Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Pyrrolidine derivatives as CB1-receptor antagonists

A technology of alkyl and compounds, applied in the field of novel pyrrolidine compounds or their pharmaceutically acceptable salts, can solve the problem of not providing antagonistic activity of pyrrolidine compounds

Inactive Publication Date: 2007-05-09
MITSUBISHI TANABE PHARMA CORP
View PDF22 Cites 7 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Meanwhile, JP1993-17434 discloses such as 4-amino-5-chloro-N-[1-(diphenylmethyl)-5-(hydroxymethyl)-3-pyrrolidinyl]-2-methoxy- Specific pyrrolidine compounds, such as benzamide, increase gastric motility in mice, but do not provide any insight into whether pyrrolidine compounds have antagonistic activity against CB1 receptors

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Pyrrolidine derivatives as CB1-receptor antagonists
  • Pyrrolidine derivatives as CB1-receptor antagonists
  • Pyrrolidine derivatives as CB1-receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0302] (3R)-1-[bis(4-chlorophenyl)methyl]-3-aminopyrrolidine (2.05 g, the compound prepared in Reference Example 11) and triethylamine (1.35 mL ) in dichloromethane (30 mL) was added dropwise 4-(trifluoromethoxy)benzoyl chloride (1.21 mL), and the mixture was stirred at room temperature for one hour. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform. After filtering the organic layer through NH-silica gel (10 g of Chromatorex NH-silica gel; Fuji Silicia Chem.), the filtrate was evaporated under vacuum. The crude product was triturated in ethyl acetate / hexanes to give (3R)-1-[bis(4-chlorophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl ]amino]pyrrolidine (2.70 g; yield: 83%) crystals.

[0303] MS(APCI) m / z: 508 / 510[M+H] + (MS(APCI): Atmospheric Pressure Chemical Ionization Mass Spectrometry)

Embodiment 2

[0305] (1) The product (2.01 g) obtained in Reference Example 8 was treated in the same manner as described in Reference Example 11-(2) and 6-(2), thereby obtaining (3,4-trans)-1-[di (4-Chlorophenyl)methyl]-3-hydroxy-4-aminopyrrolidine dihydrochloride (2.13 g; yield: 51%). MS(APCI) m / z: 337 / 339[M+H] +

[0306] (2) Add dropwise 4 - (trifluoromethoxy)benzoyl chloride (635 µL), and the mixture was stirred at the same temperature for 1 hour. The organic layer was separated and filtered through NH-silica gel beads (5 g Chromatorex NH-silica gel) and the filtrate was evaporated under vacuum. The crude product was triturated in ethyl acetate / hexanes to give (3,4-trans)-1-[bis(4-chlorophenyl)methyl]-3-hydroxy-4-[[4-( Trifluoromethoxy)benzoyl]amino]pyrrolidine (1.61 g; yield: 84%) crystals.

[0307] MS(APCI) m / z: 525 / 527[M+H] +

Embodiment 3

[0309] To a solution of the compound (26.9 mg) obtained in Reference Example 11 and 6-methylnicotinic acid (20.5 mg) in chloroform (1 mL) was sequentially added 0.5 M 1-hydroxybenzotriazole / dimethylformamide (0.4 mL ) and 0.5M 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride / chloroform (0.4 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture were added saturated aqueous sodium bicarbonate (1 mL), water (2 mL) and chloroform (2 mL), and the mixture was stirred for 15 minutes. The chloroform layer in the mixture was separated and evaporated under vacuum. The crude product was purified using HPLC (XTerra Prep MS C18 column; solvent: 10 mM ammonium carbonate / methanol=80:20→5:95), then dissolved in tert-butanol (1.5 mL), and lyophilized to obtain (3R)-1- [Bis(4-chlorophenyl)methyl]-3-[(6-methylnicotinoyl)amino]pyrrolidine powder (40.7 mg; yield: 92%). MS(ESI)m / z; 440 / 442[M+H] +

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention relates to a novel pyrrolidine compound, which has a potent antagonistic activity against central cannabinoid (CB1) receptor, having the formula [I]: wherein each of R<1> and R<2> is (A) optionally substituted aryl (or heteroaryl) group, or (B) both of the groups combine to form a group of the formula: one of R<3> and R<4> is hydrogen and another is hydrogen, hydroxyl, hydroxyalkyl, etc., or both of R<3> and R<4> combine to form oxo group, R<5> is hydrogen or alkyl, Y is single bond, oxygen atom or a group of the formula: -N(R<7>)-, R<6> is optionally substituted hydrocarbon group or optionally substituted cyclic group, R<7> is alkyl or alkyloxycarbonylalkyl, provided that R<6> is not 4-amino-5-chloro- 2-methoxyphenyl group when Y is single bond and one of the R<3> and R<4> is hydrogen and another is hydroxymethyl, or a pharmaceutically acceptable salt thereof.

Description

technical field [0001] The present invention relates to a novel pyrrolidine compound or a pharmaceutically acceptable salt thereof, which has effective antagonistic activity against central cannabinoid (central cannabinoid; CB1) receptors and can be used as drug. Background technique [0002] It is well known that the inhalation of marijuana can produce a variety of mental or neurological reactions such as confusion of sense of time or space, euphoria, memory changes, analgesia, hallucinations, etc. Compounds commonly referred to as "cannabinoids," including ⊿9-tetrahydrocannabinol (⊿9-THC), are responsible for many of the reactions described. The effects of cannabinoids are thought to arise through the interaction of the compound with its endogenous specific / high affinity receptors. Two subtypes of cannabinoid receptors (CB1 and CB2) have been identified and cloned. CB1 receptors are distributed in the central nervous system (CNS) including the brain (Nature, Vol.346, 19...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D207/14C07D401/12C07D498/04C07D403/12C07D405/12C07D417/14C07D409/12C07D417/12C07D413/12C07D403/14C07D487/04C07D491/04C07D409/14C07D405/06C07D403/06
Inventor 盛谷恭典古久保茂坪井康范冈垣智惠子奥哲平野直光
Owner MITSUBISHI TANABE PHARMA CORP
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com