945467-32-3

Upstream product

• 945465-84-9 tert-butyl (2R,3S,4R)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-2-(hydroxymethyl)-3-(4-fluorophenyl)pyrrolidine-1-carboxylate 

Downstream Products

• 945467-33-4 tert-butyl (2S,3S,4R)-4-{(1R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)-2-[(1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate 
• 1224733-53-2 C₃₀H₃₅F₇N₂O₄S 
• 1224733-58-7 C₃₂H₃₈F₇NO₆ 
• 945467-55-0 C₂₇H₃₀F₇NO₄ 
• 1028649-06-0 tert-butyl 2-[(benzylamino)methyl]-4-{1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)-pyrrolidine-1-carboxylate 
• 958005-18-0 tert-butyl (2S,3S,4R)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)-2-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate 

Relevant academic research and scientific papers

Fused tricyclic pyrrolizinones that exhibit pseudo-irreversible blockade of the NK1 receptor

Previously, we had disclosed a novel class of hNK1 antagonists based on the 5,5-fused pyrrolidine core. These compounds displayed subnanomolar hNK1 affinity along with good efficacy in a gerbil foot-tapping (GFT) model, but unfortunately they had low to moderate functional antagonist (IP-1) activity. To elaborate on the SAR of this class of hNK1 compounds and to improve functional activity, we have designed and synthesized a new class of hNK1 antagonist with a third fused ring. Compared to the 5,5-fused pyrrolidine class, these 5,5,5-fused tricyclic hNK1 antagonists maintain subnanomolar hNK1 binding affinity with highly improved functional IP-1 activity (1 binding affinity, off-target selectivity, pharmacokinetic profile and in vivo activity. Complete inhibition of agonist activity was observed at both 0 and 24 h in the gerbil foot-tapping model with an ID50 of 0.02 mpk at both 0 and 24 h, respectively.

Tetrahydroindolizinone NK1 antagonists

A new class of potent NK1 receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK1 receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK1 binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P450 inhibition and hPXR induction profiles.

Substituted fused bicyclic pyrrolizinones as potent, orally bioavailable hNK1 antagonists

Previous work on human NK1 (hNK1) antagonists in which the core of the structure is a 5,5-fused pyrrolizinone has been disclosed. The structural-activity-relationship studies on simple α- and β-substituted compounds of this series pr

Fused bicyclic pyrrolizinones as new scaffolds for human NK1 antagonists

Previous work on human NK1 antagonists in which the core of the structure is a substituted pyrrolidine has been disclosed. These compounds showed good binding affinity and functional IP activity, however, many did not exhibit the necessary brai

HEXAHYDRO-3H-PYRROLIZIN-3-ONES USEFUL AS TACHYKININ RECEPTOR ANTAGONISTS

The present invention is directed to certain hexahydroyrrolidinone compounds which are useful as neurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykinin and in particular substance P. The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, urinary incontinence, depression, and anxiety.

5,6-FUSED PYRROLIDINE COMPOUNDS USEFUL AS TACHYKININ RECEPTOR ANTAGONISTS

The present invention is directed to certain 5,6-fused pyrrolidine compounds which are useful as neurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykinin and in particular substance P. The invention is also concerned with pharmaceutical form