Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase

A pyridinyl, pyrimidinyl technology in the field of piperazinyl urea and piperidinyl urea compounds capable of addressing undisclosed catalepsy, hypothermia, or enhanced feeding behavior

Inactive Publication Date: 2008-03-19
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Experiments with FAAH-/- mice showed reduced responses in nociception tests, but not catalepsy, h

Method used

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  • Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
  • Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
  • Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0348] Example 1: tert-butyl 4-phenylcarbamoyl-piperazine-1-carboxylate (intermediate)

[0349]

[0350] A solution of tert-butyl piperazine-1-carboxylate (114g) in DCM (500ml) was cooled in an ice bath and treated with phenylisocyanate (65ml). After 1 hour (h), the ice bath was removed. After 15 hours, the resulting mixture was filtered and the solid was washed with dichloromethane (DCM, 2 x 100ml) to give the title compound as a white amorphous solid (95g).

Embodiment 2

[0351] Embodiment 2: Piperazine-1-carboxylic acid phenylamide (intermediate)

[0352]

[0353] with 2M HCL / Et 2 O (164ml) was treated with tert-butyl 4-phenylcarbamoyl-piperazine-1-carboxylate (50g) in MeOH (1L). After 48 hours, with Et 2 The resulting suspension was diluted with O (1 L) and filtered. with Et 2 The solid was washed with O (3 x 100ml) and dried in vacuo to give a white powder (32g). The powder was partitioned between DCM (400ml) and 10% aqueous KOH (400ml). The aqueous phase was extracted with DCM (2 x 400ml). The combined organic phases were dried (MgSO 4 ) and concentrated to afford the title compound as a white amorphous solid (26 g).

Embodiment 3

[0354] Example 3: tert-butyl 4-(4-fluoro-phenylcarbamoyl)-piperazine-1-carboxylate (intermediate)

[0355]

[0356] The title compound was prepared analogously to Example 1 using 4-fluorophenyl isocyanate.

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Abstract

Compounds of formula (I): wherein, Z is -N-or>CH; R<1> is -H or -C1-4alkyl; Ar<1> is 2-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-primidinyl, 5-pyrimidinyl, or phenyl, each unsubstituted or substituted at a carbon ring member with one or two R moieties; where each R moiety is independently selected from the group consisting of -C1-4alkyl, -C2-4alkenyl, -OH, -OC1-4alkyl, halo, -CF3, -OCF3, -SCF3, -SH, -S(O)0-2C1-4alkyl, -OSO2C1-4alkyl, -CO2C1-4alkyl, -CO2H, -COC1-4alkyl, -N(R)R<c>, -SO2NRR<c>, -NRSO2R<c>, -C(=O)NRR<c>, -NO2, and -CN, wherein R and R<c> are each independently -H or -C1-4alkyl; and Ar<2> is defined in the claims are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat, e.g., anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as multiple sclerosis).

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application 60 / 640,869, filed December 30, 2004 technical field [0003] The present invention relates to certain piperazinyl urea and peperidinylurea compounds, pharmaceutical compositions containing them, and their use in the treatment of disease states, disorders and conditions mediated by fatty acid amide hydrolase (FAAH) activity Methods. Background technique [0004] The medicinal benefits of the cannabis plant have been known for centuries. The main bioactive constituents of cannabis are △ 9 - Tetrahydro-cannabinol (THC). The discovery of THC eventually led to the identification of two endocannabinoid (cannabinoid) receptors responsible for its pharmacological effects, known as CB 1 and CB 2 (Goya, Exp. Opin. Ther Patents 2000, 10, 1529). These findings not only establish THC's site of action, but also interrogate endogenous agonists, or "endocannabinoid...

Claims

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Application Information

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IPC IPC(8): C07D295/20C07D215/12C07D401/12C07D405/12C07D239/42C07D241/42C07D417/12C07D317/58A61P25/22A61P25/04A61P25/28C07C275/28
CPCC07D213/56C07D209/82C07D239/42C07D211/16C07D295/195C07D319/18C07D295/215C07D213/38C07D307/81C07D215/12C07D319/16C07D215/18C07D317/58C07D213/75C07D405/12C07D317/46C07D209/08C07D333/58C07D213/61C07D307/79C07D401/12C07D333/60C07D207/335C07D417/12C07D209/14C07D241/42C07D295/20A61P1/00A61P1/04A61P1/08A61P1/12A61P1/14A61P1/16A61P11/00A61P11/04A61P15/00A61P15/04A61P15/08A61P15/10A61P15/18A61P17/00A61P17/04A61P19/02A61P25/00A61P25/02A61P25/04A61P25/06A61P25/08A61P25/14A61P25/16A61P25/20A61P25/22A61P25/28A61P25/36A61P27/02A61P27/06A61P29/00A61P3/00A61P31/00A61P31/18A61P35/00A61P37/04A61P37/06A61P37/08A61P43/00A61P9/00A61P9/12A61P3/10C07D295/18C07D295/16A61K31/495
Inventor R·阿波达卡J·G·布赖滕布赫K·帕塔比拉曼M·塞尔斯塔肖薇
Owner JANSSEN PHARMA NV
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