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Constrained compounds as cgrp-receptor antagonists

A compound, alkyl technology, applied in the field of restricted compounds as calcitonin gene-related peptide receptor antagonists, which can solve problems such as lack of molecular evidence

Active Publication Date: 2009-07-29
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, molecular evidence for the CGRP2 receptor is lacking (Brain, S.D. et al., TiPS 2002, 23, 51-53)

Method used

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  • Constrained compounds as cgrp-receptor antagonists
  • Constrained compounds as cgrp-receptor antagonists
  • Constrained compounds as cgrp-receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1107]

[1108] (S)-4-Chloro-7-(2-oxo-2-(4-(2-oxo-1,2,4,5-tetrahydrobenzo[d][1,3]diazepine -3-yl)piperidin-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepine And[3,4-e]indazol-8(3H)-one

[1109] Make [4-chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triazepine -(S)-Cyclohepta[e]inden-7-yl]acetic acid (170 mg, 0.452 mmol) was dissolved in N,N-dimethylformamide (4.0 mL). To the mixture was added N,N-diisopropylethylamine (300 μL, 1.722 mmol), followed by TBTU (152 mg, 0.473 mmol). Add 3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepine to the mixture -2(3H)-one (155 mg, 0.632 mmol). The reaction mixture was stirred at room temperature for 45 minutes. The reaction was quenched with 50% acetonitrile / water. The mixture was purified by reverse phase preparative HPLC (acetonitrile / water / trifluoroacetic acid). Acetonitrile was removed from the fractions by rotary evaporation. The remaining aqueous solution was made basic with sodium ...

Embodiment 2

[1111]

[1112] (S)-4-chloro-7-(2-oxo-2-(4-(2-oxo-3-phenyl-2,3-dihydroimidazol-1-yl)piperidin-1-yl ) ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepine And[3,4-e]indazol-8(3H)-one

[1113] Make [4-chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triazepine -(S)-Cyclohepta[e]inden-7-yl]acetic acid (97 mg, 258 μmol) was dissolved in N,N-dimethylformamide (1.5 mL). To the mixture was added N,N-diisopropylethylamine (45 μL, 258 μmol) followed by 3-phenyl-1-(piperidin-4-yl)-1H-imidazole-2(3H) - Ketone hydrochloride (86 mg, 307 micromol). The reaction mixture was stirred at room temperature for 3.5 hours. The mixture was diluted with 50% acetonitrile / water. The mixture was purified by reverse phase preparative HPLC (acetonitrile / water / ammonium acetate). Acetonitrile was removed from the fractions by rotary evaporation. The remaining aqueous solution was diluted with water. The solid was filtered and washed with water. The solid was collected an...

Embodiment 3

[1115]

[1116] (S)-4-chloro-7-(2-oxo-2-(4-(2-oxo-2,3-dihydroimidazol-1-yl)piperidin-1-yl)ethyl)- 9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepine And[3,4-e]indazol-8(3H)-one

[1117] Suspend 1-(piperidin-4-yl)-1H-imidazol-2(3H)-one hydrochloride (80 mg, 0.393 mmol) in N,N-diisopropylethylamine (33.5 μl, 0.192 mmol) and N,N-dimethylformamide (2.0 ml). Then [4-chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triazol Hetero-(S)-cyclohepta[e]inden-7-yl]acetic acid (72 mg, 0.192 mmol) was dissolved in the mixture. TBTU (61.5 mg, 0.192 mmol) was added to the mixture and quickly homogenized. The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with 50% acetonitrile / water. The mixture was purified by reverse phase preparative HPLC (acetonitrile / water / ammonium acetate). Acetonitrile was removed from the fractions by rotary evaporation. The residue was extracted twice with ethyl acetate. Organic layer with MgSO 4...

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Abstract

The invention encompasses constrained bicyclic and tricyclic CGRP-receptor antagonists, methods for identifying them, pharmaceutical compositions comprising them, and methods for their use in therapy for treatment of migraine and other headaches, neurogenic vasodilation, neurogenic inflammation, 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

technical field Background technique [0001] Calcitonin gene-related peptide (CGRP) is a natural 37 amino acid peptide first identified in 1982 (Amara, S.G. et al., Science 1982, 298, 240-244) . Two forms of the peptide (αCGRP and βCGRP) are expressed, differing by one amino acid in rats and three amino acids in humans, respectively. The peptide is widely distributed in the peripheral nervous system (PNS) and central nervous system (CNS), mainly localized in sensory afferent neurons and central neurons, and exhibits various biological effects, including vasodilation. [0002] When released from cells, CGRP binds to specific cell surface G protein-coupled receptors and exerts its biological effects mainly by activating intracellular adenylyl cyclase (Poyner, D.R. et al., BrJ Pharmacol 1992, 105, 441-7 and Van Valen, F. et al., Neurosci Lett 1990, 119, 195-8.). Based on the antagonist properties against the peptide fragment CGRP(8-37) and the ability of CGRP linear analogues...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/55C07D519/00A61P25/06
Inventor 普拉萨德·V·查特维杜拉斯蒂芬·E·默瑟方海权韩晓军罗光林吉恩·M·杜博奇克格雷厄姆·S·波因德克斯特
Owner BRISTOL MYERS SQUIBB CO
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