Pyrrolidine derivatives as oxytocin/vasopressin V1a receptors antagonists
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-methy19243-yloxime, 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]pyrrolidine-3-one O-methyloxime, wherein said compound is provided in substantially pure form.
2. The compound according to claim 1 , wherein the purity of the substantially pure form is at least in the range of 85% to 99.9%.
3. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier, diluent, or excipient.
4. The pharmaceutical composition according to claim 3 , wherein said compound is a vasopressin V1a receptor antagonist.
5. The pharmaceutical composition according to claim 3 , wherein said compound inhibits uterine contractions.
6. The compound according to claim 1 , wherein said compound is formulated for administration to a subject in need thereof in a single dose of from 50 mg to 900 mg of said compound.
7. The compound according to claim 6 , wherein said single dose comprises from 100 mg to 600 mg of said compound.
8. The compound according to claim 1 , wherein said compound is formulated for administration 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.
9. The compound according to claim 1 , wherein said compound is stable in plasma.
10. The compound according to claim 6 , wherein the subject in need thereof is a mammal.
11. The pharmaceutical composition according to claim 3 , wherein said compound is an oxytocin receptor antagonist.
12. The pharmaceutical composition according to claim 11 , wherein the compound is formulated for oral, vaginal, or intravenous administration to a subject.
13. A process for preparing and isolating a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidine-3-one O-methyloxime in substantially pure form comprising the steps of:
a) Loading a crude isomeric mixture comprising the compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime on a Silica gel chromatography column;
b) Purifying with 1% alcohol in organic solvent; and
c) Purifying with 2% alcohol in organic solvent.
14. The compound according to claim 10 , wherein the mammal is a human.