WO2026018221A1 - Compositions cristallines pour améliorer l'implantation d'embryons et leurs procédés d'utilisation - Google Patents

Compositions cristallines pour améliorer l'implantation d'embryons et leurs procédés d'utilisation

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Publication number
WO2026018221A1
WO2026018221A1 PCT/IB2025/057317 IB2025057317W WO2026018221A1 WO 2026018221 A1 WO2026018221 A1 WO 2026018221A1 IB 2025057317 W IB2025057317 W IB 2025057317W WO 2026018221 A1 WO2026018221 A1 WO 2026018221A1
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crystalline form
subject
compound
embryos
ppm
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English (en)
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Jean-Pierre Gotteland
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Repronovo Sa
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Repronovo Sa
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    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
    • 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

Definitions

  • the disclosure relates to the field of assisted reproduction technology and provides compositions and methods for treating subjects undergoing embryo transfer procedures so as to enhance, for example, endometrial receptivity and reduce the likelihood of embryo implantation failure.
  • Such treatment modalities include the administration of p-adrenergic receptor agonists and non-steroidal anti-inflammatory drugs (NSAIDS), which have not been shown to provide sufficient clinical benefit (Bernabeu et al., Human Reproduction 21 :364-368 (2006); Moon et al., Fertility and Sterility 82:816-820 (2004); and Tsirigotis et al., Human Reproduction 15:10 (2000)).
  • NSAIDS non-steroidal anti-inflammatory drugs
  • compositions and methods for treating subjects e.g., female human subjects
  • embryo transfer procedures such as in vitro fertilization (IVF), among others described herein.
  • the disclosure features crystalline forms of an oxytocin receptor antagonist, (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1 ,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O- methyloxime, as well as methods of administering the same to a subject undergoing an embryo transfer procedure.
  • compositions and methods described herein administration of the oxytocin receptor antagonist to such a subject may improve the subject’s likelihood of successful embryo implantation, as well as reduce the probability that the subject will experience a miscarriage following embryo transfer. These beneficial results can help a patient undergoing embryo transfer therapy to successfully establish pregnancy and to remain pregnant until delivery following a full gestational period.
  • Examples of beneficial responses to oxytocin receptor antagonist treatment that a subject may exhibit include reduced uterine contractility and augmented blood flow to the endometrium. Together, uterine contractility and endometrial blood flow constitute important components of endometrial receptivity to a transferred embryo.
  • an oxytocin receptor antagonist administered to a subject using the compositions and methods described herein may enhance uterine perfusion and suppress uterine contractions that could otherwise lead to embryo expulsion. These effects can collectively serve to create an environment within the endometrium that is conducive to successful embryo implantation, which can ultimately enhance the likelihood of achieving and sustaining a successful pregnancy.
  • the disclosure features a crystalline form of a compound, (3Z,5S)-5- (hydroxymethyl)-1-[(2'-methyl-1 ,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (I) wherein the crystalline form of the compound exhibits characteristic X-ray powder diffraction (XRPD) peaks at 12.86 ⁇ 0.20° 26, 16.32 ⁇ 0.20° 26, and 22.69 ⁇ 6.26° 26.
  • XRPD characteristic X-ray powder diffraction
  • the crystalline form of said compound exhibits characteristic XRPD peaks at 17.81 ⁇ 6.26° 26, 21.69 ⁇ 6.26° 26, and 24.86 ⁇ 6.26° 26. In some embodiments, the crystalline form of said compound exhibits characteristic XRPD peaks at 23.94 ⁇ 6.26° 26 and 27.93 ⁇ 6.26° 26. In some embodiments, the crystalline form of said compound exhibits characteristic XRPD peaks at 25.87 ⁇ 6.26° 26, 26.99 ⁇ 6.26° 26, and 28.74 ⁇ 6.26° 26.
  • the crystalline form of said compound exhibits characteristic XRPD peaks at 7.67 ⁇ 6.26° 26, 12.27 ⁇ 6.26° 26, 14.17 ⁇ 6.26° 26, and 18.79 ⁇ 6.26° 26. In some embodiments, the crystalline form of said compound exhibits characteristic XRPD peaks at 21.34 ⁇ 6.26° 26 and 25.72 ⁇ 6.26° 26.
  • the crystalline form of said compound exhibits characteristic XRPD peaks at 36.56 ⁇ 6.26° 26, 31 .22 ⁇ 6.26° 26, 32.56 ⁇ 6.26° 26, 33.63 ⁇ 6.26° 26, 33.35 ⁇ 6.26° 26, 33.79 ⁇ 6.26° 26, 34.67 ⁇ 6.26° 26, 34.96 ⁇ 6.26° 26, 35.67 ⁇ 6.26° 26, 36.68 ⁇ 6.26° 26, 37.42 ⁇ 6.26° 26, 37.84 ⁇ 6.26° 26, 38.25 ⁇ 6.26° 26, and 39.72 ⁇ 6.26° 26.
  • the crystalline form of said compound has the XRPD spectrum as shown in FIG. 5A.
  • the XRPD peaks at diffraction angle 26 (°) are collected by irradiating with Cu Ka.
  • the crystalline form of said compound has a differential scanning calorimetry (DSC) endotherm at about 99 °C. In some embodiments, the crystalline form of said compound has the DSC curve substantially as depicted in FIG. 5F.
  • DSC differential scanning calorimetry
  • the crystalline form of said compound exhibits 1 H nuclear magnetic resonance (NMR) peaks centered at a chemical shift (6) of about 1 .6 ppm, about 2.3 ppm, about 2.5 ppm, about 3.3 ppm, about 3.5 ppm, about 3.7 ppm, about 7.2 ppm, about 7.3 ppm, about 7.4 ppm, and about 7.6 ppm.
  • NMR nuclear magnetic resonance
  • the crystalline form is characterized by a 1 H NMR spectrum substantially as depicted in FIG. 5B.
  • the crystalline form exhibits a weight loss of from 0.01% to 5% when heated from 36 °C to 160 °C as measured by thermogravimetric analysis (TGA). In some embodiments, the crystalline form exhibits a weight loss of about 0.01% to 0.05% when heated from 36 °C to 160 °C as measured by TGA. In some embodiments, the crystalline form exhibits a weight loss of about 0.03% when heated from 36 °C to 160 °C as measured by TGA. In some embodiments, the crystalline form exhibits a TGA curve substantially as depicted in FIG. 5G.
  • the crystalline form exhibits a weight gain of from 0.01% to 5% when the relative humidity is increased from 5% to 95% as measured by dynamic vapor sorption (DVS). In some embodiments, the crystalline form exhibits a weight gain of from 1% to 5% when the relative humidity is increased from 5% to 95% as measured by DVS. In some embodiments, the crystalline form exhibits a weight gain of about 1 .65% when the relative humidity is increased from 5% to 95% as measured by DVS. In some embodiments, the crystalline form exhibits a weight loss of from 0.01% to 5% when the relative humidity is decreased from 95% to 5% as measured by DVS.
  • DVS dynamic vapor sorption
  • the crystalline form exhibits a weight loss of from 1% to 5% when the relative humidity is decreased from 95% to 5% as measured by DVS. In some embodiments, the crystalline form exhibits a weight loss of about 1 .67% when the relative humidity is decreased from 95% to 5% as measured by DVS. In some embodiments, the crystalline form exhibits a DVS curve substantially as depicted in FIG. 5H.
  • the crystalline form exhibits a Raman curve substantially as depicted in FIG. 5I or FIG. 5J.
  • the crystalline form has a solubility of from 0.100 mg/mL to 0.200 mg/mL in water after 24 hours of stirring. In some embodiments, the crystalline form has a solubility of about 0.189 mg/mL in water after 24 hours of stirring.
  • the crystalline form has an intrinsic dissolution rate (IDR) of from 0.010 mg/cm 2 /min to 0.020 mg/cm 2 /min in water. In some embodiments, the crystalline form has an IDR of about 0.013 mg/cm 2 /min in water.
  • IDR intrinsic dissolution rate
  • the crystalline form is obtainable by recrystallization from a solvent. In some embodiments, the crystalline form is obtainable by recrystallization from ethanol, methanol, or water.
  • the disclosure provides a crystalline form of a compound, (3Z,5S)-5- (hydroxymethyl)-1-[(2'-methyl-1 ,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by form wherein the crystalline form exhibits a weight loss of from 0.01% to 5% when heated from 36 °C to 160 °C as measured by TGA, optionally wherein the weight loss is from 0.01% to 0.05%, further optionally wherein the weight loss is about 0.03%.
  • the disclosure provides a crystalline form of a compound, (3Z,5S)-5- (hydroxymethyl)-1-[(2'-methyl-1 ,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (I) having (a) the XRPD spectrum as shown in FIG. 5A and optionally at least one of the following properties:
  • the disclosure provides a solid form of a compound, (3Z,5S)-5- (hydroxymethyl)-1-[(2'-methyl-1 ,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by form comprising crystalline Form B of compound (I), wherein the crystalline Form B of compound (I) is present at greater than about 80% (e.g., about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) by weight of the solid form.
  • 80% e.g., about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
  • the disclosure provides a solid form of a compound, (3Z,5S)-5- (hydroxymethyl)-1-[(2'-methyl-1 ,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by form comprising crystalline Form B of compound (I), wherein the crystalline Form B of compound (I) is present at greater than about 84% (e.g., about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) by weight of the solid form.
  • a compound, (3Z,5S)-5- (hydroxymethyl)-1-[(2'-methyl-1 ,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime represented by form comprising crystalline Form B of compound (I), wherein the crystalline Form B of compound (I) is present at greater than about 84% (e
  • the disclosure provides a solid form of a compound, (3Z,5S)-5- (hydroxymethyl)-1-[(2'-methyl-1 ,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by form comprising crystalline Form B of compound (I), wherein the crystalline Form B of compound (I) is present at greater than about 87% (e.g., about 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) by weight of the solid form.
  • crystalline Form B of compound (I) is present at greater than about 87% (e.g., about 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) by weight of the solid form.
  • the disclosure provides a solid form of a compound, (3Z,5S)-5- (hydroxymethyl)-1-[(2'-methyl-1 ,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by form comprising crystalline Form B of compound (I), wherein the crystalline Form B of compound (I) is present at greater than about 89% (e.g., about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) by weight of the solid form.
  • crystalline Form B of compound (I) is present at greater than about 89% (e.g., about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) by weight of the solid form.
  • the disclosure features a pharmaceutical composition containing the crystalline form of any one of the preceding aspects or embodiments of the disclosure, in combination with one or more carriers, diluents, or excipients.
  • the disclosure features a method of treating a subject undergoing an embryo transfer procedure in which one or more embryos are transferred to the uterus of the subject, the method comprising administering to the subject the crystalline form or pharmaceutical composition of any one of the preceding aspects or embodiments of the disclosure.
  • the disclosure features a method of reducing the likelihood of embryo implantation failure in a subject undergoing an embryo transfer procedure in which one or more embryos are transferred to the uterus of the subject, the method comprising administering to the subject the crystalline form or pharmaceutical composition of any one of the preceding aspects or embodiments of the disclosure.
  • the disclosure features a method of improving endometrial receptivity in a subject undergoing an embryo transfer procedure in which one or more embryos are transferred to the uterus of the subject, the method comprising administering to the subject the crystalline form or pharmaceutical composition of any one of the preceding aspects or embodiments of the disclosure.
  • the disclosure features a method of reducing uterine contractility in a subject undergoing an embryo transfer procedure in which one or more embryos are transferred to the uterus of the subject, the method comprising administering to the subject the crystalline form or pharmaceutical composition of any one of the preceding aspects or embodiments of the disclosure.
  • the method comprises transferring the one or more embryos to the uterus of the subject. In some embodiments, the method further comprises inducing follicular maturation in the subject, optionally wherein the inducing of follicular maturation comprises administering human chorionic gonadotropin (hCG) to the subject.
  • hCG human chorionic gonadotropin
  • from 1 to 2 embryos are transferred to the subject.
  • one embryo is transferred to the subject.
  • two embryos are transferred to the subject.
  • the subject is a mammal and the one or more embryos are mammalian embryos.
  • the mammal is a human and the one or more mammalian embryos are human embryos.
  • the one or more embryos are produced ex vivo by in vitro fertilization (IVF). In some embodiments, the one or more embryos are produced ex vivo by IVF of one or more ova derived from the subject.
  • IVF in vitro fertilization
  • the one or more embryos are produced ex vivo by intracytoplasmic sperm injection (ICSI). In some embodiments, the one or more embryos are produced ex vivo by ICSI into one or more ova derived from the subject.
  • ICSI intracytoplasmic sperm injection
  • the one or more ova are derived from one or more oocytes isolated from the subject. In some embodiments, the one or more oocytes comprise from 1 to 4 mature oocytes.
  • a gonadotropin-releasing hormone (GnRH) antagonist is administered to the subject prior to isolation of the one or more oocytes from the subject.
  • hCG is administered to the subject prior to isolation of the one or more oocytes from the subject.
  • progesterone is administered to the subject following isolation of the one or more oocytes from the subject.
  • the one or more ova are isolated directly from the subject.
  • a GnRH antagonist is administered to the subject prior to isolation of the one or more ova from the subject.
  • hCG is administered to the subject prior to isolation of the one or more ova from the subject.
  • progesterone is administered to the subject following isolation of the one or more ova from the subject.
  • the one or more embryos each comprise from 6 to 8 blastomeres immediately prior to the transfer of the one or more embryos to the subject.
  • the blastomeres are of approximately equal sizes as assessed by visual microscopy.
  • the disclosure features a kit comprising the crystalline form or pharmaceutical composition of any of the foregoing aspects or embodiments of the disclosure, as well as a package insert instructing a user of the kit to administer the crystalline form to a subject in accordance with any one or more of the preceding methods.
  • the compound represented by formula (I) i.e., (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1 , 1 '-biphenyl-4- yl)carbonyl]pyrrolidin-3-one O-methyloxime) is substantially pure.
  • the compound represented by formula (I) has a purity of at least 85%, such as a purity of from 85% to 99.9% or more (e.g., a purity of 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or more).
  • the purity of the compound represented by formula (I) may be assessed, for instance, using NMR techniques and/or chromatographic methods, such as HPLC procedures, that are known in the art and described herein.
  • the compound represented by formula (I) is substantially pure with respect to diastereomers of this compound and other by-products that may be formed during the synthesis of this compound.
  • the compound represented by formula (I) has a purity of at least 85%, such as a purity of from 85% to 99.9% or more (e.g., a purity of 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or more) with respect to diastereomers of this compound and other by-products that may be formed during the synthesis of this compound, such as a by-product that is formed during the synthesis of this compound.
  • the purity of the compound represented by formula (I) may be assessed, for instance, using NMR techniques and/or chromatographic methods
  • the compound represented by formula (I) is substantially pure with respect to its (3E) diastereomer, (3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1 , 1 '-biphenyl-4- yl)carbonyl]pyrrolidin-3-one O-methyloxime.
  • the compound represented by formula (I) has a purity of at least 85%, such as a purity of from 85% to 99.9% or more (e.g., a purity of 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or more) with respect to (3E,5S)-5- (hydroxymethyl)-1-[(2'-methyl-1 ,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime.
  • a purity of from 85% to 99.9% or more e.g., a purity of 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%
  • compound (I) may be administered in the form of a composition (e.g., a tablet, such as a dispersible tablet, capsule, gel cap, powder, liquid solution, or liquid suspension) that contains less than 15% of the (3E) diastereomer.
  • a composition e.g., a tablet, such as a dispersible tablet, capsule, gel cap, powder, liquid solution, or liquid suspension
  • compound (I) may be administered in the form of a composition (e.g., a tablet, such as a dispersible tablet, capsule, gel cap, powder, liquid solution, liquid suspension, granulate, microemulsion, or self-emulsifying dispersed system) that contains less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.1%, less than 0.01%, less than 0.001%, or less of the (3E) diastereomer.
  • the purity of the compound represented by formula (I) may be assessed, for instance, using NMR techniques and/or chromatographic methods, such as HPLC procedures, that are known in the art and described herein.
  • the subject is a human female subject, such as a human female subject of up to 44 years of age, such as a human female subject of from 18 to 44 years of age, such as a human female subject of 18 years, 19 years, 20 years, 21 years, 22 years, 23 years, 24 years, 25 years, 26 years, 27 years, 28 years, 29 years, 30 years, 31 years, 32 years, 33 years, 34 years, 35 years, 36 years, 37 years, 38 years, 39 years, 40 years, 41 years, 42 years, 43 years, or 44 years of age.
  • the subject is a human female subject of up to 42 years of age, such as a human female subject of from 18 to 42 years of age, such as a human female subject of 18 years, 19 years, 20 years, 21 years, 22 years, 23 years, 24 years, 25 years, 26 years, 27 years, 28 years, 29 years, 30 years, 31 years, 32 years, 33 years, 34 years, 35 years, 36 years, 37 years, 38 years, 39 years, 40 years, 41 years, or 42 years of age.
  • the subject is a human female subject of up to 36 years of age, such as a human female subject of from 18 to 36 years of age, such as a female subject of 18 years, 19 years, 20 years, 21 years, 22 years, 23 years, 24 years, 25 years, 26 years, 27 years, 28 years, 29 years, 30 years, 31 years, 32 years, 33 years, 34 years, 35 years, or 36 years of age. Definitions
  • the term “about” refers to a value that is within 10% above or below the value being described.
  • the phrase “about 50 mg” refers to a value between and including 45 mg and 55 mg.
  • affinity refers to the strength of a binding interaction between two molecules, such as a ligand and a receptor.
  • Ki is intended to refer to the inhibition constant of an antagonist for a particular molecule of interest, and can be expressed as a molar concentration (M). Ki values for antagonist-target interactions can be determined, e.g., using methods established in the art. Methods that can be used to determine the Ki of an antagonist for a molecular target include competitive binding experiments, such as competitive radioligand binding assays, for instance, as described in US Patent No. 9,670,155, the disclosure of which is incorporated herein by reference in its entirety.
  • Kd is intended to refer to the dissociation constant, which can be obtained, for example, from the ratio of the rate constant for the dissociation of the two molecules (kd) to the rate constant for the association of the two molecules (k a ) and is expressed as a molar concentration (M).
  • Kd values for receptor-ligand interactions can be determined, e.g., using methods established in the art. Methods that can be used to determine the Kd of a receptor-ligand interaction include surface plasmon resonance, e.g., through the use of a biosensor system such as a BIACORE® system.
  • assisted reproductive technology refers to a fertility treatment in which one or more female gametes (ova) and male gametes (sperm cells) are manipulated ex vivo so as to promote ovum fertilization and formation of a zygote or embryo. The zygote or embryo is then transferred to the uterus of a female subject, for instance, using the compositions and methods described herein.
  • assisted reproductive technology procedures include in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) techniques described herein and known in the art.
  • the terms “benefit” and “response” in the context of a subject undergoing embryo transfer therapy are used interchangeably and refer to any clinical improvement in the subject’s condition or ability to undergo successful embryo implantation and development.
  • Exemplary “benefits” (“responses”) in this context include, without limitation, an increase in the subject’s endometrial perfusion, a reduction in the subject’s uterine contractility, increase in the subject’s endometrial receptivity toward a transferred embryo, a reduction in the likelihood of embryo implantation failure, the prevention of a miscarriage, and the achievement and maintenance of a successful pregnancy, for example, until delivery at a full gestational age, in a subject following transfer of one or more embryos to the subject.
  • a subject can be determined to benefit, for instance, from oxytocin receptor antagonist treatment as described herein by observing an elevated endometrial receptivity in the subject (for instance, as assessed by detecting a reduction in prostaglandin F2a (PGF2a) signal transduction as described herein and/or by assessing the subject’s ability to sustain a pregnancy for at least 14 days, 6 weeks, 10 weeks, or more, following the transfer of one or more embryos to the subject and/or following the retrieval of one or more oocytes or ova from the subject, and/or by detecting the ability of the subject to give birth to a live offspring at least 24 weeks following the transfer of one or more embryos to the subject.
  • PPF2a prostaglandin F2a
  • a subject can be determined to benefit from oxytocin receptor antagonist treatment as described herein by monitoring the subject for a miscarriage following the transfer of one or more embryos to the subject and observing that the subject has not undergone a miscarriage.
  • controlled ovarian hyperstimulation refers to a procedure in which ovulation is induced in a subject, such as a human subject, prior to oocyte or ovum retrieval for use in embryo formation, for instance, by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).
  • Controlled ovarian hyperstimulation procedures may involve administration of human chorionic gonadotropin (hCG) and/or a gonadotropin-releasing hormone (GnRH) antagonist to the subject so as to promote “follicular maturation,” a term that refers to the development of an oocyte into a “mature oocyte,” as defined herein.
  • hCG human chorionic gonadotropin
  • GnRH gonadotropin-releasing hormone
  • “Final follicular maturation” refers to the last administration of an agent that promotes follicular maturation to a subject prior to oocyte retrieval. Controlled ovarian hyperstimulation methods are known in the art and are described, for instance, in US Patent Nos. 7,405,197 and 7,815,912, the disclosures of each of which are incorporated herein by reference as they pertain to methods for inducing follicular maturation and ovulation in conjunction with assisted reproductive technology.
  • crystalline or “crystalline form” means having a physical state that is a regular three-dimensional array of atoms, ions, molecules or molecular assemblies. Crystalline forms have lattice arrays of building blocks called asymmetric units that are arranged according to well-defined symmetries into unit cells that are repeated in three-dimensions. In contrast, the term “amorphous” or “amorphous form” refers to an unorganized (no orderly) structure.
  • the physical state of a therapeutic compound may be determined by exemplary techniques such as x-ray diffraction, polarized light microscopy, thermal gravimetric analysis, and/or differential scanning calorimetry.
  • the term “derived from” in the context of a cell derived from a subject refers to a cell, such as a mammalian ovum, that is either isolated from the subject or obtained from expansion, division, maturation, or manipulation (e.g., ex vivo expansion, division, maturation, or manipulation) of one or more cells isolated from the subject.
  • an ovum is “derived from” a subject or an oocyte as described herein if the ovum is directly isolated from the subject or obtained from the maturation of an oocyte isolated from the subject, such as an oocyte isolated from the subject from about 1 day to about 7 days prior to the subject undergoing an embryo transfer procedure (e.g., an oocyte isolated from the subject from about 3 days to about 5 days prior to the subject undergoing an embryo transfer procedure).
  • the term "dispersible tablet” refers to a tablet capable of rapidly disintegrating in water and that is swallowed by a subject, or that is intended to be disintegrated rapidly in water and subsequently swallowed by a subject, such as a subject undergoing embryo transfer therapy as described herein.
  • dose refers to a quantity of a therapeutic agent, such as an oxytocin receptor antagonist described herein, that is administered to a subject at a particular point in time for the treatment of a disorder or condition, such as to enhance endometrial receptivity and promote successful embryo implantation in the context of assisted reproductive technology.
  • a therapeutic agent as described herein may be administered in a single dose or in multiple doses.
  • the therapeutic agent may be administered using one or more unit dosage forms of the therapeutic agent.
  • a single dose of 100 mg of a therapeutic agent may be administered using, e.g., two 50 mg unit dosage forms of the therapeutic agent.
  • a single dose of 300 mg of a therapeutic agent may be administered using, e.g., six 50 mg unit dosage forms of the therapeutic agent or two 50 mg unit dosage forms of the therapeutic agent and one 200 mg unit dosage form of the therapeutic agent, among other combinations.
  • a single dose of 900 mg of a therapeutic agent may be administered using, e.g., six 50 mg unit dosage forms of the therapeutic agent and three 200 mg unit dosage forms of the therapeutic agent or ten 50 mg unit dosage form of the therapeutic agent and two 200 mg unit dosage forms of the therapeutic agent, among other combinations.
  • a single dose of 400 mg of the therapeutic agent may be administer using, e.g., one 400 mg unit dosage form of the therapeutic agent.
  • embryo refers to a multicellular, post-zygotic derivative of a fertilized ovum.
  • An embryo may contain two or more blastomeres.
  • embryos for use with the compositions and methods of the disclosure include those that contain from 6 to 8 blastomeres.
  • Embryos may be produced ex vivo, for instance, by in vitro fertilization (IVF) of an ovum, such as an ovum isolated from a subject undergoing embryo transfer therapy or from a donor, or an ovum produced by maturation of an oocyte isolated from a subject undergoing embryo transfer therapy or from a donor.
  • IVF in vitro fertilization
  • Embryos may be produced ex vivo, for instance, by intracytoplasmic sperm injection (ICS I) of an ovum, such as an ovum isolated from a subject undergoing embryo transfer therapy or from a donor, or an ovum produced by maturation of an oocyte isolated from a subject undergoing embryo transfer therapy or from a donor.
  • An embryo may have a variety of multicellular forms resulting from ovum fertilization and mitosis of the ensuing zygote.
  • an embryo may have the form of a morula, which is typically formed from about 3 days to about 4 days following ovum fertilization, and contains two or more cells (such as from 2 to 16 cells, for instance, from 6 to 8 cells) packed contiguously in a spherical arrangement.
  • a morula typically formed from about 3 days to about 4 days following ovum fertilization, and contains two or more cells (such as from 2 to 16 cells, for instance, from 6 to 8 cells) packed contiguously in a spherical arrangement.
  • An embryo may have the form of a blastula (e.g., a mammalian blastocyst), which is typically formed from about 5 days to about 7 days following ovum fertilization, characterized by a spherical morphology containing an outer lining of cells (e.g., a mammalian trophoblast or trophectoderm) surrounding an inner cell mass and a fluid-filled cavity (e.g., a mammalian blastocoele).
  • a blastula e.g., a mammalian blastocyst
  • a spherical morphology containing an outer lining of cells (e.g., a mammalian trophoblast or trophectoderm) surrounding an inner cell mass and a fluid-filled cavity (e.g., a mammalian blastocoele).
  • a blastocyst may contain, for instance, from about 20 to about 300 cells (e.g., about 20 cells, 25 cells, 30 cells, 35 cells, 40 cells, 45 cells, 50 cells, 55 cells, 60 cells, 65 cells, 70 cells, 75 cells, 80 cells, 85 cells, 90 cells, 95 cells, 100 cells, 105 cells, 110 cells, 115 cells, 120 cells, 125 cells, 130 cells, 135 cells, 140 cells, 145 cells, 150 cells, 155 cells, 160 cells, 165 cells, 170 cells, 175 cells, 180 cells, 185 cells, 190 cells, 195 cells, 200 cells, 205 cells, 210 cells, 215 cells, 220 cells, 225 cells, 230 cells, 235 cells, 240 cells, 245 cells, 250 cells, 255 cells, 260 cells, 265 cells, 270 cells, 275 cells, 280 cells, 285 cells, 290 cells, 295 cells, or 300 cells) or more.
  • cells e.g., about 20 cells, 25 cells, 30 cells, 35 cells,
  • embryo transfer therapy and “embryo transfer procedure” are used interchangeably and refer to a procedure in which one or more embryos are transferred to the uterus of a subject, such as a mammalian subject (e.g., a human subject) so as to promote implantation of the one or more embryos into the endometrium of the subject, thereby establishing pregnancy.
  • a mammalian subject e.g., a human subject
  • the embryo may be produced ex vivo, for instance, by in vitro fertilization (IVF) or by intracytoplasmic sperm injection (ICSI), optionally using one or more ova derived from the subject (e.g., one or more ova obtained from maturation of one or more oocytes isolated from the subject) or using one or more ova derived from a donor (e.g., one or more ova obtained from maturation of one or more oocytes isolated from a donor).
  • the embryo may be freshly transferred to the subject, for example, by performing intrauterine embryo transfer using one or more embryos produced by fertilization within about 1 day to about 7 days, such as within about 3 days to about 5 days, of oocyte retrieval from the subject or donor.
  • Embryo transfer is considered “fresh” when ovarian hyperstimulation and ovum/oocyte retrieval from the subject are performed during the same menstrual cycle as embryo transfer to the subject.
  • the embryo may be cryopreserved for long-term storage and subsequently thawed prior to embryo transfer. This process is referred to herein as frozen embryo transfer (FET).
  • FET frozen embryo transfer
  • a subject is considered to be “undergoing” an embryo transfer procedure if the subject is currently preparing for, is actually in the process of receiving, or has recently received, a transfer of one or more embryos to the uterus of the subject with the intention of establish pregnancy.
  • a subject is considered to be “undergoing” an embryo transfer procedure if the subject is (i) currently preparing for embryo transfer, e.g., by taking medication that stimulates follicular maturation and/or that promotes the ability of the endometrium to receive a transferred embryo, (ii) in the process of physically being transferred one or more embryos, or (iii) has undergone an embryo transfer procedure and is still clinically pregnant.
  • subjects that are “preparing for embryo transfer” include subjects that are receiving, or that have recently received, one or more therapeutic agents designed to promote follicular maturation, such as human chorionic gonadotropin (hCG). Additional examples of subjects that are “preparing for embryo transfer” include subjects that are in the process of oocyte retrieval, as well as subjects that are receiving luteal phase support following oocyte retrieval, for example, with the aim of improving the endometrial condition so as to improve the likelihood of a successful embryo implantation.
  • therapeutic agents designed to promote follicular maturation such as human chorionic gonadotropin (hCG).
  • hCG human chorionic gonadotropin
  • luteal phase support refers to administration of a progestin or progesterone to a subject undergoing embryo transfer therapy with the aim of enhancing the quality of the endometrium, for example, prior to the transfer of one or more embryos to the uterus of the subject.
  • exemplary luteal phase supports useful in conjunction with the compositions and methods of the disclosure include periodic administration of progesterone (e.g., intravaginally) starting within 24-48 hours of oocyte retrieval.
  • endogenous describes a molecule (e.g., a polypeptide, nucleic acid, or cofactor) that is found naturally in a particular organism (e.g., a human) or in a particular location within an organism (e.g., an organ, a tissue, or a cell, such as a human cell).
  • a particular organism e.g., a human
  • a particular location within an organism e.g., an organ, a tissue, or a cell, such as a human cell.
  • the term “endometrial receptivity” refers to the ability of the uterus to provide optimal conditions to promote proper implantation and development of an embryo, such as an embryo produced ex vivo by in vitro fertilization of, or intracytoplasmic sperm injection into, an ovum (e.g., an ovum obtained directly from a subject undergoing an embryo transfer procedure therapy or by maturation of one or more oocytes obtained from a subject undergoing an embryo transfer procedure, or an ovum obtained directly from a donor not undergoing an embryo transfer procedure or by maturation of one or more oocytes obtained from a donor not undergoing an embryo transfer procedure).
  • an ovum e.g., an ovum obtained directly from a subject undergoing an embryo transfer procedure therapy or by maturation of one or more oocytes obtained from a subject undergoing an embryo transfer procedure, or an ovum obtained directly from a donor not undergoing an embryo transfer procedure or by maturation of one or more oocytes obtained from a donor not
  • Exemplary factors that contribute to a subject’s level of endometrial receptivity include uterine perfusion and uterine contractility. Without being limited by mechanism, heightened uterine blood flow can augment the ability of the endometrium to successfully receive a transferred embryo in a manner conducive to implantation.
  • Another factor that contributes to a subject’s level of endometrial receptivity is uterine contractility. Uterine contractions occurring at the time of embryo transfer can serve to expel a transferred embryo. Thus, high endometrial receptivity may be achieved when a subject’s uterine contractility is low.
  • Endometrial receptivity may be enhanced (i.e., increased) using the compositions and methods described herein, for instance, by administration of an oxytocin receptor antagonist to a subject undergoing embryo transfer therapy prior to, concurrently with, and/or following the transfer of one or more embryos to the subject.
  • Enhanced endometrial receptivity may manifest clinically in one or more ways.
  • a subject exhibiting enhanced endometrial receptivity e.g., in response to treatment with an oxytocin receptor antagonist prior to, concurrently with, and/or following the transfer of one or more embryos to the subject
  • PPF2a prostaglandin F2a
  • a subject can be determined to exhibit enhanced endometrial receptivity in response to oxytocin receptor antagonist administration if the subject demonstrates a reduced concentration of one or more secondary messengers involved in PGF2a signal transduction, such as diacylglycerol (DAG), inositol-1 ,4,5-trisphosphate (IP3), and/or intracellular calcium (Ca 2+ ) released from Ca 2+ stores, such as sarcoplasmic reticula.
  • DAG diacylglycerol
  • IP3 inositol-1 ,4,5-trisphosphate
  • Ca 2+ intracellular calcium released from Ca 2+ stores
  • a subject can be determined to exhibit enhanced endometrial receptivity in response to oxytocin receptor antagonist treatment as described herein by detecting a decrease in the concentration of one or more of the foregoing secondary messengers in a tissue sample, cell sample, or blood sample isolated from the subject’s endometrium and/or myometrium of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, or more, relative to a measure of the secondary messenger prior to administration of the oxytocin receptor antagonist.
  • Enhanced endometrial receptivity in a subject undergoing embryo transfer therapy can also be observed by assessing the ability of the subject to sustain pregnancy for a period of time following embryo transfer to the uterus of the subject.
  • a subject exhibiting enhanced endometrial receptivity in response to oxytocin receptor antagonist therapy may sustain pregnancy for at least 14 days following transfer of one or more embryos to the subject, as assessed, for instance, by a blood pregnancy test, such as by detecting the presence and/or quantity of human chorionic gonadotropin (hCG) in a blood sample isolated from the subject using hCG tests known in the art and/or described herein.
  • hCG human chorionic gonadotropin
  • a subject exhibiting enhanced endometrial receptivity in response to oxytocin receptor antagonist therapy may sustain pregnancy for at least 6 weeks, such as for 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, or 40 weeks, following transfer of one or more embryos to the subject and/or following the retrieval of one or more oocytes or ova from the subject, as assessed, for instance, by detecting intrauterine embryo heartbeat.
  • a subject exhibiting enhanced endometrial receptivity in response to oxytocin receptor antagonist therapy may give birth to a live offspring at a gestational age of at least 24 weeks, for instance, at a gestational age of 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, or 40 weeks.
  • exogenous describes a molecule (e.g., a polypeptide, nucleic acid, or cofactor) that is not found naturally in a particular organism (e.g., a human) or in a particular location within an organism (e.g., an organ, a tissue, or a cell, such as a human cell).
  • Exogenous materials include those that are provided from an external source to an organism or to cultured matter extracted there from.
  • the term “gestational age” describes how far along a particular pregnancy is, and is measured from the first day of a pregnant female subject's last menstrual cycle to the current date.
  • the term “labor” (which may also be termed birth) relates to the expulsion of the fetus and placenta from the uterus of a pregnant female subject.
  • labor may occur at a gestational age of about 40 weeks.
  • Preterm labor refers to a condition in which labor commences more than three weeks before the full gestation period, which is typically about 40 weeks. That is, preterm labor occurs at any stage prior to, e.g., 38 weeks of gestation.
  • Preterm labor typically leads to the occurrence of labor, or physiological changes associated with labor in a pregnant female subject, if not treated.
  • Preterm labor may or may not be associated with vaginal bleeding or rupture of uterine membranes.
  • Preterm labor may also be referred to as premature labor.
  • the avoidance of preterm labor in a subject will prolong the term of pregnancy and may therefore avoid preterm delivery, thus reducing the risk of neonatal mortality and morbidity.
  • GnRH antagonist refers to a compound capable of inhibiting the gonadotropin-releasing hormone receptor, e.g., such that release of one or more gonadotropins (such as follicle stimulating hormone and luteinizing hormone) is inhibited.
  • GnRH antagonists include 2-phenylethylpyrimidine-2,4(1 H,3H)-dione derivatives, such as those described in US Patent Nos. 7,056,927; 7,176,21 1 ; and 7,419,983; the disclosures of each of which are incorporated herein by reference in their entirety.
  • Exemplary GnRH antagonists include elagolix, relugolix, ASP-1707, and SKI2670, among others.
  • ICso refers to the concentration of a substance (antagonist) that reduces the efficacy of a reference agonist or the constitutive activity of a biological target by 50%, for instance, as measured in a competitive ligand binding assay or in a cell-based functional assay, such as a Ca 2+ mobilization assay.
  • exemplary Ca 2+ mobilization assays that can be used to determine the IC50 of oxytocin receptor antagonist include fluorimetric imaging assays, such as those described in US Patent No. 9,670,155, the disclosure of which is incorporated herein by reference in its entirety.
  • the term “in vitro fertilization” refers to a process in which an ovum, such as a human ovum, is contacted ex vivo with one or more sperm cells so as to promote fertilization of the ovum and zygote formation.
  • the ovum can be derived from a subject, such as a human subject, undergoing embryo transfer therapy.
  • the ovum may be obtained from maturation of one or more oocytes isolated from the subject, e.g., from about 1 day to about 7 days prior to embryo transfer to the subject (such as from about 3 days to about 5 days prior to embryo transfer to the subject).
  • the ovum may also be retrieved directly from the subject, for instance, by transvaginal ovum retrieval procedures known in the art.
  • the ovum may be derived or isolated from a donor.
  • ICSI intracytoplasmic sperm injection
  • a sperm cell is injected directly into an ovum, such as a human ovum, so as to promote fertilization of the ovum and zygote formation.
  • the sperm cell may be injected into the ovum, for instance, by piercing the oolemma with a microinjector so as to deliver the sperm cell directly to the cytoplasm of the ovum.
  • the term “miscarriage” refers to a naturally-occurring, spontaneous termination of a pregnancy at a stage in which the embryo or fetus is incapable of surviving independently of the mother.
  • an embryo or fetus may be incapable of surviving independently of the mother at a gestational age of less than about 20 weeks (e.g., a gestational age of less than about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks).
  • oral bioavailability refers to the fraction of a compound administered to a subject, such as a mammal (e.g., a human) that reaches systemic circulation in the subject, and that is not sequestered in a non-target organ or excreted without absorption via the gastrointestinal tract.
  • the term refers to a blood plasma concentration that is integrated over time and is typically expressed as a percentage of the orally administered dose.
  • ovum and “mature oocyte” refer to a mature haploid female reproductive cell or gamete.
  • ova may be produced ex vivo by maturation of one or more oocytes isolated from a subject undergoing embryo transfer therapy. Ova may also be isolated directly from the subject, for example, by transvaginal ovum retrieval methods described herein or known in the art.
  • oxygen receptor antagonist As used herein, the terms “oxytocin receptor antagonist,” “OTR antagonist,” “oxytocin antagonist,” and the like are used interchangeably and refer to a compound capable of inhibiting the oxytocin receptor, for example, such that activity of one or more downstream signaling molecules in the oxytocin signal transduction cascade is inhibited.
  • Oxytocin receptor antagonists for use with the compositions and methods described herein include (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1 , 1 '-biphenyl-4- yl)carbonyl]pyrrolidin-3-one O-methyloxime.
  • the term “pharmaceutical composition” refers to a mixture containing a therapeutic compound, such as an oxytocin receptor antagonist described herein, to be administered to a subject, such as a mammal, e.g., a human, in order to prevent, treat or control a particular disease or condition affecting or that may affect the mammal, such as to reduce the likelihood of embryo implantation failure in a subject undergoing embryo transfer therapy.
  • a therapeutic compound such as an oxytocin receptor antagonist described herein
  • the term “pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms, which are suitable for contact with the tissues of a subject, such as a mammal (e.g., a human) without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
  • PGF2a signaling refers to the endogenous signal transduction cascade by which PGF2a potentiates the intracellular activity of the PGF2a receptor so as to effect one or more biological responses.
  • PGF2a signaling encompasses the PGF2a-mediated stimulation of the PGF2a receptor (FP), a G protein-coupled receptor, which leads to the activation of the G q protein and, in turn phospholipase C (PLC), phosphatidylinositol-3-kinase (PI3K), and extracellular signal-regulated kinases (ERK) 1 and 2.
  • PLC phospholipase C
  • PI3K phosphatidylinositol-3-kinase
  • ERK extracellular signal-regulated kinases
  • PGF2a signaling can be detected by observing an increase in the concentration of phosphatidylinsolitol-4,5-bisphosphate (PIP2) and/or a decrease in the concentration of one or more secondary messengers involved in PGF2a signal transduction, such as diacylglycerol (DAG), inositol-1 ,4,5-trisphosphate (IP3), and/or intracellular calcium (Ca 2+ ) released from Ca 2+ stores, such as sarcoplasmic reticula.
  • PIP2a phosphatidylinsolitol-4,5-bisphosphate
  • PGF2a signal transduction cascade is described in detail, for instance, in Xu et al., Reproduction 149:139-146 (2015), the disclosure of which is incorporated herein by reference as it pertains to the proteins and messengers involved in PGF2a signaling.
  • sample refers to a specimen (e.g., blood, blood component (e.g., serum or plasma), urine, saliva, amniotic fluid, cerebrospinal fluid, tissue (e.g., placental or dermal), pancreatic fluid, chorionic villus sample, and/or cells) isolated from a subject.
  • a specimen e.g., blood, blood component (e.g., serum or plasma), urine, saliva, amniotic fluid, cerebrospinal fluid, tissue (e.g., placental or dermal), pancreatic fluid, chorionic villus sample, and/or cells
  • the phrases “specifically binds” and “binds” refer to a binding reaction which is determinative of the presence of a particular protein in a heterogeneous population of proteins and other biological molecules that is recognized, e.g., by a ligand with particularity.
  • a ligand e.g., a protein, peptide, or small molecule
  • a ligand that specifically binds to a protein will bind to the protein, e.g., with a KD of less than 100 nM.
  • a ligand that specifically binds to a protein may bind to the protein with a KD of up to 100 nM (e.g., between 1 pM and 100 nM).
  • a ligand that does not exhibit specific binding to a protein or a domain thereof may exhibit a KD of greater than 100 nM (e.g., greater than 200 nM, 300 nM, 400 nM, 500 nM, 600 nm, 700 nM, 800 nM, 900 nM, 1 pM, 100 pM, 500 pM, or 1 mM) forthat particular protein or domain thereof.
  • KD KD of greater than 100 nM (e.g., greater than 200 nM, 300 nM, 400 nM, 500 nM, 600 nm, 700 nM, 800 nM, 900 nM, 1 pM, 100 pM, 500 pM, or 1 mM) forthat particular protein or domain thereof.
  • assay formats may be used to determine the affinity of a ligand for a specific protein. For example, solid-phase ELISA assays are routinely used to identify ligands that specifically bind a target
  • the terms “subject” and “patient” are interchangeable and refer to an organism that receives treatment for a particular disease or condition as described herein.
  • subjects and patients include mammals, such as humans, such as those undergoing embryo transfer therapy and are to receive medication so as to improve endometrial receptivity, reduce the likelihood of embryo implantation failure, or otherwise improve the likelihood of achieving and maintaining pregnancy.
  • substantially pure refers to a compound that has a purity of at least 85%, as assessed, for instance, using nuclear magnetic resonance (NMR) and/or high-performance liquid chromatography (HPLC) techniques described herein or known in the art.
  • NMR nuclear magnetic resonance
  • HPLC high-performance liquid chromatography
  • tmax refers to the time following administration of a compound to a subject at which the compound exhibits a maximum concentration in the blood (e.g., serum or plasma) of the subject.
  • a compound, salt form, crystal polymorph, therapeutic agent, or other composition described herein may be referred to as being characterized by graphical data “substantially as depicted in” a figure.
  • Such data may include, without limitation, powder X-ray diffractograms, NMR spectra, differential scanning calorimetry curves, and thermogravimetric analysis curves, among others.
  • graphical data may provide additional technical information to further define the compound, salt form, crystal polymorph, therapeutic agent, or other composition.
  • such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity.
  • a crystal form of (3Z,5S)-5- (hydroxymethyl)-1-[(2'-methyl-1 ,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime referred to herein as being characterized by graphical data "substantially as depicted in" a figure will thus be understood to include any crystal form of (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1 , 1 '-biphenyl-4- yl)carbonyl]pyrrolidin-3-one O-methyloxime characterized by the graphical data, optionally having one or more of small variations, e.g., one or more variations described above or known to one of skill in the art.
  • the terms “treat” or “treatment” in the context of a subject undergoing embryo transfer therapy refer to treatment, for instance, by administration of an oxytocin receptor antagonist, with the intention of enhancing endometrial receptivity thereby reducing the likelihood of embryo implantation failure and promoting pregnancy in the subject.
  • Those in need of treatment include, for example, female mammalian subjects, such as female human subjects, that are undergoing embryo transfer therapy, such as subjects undergoing oocyte or ovum retrieval followed by in vitro fertilization or intracytoplasmic sperm injection and subsequent embryo transfer.
  • Those in need of treatment also include, for example, female mammalian subjects, such as female human subjects, that are undergoing embryo transfer therapy, for example, using embryos produced ex vivo by in vitro fertilization or intracytoplasmic sperm injections of one or more ova derived from a donor (e.g., isolated directly from a donor by transvaginal ovum retrieval or by maturation of one or more oocytes obtained directly from the donor).
  • the subject may be undergoing fresh embryo transfer or frozen embryo transfer, and may be transferred, for instance, one, two, three, or more embryos according to the methods described herein.
  • the subject may be one that has previously undergone embryo transfer therapy, either successfully or unsuccessfully, including subjects that have previously undergone one or more cycles (for instance, one, two, three, four, five, six, seven, eight, nine, ten, or more cycles) of failed embryo transfer therapy.
  • a subject can be considered to have been treated, for instance, by administration of an oxytocin receptor antagonist according to the methods described herein, if the subject exhibits one or more beneficial outcomes following administration of the oxytocin receptor antagonist.
  • beneficial outcomes that are indicative of treatment include an increase in the subject’s endometrial perfusion, a reduction in the subject’s uterine contractility, increase in the subject’s endometrial receptivity toward a transferred embryo, a reduction in the likelihood of embryo implantation failure, the prevention of a miscarriage, and the achievement and maintenance of a successful pregnancy, for example, until delivery at a full gestational age, in a subject following transfer of one or more embryos to the subject.
  • endometrial receptivity can be observed in a variety of clinical manifestations, including a reduction in prostaglandin F2a (PGF2a) signal transduction following oxytocin receptor antagonist administration, successful implantation of the embryo into the endometrium of the subject, as well as the subject’s capacity to achieve and sustain pregnancy following embryo transfer, such as for about 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, or more, following the transfer of one or more embryos to the subject and
  • unit dosage form refers to a single, discrete composition containing a therapeutic agent, such as an oxytocin receptor antagonist described herein, formulated in a manner appropriate for administration to a subject, such as a subject undergoing embryo transfer therapy as described herein.
  • Unit dosage forms include solid and liquid formulations, such as tablets (e.g., dispersible tablets), capsules, gel caps, powders, liquid solutions, liquid suspensions, granulate, microemulsion, and self-emulsifying dispersed system.
  • a subject may be administered a single dose of a therapeutic agent by administration of one or more unit dosage forms.
  • a single dose of 100 mg of a therapeutic agent can be administered using two 50 mg unit dosage forms of the therapeutic agent.
  • uterine contractility refers to a measurement of the frequency and/or amplitude of uterine contractions that a subject exhibits at a particular time. Uterine contractility can be measured, for example, by assessing the quantity of uterine contractions that the subject exhibits over a certain time period; this is the frequency of the subject’s uterine contractions. Another measure of uterine contractility is the work done by one or more uterine contractions that the subject exhibits. Methods of measuring uterine contractility are described, for example, in US Patent No. 9,670,155, the disclosure of which is incorporated herein by reference.
  • polystyrene resin refers to a non-ionic triblock copolymer composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene. Poloxamers are also known by the trade name of "Pluronics” or “Synperonics” (BASF).
  • the block copolymer can be represented by the following formula: HO(C2H4O) x (C3H6O) y (C2H4O)zH.
  • the lengths of the polymer blocks can be customized. As a result, many different poloxamers exist.
  • Poloxamers suitable for use in conjunction with the compositions and methods of the present disclosure include those having an average molecular weight of at least about 7,000 g/mol. Since the synthesis of block copolymers is associated with a natural degree of variation from one batch to another, the numerical values recited above (and those used herein to characterize a given poloxamer) may not be precisely achievable upon synthesis, and the average value will differ to a certain extent. Thus, the term "poloxamer” as used herein can be used interchangeably with the term “poloxamers” (representing an entity of several poloxamers, also referred to as mixture of poloxamers) if not explicitly stated otherwise.
  • the term “pseudopolymorph” refers to a crystalline form of a therapeutic agent which incorporates or introduces an additional molecule.
  • the additional molecule may be, e.g., an excipient (e.g., a poloxamer), solvent, or water.
  • the term “complex” refers to a crystalline form that is associated with an additional molecular entity (e.g., an excipient, such as a poloxamer).
  • an additional molecular entity e.g., an excipient, such as a poloxamer.
  • the bonding between the components is normally weaker than in a covalent bond.
  • crystalline Form B and “Form B” are used interchangeably and refer to a solid form of compound (I) and Poloxamer 188 having one or more, or all, of the characteristic X-ray powder diffraction peaks as set forth in Table 1 .
  • crystalline Form B is a co-crystal of compound (I) and Poloxamer 188.
  • crystalline Form B is a pseudopolymorph, having a crystal lattice of compound (I) incorporated with Poloxamer 188.
  • the crystalline Form B is a complex of an anhydrous crystal lattice of compound (I), in association with Poloxamer 188.
  • Crystalline Form B is characterized by one or more of the XRPD spectrum as shown in FIG. 5A, the DSC curve substantially as depicted in FIG. 5F, the 1 H NMR spectrum substantially as depicted in FIG. 5B, the TGA curve substantially as depicted in FIG. 5G, the DVS curve substantially as depicted in FIG. 5H, and the Raman curve substantially as depicted in FIG. 5I or FIG. 5J. Crystalline Form B is further characterized in Examples 2-4, below.
  • Crystalline Form A and “Form A” are used interchangeably and refer to a solid form of anhydrous compound (I) having one or more, or all, of the characteristic X-ray powder diffraction peaks as set forth in Table 2.
  • Crystalline Form A is characterized by one or more of the XRPD spectrum as shown in FIG. 1A, the DSC curve substantially as depicted in FIG. 1 B or FIG. 1C, the TGA curve substantially as depicted in FIG. 1 D or 1 E, and the DVS curve substantially as depicted in FIG. 1 F. Crystalline Form A is further characterized in Examples 1 and 4, below.
  • FIG. 1 A is an X-ray powder diffractogram (XRPD) for crystalline Form A of compound (I). Experiments were performed as described in Example 1 .
  • FIG. 1B is an exemplary differential scanning calorimetry (DSC) curve for crystalline Form A of compound (I) prepared by crystallization from diethyl ether. Experiments were performed as described in Example 1 .
  • FIG. 1C is an exemplary DSC curve for crystalline Form A of compound (I) prepared by crystallization from ethyl acetate. Experiments were performed as described in Example 1.
  • FIG. 1D is an exemplary thermogravimetric analysis (TGA) curve for crystalline Form A of compound (I) prepared by crystallization from diethyl ether. Experiments were performed as described in Example 1 .
  • FIG. 1 E is an exemplary TGA curve for crystalline Form A of compound (I) prepared by crystallization from ethyl acetate. Experiments were performed as described in Example 1.
  • FIG. 1 F is an exemplary dynamic vapor sorption (DVS) curve for crystalline Form A of compound (I) prepared by crystallization from diethyl ether. Experiments were performed as described in Example 1.
  • FIGS. 2A-2P are XRPD spectra showing attempted crystallization of compound (I) in combination with various excipients. Experiments were performed as described in Example 2. Attempts to crystallize compound (I) from ethanol in the presence of calcium silicate, glyceryl dibehenate, povidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, saccharin sodium dihydrate, or sodium croscarmellose were unsuccessful. XRPD patterns of the resulting materials were consistent with the excipient or mixtures of amorphous compound (I) and the excipient.
  • FIG. 3A is an XRPD overlay of crystalline Form B and Form A. Experiments were performed as described in Example 2.
  • FIG. 3B is an XRPD overlay of crystalline Form B, Poloxamer 188, and amorphous compound (I). Experiments were performed as described in Example 2.
  • FIGS. 4A-4Q are XRPD spectra showing formation of crystalline Form B under various conditions. Experiments were performed as described in Example 2.
  • FIG. 5A is an XRPD of crystalline Form B. Experiments were performed as described in Example 3.
  • FIGS. 5B-5E show an exemplary proton NMR spectrum of crystalline Form B. Experiments were performed as described in Example 3.
  • FIG. 5F is an exemplary DSC curve of crystalline Form B. Experiments were performed as described in Example 3.
  • FIG. 5G is an exemplary TGA curve of crystalline Form B. Experiments were performed as described in Example 3.
  • FIG. 5H is an exemplary DVS curve of crystalline Form B. Experiments were performed as described in Example 3.
  • FIGS. 5I-5J are exemplary Raman spectra of crystalline Form B. Experiments were performed as described in Example 3.
  • FIG. 6 is a pH solubility profile of crystalline Form B after stirring at 25°C for 24 hours. Experiments were performed as described in Example 4.
  • FIG. 7A is an intrinsic dissolution rate (IDR) profile overlay of amorphous compound (I), crystalline Form A, crystalline Form B, and compound (I) in crystalline Form B in water. Experiments were performed as described in Example 4.
  • FIG. 7B is an IDR profile overlay of amorphous compound (I) and crystalline Form A in pH 7 phosphate buffer. Experiments were performed as described in Example 4.
  • FIGS. 8A-8J are XRPD of recovered solids following solubility experiments, compression experiments, and IDR experiments with amorphous compound (I) (FIGS. 8A-8C), crystalline Form A (FIGS. 8D-8G), and crystalline Form B (FIGS. 8H-8J). Experiments were performed as described in Example 4.
  • FIG. 9 is a DSC thermogram overlay of crystalline Form B and crystalline Form A. Experiments were performed as described in Example 4.
  • compositions and methods that can be used to treat a subject (e.g., a female human subject) undergoing embryo transfer procedures.
  • exemplary responses to oxytocin receptor antagonist treatment include reduced uterine contractility and enhanced blood flow to the endometrium. Collectively, these phenotypes contribute to a subject’s endometrial receptivity toward a transferred embryo.
  • an oxytocin receptor antagonist administered to a subject using the compositions and methods described herein may enhance uterine perfusion and suppress uterine contractions that could otherwise lead to embryo expulsion, ultimately serving to create an environment within the endometrium that is conducive to successful embryo implantation and the establishment and maintenance of a healthy pregnancy.
  • the disclosure features crystalline forms of the oxytocin receptor antagonist, (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1 ,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (I), below.
  • an oxytocin receptor antagonist such as a crystalline form of compound (I)
  • a subject such as a mammalian subject (e.g., a female human subject) in order to promote enhanced endometrial receptivity, reduce the likelihood of embryo implantation failure, and/or prevent miscarriage in a subject following the transfer of one or more embryos to the uterus of the subject.
  • the subject may be one that has previously undergone one or more successful or unsuccessful embryo implantation procedures. Alternatively, the subject may be one that has not undergone a previous embryo transfer cycle.
  • the one or more embryos that are ultimately transferred to the subject can be obtained, for instance, by in vitro fertilization (IFV) or intracytoplasmic sperm injection (ICSI) of an ovum isolated or derived from the subject or from a donor.
  • IVF in vitro fertilization
  • ICSI intracytoplasmic sperm injection
  • the ovum may be isolated from the subject directly or may be produced ex vivo by inducing maturation of one or more oocytes isolated from the subject.
  • the subsequently formed zygote can be matured ex vivo so as to produce an embryo, such as a morula or blastula (e.g., a mammalian blastocyst), which can then be transferred to the uterus of the subject for implantation into the endometrium.
  • Embryo transfers that can be performed using the methods described herein include fresh embryo transfers, in which the ovum or oocyte used for embryo generation is retrieved from the subject and the ensuing embryo is transferred to the subject during the same menstrual cycle. The embryo can alternatively be produced and cryopreserved for long-term storage prior to transfer to the subject.
  • Compound (I) ((3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1 ,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3- one O-methyloxime) is a non-peptide oxytocin receptor antagonist that can be used to enhance endometrial receptivity, promote successful embryo implantation, and reduce the likelihood of miscarriage in subjects undergoing or that have undergone embryo transfer therapy.
  • Compound (I) is an orally-active oxytocin receptor antagonist capable of inhibiting human oxytocin receptor with a Ki of 52 nM and suppressing Ca 2+ mobilization in cultured HEK293EBNA cells with an IC50 of 81 nM. Additionally, compound (I) selectively inhibits the oxytocin receptor over the vasopressin Via receptor, as compound (I) inhibits the vasopressin Via receptor with a Ki of 120 nM.
  • the compound represented by formula (I) i.e., (3Z,5S)-5-(hydroxymethyl)- 1-[(2'-methyl-1 ,1 '-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime) is substantially pure.
  • the compound represented by formula (I) has a purity of at least 85%, such as a purity of from 85% to 99.9% or more (e.g., a purity of 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1 %, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or more).
  • a purity of at least 85% such as a purity of from 85% to 99.9% or more (e.g., a purity of 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1 %, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or more).
  • the purity of the compound represented by formula (I) may be assessed, for instance, using NMR techniques and/or chromatographic methods, such as HPLC procedures, that are known in the art and described herein, such as those techniques that are described in US Patent No. 9,670,155, the disclosure of which is incorporated herein by reference in its entirety.
  • the compound represented by formula (I) is substantially pure with respect to diastereomers of this compound and other by-products that may be formed during the synthesis of this compound.
  • the compound represented by formula (I) has a purity of at least 85%, such as a purity of from 85% to 99.9% or more (e.g., a purity of 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or more) with respect to diastereomers of this compound and other by-products that may be formed during the synthesis of this compound.
  • the purity of the compound represented by formula (I) may be assessed, for instance, using NMR techniques and/or chromatographic methods, such as HPLC procedures, that are known in the art and described herein, such as those techniques that are described in US Patent No. 9,670,155.
  • the compound represented by formula (I) is substantially pure with respect to its (3E) diastereomer, (3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1 , 1 '-biphenyl-4- yl)carbonyl]pyrrolidin-3-one O-methyloxime.
  • compound (I) may be administered in the form of a composition (e.g., a tablet, such as a dispersible tablet, capsule, gel cap, powder, liquid solution, liquid suspension, granulate, microemulsion, or selfemulsifying dispersed system) that contains less than 15% of the (3E) diastereomer.
  • a composition e.g., a tablet, such as a dispersible tablet, capsule, gel cap, powder, liquid solution, liquid suspension, granulate, microemulsion, or selfemulsifying dispersed system
  • the purity of the compound represented by formula (I) may be assessed, for instance, using NMR techniques and/or chromatographic methods, such as HPLC procedures, that are known in the art and described herein, such as those techniques that are described in US Patent No. 9,670,155.
  • the present disclosure is based in part on the discovery of crystalline forms of compound (I), and the characterization of their ability to promote successful endometrial implantation of a transferred embryo in female human subjects.
  • Compound (I) has been found to reduce the risk of embryo implantation failure in clinical studies conducted with human subjects that previously underwent ovarian hyperstimulation and oocyte retrieval. It has been discovered that compound (I) increases the rate of successful embryo implantation as assessed by a variety of metrics. These manifestations have been found to include an increase in the rate of positive pregnancy tests at 14 days, 6 weeks, and 10 weeks following embryo transfer and/or oocyte retrieval, as well as an increase in the rate of live births at a gestational age of at least 24 weeks.
  • compound (I) is particularly effective at enhancing endometrial receptivity by multiple modes of action.
  • compound (I) has been discovered to reduce uterine contractility and augment the flow of blood to the endometrium. These effects provide important therapeutic benefits to patients undergoing embryo transfer therapy.
  • the reduced uterine contractile activity and enhanced endometrial perfusion engendered by compound (I) create an environment in the uterus that is conducive to successful embryo implantation. Without being limited by mechanism, these biological activities represent ways in which compounds of the disclosure may reduce the likelihood of embryo implantation failure and of miscarriage.
  • a subject undergoing embryo transfer therapy or a donor may be prepared for ovum or oocyte retrieval by controlled ovarian hyperstimulation, for instance, according to methods described herein or known in the art.
  • a subject or donor may be administered a GnRH antagonist so as to prevent a premature increase in the serum concentration of luteinizing hormone (LH).
  • final follicular maturation can be achieved by administration of hCG to the subject or donor prior to isolation of the one or more ova or oocytes.
  • the hCG can be administered to the subject in a single dose or in multiple doses, for instance, by intravenous injection according to procedures known in the art.
  • Embryos for use in conjunction with the compositions and methods described herein include those that are at, for example, the morula or the blastula stage of embryonic development.
  • embryos that may be transferred to a subject as described herein include those that contain from 6 to 8 blastomeres immediately prior to transfer of the one or more embryos to the subject.
  • the blastomeres may be of approximately equal sizes as assessed by visual microscopy prior to the transfer of the one or more embryos to the subject.
  • Embryos for use in conjunction with the compositions and methods described herein include those that are formed, for instance, by IVF or ICSI methods known in the art.
  • the embryos are freshly transferred to the uterus of the subject, for instance, from about 1 day to about 7 days (e.g., from about 2 days to about 5 days) following the isolation of one or more oocytes or ova from the subject for IVF or ICSI.
  • the one or more embryos are frozen and cryopreserved for long-term storage prior to thaw and transfer to the subject.
  • Techniques for assessing pregnancy for use in conjunction with the compositions and methods described herein include qualitative and quantitative assessments of a sample isolated from a subject, such as a sample of blood or urine.
  • Methods for assessing pregnancy include detecting the presence and/or quantity of hCG in a sample isolated from a subject. This can be achieved, for instance, using conventional receptor-ligand binding assays known in the art, such as through the use of competitive radioligand binding assays, which are described for the detection of hCG in US Patent No. 4,094,963, the disclosure of which is incorporated herein by reference as it pertains to methods of detecting hCG in subject samples to assess pregnancy. Additionally or alternatively, test strips may be used to determine hCG concentrations, as described, for instance, in US Patent No.
  • pregnancy may be assessed by detecting intrauterine heartbeat, such as the heartbeat of the embryo or developing fetus following successful embryo implantation.
  • intrauterine heartbeat such as the heartbeat of the embryo or developing fetus following successful embryo implantation.
  • Compositions and methods for detecting embryonic and fetal heartbeat are known in the art and are described, for instance, in US Patent Nos. 3,780,725 and 4,437,467, the disclosures of each of which are incorporated herein by reference as they pertain to methods of detecting heartbeat to assess pregnancy in a subject.
  • the present disclosure features crystalline forms of compound (I).
  • the crystalline form may be a solid form of compound (I) and a poloxamer.
  • Exemplary poloxamers are provided in the section that follows.
  • Poloxamers that may be used in conjunction with the compositions and methods of the disclosure include those having an average molar mass of polyoxypropylene subunits of greater than 1 ,600 g/mol (e.g., an average molar mass of polyoxypropylene subunits of about 1 ,700 g/mol, 1 ,800 g/mol, 1 ,900 g/mol, 2,000 g/mol, 2,100 g/mol, 2,200 g/mol, 2,300 g/mol, 2,400 g/mol, 2,500 g/mol, 2,600 g/mol, 2,700 g/mol, 2,800 g/mol, 2,900 g/mol, 3,000 g/mol, 3,100 g/mol, 3,200 g/mol, 3,300 g/mol, 3,400 g/mol, 3,500 g/mol, 3,600 g/mol, 3,700 g/mol, 3,800 g/mol, 3,900 g/mol, 4,000 g/mol, 4,100 g/mol, 4,200
  • the poloxamer has an average molar mass of polyoxypropylene subunits of from about 1 ,600 g/mol to about 4,000 g/mol (e.g., about 1 ,600 g/mol, about 1 ,650 g/mol, about 1 ,700 g/mol, about 1 ,750 g/mol, about 1 ,800 g/mol, about 1 ,850 g/mol, about 1 ,900 g/mol, about 1 ,950 g/mol, about 2,000 g/mol, about 2,050 g/mol, 2,100 g/mol, 2,150 g/mol, 2,200 g/mol, 2,250 g/mol, 2,300 g/mol,
  • the poloxamer has an average molar mass of polyoxypropylene subunits of from about 1 ,600 g/mol to about 2,000 g/mol (e.g., about 1 ,600 g/mol, 1 ,650 g/mol, 1 ,700 g/mol, 1 ,750 g/mol, 1 ,800 g/mol, 1 ,850 g/mol, 1 ,900 g/mol, 1 ,950 g/mol, or 2,000 g/mol).
  • the poloxamer has an average molar mass of polyoxypropylene subunits of from about 1 ,700 g/mol to about 1 ,900 g/mol (e.g., about 1 ,700 g/mol, 1 ,710 g/mol, 1 ,720 g/mol, 1 ,730 g/mol, 1 ,740 g/mol, 1 ,750 g/mol, 1 ,760 g/mol, 1 ,770 g/mol, 1 ,780 g/mol, 1 ,790 g/mol, 1 ,800 g/mol, 1 ,810 g/mol, 1 ,820 g/mol, 1 ,830 g/mol, 1 ,840 g/mol, 1 ,850 g/mol, 1 ,860 g/mol, 1 ,870 g/mol, 1 ,880 g/mol, 1 ,890 g/mol, or 1 ,900 g/mol
  • the poloxamer has an average ethylene oxide content of greater than 40% by mass (e.g., about 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51 %, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, or more).
  • 40% by mass e.g., about 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51 %, 52%, 53%, 54%,
  • the poloxamer has an average ethylene oxide content of greater than 60% by mass (e.g., about 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, or more).
  • 60% by mass e.g., about 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %,
  • the poloxamer has an average ethylene oxide content of from about 40% to about 90% (e.g., about 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51 %, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90%).
  • the poloxamer has an average ethylene oxide content of from about 40% to about 90% (e.g., about 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51 %, 52%, 53%, 5
  • the poloxamer has an average ethylene oxide content of from about 70% to about 90% (e.g., about 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90%).
  • the poloxamer has an average molar mass of greater than 7,000 g/mol (e.g., about 7,100 g/mol, 7,200 g/mol, 7,300 g/mol, 7,400 g/mol, 7,500 g/mol, 7,600 g/mol, 7,700 g/mol, 7,800 g/mol, 7,900 g/mol, 8,000 g/mol, 8,100 g/mol, 8,200 g/mol, 8,300 g/mol, 8,400 g/mol, 8,500 g/mol, 8,600 g/mol, 8,700 g/mol, 8,800 g/mol, 8,900 g/mol, 9,000 g/mol, 9,100 g/mol, 9,200 g/mol, 9,300 g/mol, 9,400 g/mol, 9,500 g/mol, 9,600 g/mol, 9,700 g/mol, 9,800 g/mol, 9,900 g/mol, or 10,000 g/mol).
  • 7,000 g/mol e.g., about 7,
  • average molar mass and “average molecular weight” are used interchangeable herein to refer to the same quantity.
  • the average molar mass, ethylene oxide content, and propylene oxide content of a poloxamer, as described herein, can be determined using methods disclosed in Alexandridis and Hatton, Colloids and Surfaces A: Physicochemical and Engineering Aspects 96:1-46 (1995), the disclosure of which is incorporated herein by reference in its entirety.
  • the disclosure features a crystalline Form B, which is a solid form of compound (I) and Poloxamer 188, with a molar stoichiometry of approximately 100:1 compound (l):Poloxamer 188.
  • crystalline Form B is a co-crystal of compound (I) and Poloxamer 188.
  • crystalline Form B is a pseudopolymorph, having a crystal lattice of compound (I) incorporated with Poloxamer 188.
  • crystalline Form B is a complex of an anhydrous crystal lattice of compound (I), in association with Poloxamer 188.
  • Crystalline Form B has one or more, or all, of the characteristic X-ray powder diffraction peaks as set forth in Table 1 , below. Crystalline Form B is characterized by one or more of the XRPD spectrum as shown in FIG. 5A, the DSC curve substantially as depicted in FIG. 5F, the 1 H NMR spectrum substantially as depicted in FIG. 5B, the TGA curve substantially as depicted in FIG. 5G, the DVS curve substantially as depicted in FIG. 5H, and the Raman curve substantially as depicted in FIG. 5I or FIG. 5J.
  • Crystalline Form A is characterized by one or more of the XRPD spectrum as shown in FIG. 1A, the DSC curve substantially as depicted in FIG. 1 B or FIG. 1C, the TGA curve substantially as depicted in FIG. 1 D or 1 E, and the DVS curve substantially as depicted in FIG. 1 F.
  • the disclosure provides compound (I) (e.g., a crystalline form of compound (I) described herein) for use in any of the methods described herein.
  • the disclosure features a crystalline form of compound (I) described herein for use in a method of treating a subject undergoing an embryo transfer procedure, reducing the likelihood of embryo implantation failure in a subject undergoing an embryo transfer procedure, improving endometrial receptivity in a subject undergoing an embryo transfer procedure, and/or reducing uterine contractility in a subject undergoing an embryo transfer procedure.
  • the method may feature, for example, any one or more of the method steps recited herein.
  • the disclosure provides the use of compound (I) (e.g., a crystalline form of compound (I) described herein) in the manufacture of a medicament for performing any of the methods described herein.
  • compound (I) e.g., a crystalline form of compound (I) described herein
  • the disclosure features the use of a crystalline form of compound (I) described herein in the manufacture of a medicament for use in a method of treating a subject undergoing an embryo transfer procedure, reducing the likelihood of embryo implantation failure in a subject undergoing an embryo transfer procedure, improving endometrial receptivity in a subject undergoing an embryo transfer procedure, and/or reducing uterine contractility in a subject undergoing an embryo transfer procedure.
  • the method may feature, for example, any one or more of the method steps recited herein.
  • the present Example is directed towards preparation and characterization of crystalline Form A of compound (I).
  • FIGS. 1C and 1E are the DSC and TGA curves, respectively, obtained from testing this sample. Characterization data is presented in Table 3.
  • FIGS. 1B and 1D are the DSC and TGA curves, respectively, obtained from testing this sample. Characterization data is presented in Table 4. Table 4. Characterization data of crystalline Form A from diethyl ether
  • RT ambient temperature
  • vac vacuum
  • P-N Paratone-N (non-GMP). Reported times and temperatures are approximate; temperatures measured by NIST-traceable thermometer.
  • B birefringence
  • E extinction
  • singles sample contains crystal(s) which appeared suitable for submission for single crystal x-ray.
  • One such preparation involved adding 0.897 ml of diethyl ether to 240 mg of amorphous compound (I) and the mixture was left at ambient temperature for about 24 hours. The liquid was decanted and the solid transferred to a dry container to be air dried for 5 hours. The solid was then vacuum-dried for 20 hours at ambient temperature. The resulting solid was analyzed by XRPD and confirmed to be the crystalline compound. The XRPD pattern from this sample is shown in FIG. 1A.
  • the present Example is directed towards the screening and discovery of a novel crystalline form of compound (I).
  • VD Vapor Diffusion
  • XRPD pattern was collected with a PANalytical X'Pert PRO MPD or PANalytical Empyrean diffractometer using an incident beam of Cu radiation produced using a long, fine-focus source.
  • An elliptically graded multilayer mirror was used to focus Cu Ka X-rays through the specimen and onto the detector.
  • a silicon specimen NIST SRM 640e was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position.
  • a specimen of the sample was sandwiched between 3-pm-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, and antiscatter knife edge were used to minimize the background generated by air.
  • XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu Ka radiation produced using a long, fine-focus source and a nickel filter.
  • the diffractometer was configured using the symmetric Bragg-Brentano geometry.
  • a silicon specimen NIST SRM 640e was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position.
  • a specimen of the sample was prepared as a thin, circular layer centered on a silicon zero-background substrate.
  • Antiscatter slits (SS) were used to minimize the background generated by air.
  • Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence.
  • Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software v. 2.2b.
  • amorphous compound (I) was combined with various excipients.
  • the mixtures were evaporated from ethanol or ground with a small amount of aqueous ethanol with a mortar and pestle.
  • Generated materials were analyzed by XRPD, comparing the resulting XRPD patterns to known patterns of compound (I) and the excipients.
  • Attempts to crystallize compound (I) in the presence of calcium silicate, glyceryl dibehenate, povidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, saccharin sodium dihydrate, or sodium croscarmellose were also unsuccessful (Table 7 and FIGS. 2C-2P).
  • XRPD patterns of the resulting materials were consistent with the excipient or mixtures of amorphous compound (I) and the excipient. Table 7. Attempts to crystallize compound (I) in the presence of various excipients
  • Form B An exemplary XRPD overlay of the crystalline Form B and Form A is shown in FIG. 3A. Attempts with 9, 16, 19, 23, and 50 weight % Poloxamer 188 are summarized in Table 8 and FIGS. 4A-4Q.
  • Crystalline Form A can only be crystallized from ethyl acetate or diethyl ether (Example 1), which are less environmentally friendly solvents than ethanol, methanol, or water which may be used to produce crystalline Form B.
  • the ability of Form B to crystallize from more environmentally friendly solvents than Form A is a surprising advantage from the perspective of drugsubstance manufacturing processes.
  • the present Example is directed towards the characterization of crystalline Form B of compound (I).
  • Crystalline Form B was generated by combining amorphous compound (I) with 50 wt%
  • Poloxamer 188 and ground with a small amount of aqueous ethanol with a mortar and pestle. A large amount of Poloxamer 188 was utilized in an attempt to co-crystallize the entire amount of compound (I). Any excess polymer was removed though multiple water washes.
  • DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Temperature calibration was performed using octane, phenyl salicylate, indium, tin, and zinc. The sample was placed into a hermetically sealed aluminum DSC pan, the weight was accurately recorded, the lid was pierced, and the sample was inserted into the DSC cell. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The sample was analyzed from -30 °C to 250 °C at 10 °C/min.
  • Dynamic vapor sorption (DVS) data were collected on a Surface Measurement System DVS Intrinsic instrument. Samples were not dried prior to analysis. Sorption and desorption data were collected over a range from 5% to 95% RH at 10% RH increments under a nitrogen purge. The equilibrium criterion used for analysis was less than 0.0100% weight change in 5 minutes with a maximum equilibration time of 3 hours. Data were not corrected for the initial moisture content of the samples.
  • TG analysis was performed using a Mettler-Toledo TGA/DSC3+ analyzer. Temperature calibration was performed using calcium oxalate, indium, tin, and zinc.
  • the sample was placed in an aluminum pan. The pan was hermetically sealed, the lid pierced, then inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on the reference platform. The furnace was heated under nitrogen. The samples was analyzed from 25 °C to 350 °C at 10 °C/min.
  • XRPD pattern was collected with a PANalytical X'Pert PRO MPD or PANalytical Empyrean diffractometer using an incident beam of Cu radiation produced using a long, fine-focus source.
  • An elliptically graded multilayer mirror was used to focus Cu Ka X-rays through the specimen and onto the detector.
  • a silicon specimen NIST SRM 640e was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position.
  • a specimen of the sample was sandwiched between 3-pm-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, and antiscatter knife edge were used to minimize the background generated by air.
  • Soller slits for the incident and diffracted beams were used to minimize broadening and asymmetry from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b or 5.5.
  • X'Celerator scanning position-sensitive detector
  • XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu Ka radiation produced using a long, fine-focus source and a nickel filter.
  • the diffractometer was configured using the symmetric Bragg-Brentano geometry.
  • a silicon specimen NIST SRM 640e was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position.
  • a specimen of the sample was prepared as a thin, circular layer centered on a silicon zero-background substrate.
  • Antiscatter slits (SS) were used to minimize the background generated by air.
  • Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence.
  • Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software v. 2.2b.
  • FIG. 5A A representative XRPD spectrum of crystalline Form B is shown in FIG. 5A. Indexing results for crystalline Form B and Form A are summarized in Table 9. The space group was determined to be P3i. Form B has a longer c-axis and a larger unit cell volume than Form A. This indicates a different molecule packing and is manifest in the observation that the two polymorphs have distinct XRPD patterns.
  • FIGS. 5B-5E A representative proton NMR spectrum of crystalline Form B is shown in FIGS. 5B-5E and is consistent with a cocrystal of compound (I) and Poloxamer 188. Calculations based on the integration of the Poloxamer 188 peaks suggest a molar stoichiometry of approximately 100:1 compound (I) /Poloxamer 188. Residual ethanol is not evident in the spectrum.
  • FIGS. 5F-5G Representative thermograms of crystalline Form B are provided in FIGS. 5F-5G.
  • the DSC curve (FIG. 5F) exhibits a likely melt endotherm with an onset of 99 °C, followed by a decomposition exotherm at 237 °C (peak maximum). Negligible weight loss from 36 °C to 160 °C is observed by TGA (0.03% weight loss when heated from 36 °C -160 °C) (FIG. 5G), consistent with unsolvated material.
  • the DVS isotherm indicates crystalline Form B exhibits limited hygroscopicity (FIG. 5H).
  • a weight change of ⁇ 1 .7% was observed though the sorption/desorption cycle with no significant hysteresis.
  • a weight gain of 1 .65% was observed when the relative humidity was increased from 5% to 95%.
  • a weight loss of 1 .67% was observed when the relative humidity was decreased from 95% to 5%.
  • the material recovered from the DVS experiment remained crystalline Form B by XRPD.
  • the present Example is directed towards analyzing the comparative stability of the various crystal forms that compound (I) may adopt.
  • Comparative solubility studies may be used to evaluate the stability of compound (I) polymorphs.
  • a lower solubility is indicative of a higher thermodynamic stability. This coincides with the hypothesis that a lower stability crystalline form, having weaker lattice energy, is more easily solubilized and has a readily disrupted lattice structure. Thus, a polymorph having a lower solubility is likely to be able to withstand long-term storage without degradation.
  • the intrinsic dissolution rates may be measured, which is defined as the mass dissolved in unit time from a unit surface area.
  • IDR intrinsic dissolution rates
  • the IDR is proportional to the equilibrium solubility of the crystal. Therefore, a crystal form having a higher IDR, and therefore a higher solubility, is indicative of a lower thermodynamic stability. Accordingly, a crystalline form having a lower IDR is desirable for achieving superior stability.
  • Another comparison of the relative stabilities of the various crystal forms that compound (I) may adopt may be determined by investigating whether the integrity of the crystal lattice may be perturbed from prolonged exposure to water. For example, following solubility studies or IDR studies, the remaining excess solids may be isolated and analyzed by XRPD to determine whether the extended exposure to water has altered the crystal form. An unchanged XRPD spectrum following exposure to water indicates that the crystal form may be stored for long-term usage without being susceptible to water-induced degradation.
  • the relative stabilities of the various crystal forms that compound (I) may adopt may be assessed by comparing their susceptibility to hysteresis upon changes in humidity using dynamic vapor sorption (DVS) experiments.
  • Hysteresis which is a difference in water vapor uptake between sorption (increase in humidity) and desorption (decrease in humidity) cycles is indicative of structural changes upon exposure to water.
  • a further comparison of the relative stabilities of the various crystal forms that compound (I) may adopt may be determined through differential scanning calorimetry (DSC) experiments.
  • DSC permits the determination of the melting point of a crystal form, with a higher melting point indicative of higher thermal stability.
  • XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source.
  • An elliptically graded multilayer mirror was used to focus Cu Ka X-rays through the specimen and onto the detector.
  • a silicon specimen NIST SRM 640e was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position.
  • a specimen of the sample was sandwiched between 3- -thick films and analyzed in transmission geometry.
  • a beam-stop, short antiscatter extension, and antiscatter knife edge were used to minimize the background generated by air.
  • Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 5.5.
  • X'Celerator scanning position-sensitive detector
  • XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu K radiation produced using a long, fine-focus source and a nickel filter.
  • the diffractometer was configured using the symmetric Bragg-Brentano geometry.
  • a silicon specimen NIST SRM 640e was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position.
  • the specimen was put in at the center of a backfill holder.
  • Antiscatter slits (SS) were used to minimize the background generated by air.
  • Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence.
  • Diffraction patterns were collected using a scanning position- sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software v.5.5.
  • Solubility for amorphous compound (I), crystalline Form A, and crystalline Form B was evaluated in water in duplicate at 24 hours. Amounts of samples resulting in a 5 mg/mL loading were dissolved in water and stirred at 25°C. At the end of the 24-hour stirring, slurries were centrifuged and the supernatant was analyzed by LC.
  • Aqueous media solubility for crystalline Form B was performed in duplicate at 24 hours. Amounts of crystalline Form B resulting in a 20 mg/mL loading were dissolved in 4 different media (pH 1 , 3, 5, and 7 buffers) and stirred at 25°C. At the end of the 24 hour stirring period, slurries were filtered using a PVDF syringe filter and the supernatant was analyzed by LC.
  • Solubility of crystalline Form A and amorphous compound (I) was also evaluated in pH 1 , 3, 5, and 7 buffer.
  • Suspensions of crystalline Form A and amorphous compound (I) were prepared by adding about 30 mg material to 3 mL of media. Samples were stirred for 24 hours at 25.0 °C. At the end of 24 hours of stirring, the suspensions were centrifuged and the clear supernatants were analyzed for concentration by HPLC.
  • Intrinsic dissolution experiments were performed using a VanKel VK7010 dissolution tester equipped with a VK750D heater/circulator.
  • a Wood's Apparatus (0.50 cm 2 sample surface area) as described in USP ⁇ 1087> was used.
  • Approximately 150 mg of AGIO HCI was compressed with an applied load of approximately 1000 pounds for 1 minute in the Wood's apparatus using a hydraulic press.
  • the intrinsic dissolution medium was pH 7 Phosphate Buffer or water.
  • the medium (500 mL) was equilibrated to 37 °C ⁇ 0.5° C.
  • the disks were rotated at 100 rpm. Sampling of 1 mL aliquots was performed at the given time points of 5, 10, 15, 30, 60, 90, 120, and 180 minutes using a 3 mL syringe equipped with a stainless steel cannula.
  • DVS experiments for crystalline Form A were performed according to the materials and methods described in Example 1 .
  • DVS experiments for crystalline Form B were performed according to the materials and methods described in Example 3.
  • DSC DSC
  • DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Temperature calibration was performed using octane, phenyl salicylate, indium, tin, and zinc. The sample was placed into a hermetically sealed aluminum DSC pan, the weight was accurately recorded, the lid was pierced, and the sample was inserted into the DSC cell. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The sample was analyzed from -30 °C to 250 °C at 10 °C/min.
  • Solubility for the amorphous compound (I), crystalline Form A, and crystalline Form B was evaluated in water in duplicate at 24 hours. Amounts of samples resulting in a 5 mg/mL loading were dissolved in water and stirred at 25°C. At the end of the 24-hour stirring, slurries were centrifuged and the supernatant was analyzed by LC. Results are shown in Table 10. Surprisingly, crystalline Form B was less soluble than Form A and the amorphous form of compound (I). The lower solubility observed with crystalline Form B is advantageous because it can better withstand exposure to water without loss of lattice integrity, enabling long-term shelf storage.
  • Aqueous solubility data for amorphous compound (I) and crystalline Form A (centrifugation) Aqueous media solubility for crystalline Form B was also performed in duplicate at 24 hours using filtration. Amounts of crystalline Form B resulting in a 20 mg/mL loading were dissolved in 4 different media (pH 1 , 3, 5, and 7 buffers) and stirred at 25°C. At the end of the 24 hour stirring period, slurries were filtered using a PVDF syringe filter and the supernatant was analyzed by LC. Results are shown in Table 13.
  • the average IDR of crystalline Form B was 0.013 mg/cm 2 /min (Table 14), the IDR of the crystalline Form A was 0.034 mg/cm 2 /min (Table 15), and the average IDR of the amorphous Form was 0.032 mg/cm 2 /min (Table 16).
  • the IDR of crystalline Form B is lower than the rates of the crystalline Form A and amorphous material.
  • An overlay of another IDR experiment following the same methods set forth above is shown in FIG. 7A.
  • Intrinsic dissolution experiments were performed in duplicate using crystalline Form B pellets to determine the IDR.
  • the experiment was run in 500 mL of a pH 7 0.2 M phosphate buffer at 37°C with a rotation speed of 100 rpm. Sampling was done by pulling a 1 mL aliquot from the vessel and transferring it to HPLC vials at each given sampling point. Following intrinsic dissolution, the pulled samples were analyzed by HPLC. The average IDR of the crystalline Form B replicates was 0.011 mg/cm 2 /min (Table 17).
  • a similar experiment was performed for crystalline Form A and amorphous compound (I) (FIG.
  • the IDR of crystalline Form B was lower than the IDR of crystalline Form A (0.027 mg/cm 2 /min) and amorphous material (0.031 mg/cm 2 /min). As discussed above, the lower IDR of crystalline Form B imparts the crystal form with important benefits for shelf-life storage.
  • the DVS isotherm of crystalline Form B is provided in FIG. 5H, and the DVS isotherm of crystalline Form A is provided in FIG. 1 F.
  • Crystalline Form A exhibited hysteresis, as evidenced by the non-overlapping sorption and desorption curves. Surprisingly, no significant hysteresis was observed for crystalline Form B. These results show that, although crystalline Form B appears to absorb water to a higher degree than Form A, Form B has a superior ability to resist water-induced degradation of the crystal lattice, which is indicative of greater stability.
  • the DSC curve exhibits a likely melt endotherm with an onset of 99 °C, followed by a decomposition exotherm at 237 °C (peak maximum).
  • the melting point of Form B (99 °C) is higher than the melting point of Form A (75°C) (FIG. 9), demonstrating that crystalline Form B is more stable than Form A since more heat is required to compromise the integrity of the crystal lattice.
  • XRPD characteristic X-ray powder diffraction
  • E4 The crystalline Form B of any one of E1 -E3, wherein the crystalline Form B of said compound exhibits characteristic XRPD peaks at 25.87 ⁇ 0.20° 20, 26.99 ⁇ 0.20° 20, and 28.74 ⁇ 0.20° 20.
  • E5. The crystalline Form B of any one of E1 -E4, wherein the crystalline Form B of said compound exhibits characteristic XRPD peaks at 7.07 ⁇ 0.20° 20, 12.27 ⁇ 0.20° 20, 14.17 ⁇ 0.20° 20, and 18.79 ⁇ 0.20° 20 .
  • E6 The crystalline Form B of any one of E1 -E5, wherein the crystalline Form B of said compound exhibits characteristic XRPD peaks at 21 .34 ⁇ 0.20° 20 and 25.72 ⁇ 0.20° 20.
  • E7 The crystalline Form B of any one of E1 -E6, wherein the crystalline Form B of said compound exhibits characteristic XRPD peaks at 30.56 ⁇ 0.20° 20, 31 .22 ⁇ 0.20° 20, 32.56 ⁇ 0.20° 20, 33.03 ⁇ 0.20° 20, 33.35 ⁇ 0.20° 20, 33.79 ⁇ 0.20° 20, 34.67 ⁇ 0.20° 20, 34.90 ⁇ 0.20° 20, 35.67 ⁇ 0.20° 20, 36.08 ⁇ 0.20° 20, 37.42 ⁇ 0.20° 20, 37.84 ⁇ 0.20° 20, 38.25 ⁇ 0.20° 20, and 39.72 ⁇ 0.20° 20.
  • E12 The crystalline Form B of any one of E1-E11 , exhibiting 1 H nuclear magnetic resonance (NMR) peaks centered at a chemical shift (6) of about 1 .0 ppm, about 2.3 ppm, about 2.5 ppm, about 3.3 ppm, about 3.5 ppm, about 3.7 ppm, about 7.2 ppm, about 7.3 ppm, about 7.4 ppm, and about 7.6 ppm.
  • NMR nuclear magnetic resonance
  • E14 The crystalline Form B of any one of E1-E13, wherein the crystalline Form B exhibits a weight loss of from 0.01 % to 5% when heated from 36 °C to 160 °C as measured by thermogravimetric analysis (TGA), optionally wherein the weight loss is from 0.01 % to 0.05%, further optionally wherein the weight loss is about 0.03%.
  • TGA thermogravimetric analysis
  • E16 The crystalline Form B of any one of E1-E15, wherein the crystalline Form B exhibits a TGA curve substantially as depicted in FIG. 5G.
  • E17 The crystalline Form B of any one of E1-E16, wherein the crystalline Form B exhibits a weight gain of from 0.01 % to 5% when the relative humidity is increased from 5% to 95% as measured by dynamic vapor sorption (DVS) , optionally wherein the weight gain is from 1% to 5%, further optionally wherein the weight gain is about 1 .65%.
  • DVS dynamic vapor sorption
  • E19 The crystalline Form B of any one of E1-E18, wherein the crystalline Form B exhibits a weight loss of from 0.01% to 5% when the relative humidity is decreased from 95% to 5% as measured by DVS, optionally wherein the weight loss is from 1% to 5%, further optionally wherein the weight loss is about 1 .67%.
  • E21 The crystalline Form B of any one of E1-E20, wherein the crystalline Form B exhibits a DVS curve substantially as depicted in FIG. 5H.
  • E22 The crystalline Form B of any one of E1-E21 , wherein the crystalline Form B exhibits a Raman curve substantially as depicted in FIG. 5I or FIG. 5J.
  • E23 The crystalline Form B of any one of E1-E22, wherein the crystalline Form B has a solubility of from 0.100 mg/mL to 0.200 mg/mL in water after 24 hours of stirring.
  • E25 The crystalline Form B of any one of E1-E24, wherein the crystalline Form B has an intrinsic dissolution rate (IDR) of from 0.010 mg/cm 2 /min to 0.020 mg/cm 2 /min in water.
  • IDR intrinsic dissolution rate
  • E27 The crystalline Form B of any one of E1-E26, wherein the crystalline Form B is obtainable by recrystallization from a solvent.
  • E28 The crystalline Form B of E27, wherein the crystalline Form B is obtainable by recrystallization from ethanol, methanol, or water.
  • formula (I) comprising crystalline Form B of compound (I)
  • the crystalline Form B of compound (I) is present at greater than about 84% (e.g., about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) by weight of
  • a pharmaceutical composition comprising the crystalline Form B of any one of E1-E31 or the solid form of any one of E32-E35, and one or more carriers, diluents, or excipients.
  • E37 A method of treating a subject undergoing an embryo transfer procedure in which one or more embryos are transferred to the uterus of the subject, the method comprising administering to the subject the crystalline Form B of any one of E1 -E31 , the solid form of any one of E32-E35, or the pharmaceutical composition of E36.
  • E38 A method of reducing the likelihood of embryo implantation failure in a subject undergoing an embryo transfer procedure in which one or more embryos are transferred to the uterus of the subject, the method comprising administering to the subject the crystalline Form B of any one of E1-E31 , the solid form of any one of E32-E35, or the pharmaceutical composition of E36.
  • E39 A method of improving endometrial receptivity in a subject undergoing an embryo transfer procedure in which one or more embryos are transferred to the uterus of the subject, the method comprising administering to the subject the crystalline Form B of any one of E1-E31 , the solid form of any one of E32-E35, or the pharmaceutical composition of E36.
  • E40 A method of reducing uterine contractility in a subject undergoing an embryo transfer procedure in which one or more embryos are transferred to the uterus of the subject, the method comprising administering to the subject the crystalline Form B of any one of E1 -E31 , the solid form of any one of E32-E35, or the pharmaceutical composition of E36.
  • E41 The method of any one of E37-E40, wherein the method comprises transferring the one or more embryos to the uterus of the subject.
  • E42 The method of any one of E37-E41 , wherein the method further comprises inducing follicular maturation in the subject, optionally wherein the inducing of follicular maturation comprises administering human chorionic gonadotropin (hCG) to the subject.
  • hCG human chorionic gonadotropin
  • E43 The method of any one of E37-E42, wherein from 1 to 2 embryos are transferred to the subject.
  • E44 The method of E43, wherein 1 embryo is transferred to the subject.
  • E45 The method of E43, wherein 2 embryos are transferred to the subject.
  • E46 The method of any one of E37-E45, wherein the subject is a mammal and the one or more embryos are mammalian embryos.
  • E47 The method of E46, wherein the mammal is a human and the one or more mammalian embryos are human embryos.
  • E48 The method of any one of E37-E47, wherein the one or more embryos are produced ex vivo by in vitro fertilization (IVF).
  • E49 The method of E48, wherein the one or more embryos are produced ex vivo by IVF of one or more ova derived from the subject.
  • E50 The method of any one of E37-E47, wherein the one or more embryos are produced ex vivo by intracytoplasmic sperm injection (ICSI).
  • ICSI intracytoplasmic sperm injection
  • E51 The method of E50, wherein the one or more embryos are produced ex vivo by ICSI into one or more ova derived from the subject.
  • E52 The method of E49 or E51 , wherein the one or more ova are derived from one or more oocytes isolated from the subject.
  • E53 The method of E52, wherein the one or more oocytes comprise from 1 to 4 mature oocytes.
  • E54 The method of E52 or E53, wherein a gonadotropin-releasing hormone (GnRH) antagonist is administered to the subject prior to isolation of the one or more oocytes from the subject.
  • GnRH gonadotropin-releasing hormone
  • E55 The method of any one of E52-E54, wherein hCG is administered to the subject prior to isolation of the one or more oocytes from the subject.
  • E56 The method of any one of E52-E55, wherein progesterone is administered to the subject following isolation of the one or more oocytes from the subject.
  • E57 The method of E49 or E51 , wherein the one or more ova are isolated directly from the subject.
  • E58 The method of E57, wherein a GnRH antagonist is administered to the subject prior to isolation of the one or more ova from the subject.
  • E59 The method of E57 or E58, wherein hCG is administered to the subject prior to isolation of the one or more ova from the subject.
  • E60 The method of any one of E57-E59, wherein progesterone is administered to the subject following isolation of the one or more ova from the subject.
  • E61 The method of any one of E37-E60, wherein the one or more embryos each comprise from 6 to 8 blastomeres immediately prior to the transfer of the one or more embryos to the subject.
  • E62 The method of E61 , wherein the blastomeres are of approximately equal sizes as assessed by visual microscopy.
  • a kit comprising the crystalline Form B of any one of E1 -E31 , the solid form of any one of E32- E35, or the pharmaceutical composition of E36, wherein the kit further comprises a package insert instructing a user of the kit to administer the crystalline Form B to a subject in accordance with the method of any one of E37-E62.

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Abstract

L'invention concerne des formes cristallines de (3Z,5S)-5-(hydroxyméthyl)-1-[(2'-méthyl-1,1'-biphényl-4-5 yl)carbonyl]pyrrolidin-3-one O-méthyloxime, ainsi que des procédés d'utilisation de ce matériau cristallin pour améliorer les résultats d'implantation d'embryons chez des patients subissant une opération de technologie de reproduction assistée (ART), telle qu'une fécondation in vitro (FIV) ou une injection de sperme intracytoplasmique (ICSI).
PCT/IB2025/057317 2024-07-18 2025-07-18 Compositions cristallines pour améliorer l'implantation d'embryons et leurs procédés d'utilisation Pending WO2026018221A1 (fr)

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