PYRROLIDINE DERIVATIVES AS OXYTOCIN/VASOPRESSIN V1a RECEPTORS ANTAGONISTS

Abstract

The present invention relates to a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methl9243yloxime, and/or an active metabolite thereof having antagonist action at the oxytocin receptor and/or vasopressin V1a receptor, to processes for their preparation, pharmaceutical compositions containing them and their use.

1 . A compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime. 
     
     
         2 . The compound according to  claim 1 , wherein said compound is provided in substantially pure form. 
     
     
         3 . The compound according to  claim 2 , wherein the purity of the substantially pure form is at least in the range of 85% to 99.9%. 
     
     
         4 . The compound according to  claim 1 , wherein said compound is an oxytocin receptor antagonist. 
     
     
         5 . The compound according to  claim 1 , wherein said compound is a vasopressin V1a receptor antagonist. 
     
     
         6 . The compound according to  claim 1 , wherein said compound inhibits the uterine contractions. 
     
     
         7 . The compound according to  claim 1 , wherein said compound is administered to a subject in need thereof in a single dose of 50 mg to 900 mg. 
     
     
         8 . The compound according to  claim 7 , wherein said single dose is 100 mg to 600 mg. 
     
     
         9 . The compound according to  claim 1 , wherein said compound is administered concomitantly or separately with at least one compound selected from the group consisting of calcium channel blockers, magnesium sulfate, selective prostaglandin modulators, beta-2-adrenergic agonists, beta-3-adrenergic receptor agonists, corticosteroids, and any combination thereof. 
     
     
         10 . The compound according to  claim 1 , wherein said compound is stable in the plasma. 
     
     
         11 . The compound according to  claim 1 , wherein the subject in need thereof is a mammal. 
     
     
         12 . A compound according to  claim 1 , for use as a medicament. 
     
     
         13 . (canceled) 
     
     
         14 . The compound according to  claim 1 , for use in treatment and/or prevention, in a subject in need thereof, of a disorder associated with oxytocin receptor activity, wherein the disorder associated with the oxytocin receptor activity is selected from the group consisting of preterm labor, premature birth, dysmenorrhea, premature ejaculation, sexual dysfunction, endometriosis, embryo implantation failure due to uterine contractions, infertility, benign prostatic hyperplasia, a neuro-psychiatric disorder, autism, a social behavior disorder, psycho-social stress, a cardiovascular disorder, and any combination thereof. 
     
     
         15 . A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         16 . The pharmaceutical composition according to  claim 15 ,
 wherein the administration is made by oral, vaginal or intravenous route.   
     
     
         17 . A process for preparing and isolating the compound according to  claim 1  in substantially pure form comprising the steps of:
 a) Loading a crude isomeric mixture comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, and/or an active metabolite thereof, on a Silica gel chromatography column; 
 b) Purifying with 1% alcohol in organic solvent; and 
 c) Purifying with 2% alcohol in organic solvent. 
 
     
     
         18 . A compound according to  claim 1 , for use in assisted reproduction technology. 
     
     
         19 . A compound according to  claim 1 , for use in the treatment of infertility by in vitro fertilization-embryo transfer method. 
     
     
         20 . A compound according to  claim 1 , for use in reducing embryo implantation failure due to uterine contractions. 
     
     
         21 . A compound according to  claim 1 , for use in reducing contractions occurring during the embryo transfer. 
     
     
         22 . A compound according to  claim 1 , for use in the treatment and/or prevention of a disease relating to oxytocin-induced vascular contractility, vasopressin-induced vascular contractility, oxytocin-induced muscular contractility, or vasopressin-induced muscular contractility.