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Constrained compounds as cgrp-receptor antagonists

A compound, combined technology, applied in the field of restricted compounds as CGRP receptor antagonists, able to solve problems such as greater than other species

Inactive Publication Date: 2007-12-26
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Known species-specific differences in the binding of small molecule antagonists to CGRP receptors, antagonism in human receptors was generally observed to be greater than in other species (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

[1007]

[1008] 4-(2-Oxo-1,4-dihydro-2H-quinolin-3-yl)piperidine-1-carboxylic acid (9-benzyl-8-oxo-3,6,7,8,9, 10-Hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)amide

[1009] To 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-1-carboxylic acid (3-acetyl-9-benzyl-8-oxo-3,6, 7,8,9,10-Hexahydro-2,3,9-Triaza-(R)-Cycloheptatrien[e]inden-7-yl)amide (19 mg, 0.03 mmol) was added Potassium carbonate (25 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 1.25 hours. The reaction was quenched with 1N hydrochloric acid (5 mL). Methanol was removed from the mixture under reduced pressure, and the remaining aqueous solution was made basic with sodium bicarbonate. The mixture was extracted with dichloromethane (3 x 10 mL). The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The title compound was obtained as an off-white solid in 90% yield.

[1010] 1 H NMR (300MHz, CDCl 3 ): δ=7.64(s, 1H), 7.18(...

Embodiment 2

[1012]

[1013] 4-(2-Oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxylic acid (9-methyl-8-oxo-3,6,7,8,9,10- Hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)amide

[1014] To (3-acetyl-9-methyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cycloheptatrieno[ e] A mixture of inden-7-yl)benzyl carbamate (30 mg, 0.07 mmol) and acetic acid (20 μL, 0.35 mmol) in methanol (6 ml) and ethyl acetate (3 ml) was added with a catalytic amount of 10% palladium on carbon . The reactor was placed in a parr hydrogenation unit and charged with 50 psi of hydrogen. The reaction mixture was shaken at room temperature for 1.5 hours. The mixture was filtered, the filtrate was concentrated, and the residue was treated with chloroform (3 mL) and saturated aqueous sodium bicarbonate (1 mL). To the mixture was added 20% phosgene / toluene (48 μL, 0.09 mmol). The reaction mixture was stirred at room temperature for 5 minutes. Acetic acid 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-(25m...

Embodiment 3

[1017]

[1018] 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-1-carboxylic acid [8-oxo-9-(2-piperidin-1-ylethyl) -3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cycloheptatrieno[e]inden-7-yl]amide

[1019] To 7-(R)-amino-9-(2-piperidin-1-ylethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triazepine A mixture of inden-8-one (60 mg, 0.18 mmol) and triethylamine (150 μL, 1.1 mmol) in dichloromethane (3 mL) was added to N,N'-disuccinimidyl carbonate ( 55 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-acetate (65 mg, 0.22 mmol) was added. The reaction mixture was stirred until complete as judged by HPLC (1.75 hours). The mixture was washed successively with water (2 x 5 mL) and brine (1 x 5 mL). The organic phase was concentrated under reduced pressure. C18 preparative HPLC (acetonitrile-water-trifluoroacetic acid) gave the desired product as a tan solid in 34% yield.

[1020] 1 H NMR (300MHz, D...

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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

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Patent Applications 60 / 624,655, filed November 3, 2004 and 60 / 678,099, filed May 5, 2005. Background of the invention [0003] 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). Two forms of this peptide (αCGRP and βCGRP) expressed in rat and human differ by 1 and 3 amino acids, respectively. The peptide is widely distributed in the peripheral nervous system (PNS) and central nervous system (CNS), mainly located in sensory afferent neurons and central neurons, showing various biological effects, including vasodilation. [0004] When released from cells, CGRP binds to specific cell surface G protein-coupled receptors and exerts its biological effects mainly through the activation of intracellular adenylyl cyclase (Poyner, D.R., etc., Br J Pharmacol 1992, 105,...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P25/06C07D401/14A61K31/55C07D519/00
Inventor P·V·查图尔韦杜拉S·E·默瑟方海权
Owner BRISTOL MYERS SQUIBB CO
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