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Intermediate for heterocyclic compound in preparing rotamase inhibitor

A technology of compound and cycloalkyl, applied in the direction of active ingredients of heterocyclic compounds, drug combination, organic chemistry, etc., can solve the problem of unclear mechanism of neurotrophic effect

Inactive Publication Date: 2004-07-14
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the mechanism by which this interaction with FKBP-type immunophilins elicits neurotrophic effects is unclear

Method used

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  • Intermediate for heterocyclic compound in preparing rotamase inhibitor
  • Intermediate for heterocyclic compound in preparing rotamase inhibitor
  • Intermediate for heterocyclic compound in preparing rotamase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0161] (2S)-1-(1,3-Benzo Oxazole -2-yl)-N 2 -[(3R)-1-Benzylpyrrolidin-3-yl]-2-

[0162] piperidine carboxamide

[0163]

[0164] Triethylamine (0.167 ml) was added to (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid (100 mg) [see Preparation 3], 1-hydroxybenzene Triazole hydrate (60.4 mg), (3R)-1-benzylpyrrolidin-3-ylamine (78.7 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiene Amine hydrochloride (85.4mg) in dichloromethane (30ml) solution. The reaction mixture was stirred at room temperature for 18 hours, then the mixture was diluted with water and the organic phase was separated, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with a solvent gradient of 50:50:0 → 25:75:0 → 20:80:1 (volume ratio) hexane: ethyl acetate: 0.88 ammonia water to obtain ( 2S)-1-(1,3-Benzoxazol-2-yl)-N2 -[(3R)-1-Benzylpyrrolidin-3-yl]-2-piperidinecarboxamid...

Embodiment 2

[0169] (2S)-1-(1,3-Benzo Oxazole -2-yl)-N 2 -[(3S)-1-Benzylpyrrolidin-3-yl]-2-

[0170] piperidine carboxamide

[0171]

preparation example 3

[0172] The title compound was obtained from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and (3S)-1- Benzylpyrrolidin-3-ylamine Preparation. The crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of 50:50:1→20:80:1 (by volume) hexane:ethyl acetate:0.88 ammonia in 10% increments. The product was further purified by recrystallization from ethyl acetate: hexanes to afford (2S)-1-(1,3-benzoxazol-2-yl)-N as a white solid 2 -[(3S)-1-Benzylpyrrolidin-3-yl]-2-piperidinecarboxamide.

[0173] 1 H-NMR (CDCl 3 )δ: 7.40(1H,d), 7.30(1H,m), 7.20(6H,s), 7.05(1H,t), 6.60(1H,d), 4.85(1H,s), 4.45(1H,bs ), 4.25(1H, d), 3.60(2H, s), 3.20(1H, t), 2.75(1H, m), 2.55(2H, m), 2.35(1H, m), 2.25(2H, m) , 1.80-1.50(4H, m), 1.30(2H, m).

[0174] Analysis: Found C, 71.00; H, 7.00; N, 13.80; C 24 h 28 N 4 o 2 Theoretical values ​​for C, 71.26; H, 6.98; N, 13.85%.

[0175] Optical rotation: [◇] 25 D =-102.0° (c=0.1, m...

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Abstract

Compounds of the formula (I) wherein A is unbranched C3-C5 alkylene optionally substituted by C1-C6 alkyl; X is O, S, NH or N(C1-C6 alkyl); Y is O, S, NH or N(C1-C6 alkyl); R is a C-linked, 4- to 6-membered ring, non-aromatic, heterocyclic group containing one nitrogen heteroatom, said group being optionally substituted by 1, 2 or 3 substituent(s) each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, aryl, het, -CO2(C1-C6 alkyl), -CO(het), -CONR5R6 and -CO(aryl), said alkyl and alkenyl being optionally substituted by 1 or 2 substituent(s) each independently selected from C3-C7 cycloalkyl, aryl, het, -O(aryl), -O(C1-C2 alkylene) aryl, -CO(het), -CONR5R6 and -CO(aryl); are inhibitors of rotamase enzymes in particular FKBP-12 and FKBP-52. The compounds therefore moderate neuronal regeneration and outgrowth and can be used for treating neurological disorders arising from neurodegenerative diseases or other disorders involving nerve damage.

Description

[0001] This application is a divisional application of an invention patent application with the application number 99808997.4 (PCT / IB99 / 01211) filed on June 28, 1999, and the title of the invention is "Heterocyclic Compounds Used as Rotamase Inhibitors" . technical field [0002] The present invention relates to 1-heteroaryl-pyrrolidine, -piperidine and -homopiperidine derivatives, processes for their preparation, intermediates used in their preparation, compositions containing the derivatives and uses of said derivatives. Background technique [0003] It has been reported that the immunosuppressant FK-506 can promote axonal branching in neural cell lines and culture models in vitro (see Lyons et al., "Proceedings of the National Academy of Sciences of the United States of America)" (Pro.Natl.Acad.Sci.), 1994 , 91, 3191-95 and Snyder et al., "Nature Medicine", 1995, 1, 32-37). WO-A-96 / 40140, WO-A-96 / 40633 and WO-A-97 / 16190 disclose compounds having neurotrophic activity but...

Claims

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Application Information

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IPC IPC(8): A61K31/44A61K31/4427A61K31/454A61K31/4545A61K31/4709A61P19/00A61P21/00A61P21/04A61P25/00A61P25/02A61P25/14A61P25/16A61P25/28A61P27/02A61P27/16A61P37/00A61P43/00C07D235/24C07D401/04C07D401/14C07D413/04C07D413/14C07D417/04C07D417/14C07D471/04C07D471/14C07D521/00
CPCC07D401/14C07D231/12C07D417/14C07D413/04C07D413/14C07D417/04C07D249/08C07D233/56A61P19/00A61P21/00A61P21/04A61P25/00A61P25/02A61P25/14A61P25/16A61P25/28A61P27/02A61P27/16A61P37/00A61P43/00
Inventor M·I·科普M·J·帕尔梅M·A·桑纳M·J·威思斯
Owner PFIZER INC