178312-08-8

Upstream product

• 480421-67-8 2-(3,4-Dichloro-phenyl)-2-[2-((S)-4-isopropyl-4,5-dihydro-oxazol-2-yl)-ethyl]-pent-4-enenitrile 
• 178312-14-6 5(S)-5-Allyl-5-(3,4-dichlorophenyl)-2(1H)-piperidone 
• 178312-64-6 2-(3,4-dichlorophenyl)-pent-4-ene-nitrile 
• 3218-49-3 3,4-dichloro-benzeneacetonitrile 
• 178310-89-9 (5S)-5-(3,4-Dichlorophenyl)-5-(1,3-dioxolan-2-ylmethyl)tetrahydro-2(1H)-pyridinone 
• 178312-12-4 (S)-5-Allyl-1-cyclohexylmethyl-5-(3,4-dichloro-phenyl)-piperidin-2-one 

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. Part 2: Improving oral absorption

A series of piperidone analogues of 1b-q, seeking replacements for the polar sulfamide moiety in clinical candidate UK-224,671 1a, possessing reduced H-bonding potential as a strategy to improve oral absorption, were prepared. These studies led to the successful identification of 1n, which demonstrated equivalent pharmacology and metabolic stability to 1a, and greatly improved oral absorption as assessed in rat PK studies.

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.