194427-16-2

Upstream product

• 178312-64-6 2-(3,4-dichlorophenyl)-pent-4-ene-nitrile 
• 178312-17-9 4(S)-4-cyano-4-(3,4-dichlorophenyl)hept-6-enoic acid 

Downstream Products

• 194427-18-4 5(S)-5-Allyl-1-cyclohexyl-5-(3,4-dichlorophenyl)piperidin-2-one 
• 194427-23-1 [(S)-1-Cyclohexyl-3-(3,4-dichloro-phenyl)-6-oxo-piperidin-3-yl]-acetaldehyde 
• 194427-17-3 Methyl 4(S)-4-(3,4-dichlorophenyl)-4-formylhept-6-enoate 

Relevant academic research and scientific papers

Structure-activity relationships of 1-alkyl-5-(3,4-dichlorophenyl)-5-{2-[(3-substituted)-1-azetidinyl]ethyl} -2-piperidones. 1. Selective antagonists of the neurokinin-2 receptor

The design, synthesis, and pharmacological evaluation of a novel class of neurokinin-2 (NK2) antagonists 1-alkyl-5-(3,4-dichlorophenyl)-5-{2-[(3-substituted)- 1-azetidinyl]ethyl}-2-piperidones (5-44) are described. These compounds are formally derived from 2 by incorporating the metabolically vulnerable N-methylamide function into a more stable six-membered ring lactam 4, resulting in increased stability in human liver microsome (HLM) preparations relative to 2 (T1/2(HLM) of 30 min vs 2 receptor in the Rabbit pulmonary artery (RPA) assay (pA2 = 9.3) and increased in vitro metabolic stability (T1/2(HLM) = 70 min) relative to 4. Metabolic route identification studies revealed that N-benzyl oxidation was a major route in this relatively lipophilic lead (log D = 3.2). Further exploration of the N-lactam substituent SAR targeting reduced lipophilicity to attenuate P-450 metabolism revealed that incorporation of a cyclopropylmethyl group in this region of the molecule gave a balance of good potency and high metabolic stability. For example, the significantly less lipophilic analogue 29 (log D = 2.3) possessed both good functional potency (RPA, pA2 = 8. 1) and high in vitro metabolic stability (T1/2(HLM) = 120 min). Optimization in this N-cyclopropylmethyllactam series by modification of the nature of the azetidine 3-substituent as a strategy to further increase potency and moderate log D led to the identification of sulfamide analogue 33, which possessed both excellent metabolic stability in vitro (T1/2(HLM) > 120 min) and high potency in both RPA (pA2 = 8.9) and human bladder smooth muscle (pKb = 8.9) functional assays. In addition, NK2 antagonist 33 (IC50 = 4 nM) showed excellent selectivity over both the related human neurokinin receptors h-NK1 (IC50 = 7.9 μM) and h-NK3 (IC50 = 1.8 μM) in radioligand binding studies.

Piperidone tachykinin antagonists

The present invention provides compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof, wherein X is a direct link or C1-C4alkylene; and R is C3-C7cycloalkyl optionally substituted by 1 or 2 substituents each independently selected from fluoro and C3-C7cycloalkyl: with the proviso that X is not methylene when R is cyclopropyl, together with processes for the preparation of, intermediates used in the preparation of, compositions containing and uses of, such compounds. These compounds are useful as tachykinin antagonists.