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US 2007/0066655 A1Published application
Diarylmethylidene piperidine derivatives and their use as delta opiod receptor agonists
AssigneeAtraZeneca AB
InventorsWilliam Brown, Andrew Griffin
Life of this patent
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Abstract
Compounds of general formula: (Formula (I)) wherein R1, R2, R3, R4 and R5 are as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain and anxiety.
Claims12
A compound of formula I, a pharmaceutically acceptable salt thereof, diasteromers, enantiomers, or mixtures thereof:
- wherein
- R1 is selected from hydrogen, C1-6alkyl-O—C(═O)—, optionally substituted C1-6alkyl, optionally substituted C3-6cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C6-10aryl-C1-3alkyl, optionally substituted C2-9heterocyclyl-C1-3alkyl, and
- wherein D is a divalent group selected from optionally substituted C1-6alkylene, optionally substituted phenylene, optionally substituted phenylene-C1-3alkyl, optionally substituted C3-5heteroarylene, and optionally substituted C3-5heteroarylene-C1-3alkyl;
- R2 and R3 are, independently, selected from hydrogen, optionally substituted C1-6alkyl and optionally substituted C3-6cycloalkyl;
- and
- R4 and R5 are independently selected from —H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C6-10aryl-C1-6alkyl, optionally substituted C2-9heterocyclyl-C1-6alkyl, —C(═O)—NR8R9 and —C(═O)—R8, wherein R8 and R9 are independently selected from —H, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C6-10aryl-C1-6alkyl, and optionally substituted C2-9heterocyclyl-C1-6alkyl.
3 more elements
A compound selected from:
- 4-[[4-[(diethylamino)carbonyl]phenyl][1-(2-pyridinylmethyl)-4-piperidinylidene]methyl]benzamide;
- 4-[[4-[(diethylamino)carbonyl]phenyl][1-(2-thienylmethyl)-4-piperidinylidene]methyl]benzamide;
- 4-[[4-[(diethylamino)carbonyl]phenyl][1-(2-furanylmethyl)-4-piperidinylidene]methyl]benzamide;
- 4-[[1-[(5-chloro-2-furanyl)methyl]-4-piperidinylidene][4-[(diethylamino)carbonyl]phenyl]methyl]benzamide;
- 4-[[4-[(diethylamino)carbonyl]phenyl][1-[(5-methyl-2-furanyl)methyl]-4-piperidinylidene]methyl]benzamide;
- 4-[[4-[(diethylamino)carbonyl]phenyl][1-[(3-methyl-2-thienyl)methyl]-4-piperidinylidene]methyl]benzamide;
- 4-[[1-[(3-chloro-2-thienyl)methyl]-4-piperidinylidene][4-[(diethylamino)carbonyl]phenyl]methyl]benzamide;
- 4-[[1-[(5-chloro-2-thienyl)methyl]-4-piperidinylidene][4-[(diethylamino)carbonyl]phenyl]methyl]benzamide;
- 4-[[4-[(diethylamino)carbonyl]phenyl][1-[(5-methyl-2-thienyl)methyl]-4-piperidinylidene]methyl]benzamide;
- 4-[[1-[(6-chloro-3-pyridinyl)methyl]-4-piperidinylidene][4-[(diethylamino)carbonyl]phenyl]methyl]-benzamide;
- 4-[[4-[(diethylamino)carbonyl]phenyl][1-(3-hydroxypropyl)-4-piperidinylidene]methyl]benzamide;
- 4-[[4-[(diethylamino)carbonyl]phenyl][1-(2-methoxyethyl)-4-piperidinylidene]methyl]benzamide;
- 4-[[4-[(diethylamino)carbonyl]phenyl][1-(3-pyridinylmethyl)-4-piperidinylidene]methyl]benzamide;
- 4-[[4-[(diethylamino)carbonyl]phenyl][1-(4-pyridinylmethyl)-4-piperidinylidene]methyl]benzamide;
- 4-[[4-[(diethylamino)carbonyl]phenyl][1-[(6-methyl-2-pyridinyl)methyl]-4-piperidinylidene]methyl]benzamide;
- 4-[[4-[(diethylamino)carbonyl]phenyl][1-(3-methoxypropyl)-4-piperidinylidene]methyl]benzamide;
- 4-[[4-[(diethylamino)carbonyl]phenyl][1-(phenylmethyl)-4-piperidinylidene]methyl]-benzamide;
- 4-[[4-[(diethylamino)carbonyl]phenyl][1-(4-thiazolylmethyl)-4-piperidinylidene]methyl]benzamide;
- 3-[[4-[(diethylamino)carbonyl]phenyl][1-(5-thiazolylmethyl)-4-piperidinylidene]methyl]benzamide;
- 4-[[4-(aminocarbonyl)phenyl](1-butylpiperidin-4-ylidene)methyl]-N,N-diethylbenzamide;
- and pharmaceutically acceptable salts thereof.
18 more elements
7-8. (canceled)
A process for preparing a compound of formula II, comprising:
- reacting a compound of formula III with R7—CH2X or R7—CHO:
- wherein
- R2 and R3 are ethyl;
- X is selected from Cl, I, Br, —OTs and —OMs;
- R4 and R5 are independently selected from —H, optionally substituted phenyl, optionally substituted C3-5heterocyclyl, optionally substituted phenyl-C1-3alkyl, optionally substituted C3-5heterocyclyl-C1-3alkyl, optionally substituted C1-6alkyl, optionally substituted C3-6cycloalkyl, optionally substituted C3-6cycloalkyl-C1-3alkyl, —C(═O)—N—R8R9, and —C(═O)—R8, wherein R8 and R9 are independently selected from —H, optionally substituted phenyl, optionally substituted C3-5heterocyclyl, optionally substituted phenyl-C1-3alkyl, optionally substituted C3-5heterocyclyl-C1-3alkyl, optionally substituted C1-6alkyl, optionally substituted C3-6cycloalkyl, optionally substituted C3-6cycloalkyl-C1-3alkyl;
- R7 is selected from
- C1-6alkyl, C3-6cycloalkyl, phenyl, phenyl-C1-3alkyl, C3-5heteroaryl, and C3-5heteroaryl-C1-3alkyl, wherein said C1-6alkyl, C3-6cycloalkyl, phenyl, phenyl-C1-3alkyl, C3-5heteroaryl, and C3-5heteroaryl-C1-3alkyl are optionally substituted by one or more groups selected from selected from C1-6alkyl, halogenated C1-6alkyl, —OH, —NO2, —CF3, C1-6 alkoxy, chloro, fluoro, bromo, and iodo;
- and
- D is a divalent group selected from optionally substituted C1-6alkylene, optionally substituted phenylene, optionally substituted phenylene-C1-3alkyl, optionally substituted C3-5heteroarylene, and optionally substituted C3-5heteroarylene-C1-3alkyl.
6 more elements
A process for preparing a compound of formula I, comprising:
- reacting a compound of formula IV with a compound of formula V:
- wherein
- wherein R1 is selected from C1-6alkyl-O—C(═O)—,
- C1-6alkyl, C3-6cycloalkyl, phenyl, phenyl-C1-3alkyl, C3-5heterocyclyl, and C3-5heterocyclyl-C1-3alkyl, wherein said C1-6alkyl, C3-6cycloalkyl, phenyl, phenyl-C1-3alkyl, C3-5heterocyclyl, and C3-5heterocyclyl-C1-3alkyl are optionally substituted by one or more groups selected from selected from C1-6alkyl, halogenated C1-6alkyl, —OH, —NO2, —CF3, C1-6 alkoxy, chloro, fluoro, bromo, and iodo;
- D is a divalent group selected from optionally substituted C1-6alkylene, optionally substituted phenylene, optionally substituted phenylene-C1-3alkyl, optionally substituted C3-5heteroarylene, and optionally substituted C3-5heteroarylene-C1-3alkyl;
- X is selected from I, Br and Cl;
- R10 is selected from H and C1-6alkyl, or (R10O)2B— is
- R2 and R3 are ethyl;
- and
- R4 and R5 are independently selected from —H, optionally substituted phenyl, optionally substituted C3-5heterocyclyl, optionally substituted phenyl-C1-3alkyl, optionally substituted C3-5heterocyclyl-C1-3alkyl, optionally substituted C1-6alkyl, optionally substituted C3-6cycloalkyl, optionally substituted C3-6cycloalkyl-C1-3alkyl, —C(═O)—N—R8R9, and —C(═O)—R8, wherein R8 and R9 are independently selected from —H, optionally substituted phenyl, optionally substituted C3-5heterocyclyl, optionally substituted phenyl-C1-3alkyl, optionally substituted C3-5heterocyclyl-C1-3alkyl, optionally substituted C1-6alkyl, optionally substituted C3-6cycloalkyl, optionally substituted C3-6cycloalkyl-C1-3alkyl.
7 more elements
Dependencies are inferred from the claim text.