1365037-83-7

Upstream product

• 162758-35-2 rimonabant acid 
• 87120-72-7 1-(tert-butoxycarbonyl)-4-aminopiperidine 

Downstream Products

• 1443990-77-9 4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)-N-((4αS,7S,7αR,12βS)-4α,9-dihydroxy-3-methyl-2,3,4,4α,5,6,7,7α-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)piperidine-1-carboxamide 
• 1443990-82-6 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(1-(3,7,14-trioxo-5,16-dioxa-2,8,13-triazaoctadecan-18-oyl)piperidin-4-yl)-1H-pyrazole-3-carboxamide 
• 1443990-84-8 N-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide 
• 1443990-78-0 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(1-(2-(2-(((4αS,7S,7αR,12βS)-4α,9-dihydroxy-3-methyl-2,3,4,4α,5,6,7,7α-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)amino)-2-oxoethoxy)acetyl)piperidin-4-yl)-4-methyl-1H-pyrazole-3-carboxamide 
• 1443990-85-9 2-(2-(4-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamido)piperidin-1-yl)-2-oxoethoxy)acetic acid 
• 1443990-79-1 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(1-(14-(((4αS,7S,7αR,12βS)-4α,9-dihydroxy-3-methyl-2,3,4,4α,5,6,7,7α-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)amino)-5,10,14-trioxo-3,12-dioxa-6,9-diazatetradecan-1-oyl)piperidin-4-yl)-4-methyl-1H-pyrazole-3-carboxamide 
• 1443990-80-4 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(1-(18-(((4αS,7-S,7αR,12βS)-4α,9-dihydroxy-3-methyl-2,3,4,4α,5,6,7,7α-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)amino)-5,14,18-trioxo-3,16-dioxa-6,13-diazaoctadecan-1-oyl)piperidin-4-yl)-4-methyl-1H-pyrazole-3-carboxamide 
• 1443990-81-5 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(1-(19-(((4αS,7S,7αR,12βS)-4α,9-dihydroxy-3-methyl-2,3,4,4α,5,6,7,7α-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)amino)-5,15,19-trioxo-3,17-dioxa-6,14-diazanonadecan-1-oyl)piperidin-4-yl)-4-methyl-1H-pyrazole-3-carboxamide 
• 1416320-49-4 propan-2-yl-4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate 
• 1416320-59-6 4-nitrophenyl-4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate 
• 1365037-89-3 N-(1-acetylpiperidin-4-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide 
• 1365037-98-4 1-N-tert-butyl-4-C-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-piperidine-1,4-diamido 
• 1365037-92-8 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(1-methanesulfonylpiperidin-4-yl)-4-methyl-1H-pyrazole-3-carboxamide 
• 1365038-16-9 ethyl 4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate 

Relevant academic research and scientific papers

Bivalent ligands that target μ opioid (MOP) and cannabinoid1 (CB 1) receptors are potent analgesics devoid of tolerance

Given that μ opioid (MOP) and canabinoid (CB1) receptors are colocalized in various regions of the central nervous system and have been reported to associate as heteromer (MOP-CB1) in cultured cells, the possibility of functional, endogenous MOP-CB1 in nociception and other pharmacologic effects has been raised. As a first step in investigating this possibility, we have synthesized a series of bivalent ligands 1-5 that contain both μ agonist and CB1 antagonist pharmacophores for use as tools to study the functional interaction between MOP and CB1 receptors in vivo. Immunofluorescent studies on HEK293 cells coexpressing both receptors suggested 5 (20-atom spacer) to be the only member of the series that bridges the protomers of the heteromer. Antinociceptive testing in mice revealed 5 to be the most potent member of the series. As neither a mixture of monovalent ligands 9 + 10 nor bivalents 2-5 produced tolerance in mice, MOR-CB1 apparently is not an important target for reducing tolerance.

Design and synthesis of cannabinoid receptor 1 antagonists for peripheral selectivity

Antagonists of cannabinoid receptor 1 (CB1) have potential for the treatment of several diseases such as obesity, liver disease, and diabetes. Recently, development of several CB1 antagonists was halted because of adverse central nervous system (CNS) related side effects observed with rimonabant, the first clinically approved CB1 inverse agonist. However, recent studies indicate that regulation of peripherally expressed CB1 with CNS-sparing compounds is a viable strategy to treat several important disorders. Our efforts aimed at rationally designing peripherally restricted CB1 antagonists have resulted in compounds that have limited blood-brain barrier (BBB) permeability and CNS exposure in preclinical in vitro and in vivo models. Typically, compounds with high topological polar surface areas (TPSAs) do not cross the BBB passively. Compounds with TPSAs higher than that for rimonabant (rimonabant TPSA = 50) and excellent functional activity with limited CNS penetration were identified. These compounds will serve as templates for further optimization.

PYRAZOLE DERIVATIVES AS CANNABINOID RECEPTOR 1 ANTAGONISTS

The invention provides compounds capable of acting as antagonists at cannabanoid receptors according to the following formula: Such compounds may be used to treat conditions for which the cannabinoid receptor system has been implicated, such as obesity, liver disease, diabetes, pain, and inflammation.