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Alpha-(aryl-or heteroaryl-methyl)-beta piperidino propanamide compounds as ORL1-receptor antagonists

A compound, heteroaryl technology, applied in the field of its medical use, can solve problems such as drug addiction

Inactive Publication Date: 2008-06-11
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Opiates have been widely used as medicaments, but drugs such as morphine and heroin can cause some side effects such as drug addiction and euphoria

Method used

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  • Alpha-(aryl-or heteroaryl-methyl)-beta piperidino propanamide compounds as ORL1-receptor antagonists
  • Alpha-(aryl-or heteroaryl-methyl)-beta piperidino propanamide compounds as ORL1-receptor antagonists
  • Alpha-(aryl-or heteroaryl-methyl)-beta piperidino propanamide compounds as ORL1-receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0058] It schematically illustrates the preparation of compounds of formula (I).

[0059]

[0060] In the above formula, G represents a hydrogen atom or a hydroxyl group. R a represents an alkyl group having 1 to 4 carbon atoms. L 1 represents a leaving group. Examples of suitable leaving groups include: halogen atoms such as chlorine, bromine and iodine; sulfonates such as TfO (trifluoromethanesulfonate), MsO (methanesulfonate), TsO (toluenesulfonate) ; and similar groups.

[0061] Step 1A

[0062] In this step, where L 1 The compound of formula 1-2 representing a halogen atom can be prepared by halogenating the compound of formula 1-1 wherein G represents a hydrogen atom with a halogenating agent in a reaction-inert solvent under halogenation conditions. when R 5 When the substituent of is a hydroxyl group, the hydroxyl group is protected with a protecting group according to conventional methods.

[0063] Examples of suitable solvents include: tetrahydrofuran; ...

Embodiment 1

[0269] N,N-Dimethyl-3-(3’H,8H-spiro[8-azabicyclo[3.2.1]octane-3-1’-[2]benzofuran]-8- yl)-2-(1,3-thiazol-4-ylmethyl)propionamide citrate

[0270]

[0271] Step 1. tert-Butyl 2-(diethoxyphosphoryl)-3-(1,3-thiazol-4-yl)propanoate

[0272] 4-Methylthiazole (5.85 g, 59 mmol), N-bromosuccinimide (11 g, 62 mmol) and 2,2'-azobisisobutyronitrile (968 mg, 5.9 mmol) ) in carbon tetrachloride (200 mL) at reflux for 5 hours. After cooling, the mixture was filtered. Toluene (100 mL) was added to the filtrate, and the mixture was concentrated to obtain a toluene solution of 4-(bromomethyl)-1,3-thiazole (27 g).

[0273] To a solution of tert-butyl diethylphosphorylacetate (15.6 g, 62 mmol) in dimethylformamide (50 mL) was added sodium hydride (60% in mineral) at 0°C under nitrogen atmosphere dispersion in oil, 2.48 g, 62 mmol). After 45 minutes, a solution of 4-(bromomethyl)-1,3-thiazole in toluene (27 g) was added to the mixture. The mixture was stirred at room temperature over...

Embodiment 2

[0295] N,N-Dimethyl-3-(1H-pyrazol-1-yl)-2-(3’H,8H-spiro[8-azabicyclo[3.2.1]octane -3,1'-[2]benzofuran]-8-ylmethyl)propionamide citrate

[0296]

[0297] Step 1. Ethyl 2-(1H-pyrazol-1-ylmethyl)acrylate

[0298] A mixture of ethyl 2-(hydroxymethyl)acrylate (4.1 g, 32 mmol), pyrazole (2.6 g, 38 mmol) and potassium carbonate (11 g, 79 mmol) in acetonitrile (30 mL) Refluxed for 20 hours, quenched by addition of water (100 mL), and extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel, eluting with hexane / ethyl acetate (7 / 1) to give 1.0 g (18%) of the title compound as a colorless oil.

[0299] 1 H-NMR (CDCl 3 ) 7.57-7.53(1H,m), 7.48-7.45(1H,m), 6.36-6.32(1H,m), 6.28(1H,t, J=2.0Hz), 5.48-5.44(1H,m), 5.01( 2H, s), 4.24 (2H, q, J=7.1Hz), 1.30 (3H, t, J=7.1Hz).

[0300] Step 2. 3-(1H-pyrazol-1-yl)-2-(3'H,8H-spiro[8-azab...

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Abstract

This invention provides the compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R<1> and R<2> independently represent hydrogen or the like; R<3> and R<4> independently represents hydrogen or the like; R<5> represents aryl or the like; -X-Y- represents -CH2O- or the like; and n represents 0, 1 or 2.These compounds have ORL1 -receptor antagonist activity; and therefore, are useful to treat diseases or conditions such as pain, various CNS diseases etc.

Description

technical field [0001] The present invention relates to alpha-(aryl- or heteroaryl-methyl-)-beta piperidinopropionamide compounds and pharmaceutically acceptable salts thereof, and to their medical use. Furthermore, the present invention relates to a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt thereof. The compounds of the present invention have binding affinity for the ORL-1 receptor. In particular, the compounds of the present invention have antagonist activity at said receptors. The compounds of the present invention are useful in the treatment or prevention of dysfunctional or medical conditions selected from pain, CNS disorders, and the like, caused by overactivity of said receptors. Background technique [0002] Three types of opioid receptors have been identified, mu (mu), delta (delta) and kappa (kappa). These receptors can be represented by OP (abbreviation for opioid peptide) and a numerical subscript as suggested by...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D451/06A61P25/04A61K31/46
CPCC07D451/06A61P1/00A61P1/14A61P1/16A61P11/00A61P13/12A61P15/10A61P21/00A61P25/00A61P25/04A61P25/08A61P25/16A61P25/18A61P25/20A61P25/22A61P25/28A61P25/30A61P25/36A61P3/04A61P35/04A61P37/00A61P43/00A61P9/00A61K31/46
Inventor Y·桥爪M·广田H·小池Y·松本S·三原H·中村
Owner PFIZER INC
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