494846-26-3

Upstream product

• 93085-88-2 (+/-)-trans-2,2-dimethyl-3-phenylcyclopropanecarboxamide 
• 99647-67-3 (+/-)-trans-2,2-dimethyl-3-phenylcyclopropanecarbonitrile 
• 768-49-0 (2-methyl-1-propenyl)-benzene 
• 61751-36-8 (±)-trans-ethyl 2,2-dimethyl-3-phenylcyclopropanecarboxylate 
• 103-36-6 ethyl 3-phenyl-2-propenoate 
• 50672-13-4 (±)-trans-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid 
• 4192-77-2 ethyl cinnamate 
• 4489-17-2 (+/-)-2,2-dimethyl-3t-phenyl-cyclopropane-r-carbonyl chloride 
• 1557242-99-5 (4S)-4-benzyl-3-{[(1R,3R)-2,2-dimethyl-3-phenylcyclopropyl]carbonyl}-1,3-oxazolidin-2-one 

Downstream Products

• 494846-56-9 (+)-trans-(1R,3R)-2,2-dimethyl-3-phenylcyclopropanecarboxamide 
• 1557243-20-5 (1R,3R)-N-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2,2-dimethyl-3-phenylcyclopropanecarboxamide 
• 1610023-35-2 C₁₂H₁₃ClO 
• 1557244-86-6 4-[(1R,3R)-3-(hydroxymethyl)-2,2-dimethylcyclopropyl]benzenesulfonamide 

Relevant academic research and scientific papers

Discovery of BNC375, a Potent, Selective, and Orally Available Type i Positive Allosteric Modulator of α7 nAChRs

Positive allosteric modulators (PAMs) of α7 nAChRs can have different properties with respect to their effects on channel kinetics. Type I PAMs amplify peak channel response to acetylcholine but do not appear to influence channel desensitization kinetics, whereas Type II PAMs both increase channel response and delay receptor desensitization. Both Type I and Type II PAMs are reported in literature, but there are limited reports describing their structure-kinetic profile relationships. Here, we report a novel class of compounds with either Type I or Type II behavior that can be tuned by the relative stereochemistry around the central cyclopropyl ring: for example, (R,R)-13 (BNC375) and its analogues with RR stereochemistry around the central cyclopropyl ring are Type I PAMs, whereas compounds in the same series with SS stereochemistry (e.g., (S,S)-13) are Type II PAMs as measured using patch-clamp electrophysiology. Further fine control over the kinetics has been achieved by changing the substitutions on the aniline ring: generally the substitution of aniline with strong electron withdrawing groups reduces the Type II character of these compounds. Our structure-activity optimization efforts have led to the discovery of BNC375, a small molecule with good CNS-drug like properties and clinical candidate potential.

SUBSTITUTED BICYCLIC HETEROARYL ALLOSTERIC MODULATORS OF NICOTINIC ACETYLCHOLINE RECEPTORS

The present disclosure relates to compounds of formula (I) that are useful as modulators of α7 nAChR, compositions comprising such compounds, and the use of such compounds for preventing, treating, or ameliorating disease, particularly disorders of the central nervous system such as cognitive impairments in Alzheimer's disease, Parkinson's disease, and schizophrenia, as well as for L-DOPA induced-dyskinesia and inflammation.

ALLOSTERIC MODULATORS OF NICOTINIC ACETYLCHOLINE RECEPTORS

The present disclosure relates to compounds of formula I that are useful as modulators of α7 nAChR, compositions comprising such compounds, and the use of such compounds for preventing, treating, or ameliorating disease, particularly disorders of the central nervous system such as cognitive impairments in Alzheimer's disease, Parkinson's disease, and schizophrenia, as well as for L-DOPA induced-dyskinesia and inflammation

ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTOR MODULATORS AND USES THEREOF

Disclosed are compounds of Formula (IVA), or a salt thereof, and pharmaceutical formulations (pharmaceutical compositions) comprising those compounds, or a salt thereof: Formula (IVA), wherein "RIa", "RIb", "RIc", "RId", "RIe", are defined herein above, which compounds are believed suitable for use in positive modulation of the alpha 7 nicotinic acetylcholine receptor (α7 nAChR) receptors, for example, those found in the cerebral cortex and the hippocampus. Such compounds and pharmaceutical formulations are believed to be useful in treatment or management of neurodegenerative diseases, for example, Alzheimer's disease (AD), schizophrenia, and Parkinson's disease (PD), or movement disorders arising from use of certain medications used in the treatment or management of Parkinson's disease.

α7 NICOTINIC ACETYLCHOLINE RECEPTOR MODULATORS AND USES THEREOF-I

The present invention relates to chemical compounds of formula (I), with the substituents as described in the specification, useful in the positive modulation of the alpha 7 nicotinic acetylcholine receptor (α7 nAChR). The invention also relates to the use of these compounds in the treatment or prevention of a broad range of diseases in which the positive modulation of α7 nAChR is advantageous, including neurodegenerative and neuropsychiatric diseases and also neuropathic pain and inflammatory diseases.

Synthesis of high enantiomeric purity gem-dihalocyclopropane derivatives from biotransformations of nitriles and amides

Enantioselective biotransformations of geminally dihalogenated cyclopropanecarbonitriles and amides are described. Both the reaction rate and enantioselectivity of the nitrile hydratase and amidase involved in Rhodococcus sp. AJ270 microbial cells are strongly governed by the nature of gem-disubstituents on the cyclopropane ring; the amidase generally exhibits steric dependence on the substituents while both the steric and electronic factors of the substituents may affect the action of the nitrile hydratase. The match of steric bulkiness of the substituents at 2- with that at 3-positions on the cyclopropane ring benefits the efficient and highly enantioselective reaction. Coupled with facile chemical transformations, biocatalytic transformations of nitrile and amide supply an effective synthesis of optically active 2,2-disubstitued-3-phenylcyclopropanecarboxylic acid and amide in both enantiomeric forms.

Nitrile and Amide Biotransformations for Efficient Synthesis of Enantiopure gem-Dihalocyclopropane Derivatives

Catalyzed by Rhodococcus sp. AJ270 microbial cells, trans-2,2-dihalo-3- phenylcyclopropanecarbonitriles and -amides underwent enantioselective hydrolysis under very mild conditions. Both the efficiency and enantioselectivity of the nitrile hydratase and a

Nitrile biotransformation for highly enantioselective synthesis of 3-substituted 2,2-dimethylcyclopropanecarboxylic acids and amides

Biotransformations of differently configured 2,2-dimethyl-3-substitued-cyclopropanecarbonitriles were studied using a nitrile hydratase/amidase-containing Rhodococcus sp. AJ270 whole-cell catalyst under very mild conditions. Although all of the cis-3-aryl-2,2-dimethylcyclopropanecarbonitriles appeared inert toward the biocatalyst, a number of racemic trans-isomers efficiently underwent a highly enantioselective hydrolysis to produce (+)-(1R,3R)-3-aryl-2,2-dimethylcyclopropanecarboxylic acids and (-)-(1S,3S)-3-aryl-2,2-dimethylcyclopropanecarboxamides in high yields with excellent enantiomeric excesses in most cases. The overall enantioselectivity of the biotransformations of nitriles originated from the combined effects of 1R-enantioselective nitrile hydratase and amidase, with the later being a dominant factor. The influence of the substrates on both reaction efficiency and enantioselectivity was discussed in terms of steric and electronic effects. Coupled with chemical transformations, biotransformations of nitriles provided convenient syntheses of optically pure geminally dimethyl-substituted cyclopropanecarboxylic acids and amides, including chrysanthemic acids, in both enantiomeric forms.