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Calcitonin gene related peptide receptor antagonists

A methyl and cyano technology, applied in the field of calcitonin gene-related peptide receptor antagonists, can solve the problem of not showing the effect of arterial dilatation or increased blood flow interruption.

Inactive Publication Date: 2007-02-21
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these models are invasive terminal procedures and none have been shown to reverse well-documented arterial dilation or clinically important interruptions in increased blood flow upon post-treatment with CGRP-receptor antagonists sexual influence

Method used

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  • Calcitonin gene related peptide receptor antagonists
  • Calcitonin gene related peptide receptor antagonists
  • Calcitonin gene related peptide receptor antagonists

Examples

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preparation example Construction

[0293] HNR 1 R 2 and the preparation of formula VIII amine

[0294] Formula VIII and HNR 1 R 2 Amines are either commercially available or can be prepared by literature methods or methods described therein.

[0295]

[0296] Preparation of Amino Acids of Formula II and V

[0297]

[0298] Amino acids of Formula II and V are either commercially available or can be prepared as described in Scheme 4.

[0299] Scheme 4. Synthesis of Formula II and Formula V Compounds

[0300]

[0301] The synthesis described in Scheme 4 begins with an aldehyde of formula IX which is reacted with a glycine phosphonate of formula X via Wadsworth-Emmons coupling. Compounds of formula X are deprotonated with a base such as diazabicycloundecene or tetramethylguanidine or other organic or inorganic bases well known in the art. Reduction of the double bond of the resulting compound of formula XI affords the compound of formula XII. This reduction is carried out to give the racemate, or b...

Embodiment 1

[0447] (±)-3-(1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1-Carbonyl]-amino}-propionic acid

[0448]

[0449] 5-(2-Methoxycarbonyl-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piper A solution of pyridine-1-carbonyl]-amino}-ethyl)-indazole-1-carboxylic acid tert-butyl ester (168 mg, 0.29 mmol) was cooled to 0 °C in methanol (5 mL). An aqueous solution (5 mL) of lithium hydroxide monohydrate (49 mg, 2.04 mmol) was added. The reaction mixture was stirred at 0°C for 6 hours and then placed in the freezer for an additional 16 hours. The solvent was removed in vacuo, and the residue was dissolved in water (15 mL). The pH of the aqueous solution was adjusted to about 1 with 1N hydrochloric acid. The precipitated white solid was collected by filtration. The solid was dried in vacuo to give the title compound (108 mg, 80%).

[0450] 1 H-NMR (DMSO-d 6 , 300MHz) δ12.94(bs, 1H), 9.19(s, 1H), 8.01(s, 1H), 7.61(s, 1H), 7.46(d, J=8.4Hz, 1H), 7.28(dd,...

Embodiment 2

[0495] (R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4′]bipiperidine- 1'-yl-1-(1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide ()

[0496]

[0497] (R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4′]bipiperidine -1'-yl-2-oxo-1-[1-(2-trimethylsilyl-ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl}-amide (568 mg, 0.73 mmol) and cesium fluoride (1.11 g, 7.31 mmol) in acetonitrile (50 mL) was heated at 80°C for 4.5 hours. The reaction mixture was concentrated, and the residue was subjected to flash column chromatography (dichloromethane / methanol / triethylamine, 94:5:1) to afford 280 mg (63% yield) of the title compound as a white solid, which was recovered by using Chirocel HPLC analysis of the OD column determined to have 98.2% ee with 20% B (A = ethanol, B = 0.05% diethylamine in hexane) as eluent (retention time: 9.51 min for the title compound, and 9.51 min for the S- Enantiomer 15.9 minutes). 1 H-NMR (CD 3 OD, 500...

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PUM

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Abstract

The present invention relates to compounds of Formula (I) as antagonists of calcitonin gene-related peptide receptors ('CGRP-receptor'), pharmaceutical compositions comprising them, methods for identifying them, methods of treatment using them and their use in therapy for treatment of neurogenic vasodilation, neurogenic inflammation, migraine and other headaches, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and other conditions the treatment of which can be effected by the antagonism of CGRP-receptors.

Description

field of invention [0001] The present invention relates to novel small molecule antagonists of the calcitonin gene-related peptide receptor ("CGRP-receptor"), pharmaceutical compositions containing them, methods of identifying them, methods of using them in therapy, and their use in therapy Neurogenic vasodilation, neurogenic inflammation, migraine, cluster and other headaches, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory disease (eg, asthma and chronic obstructive pulmonary disease (COPD)) and other conditions that can be treated by CGRP-receptor antagonism. Background of the invention [0002] Calcitonin gene-related peptide (CGRP) is a naturally occurring 37-amino acid peptide first identified in 1982 (Amara, S.G. et al., Science 1982, 298, 240-244). The peptide is expressed in two forms (αCGRP and βCGRP), which differ by 1 and 3 amino acids in rat and human, respectively. The peptide is widely distributed in both the periph...

Claims

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Application Information

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IPC IPC(8): A61P25/06A61K31/535A61K31/52A61K31/55A61K31/54A61K31/495A61K31/50C07D239/00C07D243/10C07D265/00C07D285/00A61K31/517C07D209/08C07D213/64C07D221/00C07D231/56C07D239/80C07D249/18C07D263/58C07D317/00C07D401/06C07D401/12C07D403/12C07D403/14C07D405/14C07D413/12C07D417/14C07D471/04C07D471/10C07D491/10C07D498/10
CPCC07D417/14C07D231/56C07D405/14C07D403/12C07D401/06C07D471/04C07D403/14C07D209/08C07D491/10C07D471/10C07D249/18C07D401/14A61P11/00A61P11/06A61P15/12A61P17/02A61P25/06A61P29/00A61P9/00
Inventor 安德鲁·P·德格南陈岭丽塔·西维洛吉恩·M·杜鲍奇克韩晓军西昂·J·J·姜约翰·E·马科乔治·托拉罗光林
Owner BRISTOL MYERS SQUIBB CO
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