US20160221944A1 - PYRROLIDINE DERIVATIVES AS OXYTOCIN/VASOPRESSIN V1a RECEPTORS ANTAGONISTS - Google Patents

PYRROLIDINE DERIVATIVES AS OXYTOCIN/VASOPRESSIN V1a RECEPTORS ANTAGONISTS Download PDF

Info

Publication number
US20160221944A1
US20160221944A1 US14/917,847 US201414917847A US2016221944A1 US 20160221944 A1 US20160221944 A1 US 20160221944A1 US 201414917847 A US201414917847 A US 201414917847A US 2016221944 A1 US2016221944 A1 US 2016221944A1
Authority
US
United States
Prior art keywords
compound
methyl
biphenyl
carbonyl
compound according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US14/917,847
Other languages
English (en)
Inventor
Andre CHOLLET
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Obseva SA
Original Assignee
Obseva SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Obseva SA filed Critical Obseva SA
Assigned to ObsEva S.A. reassignment ObsEva S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHOLLET, ANDRE
Publication of US20160221944A1 publication Critical patent/US20160221944A1/en
Assigned to OXFORD FINANCE LLC, AS COLLATERAL AGENT reassignment OXFORD FINANCE LLC, AS COLLATERAL AGENT SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ObsEva SA
Assigned to ObsEva S.A. reassignment ObsEva S.A. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: OXFORD FINANCE LLC
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • 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-methyloxime, 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 in medicine.
  • Oxytocin is a cyclic nona-peptide that mediates its physiological actions through activation of the oxytocin receptor (OT-R), a cell membrane receptor belonging to the class of G protein-coupled receptors that is similar to arginine vasopressin receptors.
  • OTR oxytocin receptor
  • One important action of Oxytocin (OT) is to cause the contraction of the uterus of mammals during labor. Repeated, concerted and regular contraction of the uterus will cause the dilatation of the cervix, the rupture of fetal membranes and lead to expulsion of the fetus. Premature labor is when these contractions occur before the normal term of pregnancy. Preterm increase of uterine activity is the most common expression of preterm labor.
  • Premature labor leads to undesired premature birth, a serious health problem that remains the major cause of perinatal mortality and severe morbidity, especially respiratory distress syndrome, intraventricular haemorrhage, bronchopulmonary dysplasia and necrotising enterocolitis that are far more common in preterm than in term infants. Long-term impairments such as cerebral palsy, visual impairment and hearing loss are also more common in preterm infants.
  • preterm birth remains the leading cause of infant mortality and morbidity in industrialized nations, where, despite the significant improvements in obstetrical medicine, it is causing high costs for neonatal intensive care of premature babies.
  • preterm childbirth-related ailments such as respiratory distress syndrome, heart conditions, cerebral palsy, epilepsy, and severe learning disabilities.
  • the management of preterm labor represents a significant problem in the field of obstetrics.
  • the OT/OT-R system plays a vital role in initiating labor in mammals, in particular in humans.
  • the density of OT-R increases markedly in the myometrium before the onset and during labor.
  • the local OT peptide hormone concentration increases markedly before parturition in human.
  • the high circulating concentrations of progesterone induce uterine quiescence while the uterus acquires contractile ability.
  • plasma progesterone concentrations fall, OT-R expression in the uterus increases markedly, OT is released and uterine contractile activity increases. At term, the contractions rise to a crescendo, resulting in delivery as a result of two interacting positive feedback loops.
  • the first is a local uterine loop: within the uterus itself, contractile prostaglandins are produced and released in response to OT and uterine contractions. These prostaglandins may play a further role in cervical ripening and weakening of fetal membranes.
  • the second loop involves the hypothalamus: in response to uterine contractions and vaginal and cervical distension, magnocellular oxytocin neurons in the hypothalamus increase their activity resulting in the release of OT from their axon terminals in the posterior pituitary.
  • the released OT acts upon the uterus both to stimulate the further production of prostaglandins and to contribute further to the contractions of the uterus.
  • blocking the effect of OT by antagonizing OT-R might represent an attractive modality for the treatment of diseases related to the OT-R activity, in particular preterm labor.
  • Tocolytic i.e. uterus relaxing agents
  • Tocolytic i.e. uterus relaxing agents
  • Most of these agents are used off-label. They have shown very limited efficacy, if any, in prolonging gestation and without clear demonstration of improvement of neonate outcome.
  • Current tocolytics are very often associated with unwanted adverse effects on women, foetus or neonate.
  • Such tocolytics include beta-2-adrenergic agonists, prostaglandin synthesis inhibitors, magnesium sulfate, nitric acid donors and calcium channel blockers.
  • Beta-2-adrenergic agonists such as ritodrine or terbutaline cause a number of cardiovascular and metabolic side effects including maternal tachycardia, palpitations, hypotension, altered thyroid function and fetal and neonatal hypoglycaemia, tachycardia.
  • Ritodrine is no longer FDA approved.
  • the calcium channel blocker nifedipine is also a medicine that is used to try to stop contractions. Some of the side effects that may occur include facial flushing, headache, nausea, palpitations, and lightheadedness.
  • the total prostaglandin synthesis inhibitor (NSAID) indomethacin has been used.
  • a newborn who has been exposed to magnesium sulfate may show lethargy, hypotonia, respiratory depression, bone problems, osteopenia and fractures. Recently, the FDA is advising healthcare professionals against using magnesium sulfate injection for longer than 5-7 days to stop preterm labor in women.
  • Atosiban a dual vasopressin V1a receptor and OT-R antagonist is marketed in EU and used to stop contractions and delay preterm delivery by a few days.
  • Atosiban is a peptide that is not orally bioavailable and must be administered parenterally. It is rapidly degraded in circulation by enzymes and its use is limited to maximum 48 h.
  • non-peptide OT-R antagonists were developed such as pyrrolidine derivatives (WO 01/72705, WO 02/102799, WO 2002/074741, WO 2004/005249) as mixtures of isomers.
  • the present invention provides 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.
  • the invention also provides 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, for use as a medicament and pharmaceutical compositions comprising said compound.
  • the invention further provides a process for preparing and isolating a compound of formula (3Z,5 S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, and/or an active metabolite thereof in substantially pure form.
  • the present invention relates to the 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, said compound being in the Z isomeric configuration at the O-methyloxime functional group.
  • the compound of formula (3E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime differs from compounds of the present invention at the O-methyloxime functional group being in the E isomeric configuration.
  • active metabolite thereof refers to a product produced through metabolism in the body or in vitro of a specified compound, in the present case (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime and which exhibits the same biological activity as (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime.
  • O-methyloxime Active metabolites of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such metabolites may result for example from the oxidation, glucuronidation or other conjugation, hydrolysis, reduction and the like, of the administered Z form.
  • the invention includes active metabolites of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such metabolite may also be produced in vitro by oxidation, reduction, hydrolysis, glucuronidation or other conjugation transformation of the corresponding (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime.
  • Examples of actives metabolites of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime include compounds those structures are shown below:
  • a compound which, upon administration to the recipient, is capable of being converted into a compound of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, and/or an active metabolite thereof as described above, is known as a “prodrug”.
  • a prodrug may, for example, be converted within the body, e. g. by hydrolysis in the blood, into its active form that has medical effects.
  • Pharmaceutical acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series (1976); “Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.
  • the compound of the present invention is produced by methods such as those disclosed for example in WO2004/005249 and WO2005/082848. However, said compound is synthesized and obtained in isomeric mixtures (3Z/E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime comprising (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime and (3E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime.
  • the present invention relates to a compound of formula (3Z/E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, and/or an active metabolite thereof comprising at least 85% to 100% of a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime and/or metabolite thereof, preferably 85% to 99.9%, more preferably 90% to 99.9%, and even more preferably 95% to 99.9% of said compound.
  • 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-methyloxime, and/or an active metabolite thereof, provided in substantially pure form.
  • the term “substantially pure” refers to a compound provided in a form which is substantially free of other compounds.
  • said “other compounds” include (3E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one, (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one oxime, (3R,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-3-methoxyamino-pyrrolidine, (3S,5S)-5-(hydroxymethyl)-1-
  • the 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 is substantially free of the compound of formula (3E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime.
  • the purity of a substantially pure form 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 is at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9% or at least 100% and is therefore substantially free of compound of formula (3E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, i.e less than 45%, less than
  • the purity of the substantially pure form 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 is at least in the range of 85% to 100%, preferably 85% to 99.9%, more preferably 90% to 99.9%, and even more preferably in the range of 95% to 99.9%.
  • the compound of the invention “(3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime” can also be defined as “(4Z,2S)-2-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl-carbonyl)]pyrrolidine-4-one O-methyloxime.
  • the 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, is an oxytocin receptor antagonist.
  • oxytocin receptor antagonist refers to a compound that functions by inhibiting (partially or completely) or blocking the oxytocin receptor (OT-R), thereby preventing activation of the receptor by oxytocin.
  • the present invention provides 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 wherein said compound is a partial or complete oxytocin receptor antagonist and wherein the inhibitor constant Ki is less than about 1 ⁇ M.
  • said inhibitor constant Ki is less than about 0.1 ⁇ M, more preferably less than about 0.06 ⁇ M.
  • the present invention further provides 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 wherein said compound is an oxytocin receptor antagonist and wherein the half maximal inhibitory concentration IC50 is less than about 1 ⁇ M.
  • said IC50 is less than about 0.1 ⁇ M, more preferably less than about 0.09 ⁇ M.
  • the 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 is a vasopressin V1a receptor antagonist.
  • vasopressin V1a receptor antagonist refers to a compound that functions by inhibiting (partially or completely) or blocking the vasopressin V1a receptor (also known as Arginine vasopressin receptor 1A), thereby preventing activation of the receptor by vasopressin.
  • Vasopressin V1a receptor is one of the three major receptor types for the peptide hormone arginine vasopressin, the others being V1b and V2 receptors
  • the 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 is a vasopressin V1a receptor antagonist, wherein the inhibitor constant Ki is less than about 1 ⁇ M. Most preferably, said inhibitor constant Ki is less than about 0.5 ⁇ M, even more preferably less than about 0.15 ⁇ M.
  • the present invention also relates to 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, that is an oxytocin receptor antagonist and a vasopressin V1a receptor antagonist.
  • the 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 inhibits the uterine contractions.
  • said compound inhibits uterine contractions rapidly in a time lapse of 2-30, preferably 5-20 minutes following its administration.
  • the inhibitory activity is specific to the substantially pure Z form of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, and/or metabolite thereof.
  • the substantially pure E form of formula (3E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime shows no efficacy as it does not inhibit the uterine contractions.
  • the dosage regimen regarding the compound of the present invention and/or an active metabolite thereof is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or active metabolite thereof employed.
  • An ordinarily skilled physician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • a compound of the present invention and/or an active metabolite thereof may be administered in a single dose, or the total dosage may be administered in divided doses of two, three or four times daily.
  • the present invention provides 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, wherein said compound is administered to a subject in a single dose of 50 mg to 900 mg, more preferably in a single dose of 100 mg to 600 mg.
  • a compound of the invention and/or an active metabolite thereof may be used as the sole active ingredient in a medicament, it is also possible for the compound to be used in combination with at least one or more further active compounds.
  • Such further active compounds may be further compounds according to the invention, or other active compounds selected from the group comprising calcium channel blockers, magnesium sulfate, selective prostaglandin modulators, beta-2-adrenergic agonists, beta-3-adrenergic receptor agonists, and/or corticosteroids.
  • the compound of the invention and/or an active metabolite thereof can be administered concomitantly or separately with at least one compound selected from the group comprising calcium channel blockers (such as nifedipine), magnesium sulfate, prostaglandin receptors modulators (such as agonists or antagonists of either EP1 or EP2 or EP3 or EP4 or FP receptors), prostaglandin synthesis inhibitors (such as indomethacin, nimesulide, sulindac, rofecoxib, celecoxib), beta-2-adrenergic agonists (such as ritodrine, terbutaline, salbutamol), beta-3-adrenergic receptor agonists, nitric acid donors (such as glyceryl trinitrate) and/or corticosteroids (such as dexamethasone, betamethasone).
  • calcium channel blockers such as nifedipine
  • magnesium sulfate such as agonists or antagonists of
  • the term “concomitantly” refers to the administration of 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, which is then immediately followed by the administration of at least one compound selected from the group disclosed supra.
  • the term “separately (encompassing sequential or subsequent administration)” refers to the administration of 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, followed by a time period of discontinuance, which is then followed by the administration of at least one compound disclosed supra.
  • the compound of the invention is stable in the plasma.
  • stable refers to the presence of the 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 in the plasma of the subject following administration and wherein isomeric interconversion of said compounds is substantially prevented.
  • the subject in need thereof is preferably a mammal, most preferably a human, more preferably a woman, and most preferably a human female of child bearing age.
  • the present invention also relates to 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, for use as a medicament.
  • Also envisioned in the present invention is 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, for use in the treatment and/or prevention of disorders associated with the oxytocin receptor activity and/or vasopressin V1a receptor activity.
  • the disorders associated with the oxytocin receptor activity and/or vasopressin V1a receptor activity are selected from the non-limiting group comprising preterm labor, premature birth, dysmenorrhea, premature ejaculation, sexual dysfunction, endometriosis, embryo implantation failure due to uterine contractions, infertility, benign prostatic hyperplasia, neuro-psychiatric disorders, autism, social behavior disorders, psycho-social stress, and/or cardiovascular disorders.
  • premature labor referring also to premature labor, shall mean expulsion from the uterus of a viable infant before the normal end of gestation, or more particularly, onset of labor with effacement and dilation of the cervix before the 37th week of gestation. It may or may not be associated with vaginal bleeding or rupture of the membranes.
  • dismenorrhea refers to a condition characterized by cyclic pain associated with menses during ovulatory cycles. The pain is thought to result from uterine contractions and ischemia.
  • sexual dysfunction refers to any disturbance or variation in the four phases—excitement phase, plateau phase, orgasmic phase and resolution phase characterizing the human sexual response.
  • neuro-psychiatric disorders refers to mental disorders attributable to diseases of the nervous system, e.g. depression, obsessive-compulsive disorder and others.
  • social behavior disorders refers to emotional disturbance, inappropriate types of behavior or feelings, pervasive mood of unhappiness or depression and a range of perceived difficulties to build or maintain satisfactory interpersonal relationships.
  • psycho-social stress refers to a condition resulting from a perceived threat to the social status, social esteem, self-worth, respect or acceptance within a group, and that lead to development of a stress response in the body and physical symptoms.
  • Assisted reproduction technologies are methods applied in humans for the treatment of infertility and in animals for producing pregnancies.
  • Infertility which affects about 10% of human pairs worldwide, may be treated by in vitro fertilization and embryo transfer (IVF-ET) or in less complicated cases, by artificial insemination.
  • IVF-ET in vitro fertilization and embryo transfer
  • a success of an embryo transfer is dependant on uterine receptivity, an entity that is defined as an ability of uterus to provide optimal conditions mandating proper implantation and embryo development.
  • Basic components of uterine receptivity are uterine contractile activity and the condition of endometrium.
  • Uterine contractions occurring during the embryo transfer may expel embryos from the uterus towards vagina or oviducts, which may be a cause of unsuccessful treatment, or in latter case a cause of extrauterine pregnancy, a serious, potentially life-threatening complication.
  • 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-methyloxime, and/or an active metabolite thereof, for use in assisted reproduction technology.
  • 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-methyloxime, and/or an active metabolite thereof, for use in the treatment of infertility by in vitro fertilization-embryo transfer (IVF-ET) method.
  • IVF-ET in vitro fertilization-embryo transfer
  • the present invention also relates to 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, for use in reducing embryo implantation failure due to uterine contractions.
  • Also envisioned in the present invention is 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, for use in reducing contractions occurring during the embryo transfer.
  • 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-methyloxime, and/or an active metabolite thereof, 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, vasopressin-induced muscular contractility.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition 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, and a pharmaceutically acceptable carrier, diluent or excipient.
  • a “pharmaceutically acceptable carrier, diluent or excipient” used herein is a medium generally accepted in the art for the delivery of biologically active agents to patients.
  • a person skilled in the art is aware of a whole variety of such carriers, diluents or excipients suitable to formulate a pharmaceutical composition (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Publishing Company, 1990, pp. 1289-1329).
  • the carrier(s), diluent(s) or excipient(s) must be compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof.
  • the compound of the invention and/or an active metabolite thereof, together with a conventionally employed carrier, diluent or excipient may be formulated as pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient, i.e. the compound of the invention, commensurate with the intended daily dosage range to be employed.
  • compositions of the invention can be administered by a variety of routes including oral, rectal, vaginal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • the compounds are preferably formulated as either injectable or oral compositions.
  • the compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound of the invention is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • the pharmaceutical composition 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, and a pharmaceutically acceptable carrier, diluent or excipient is administered by oral, vaginal or intravenous route.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as pepper-mint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatine
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • the compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can also be found in Gennaro, A. R. et al, Remington's Pharmaceutical Sciences. 18th ed. Easton: The Mack Publishing Company, 1995.
  • the present invention also relates to a process for preparing and isolating the compound of formula (3Z,5 S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, and/or an active metabolite thereof, 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 gel chromatography column; b) Purifying with 1% alcohol in organic solvent; and c) Purifying with 2% alcohol in organic solvent.
  • the term “crude isomeric mixture” refers to a mixture of compounds resulting from the synthesis of 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, as described herein and comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime and a compound of formula (3E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime.
  • the invention relates to a process for preparing and isolating the 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, in substantially pure form comprising the steps of:
  • the silica gel chromatography column is chosen from Biotage® Flash 150 flash chromatography system, Biotage KP-SIL, Biotage KP-C18-HS, Biotage KP-C18-WP, Biotage KP-C-WP, Biotage FLASH-WAC 400 (Biotage AB, 751 03 Uppsala, Sweden).
  • Other gel chromatography columns include columns loaded with Mitsubishi DiaionTM HP20 or HP20SS SDVB resins (Mitsubishi Chemical Corporation, Tokyo 100-8251, Japan).
  • the present invention relates to the synthesis and purification of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime obtained as a crude isomeric mixture comprising (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime and (3E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime.
  • Synthetic pathways of compounds of the invention are for example those described in WO2004005249 and WO2005082848.
  • compound of the invention (3Z/E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime can also be prepared following stages 1 to 7 as described below:
  • Toluene (4.41 L, 10.0 vol) and tetrahydrofuran (4.41 L, 10.0 vol) were added to the residue, the resulting mixture stirred vigorously and acidified to pH 1 with hydrochloric acid (6M, 2.00 L, 4.5 vol). The contents were stirred vigorously for 30 to 60 minutes and the layers separated. Toluene (2.20 L, 5.0 vol) and tetrahydrofuran (2.20 L, 5.0 vol) were added to the aqueous phase and the mixture stirred for 5 to 10 minutes. The layers were separated, the combined organic phases filtered and concentrated to 10.0 vol under vacuum at 35 to 40° C.
  • Toluene (4.41 L, 10.0 vol) was added to the residue and the resultant concentrated under vacuum at 35 to 40° C.
  • the tetrahydrofuran content of the resulting slurry was determined by 'H NMR analysis (d6-DMSO) (Pass level: ⁇ 1.0% w/w tetrahydrofuran with respect to toluene).
  • the slurry was cooled to and aged at 0 to 5° C. for 30 to 60 minutes, the solid collected by filtration and the filter-cake washed with toluene (2.20 L, 5.0 val).
  • the solid was dried in a vacuum oven at 35 to 40° C. to give 4-(2-methylphenyl)benzoic acid [0.438 Kg, 94.1% th, 99.3% w/w, 1H NMR (d6-DMSO) concordant with structure] as a pale yellow solid.
  • Thionyl chloride (0.300 L, 4.11 mol, 0.685 vol) was added to a slurry of 4-(2-methylphenyl)benzoic acid (0.435 Kg, 2.05 mol, 1.0 wt) in toluene (4.35 L, 10.0 vol) at 10 to 25° C. and the mixture heated to and maintained at 75 to 80° C.3 until complete by 1H NMR analysis (d6-benzene,), typically 4 to 5 hours. Reaction completion was accompanied by the formation of a hazy solution. The resultant was concentrated to 5.0 vol by removal of toluene under reduced pressure at 35 to 45° C.
  • Toluene (2.18 L, 5.0 vol) was added to the concentrate and the mixture concentrated to 4.0 vol by removal of toluene under reduced pressure at 35 to 45° C.
  • the resultant was filtered through glass microfibre paper and the filter-cake washed with toluene (0.44 L, 1.0 vol).
  • the toluene solution of 4-(2-methylphenyl)benzoic acid chloride [0.439 Kg, 92.8% th, 100.9% w/w, 1H NMR (d6-benzene) concordant with structure] was used directly in Stage 3.
  • a solution of potassium carbonate (0.526 Kg, 3.81 mol, 1.2 wt) in water (0.57 L, 1.3 vol) was charged to a solution of 4-hydroxy-L-proline (0.274 Kg, 2.09 mol, 0.625 wt) in tetrahydrofuran (2.20 L, 5.0 vol) and water (0.44 L, 1.0 vol) at 15 to 25° C. followed by a line rinse of water (0.44 L, 1.0 vol). The mixture was cooled to 0 to 5° C.
  • hydrochloric acid (2M, 0.88 L, 2.0 vol) at 15 to 25° C.
  • the mixture was cooled to and aged at 0 to 5° C. for 30 to 60 minutes, the precipitated solid collected by filtration, the filter-cake washed with water (2 ⁇ 1.75 L, 2 ⁇ 4.0 vol) and toluene (0.88 L, 2.0 vol) and pulled dry on the filter for 12 to 24 hours.
  • the collected solid was dried under vacuum at 40 to 45° C.
  • Triethylamine (1.80 L, 13.56 mol, 3.0 vol) was charged to a solution of (4R)-4-hydroxy-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-L-proline (0.598 Kg, 1.84 mol, 1.0 wt) in dimethyl sulfoxide (4.42 L, 7.4 vol) at 15 to 20° C.
  • Pyridine-sulphur trioxide complex 0.879 Kg, 5.52 mol, 1.47 wt was charged portion-wise at 15 and 25° C. and the reaction mixture stirred at that temperature until reaction completion, as determined by TLC analysis (typically 1 to 3 hours). 7 The reaction was quenched with aq.
  • hydrochloric acid (3M, 4.80 L, 8.0 vol) at 0 to 30° C., tetrahydrofuran (3.00 L, 5.0 vol) and heptanes (0.60 L, 1.0 vol) charged, the layers separated and the aqueous phase extracted with tetrahydrofuran (2 ⁇ 3.00 L, 2 ⁇ 5.0 vol).
  • the combined organic phases were washed with aq. hydrochloric acid (1 M, 2 ⁇ 1.20 L, 2 ⁇ 2.0 vol) and saturated sodium chloride solution (2 ⁇ 1 0.20 L, 2 ⁇ 2.0 vol), the aqueous washes combined and back-extracted with tetrahydrofuran (2 ⁇ 0.60 L, 2 ⁇ 1.0 vol).
  • the concentrate was transferred to a suitable vessel with a line rinse of ethyl acetate (0.30 L, 0.5 vol) and heated to 70 to 80° C. Additional ethyl acetate (0.30 L, 0.5 vol) was added as necessary to achieve dissolution.
  • Heptanes (1.80 L, 3.0 vol) was added at 70 to 80° C. and the contents allowed to cool to between 15 and 25° C. over 1 to 2 hours.
  • the slurry was further cooled to and aged at 0 to 5° C. for 2 to 3 hours, filtered and the filtercake washed with ethyl acetate:heptanes (1:1, 0.60 L, 1.0 vol) at 0 to 5° C. followed by heptanes (3.0 L, 2.5 vol).
  • Triethylamine (0.40 L, 2.85 mol, 0.92 vol) was added to a solution of 1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-4-oxo-L-proline (0.434 Kg, 1.34 mol, 1.0 wt) in dichloromethane (4.40 L, 10.0 vol) at 10 to 25° C. followed by a line rinse of dichloromethane (0.43 L, 1.0 vol). Methoxylamine hydrochloride (0.130 Kg, 1.56 mol, 0.30 wt) was added portionwise at 10 to 25° C.
  • Potassium carbonate (0.476 Kg, 3.44 mol, 1.0 wt) was added to a solution of 4-methoxyimino-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-L-proline (0.475 Kg, 1.35 moI, 1.0 wt) in acetone (4.75 L, 10.0 vol) and the mixture cooled to 0 to 10° C.
  • Dimethyl sulfate (0.128 L, 1.35 mol, 0.27 vol) was added at 0 to 15° C. and the mixture stirred at 15 to 25° C. until reaction completion, as determined by TLC analysis, typically 3 to 16 hours. The solvent was removed under vacuum at 40 to 45° C.
  • Lithium borohydride (0.049 Kg, 2.26 mol, 0.1 wt) was added portionwise under nitrogen to a stirred solution of (4Z/E, 2S)-methyl-1-[(2′-methyl-1,1′-biphenyl-4-yl)-carbonyl]-4-methoxyimino pyrrolidine-2-carboxylate (0.492 Kg, 1.34 mol, 1.0 wt) in tetrahydrofuran (2.31 L, 4.7 vol) and methanol (2.31 L, 4.7 vol) at 0 to 30° C. The mixture was stirred at 15 to 25° C.
  • reaction completion as determined by TLC analysis (Eluent: ethyl acetate; Visualisation: ninhydrin), typically 2 to 6 hours.
  • the reaction mixture was quenched with water (0.40 L, 0.8 val) at 15 to 25° C. and stirred at 15 to 25° C. for 16 to 20 hours.
  • the resultant was concentrated under vacuum at 40 to 45° C. and the residue partitioned between water (2.46 L, 5.0 vol) and ethyl acetate (4.92 L, 10.0 vol).
  • the layers were separated, the organic phase washed sequentially with aq. hydrochloric acid (1M, 2.46 L, 5.0 vol), sat. aq. sodium hydrogen carbonate solution (2.46 L, 5.0 vol) and sat.
  • the dry-flash chromatography of the crude isomeric mixture does not allow the purification of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime.
  • the E/Z ratio pre and post dry-flash remain in the range of 30/70 to 40/60.
  • the initial solubility screen showed that pure (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime isomer is soluble in a range of solvents.
  • the water (anti-solvent) was added to a warm (40-50° C.) solution of (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime in IPA until cloudiness was reached and the mixture was allowed to cool to room temperature.
  • the IPA/water crystallisation conditions were applied to a crude isomeric mixture.
  • the toluene solution was first concentrated to dryness prior to dissolution in IPA (8 vol) and addition of water (18 vol). Unfortunately, this resulted in material de-mixing as oil.
  • the antisolvent was added to a solution of crude (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime (90.4% area purity, contained 0.5% w/w toluene and 3.7% w/w THF) at room temperature until cloudiness was reached and the mixture was left to stand at room temperature (Table IV).
  • the level of residual solvent was determined by 1 H NMR analysis (CDCl 3 ) and when found to be ⁇ 1.0% w/w the solid was passed through a 500 ⁇ m aperture sieve. The solid was returned to the oven and dried at 40 to 42° C. until the solvent level was ⁇ 0.40% w/w to afford (3Z,5S)-1-[(biphenyl-4-yI-carbonyl)-5-hydroxy-methyl]-pyrrolidine-3-one-O-methyloxime (2.633 Kg, 97.1% w/w, 1H NMR (CDCI3) concordant with structure, 98.65% area by HPLC.
  • This assay allows determining the affinity of the test compounds for OT-R.
  • Membranes from HEK293EBNA (cells expressing OT-R) were suspended in buffer containing 50 mM Tris-HCl, pH 7.4, 5 mM MgCl2 and 0.1% BSA (w/v). The membranes (2-4 ⁇ g) were mixed with 0.1 mg SPA bead coated with wheat-germ aglutinin (WGA-PVT-Polyethylene Imine beads from Amersham) and 0.2 nM of the 125 radiolabelled [I]-OVTA (OVTA being Ornithin Vasoactive, an analogue of OT for competitive binding experiments). Non-specific binding was determined in the presence of 1 ⁇ M Oxytocin.
  • the total assay volume was 100 ⁇ l.
  • the plates (Corning 0 NBS plate) were incubated at room temperature for 30 min and counted on a Mibrobeta® plate scintillation counter.
  • Competitive binding was performed in presence of compounds of the present invention at the following concentrations: 30 ⁇ M, 10 ⁇ M, 1 ⁇ M, 300 nM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM.
  • the competitive binding data were analysed using the iterative, nonlinear, curve-fitting program, “Prism” (GraphPad Software, Ine).
  • test compounds of the present invention were assessed using the above described in vitro biological assay.
  • the binding affinity of test compounds from the above examples is expressed by the inhibition constant (Ki; nM). From these values, it can be derived that said test compounds according to the present invention do show a significant binding to the oxytocin receptor.
  • Ki (nM) 120 nM.
  • O-methyloxime is a OT-R Antagonist
  • the inhibition of oxytocin-induced Ca2+ mobilization in OT-R transfected HEK293EBNA cells was measured by FLIPR (fluorimetric imaging plate reader).
  • This assay allows the measurement of the inhibition of OT/OT-R mediated calcium mobilization by the compound (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime.
  • FLIPR® is a fluorimetric imaging device using a laser (Argon-ion laser) for simultaneous illumination and reading (cooled CCD camera) of each well of a 96-well-plate, thus enabling rapid measurements on a large number of samples.
  • FLIPR-plates were pre-coated with PLL (Poly-L-Lysine) 10 ⁇ g/ml+0.1%) gelatine to attach HEK293EBNA cells (Human Embryonic Kidney cells expressing OT-R) and incubated for 30 min up to 2 days at 37° C. The cells were plated out into 96-well-plates (60000 cells/well).
  • PLL Poly-L-Lysine
  • Fluo-4 (Ca2+ sensitive fluorescent dye) were dissolved in 20 ⁇ l pluronic acid (20% in DMSO). The dissolved fluo-4 was then diluted in 10 ml DMEM (Dubecco's Minimal Essential Medium)-F12 culture medium. The plates were washed one time with DMEM-F12 medium. 100 ⁇ l of the Fluo-4 containing-DMEM-F12 medium were added to the HEK-cells which were incubated for 1.5-2 h in this fluorescent medium. Fluo-4 is taken up by the cytoplasm of the cells.
  • DMEM Dubecco's Minimal Essential Medium
  • Buffer 145 mM NaCl, 5 mM KCl, 1 mM MgCl2, 10 mM Hepes, 10 mM Glucose, EGTA (Ethylene-bis oxyethylene nitrilo tetraacetic acid). The pH was adjusted to 7.4.
  • O-methyloxime was added to the 96-well-plates at different concentrations (30 ⁇ M, 10 ⁇ M, 1 ⁇ M, 300 nM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM).
  • Oxytocin (OT) was added at a concentration of 40 nM.
  • the fluorescence of the marker being sensitive to the amount of Ca2+, the Ca2+ movements can be detected.
  • Late-term pregnant (certified at days 19-21 of pregnancy) Sprague Dawley CD (SD) BR female rats (Charles River, Calco, Italy), weighing 350-400 g were anesthetized with urethane (1.05 g/kg, i.p.) and placed on a homeothermic operating table. A midline incision at the hypogastrium level was made, one pregnant uterine horn exposed and its tubal end (near the ovary) was closed by a ligature with surgical silk.
  • SD Sprague Dawley CD
  • the uterine-horn wall was incised taking care not to injure the adjacent placenta and PE240 tubing with a latex balloon (9 mm length when empty, capacity 0.1 mL; Radnoti, Monrovia, Calif., USA) on the top was inserted into the lumen and secured to the uterine wall with surgical silk.
  • the catheter was connected to an amplifying/recording system (MacLab, ADInstruments Pty Ltd, Castle Hill, Australia) via a P23ID Gould-Statham pressure transducer.
  • One jugular vein was isolated and cannulated with a PE60 polyethylene cannula for the i.v. administration. After the surgical preparation, a 30-min stabilization period was observed and then the effects of increasing doses of compounds of the present invention (given as 10-min i.v. infusion, bolus i.v. or p.o.) were evaluated by measuring the resulting uterine contractions.
  • the uterine contractile activity was quantified by calculating the AUC during the 10-min injection period.
  • the percent variation of the AUC values relative to the spontaneous uterine response observed after each compound administration was calculated in comparison to the value recorded before the first dose-administration (basal value).
  • the effect of test compounds of the present invention was evaluated by comparing pre- and post-treatment luminal uterine pressure values.
  • the y-axis represents uterine contractions as % of value compared to pre-dose set at 100%.
  • the x-axis represents the time post-dose in minutes. Contractions were continuously recorded and area-under-the-curve (AUC) integrated over 10-min time intervals.
  • AUC area-under-the-curve
  • the present invention shows that the substantially pure Z form having formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime inhibits uterine contraction whereas the substantially pure E form has no efficacy.
  • the present invention advantageously relates to biologically active compounds of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime and/or metabolite thereof in substantially pure form that can be administered at lower dosage compared to said compounds provided in isomeric mixture.
  • mice used in this study were Sprague-Dawley, Crl: CD®BR albino rats. All animals were supplied by Charles River UK Ltd (Margate, Kent, UK). Animals were in the weight range 200-260 g and were approximately 2 months old. Rats were given a unique identity number and were identified by unique tail markings plus cage location.
  • the dose groups were as follows: 4 female were given an oral dose and 4 female were given an intravenous dose.
  • O-methyloxime oral and intravenous dosing formulations were prepared separately at each dose phase at a target dose level of 30 mg/kg, and at a radioactive concentration of approximately 25 ⁇ Ci/rat.
  • Dose formulations were prepared in an appropriate matrix; intravenous doses were prepared in NP3S, whilst oral doses were prepared in Labrasol:water (1:1 v/v).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Diabetes (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pain & Pain Management (AREA)
  • Obesity (AREA)
  • Psychology (AREA)
  • Hematology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pyrrole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US14/917,847 2013-09-10 2014-07-25 PYRROLIDINE DERIVATIVES AS OXYTOCIN/VASOPRESSIN V1a RECEPTORS ANTAGONISTS Abandoned US20160221944A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP13183723.9 2013-09-10
EP13183723.9A EP2845850A1 (en) 2013-09-10 2013-09-10 Pyrrolidine derivatives as oxytocin/vasopressin V1a receptors antagonists
PCT/EP2014/066075 WO2015036160A1 (en) 2013-09-10 2014-07-25 PYRROLIDINE DERIVATIVES AS OXYTOCIN / VASOPRESSIN V1a RECEPTORS ANTAGONISTS

Publications (1)

Publication Number Publication Date
US20160221944A1 true US20160221944A1 (en) 2016-08-04

Family

ID=49118429

Family Applications (7)

Application Number Title Priority Date Filing Date
US14/917,847 Abandoned US20160221944A1 (en) 2013-09-10 2014-07-25 PYRROLIDINE DERIVATIVES AS OXYTOCIN/VASOPRESSIN V1a RECEPTORS ANTAGONISTS
US14/479,664 Active US9670155B2 (en) 2013-09-10 2014-09-08 Pyrrolidine derivatives as oxytocin/vasopressin V1a receptors antagonists
US15/476,325 Active US10047048B2 (en) 2013-09-10 2017-03-31 Pyrrolidine derivatives as oxytocin/vasopressin V1a receptors antagonists
US15/938,729 Active US10604482B2 (en) 2013-09-10 2018-03-28 Pyrrolidine derivatives as oxytocin/vasopressin via receptors antagonists
US16/831,135 Active US11312683B2 (en) 2013-09-10 2020-03-26 Pyrrolidine derivatives as oxytocin/vasopressin via receptors antagonists
US17/587,460 Abandoned US20230097933A1 (en) 2013-09-10 2022-01-28 Pyrrolidine derivatives as oxytocin/vasopressin v1a receptors antagonists
US18/233,160 Pending US20240228439A1 (en) 2013-09-10 2023-08-11 Pyrrolidine derivatives as oxytocin/vasopressin v1a receptors antagonists

Family Applications After (6)

Application Number Title Priority Date Filing Date
US14/479,664 Active US9670155B2 (en) 2013-09-10 2014-09-08 Pyrrolidine derivatives as oxytocin/vasopressin V1a receptors antagonists
US15/476,325 Active US10047048B2 (en) 2013-09-10 2017-03-31 Pyrrolidine derivatives as oxytocin/vasopressin V1a receptors antagonists
US15/938,729 Active US10604482B2 (en) 2013-09-10 2018-03-28 Pyrrolidine derivatives as oxytocin/vasopressin via receptors antagonists
US16/831,135 Active US11312683B2 (en) 2013-09-10 2020-03-26 Pyrrolidine derivatives as oxytocin/vasopressin via receptors antagonists
US17/587,460 Abandoned US20230097933A1 (en) 2013-09-10 2022-01-28 Pyrrolidine derivatives as oxytocin/vasopressin v1a receptors antagonists
US18/233,160 Pending US20240228439A1 (en) 2013-09-10 2023-08-11 Pyrrolidine derivatives as oxytocin/vasopressin v1a receptors antagonists

Country Status (23)

Country Link
US (7) US20160221944A1 (pt)
EP (4) EP2845850A1 (pt)
JP (6) JP2016529258A (pt)
KR (3) KR101804739B1 (pt)
CN (4) CN105531259A (pt)
AU (3) AU2014320694B2 (pt)
BR (1) BR112016005276B1 (pt)
CA (2) CA2979461C (pt)
CY (1) CY1120152T1 (pt)
DK (1) DK3044206T3 (pt)
EA (2) EA202092300A1 (pt)
ES (2) ES2914776T3 (pt)
HK (2) HK1221716A1 (pt)
HU (1) HUE037578T2 (pt)
IL (2) IL244152A (pt)
MX (1) MX370602B (pt)
PT (1) PT3044206T (pt)
SG (2) SG10201800624SA (pt)
SI (1) SI3044206T1 (pt)
TR (1) TR201807175T4 (pt)
UA (1) UA115708C2 (pt)
WO (1) WO2015036160A1 (pt)
ZA (1) ZA201704072B (pt)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9718772B2 (en) 2014-07-02 2017-08-01 ObsEva S.A. Crystalline (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, and methods of using the same
US9962367B2 (en) 2013-12-17 2018-05-08 ObsEva S.A. Oral formulations of pyrrolidine derivatives
US10047048B2 (en) 2013-09-10 2018-08-14 ObsEva S.A. Pyrrolidine derivatives as oxytocin/vasopressin V1a receptors antagonists

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6933322B2 (ja) 2016-01-04 2021-09-08 メルク セローノ エス．エー． ヒドロキシプロピルチアゾリジンカルボキサミド誘導体のｌ−バリネート及びその塩形態、結晶多形
WO2017180781A1 (en) * 2016-04-12 2017-10-19 Trigemina, Inc. Magnesium-containing oxytocin formulations and methods of use
CA3031252A1 (en) * 2016-07-21 2018-01-25 ObsEva S.A. Oxytocin antagonist dosing regimens for promoting embryo implantation and preventing miscarriage
WO2021043726A1 (en) 2019-09-03 2021-03-11 ObsEva S.A. Oxytocin antagonist dosing regimens for promoting embryo implantation and preventing miscarriage
US20230102503A1 (en) 2020-02-10 2023-03-30 ObsEva S.A. Biomarkers for oxytocin receptor antagonist therapy
RU2756027C1 (ru) * 2021-02-24 2021-09-24 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт акушерства, гинекологии и репродуктологии имени Д.О. Отта" Способ диагностики наружного генитального эндометриоза
WO2024073451A1 (en) * 2022-09-30 2024-04-04 Ocelot Bio, Inc. Mixed vasopressin receptor agonist-antagonist for treating end-stage liver disease and complications associated thereof
WO2024165071A1 (zh) * 2023-02-09 2024-08-15 上海葆正医药科技有限公司 亚胺化合物及其制备方法和应用

Family Cites Families (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3482815A (en) 1967-07-07 1969-12-09 Victor Naturale Collapsible core for a mold
YU120988A (en) 1988-06-23 1990-06-30 Lek Tovarna Farmacevtskih Process for preparing new dispersion pills of cimetidine
US4832307A (en) 1988-09-15 1989-05-23 Toshiba Kikai Kabushiki Kaisha Injection mold
YU183988A (en) 1988-09-30 1990-08-31 Lek Tovarna Farmacevtskih Process for preparing dispersion pills of dihydroergotoxine
JP2927532B2 (ja) * 1989-11-09 1999-07-28 塩野義製薬株式会社 含窒素異項環オキシーフェノキシ酢酸誘導体およびその除草剤としての用途
US5889001A (en) 1993-07-29 1999-03-30 American Cyanamid Company Tricyclic diazepine vasopressin antagonists and oxytocin antagonists
JP2869854B2 (ja) 1994-10-19 1999-03-10 株式会社トスカ 合成樹脂の成形方法とその装置
JP3534903B2 (ja) * 1995-06-09 2004-06-07 鐘淵化学工業株式会社 １−［３−クロロ−（２ｓ）−メチルプロピオニル］−ピロリジン−（２ｓ）−カルボン酸の製造方法
GB9603699D0 (en) 1996-02-21 1996-04-17 Boots Co Plc Therapeutic composition
US6696484B2 (en) 1997-10-31 2004-02-24 University Of Chicago Office Of Technology And Intellectual Property Method and compositions for regulation of 5-alpha reductase activity
US6329418B1 (en) 1998-04-14 2001-12-11 The Procter & Gamble Company Substituted pyrrolidine hydroxamate metalloprotease inhibitors
US20030180352A1 (en) 1999-11-23 2003-09-25 Patel Mahesh V. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
SK285706B6 (sk) 1999-12-09 2007-06-07 Reckitt Benckiser Healthcare (Uk) Limited Lisovaná tabletová kompozícia, spôsob jej prípravy a jej použitie
AU5620901A (en) 2000-03-27 2001-10-08 Applied Research Systems Pharmaceutically active pyrrolidine derivatives as bax inhibitors
EP1268418B1 (en) 2000-03-27 2006-06-14 Applied Research Systems ARS Holding N.V. Pharmaceutically active pyrrolidine derivatives as bax inhibitors
EP1390347B1 (en) 2001-03-20 2008-05-07 Laboratoires Serono SA Pyrrolidine ester derivatives with oxytocin modulating activity
SK15552003A3 (sk) 2001-06-18 2004-05-04 Applied Research Systems Ars Holding N. V. Oxadiazolové a tiadiazolové deriváty pyrolidínu, spôsob ich výroby, farmaceutický prostriedok s ich obsahom a ich použitie
JP2003192582A (ja) 2001-12-12 2003-07-09 Merck Patent Gmbh ナプロキセンナトリウムを含む速放性錠剤
UA78058C2 (en) * 2002-07-05 2007-02-15 Applied Research Systems Pyrrolidine derivative as oxitocin antagonists
JP4773335B2 (ja) 2003-02-27 2011-09-14 メルク セローノ ソシエテ アノニム オキシトシンアンタゴニストとしてのピロリジン誘導体
KR20060124775A (ko) 2004-02-26 2006-12-05 어플라이드 리서치 시스템스 에이알에스 홀딩 엔.브이. 피롤리딘 옥심의 제조방법
GB2411355B (en) 2004-02-27 2006-02-22 Niche Generics Ltd Pharmaceutical composition
RU2385735C2 (ru) 2005-05-10 2010-04-10 Ферринг Интернэшнл Сентер С.А. Применение антагонистов окситоцина при вспомогательной репродукции
US9198862B2 (en) 2005-07-22 2015-12-01 Rubicon Research Private Limited Dispersible tablet composition
WO2007074472A2 (en) 2005-12-27 2007-07-05 Jubilant Organosys Limited Mouth dissolving pharmaceutical composition and process for preparing the same using a high amount of silicon dioxide
JP2008189732A (ja) * 2007-02-01 2008-08-21 Fujifilm Corp セルロースアシレート組成物、セルロースアシレートフィルム、光学補償シート、偏光板および液晶表示装置
US20090152770A1 (en) 2007-08-07 2009-06-18 Canon Virginia Inc. Mechanically collapsible core for injection molding
PL2572705T3 (pl) 2007-10-01 2018-01-31 Lesvi Laboratorios Sl Tabletki ulegające rozpadowi w jamie ustnej
WO2009146013A1 (en) * 2008-03-31 2009-12-03 Georgetown University Myosin light chain phosphatase inhibitors
US9201077B2 (en) 2009-07-27 2015-12-01 Colorado State University Research Foundation Direct enzyme immunoassay for measurement of serum progesterone levels
EP2922475A1 (en) 2012-11-26 2015-09-30 Ferring BV Method and system for diagnosing uterine contraction levels using image analysis
JP5942815B2 (ja) 2012-11-26 2016-06-29 株式会社ジェイテクト 等速ジョイント用ブーツの成形金型
EP2845850A1 (en) 2013-09-10 2015-03-11 ObsEva S.A. Pyrrolidine derivatives as oxytocin/vasopressin V1a receptors antagonists
EP2886107A1 (en) 2013-12-17 2015-06-24 ObsEva S.A. Oral formulations of pyrrolydine derivatives
CA2953722C (en) 2014-07-02 2022-09-13 ObsEva SA Crystalline (3z,5s)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one o-methyloxime, and methods of using the same
ES2716862T3 (es) 2014-12-22 2019-06-17 Ferring Bv Terapia con antagonistas del receptor de oxitocina en la fase lútea para la implantación y embarazo en mujeres que se someten a tecnologías de reproducción asistida

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Jorand-Lebrun, et al. Document No. 140:93917, retrieved from CAPLUS; January 18, 2004. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10047048B2 (en) 2013-09-10 2018-08-14 ObsEva S.A. Pyrrolidine derivatives as oxytocin/vasopressin V1a receptors antagonists
US10604482B2 (en) 2013-09-10 2020-03-31 ObsEva S.A. Pyrrolidine derivatives as oxytocin/vasopressin via receptors antagonists
US11312683B2 (en) 2013-09-10 2022-04-26 ObsEva S.A. Pyrrolidine derivatives as oxytocin/vasopressin via receptors antagonists
US9962367B2 (en) 2013-12-17 2018-05-08 ObsEva S.A. Oral formulations of pyrrolidine derivatives
US10478420B2 (en) 2013-12-17 2019-11-19 ObsEva S.A. Oral formulations of pyrrolidine derivatives
US11419851B2 (en) 2013-12-17 2022-08-23 ObsEva S.A. Oral formulations of pyrrolidine derivatives
US9718772B2 (en) 2014-07-02 2017-08-01 ObsEva S.A. Crystalline (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, and methods of using the same
US10752583B2 (en) 2014-07-02 2020-08-25 ObsEva S.A. Crystalline (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, and methods of using the same

Also Published As

Publication number Publication date
AU2014320694B2 (en) 2017-12-14
PT3044206T (pt) 2018-05-09
EA202092300A1 (ru) 2021-06-30
JP2018150376A (ja) 2018-09-27
CA2979461A1 (en) 2015-03-19
UA115708C2 (uk) 2017-12-11
CA2921580A1 (en) 2015-03-19
AU2019201859B2 (en) 2019-11-21
HUE037578T2 (hu) 2018-09-28
US20210047266A1 (en) 2021-02-18
JP2023182673A (ja) 2023-12-26
SI3044206T1 (en) 2018-05-31
CN105531259A (zh) 2016-04-27
JP6659078B2 (ja) 2020-03-04
CA2921580C (en) 2017-11-14
CA2979461C (en) 2021-08-31
JP6462030B2 (ja) 2019-01-30
CN109928905A (zh) 2019-06-25
US9670155B2 (en) 2017-06-06
US11312683B2 (en) 2022-04-26
EA201690480A1 (ru) 2016-08-31
IL254246A0 (en) 2017-10-31
AU2019201859A1 (en) 2019-04-11
EA036830B1 (ru) 2020-12-24
SG11201601743RA (en) 2016-04-28
EP3252037A1 (en) 2017-12-06
IL244152A (en) 2017-09-28
EP4129979A1 (en) 2023-02-08
US20170240508A1 (en) 2017-08-24
AU2014320694A1 (en) 2016-04-21
BR112016005276B1 (pt) 2022-10-18
AU2018201730A1 (en) 2018-04-05
KR101907338B1 (ko) 2018-10-11
IL254246B (en) 2019-08-29
US20230097933A1 (en) 2023-03-30
ES2664403T3 (es) 2018-04-19
KR20160053990A (ko) 2016-05-13
WO2015036160A1 (en) 2015-03-19
IL244152A0 (en) 2016-04-21
TR201807175T4 (tr) 2018-06-21
JP2021193084A (ja) 2021-12-23
KR20170054553A (ko) 2017-05-17
KR101749877B1 (ko) 2017-06-21
ES2914776T3 (es) 2022-06-16
HK1221716A1 (zh) 2017-06-09
MX370602B (es) 2019-12-18
US10604482B2 (en) 2020-03-31
US20240228439A1 (en) 2024-07-11
JP2017141281A (ja) 2017-08-17
EP2845850A1 (en) 2015-03-11
EP3044206A1 (en) 2016-07-20
DK3044206T3 (en) 2018-05-28
MX2016003042A (es) 2016-06-10
AU2018201730B2 (en) 2019-01-03
ZA201704072B (en) 2018-08-29
EP3044206B1 (en) 2018-02-28
CY1120152T1 (el) 2018-12-12
JP2020015728A (ja) 2020-01-30
HK1247612A1 (zh) 2018-09-28
SG10201800624SA (en) 2018-03-28
US20150073032A1 (en) 2015-03-12
JP2016529258A (ja) 2016-09-23
US20180215708A1 (en) 2018-08-02
EP3252037B1 (en) 2022-03-09
US10047048B2 (en) 2018-08-14
KR20170133525A (ko) 2017-12-05
CN107674011A (zh) 2018-02-09
BR112016005276A2 (pt) 2017-08-01
KR101804739B1 (ko) 2017-12-05
CN109748836A (zh) 2019-05-14

Similar Documents

Publication Publication Date Title
US11312683B2 (en) Pyrrolidine derivatives as oxytocin/vasopressin via receptors antagonists
US20200281892A1 (en) Oral formulations of pyrrolidine derivatives

Legal Events

Date Code Title Description
AS Assignment

Owner name: OBSEVA S.A., SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CHOLLET, ANDRE;REEL/FRAME:038814/0564

Effective date: 20160411

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: OXFORD FINANCE LLC, AS COLLATERAL AGENT, VIRGINIA

Free format text: SECURITY INTEREST;ASSIGNOR:OBSEVA SA;REEL/FRAME:049994/0930

Effective date: 20190807

AS Assignment

Owner name: OBSEVA S.A., SWITZERLAND

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:OXFORD FINANCE LLC;REEL/FRAME:060410/0839

Effective date: 20211012