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Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related therto

A technology of solvates and alkyls, applied in anti-inflammatory agents, metabolic diseases, drug combinations, etc.

Inactive Publication Date: 2006-08-30
ARENA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Both have antipsychotic effects, but typical treatment also includes concomitant motor-related side effects (extrapyramidal syndrome, eg lip twitching, tongue knotting, displacement movements, etc.)

Method used

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  • Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related therto
  • Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related therto
  • Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related therto

Examples

Experimental program
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preparation example Construction

[0618] for the active content of 125 Synthetic methods for I to be incorporated into target molecules include:

[0619] A. The Sandmeyer reaction and similar reactions - This procedure converts an aryl or heteroaryl amine to a diazonium salt, such as tetrafluoroborate, and subsequently uses Na 125 I convert it into 125 I labeled compound. Representative procedures are reported by Zhu, D.-G. and co-workers in J. Org. Chem., 2002, 67, 943-948.

[0620] B. Ortho-iodine of phenols [ 125 I] Reaction - This procedure allows the 125 I was incorporated in the ortho position of the phenol as reported by Collier, T.L. and co-workers, J. Labeled Compd. Radiopharm., 1999, 42, S264-S266.

[0621] C. use 125 I Substitution of Brominated Aryl and Heteroaryl - This method generally consists of a two-step process. The first step is: in trialkyltin halide or hexaalkylditin [eg (CH 3 ) 3 SnSn(CH 3 ) 3 ] in the presence of, for example, Pd-catalyzed reactions [ie, Pd(Pd(Ph 3 P) 4 )] ...

example 1

[0627] Example 1 Synthesis of Compounds of the Invention.

[0628] The compound syntheses illustrated in the present invention are shown in Figures 17 to 21 and Figures 29 to 34, where the symbols have the same definitions as used throughout this disclosure.

[0629] The compounds of the present invention and their synthesis are further illustrated by the following examples. However, the following examples are provided to further illustrate the invention without limiting the invention to these particular examples. Compounds described herein (above and below) were named according to CS Chem DrawUltra Version 7.0.1, AutoNom version 2.2. In certain instances, common names are used and it is understood that such common names should be recognized by those skilled in the art.

[0630] Chemistry: on a Varian Mercury Vx-400 equipped with 4-nuclei automatic switchable probe and z-gradient or on a Varian equipped with QNP (Quad Nucleus Probe) or BBI (Broad Band Inverse) and z-gradient...

example 11

[0633] Example 1.1: Preparation of intermediate 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-aniline.

[0634] To a stirred solution of 4-bromo-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (1.799 g, 5.76 mmol) in EtOH (20 mL) was added SnCl 2 2H 2 O (5.306 g, 23.05 mmol, 4.0 equiv), the mixture was stirred at reflux for 2 hours, and the EtOH was removed under vacuum. The resulting solid was dissolved in EtOAc, 1N NaOH (30 mL) was added, and the mixture was stirred overnight. The white precipitate was filtered off through celite, and the aqueous phase was extracted with EtOAc (3 x 80 mL). with anhydrous MgSO 4 The combined organic phases were dried, filtered and evaporated. through SiO 2 The crude reaction mixture was purified by column chromatography (eluent: EtOAc / hexane = 1 / 3, then 1 / 1) to yield 3-(4-bromo-2-methyl-2H-pyridine as a white solid Azol-3-yl)-4-methoxy-aniline (1.430 g, 5.07 mmol, 88%): LCMS m / z (%) = 282 (M+H 79 Br, 98), 284 (M+H 81 Br, 100). 1 ...

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Abstract

The present invention relates to certain pyrazole derivatives of Formula (I) and pharmaceutical compositions thereof that modulate the activity of the 5-HT2A serotonin receptor. Compounds and pharmaceutical compositions thereof are directed to methods useful in the prophylaxis or treatment of platelet aggreagation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, reducing the risk of blood clot formation, asthma or symptoms thereof, agitation or a symptom, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, and sleep disorders, sleep disorders, diabetic-related disorders and the like. The present invention also relates to the method of prophylaxis or treatment of 5-HT2A serotonin receptor mediated disorders in combination with a dopamine D2 receptor antagonist such as haloperidol, administered separately or together.

Description

technical field [0001] The present invention relates to certain diaryl and arylheteroaryl urea derivatives of formula (I) and pharmaceutical compositions thereof, which modulate 5-HT 2A Serotonin receptor activity. Compounds and pharmaceutical compositions thereof are directed to methods for preventing or treating the following diseases: platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina pectoris, stroke, atrial fibrillation, reducing the risk of thrombosis, asthma or its symptoms, agitation or symptom, behavioral disorder, drug-induced psychosis, excitatory psychosis, Durett's syndrome, mood disorder, organic or NOS psychosis, psychosis, psychosis, acute schizophrenia, chronic schizophrenia, NOS Schizophrenia and related disorders, sleep disorders, diabetes related disorders and similar disorders. [0002] The invention also relates to combination with a dopamine D2 receptor antagonist such as haloperidol, administered se...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/16A61K31/415C07D231/12C07D405/12
CPCC07D231/12C07D405/12C07D231/16C07D401/12A61K31/4155A61K31/454A61K31/496A61K31/5377A61K31/415A61P1/04A61P1/08A61P1/14A61P11/00A61P11/06A61P13/12A61P19/02A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/28A61P25/32A61P27/02A61P29/00A61P3/08A61P43/00A61P7/02A61P7/04A61P9/00A61P9/10A61P3/10
Inventor 布拉德利·特加登洪纳帕·贾亚库马尔李红梅索尼娅·斯特拉-普莱内特彼得·伊恩·多萨
Owner ARENA PHARMA
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