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3-pyraz0lyl-benzamide-4-ethers, secondary amines and derivatives thereof as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto

An alkyl and acyl technology, applied in blood diseases, cardiovascular system diseases, resistance to vector-borne diseases, etc.

Inactive Publication Date: 2009-07-08
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 the typical treatments also include concomitant motor-related side effects (extrapyramidal syndromes, such as lip movements, tongue jerks, locomotion movements, etc.)

Method used

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  • 3-pyraz0lyl-benzamide-4-ethers, secondary amines and derivatives thereof as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto
  • 3-pyraz0lyl-benzamide-4-ethers, secondary amines and derivatives thereof as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto
  • 3-pyraz0lyl-benzamide-4-ethers, secondary amines and derivatives thereof as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto

Examples

Experimental program
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preparation example Construction

[0488] for the active content of 125 The synthetic method that I incorporates target molecule comprises:

[0489] A. Sandmeyer and similar reactions - this procedure converts an aryl or heteroaryl amine to a diazonium salt such as tetrafluoroborate and then uses Na 125 I converted to 125 I labeled compound. A representative procedure is reported by Zhu, D.-G. and co-workers in J. Org. Chem. 2002, 67, 943-948.

[0490] B. Phenol ortho 125 Iodination - This procedure allows 125 I was incorporated in the ortho position to the phenol as reported by Collier, T.L. and coworkers in J. labeled Compd Radiopharm. 1999, 42, S264-S266.

[0491] C. Aryl bromides and heteroaryl bromides with 125 I Interchange - This method is usually a two-step procedure. The first step is to use such as Pd to catalyze the reaction [ie Pd(Ph 3 P) 4 ] or via aryllithium or heteroaryllithium in a trialkyltin halide or hexaalkylditin [e.g., (CH 3 ) 3 SnSn(CH 3 ) 3 ] to convert aryl and heteroaryl ...

example 1

[0497] Example 1: Synthesis of Compounds of the Invention.

[0498] Exemplary syntheses of compounds of the invention are shown in Figures 1 to 8 , where the symbols used have the same definitions throughout this disclosure.

[0499] The compounds of the invention and their synthesis are further illustrated by the following examples. The following examples are provided to further define the invention without, however, limiting the invention to the details of these examples. Compounds described herein above and below are named according to CS Chem Draw Ultra Version 7.0.1 or AutoNom 2000. Common names are used in certain instances and it is understood that those skilled in the art will recognize these common names.

[0500] Chemical Properties: Proton NMR ( 1 H NMR) spectra were performed on a Varian Mercury Vx-400 equipped with 4-nuclear autotransform probes and z-gradients or a Bruker Avance equipped with QNP (Quad nuclear probes) or BBI (broadband inverse probes) and z-...

example 11

[0503] Example 1.1: Preparation of N-{3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(1-methyl-piperidin-4-ylamino)-ethyl Oxy]-phenyl}-3-trifluoromethyl-benzamide (Compound 45).

[0504] To N-(4-(2-bromo-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-trifluoromethyl-benzyl To a solution of amide (0.050 g, 99.5 μmol) in DMA (3 mL) was added 1-methyl-piperidin-4-ylamine (17.0 mg, 149 μmol) and N,N-diisopropylethylamine (34.7 μL, 199 μmol). The reaction mixture was heated at 150° C. for 30 minutes in a thick-walled sealed tube under microwave irradiation and then purified by preparative HPLC. The corresponding fractions were collected and lyophilized to afford the diTFA salt of the title compound (hygroscopic) as a white solid in 40.1% yield. LCMSm / z(%)=536(M+H, 35 Cl, 100), 538 (M+H, 37 Cl, 43). 1 H NMR (400MHz, DMSO-d 6 )δ 10.56(s, 1H), 9.11-8.92(m, 2H), 8.31-8.24(m, 2H), 8.01-7.95(m, 2H), 7.80(t, J=7.8Hz, 1H), 7.73( d, J=2.6Hz, 1H), 7.71(s, 1H), 7.31(d, J=9.1Hz, 1H...

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PUM

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Abstract

The present invention pertains to certain compounds of Formula (Ia) 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 treatment of platelet aggreagation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, 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, progressive multifocal leukoencephalopathy and the like. The present invention also relates to the methods for the treatment of 5-HT2A serotonin receptor associated disorders in combination with other pharmaceutical agents administered separately or together.

Description

technical field [0001] The present invention is about regulating 5-HT 2A Certain compounds of formula (Ia) with serotonin receptor activity and pharmaceutical compositions thereof. The compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, asthma or its symptoms, anxiety or its symptoms, behavioral disturbance, drug-induced psychosis, excitatory psychosis, Gilles de la Tourette syndrome, manic psychosis, organic or NOS psychosis, mental disorder, psychosis , acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, sleep disorders, diabetes-related disorders, progressive multifocal leukoencephalopathy, and the like. [0002] The present invention also relates to the treatment of 5-HT in combination with other agents administered separately or simulta...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D231/12C07D231/16C07D403/12C07D411/12A61K31/42A61K31/4192A61K31/427A61K31/454A61P7/02A61P9/10A61P25/00
CPCC07D401/12C07D403/12C07D231/12C07D405/12C07D417/12C07D413/12A61K31/415C07D207/335C07D207/34A61P11/06A61P25/00A61P25/02A61P25/04A61P25/14A61P25/18A61P25/20A61P25/24A61P29/00A61P43/00A61P7/02A61P9/00A61P9/10A61P9/12A61P3/10Y02A50/30
Inventor 布拉德利·蒂加登丹尼斯·查普曼马克·德凯尔彼得·I·多莎康拉德·费什廷吉洪纳帕·贾亚库马尔索尼娅·斯特拉-普莱内特翠英·陈徐静东
Owner ARENA PHARMA
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