781649-09-0

Basic information

• Product Name: MK 0974, Telcagepant
• Synonyms: MK 0974, Telcagepant;Telcagepant;N-[(3R,6S)-6-(2,3-Difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepin-3-yl]-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxamide;Mk 0974;Mk0974;Mk-0974;N-(6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl)-4-(2-oxo-2,3-dihydro-1H-imidazo(4,5-B)pyridin-1-yl)piperidine-1-carboxamide;MK0947
• CAS NO: 781649-09-0
• Molecular Formula: C₂₆H₂₇F₅N₆O₃
• Molecular Weight: 566.528
• Product Categories: API
• Mol File: 781649-09-0.mol

Chemical Properties

• Appearance: /
• Density: 1.54
• Solubility: Soluble in DMSO
• PKA: 12.03±0.20(Predicted)
• CAS DataBase Reference: MK 0974, Telcagepant(CAS DataBase Reference)
• NIST Chemistry Reference: MK 0974, Telcagepant(781649-09-0)
• EPA Substance Registry System: MK 0974, Telcagepant(781649-09-0)

Safety Data

• Hazardous Substances Data: 781649-09-0(Hazardous Substances Data)

Usage

Biological Activity

mk-0974 (telcagepant) is a highly potent, selective, and orally bioavailable antagonist of cgrp receptor with ic50 value of 0.77 nm [1].calcitonin gene-related peptide (cgrp) receptor is a heteromeric transmembrane receptor composed of a g protein-coupled receptor which is called calcitonin receptor-like receptor (calcrl) and a receptor activity modifying protein 1 (ramp1). cgrp receptor is functional for mediating the activity of cgrp, which is widely distributed in human peripheral and central neuron system. the cgrp/cgrp receptor signaling pathway modulate a variety of physiological functions of respiratory, immune and cardiovascular system, and play a key role in the pathophysiology of migraine headache.when binding study was carried out, it was found mk-0974 had high affinity for cgrp receptor but had no affinity for related human adrenomedullin receptors, which suggested the high specificity of mk-0974 [1]. in human hek293 cells expressing cgrp receptor, treatment of mk-0974 resulted in potent blockage of α-cgrp-stimulated camp producation, which indicated a significant inhibition of cgrp receptor activity. however, addition of 50% human serum reduced the inhibition potency of mk-0974 by 5-fold [1]. mk-0974 displayed reversible and saturable binding to both sk-n-mc membranes and rhesus cerebellum with a kd of 1.9 nm and 1.3 nm, respectively [2].in rhesus model, capsaicin-induced release of endogenous cgrp resulted in dermal vasodilation. following treatment of mk-0974 produced a dose-dependent inhibition of dermal vasodilation, with plasma concentrations of 127 and 994 nm required to block 50 and 90% of the blood flow increase, respectively. the suppression of cgrp function indicated the inhibition of cgrp receptor by mk-0974 [1]. in monkey model, mk-0974 showed moderate clearance (14-20 ml min-1 kg-1), while oral bioavailability was 6%. the pharmacokinetics of mk-0974 remained linear across 0.5-10 mg kg-1 intravenous dose in monkeys, but the oral area under the plasma concentration-time curve (auc) increase (5-30 mg kg-1) was 15-fold over dose-proportional [3].

references

[1] salvatore c a et al. , pharmacological characterization of mk-0974 [n-[(3r,6s)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraine. j pharmacol exp ther. 2008, 324(2): 416-421.[2] moore e l et al. , examining the binding properties of mk-0974: a cgrp receptor antagonist for the acute treatment of migraine. eur j pharmacol. 2009, 602(2-3): 250-254.[3]. roller s et al., preclinical pharmacokinetics of mk-0974, an orally active calcitonin-gene related peptide (cgrp)-receptor antagonist, mechanism of dose dependency and species differences. xenobiotica. 2009, 39(1): 33-45.

Upstream product

• 953081-45-3 C₁₈H₁₇F₅N₄O₂ 
• 781650-41-7 (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one 
• 7693-46-1 4-Nitrophenyl chloroformate 
• 530-62-1 1,1'-carbonyldiimidazole 
• 906532-82-9 4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylic acid ethyl ester 
• 906532-72-7 4-[1-(2-chloro-pyridin-3-yl)ureido]piperidine-1-carboxylic acid ethyl ester 
• 953077-37-7 (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)-azepan-2-one hydrochloride 

Relevant articles and documents

Process for the preparation of Caprolactam Cgrp Antagonist

An efficient syntheses for the preparation of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one.

Synthesis of the (3R,6S)-3-amino-6-(2,3-difluorophenyl)azepan-2-one of telcagepant (MK-0974), a calcitonin gene-related peptide receptor antagonist for the treatment of migraine headache

(Chemical Equation Presented) Two novel routes have been developed to the (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one 2 of the CGRP receptor antagonist clinical candidate telcagepant (MK-0974, 1). The first employs a ring-closing metathesis of the styrene 7 as the key reaction, while the second makes use of a highly diastereoselective Hayashi-Miyaura Rh-catalyzed arylboronic acid addition to nitroalkene 16. The latter route has been implemented to produce multigram quantities of telcagepant for extensive preclinical evaluation.

PROCESS FOR THE PREPARATION OF PYRIDINE HETEROCYCLE CGRP ANTAGONIST INTERMEDIATE

An efficient syntheses for the preparation of the intermediate 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride, and other salt forms of 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine.

PROCESS FOR THE PREPARATION OF CGRP ANTAGONIST

An efficient synthesis for the preparation of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine -1-carboxamide, by coupling (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one and 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride with 1,1''-carbonyldiimidazole (""CDI"") as carbonyl source; and an efficient preparation of the potassium salt of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine -1-carboxamide.

CGRP ANTAGONIST SALT

An efficient synthesis for the preparation of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine -1-carboxamide, by coupling (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one and 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride with 1,1'-carbonyldiimidazole ("CDI") as carbonyl source; an efficient preparation of the potassium salt of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine -1-carboxamide; efficient syntheses for the preparation of intermediates (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one and 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride, and the potassium salt of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine -1-carboxamide including the potassium salt ethanolate and potassium salt hydrate.

Potent, orally bioavailable calcitonin gene-related peptide receptor antagonists for the treatment of migraine: Discovery of N-(3R,6S)-6-(2,3- difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl-4-(2-oxo-2, 3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)

Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Herein we describe optimization of CGRP receptor antagonists based on an earlier lead structure containing a (3R)-amino-(6S)- phenylcaprolactam core. Replacement of the phenylimidazolinone with an azabenzimidazolone gave stable derivatives with lowered serum shifts. Extensive SAR studies of the C-6 aryl moiety revealed the potency-enhancing effect of the 2,3-difluorophenyl group, and trifluoroethylation of the N-1 amide position resulted in improved oral bioavailabilities, ultimately leading to clinical candidate 38 (MK-0974).

CGRP RECEPTOR ANTAGONISTS

The present invention is directed to compounds of Formula (I) and Formula (II) (where variables R1, R2, R3, R4, A, B, G, J, Q, T, U, V, W, X and Y are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.