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Calcitonin gene related peptide receptor antagonists

An alkyl, phenyl technology, applied in the field of calcitonin gene-related peptide receptor antagonists, which can solve the problem of not showing the disruptive effect of arterial dilatation

Inactive Publication Date: 2005-09-21
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, none of these models were invasive at the limit and none of them were shown to reverse the clinically important disruptive effects of well-documented arterial dilation or increased blood flow when post-treatment with a CGRP-receptor antagonist

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

Experimental program
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preparation example Construction

[0312] HNR 1 R 2 and the preparation of formula VIII amine

[0313] Formula VIII and HNR 1 R 2 Amines are available commercially or may be prepared by literature methods or methods described herein.

[0314]

[0315] Preparation of Amino Acids of Formula II and V

[0316]

[0317] Amino acids of Formula II and V may be commercially available or prepared as described in Scheme 4.

[0318] Scheme 4. Synthesis of Formula II and Formula V Compounds

[0319]

[0320] The synthesis described in Scheme 4 starts with an aldehyde of formula IX which is reacted with a phosphonoglycinate 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 a compound of formula XII. Reduction can be carried out to give the racemate, or by using a stereoselecti...

Embodiment 1

[0485] (±)-3-(1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine- 1-Carbonyl]-amino}-propionic acid

[0486]

[0487] 5-(2-methoxycarbonyl-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino }-Ethyl)-indazole-1-carboxylic acid tert-butyl ester (168 mg, 0.29 mmol) dissolved in THF (5 mL) in methanol (5 mL) was cooled to 0°C. Lithium hydroxide monohydrate (49mg, 2.04mmol) in water (5ml) was added. The reaction mixture was stirred at 0°C for 6 hours, then placed in the refrigerator 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%).

[0488] 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, J =8.5, 1...

Embodiment 2

[0543] (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-oxoethyl]-amide ()

[0544]

[0545] At 80°C, (R)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4'] Bipiperidin-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) were heated 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 obtain 280 mg (63% yield) of the title compound as a white solid, which was determined to be 98.2 by HPLC analysis. %ee, using a ChirocelOD column with 20% B (A = ethanol, B = 0.05% diethylamine in hexane) as eluent (retention time: 9.51 min for the title compound and 15.9 min for the S-enantiomer minute).

[0546] 1 H-NMR (CD 3 OD, 500MHz) δ8.04(s, ...

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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 treatment using them and their use in the treatment of Use in diseases such as neurogenic vasodilation, neurogenic inflammation, migraine, migraine neuralgia and other headaches, thermal burns, circulatory shock, flushing associated with menopause, respiratory inflammatory disease ( Such as asthma and chronic obstructive pulmonary disease (COPD)) and other diseases for which treatment by CGRP-receptor antagonism can be effective. Background of the invention [0002] Calcitonin gene-related peptide receptor (CGRP) is a naturally occurring 37-amino acid peptide that was first identified in 1982 (Amara, S.G. et al., Science 1982, 298, 240-244). Two forms of the peptide (αCGRP and βCGRP) are expressed, which differ by 1 and 3 amino acids ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A01K67/027A61K31/438A61K31/4427A61K31/4545A61K31/496A61K31/517A61K31/519A61K31/527A61K31/537A61K31/5377A61K49/00A61P9/00A61P11/00A61P11/06A61P15/12A61P17/00A61P25/00A61P25/04A61P25/06A61P29/00C07D401/14C07D403/14C07D405/14C07D409/14C07D413/14C07D471/04C07D471/10C07D487/14C07D487/22C07D491/10C07D491/113C07D498/10C07D519/00C12N15/85G01N33/566
CPCA01K67/0275A01K2217/05C07D409/14A01K2217/00C07D471/10G01N2500/10C07D401/14C12N15/8509C07D487/14A61K49/0008C07D405/14A01K2227/106G01N2800/2807C07D487/04C07D491/10G01N33/566A01K2267/0306A01K2207/15A61P11/00A61P11/06A61P15/12A61P17/00A61P25/00A61P25/04A61P25/06A61P29/00A61P9/00C07D487/20
Inventor P·V·查图尔维杜拉L·陈R·西维洛C·M·康维A·P·德南G·M·杜博基克X·韩G·N·卡拉乔治G·罗J·E·麦科尔G·波因德克斯特S·维格
Owner BRISTOL MYERS SQUIBB CO
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