalkyl or alkylheterocycloalkyl in which the heterocyclic ring moiety of the heterocycloalkyl or alkylheterocycloalkyl contains only one heteroatom, wherein the heteroatom is nitrogen, then the heterocyclic ring moiety is connected to —(CHR9)m— through a heterocyclic ring carbon atom;
- or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid hydrate, N-oxide or isomorphic crystalline form thereof.
20 more elements
A pharmaceutical composition, comprising:
- a pharmaceutically acceptable carrier;
- an effective amount of at least one opioid;
- and
- an effective amount of a compound according to formula I:
- wherein:
- R1 is —OR7, —NR7R8, —COOR7, —CONR7R8, or —CH2OH;
- each R7 is independently H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;
- each R8 is independently H, alkyl, aralkyl, or aryl;
- R2, R3, R4, and R5 are selected such that:
- R2 and R5 together form —(CH2)q—, where q is 2 to 4, R3 is alkyl, and R4 is H;
- or
- R2 and R3 together with the carbon atoms to which they are attached form a fused carbocycle, R4 is alkyl, and R5 is H;
- R6 is H or —(CHR9)mW;
- each R9 is independently H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl or heteroaryl;
- W is H, alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, —CH2OH, —CH2OR7, or —C(═O)R10;
- R10 is —OR7 or —NR7R11;
- R11 is H, alkyl, aralkyl, aryl or —(CHR9)nC(═O)R12;
- R12 is —OR7 or —NR7R8;
- m is an integer from 1 to 4;
- and
- n is an integer from 1 to 4;
- provided that when R1 is —OH, then W is heterocycloalkyl, alkylheterocycloalkyl, —CH2OH, or —C(═O)R10;
- and when R1 is —OH and W is heterocycloalkyl or alkylheterocycloalkyl in which the heterocyclic ring moiety of the heterocycloalkyl or alkylheterocycloalkyl contains only one heteroatom, wherein the heteroatom is nitrogen, then the heterocyclic ring moiety is connected to —(CHR9)m— through a heterocyclic ring carbon atom;
- or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid hydrate, N-oxide or isomorphic crystalline form thereof.
21 more elements
A method of binding opioid receptors in a patient in need thereof, comprising the step of:
- administering to the patient a composition comprising an effective amount of a compound according to formula I:
- wherein:
- R1 is —OR7, —NR7R8, —COOR7, —CONR7R8, or —CH2OH;
- each R7 is independently H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;
- each R8 is independently H, alkyl, aralkyl, or aryl;
- R2, R3, R4, and R5 are selected such that:
- R2 and R5 together form —CH2)q—, where q is 2 to 4, R3 is alkyl, and R4 is H;
- or
- R2 and R3 together with the carbon atoms to which they are attached form a fused carbocycle, R4 is alkyl, and R5 is H;
- R6 is H or —(CHR9)mW;
- each R9 is independently H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl or heteroaryl;
- W is H, alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, —CH2OH, —CH2OR7, or —C(═O)R10;
- R10 is —OR7 or —NR7R11;
- R11 is H, alkyl, aralkyl, aryl or —(CHR9)nC(═O)R12
- R12 is —OR7 or —NR7R8;
- m is an integer from 1 to 4;
- and
- n is an integer from 1 to 4;
- provided that when R1 is —OH, then W is heterocycloalkyl, alkylheterocycloalkyl, —CH2OH, or —C(═O)R10;
- and when R1 is —OH and W is heterocycloalkyl or alkylheterocycloalkyl in which the heterocyclic ring moiety of the heterocycloalkyl or alkylheterocycloalkyl contains only one heteroatom, wherein the heteroatom is nitrogen, then the heterocyclic ring moiety is connected to —(CHR9)m— through a heterocyclic ring carbon atom;
- or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid hydrate, N-oxide or isomorphic crystalline form thereof.
18 more elements
Dependencies are inferred from the claim text.