OXYTOCIN ANTAGONIST DOSING REGIMENS FOR PROMOTING EMBRYO IMPLANTATION AND PREVENTING MISCARRIAGE

FIELD OF THE INVENTION

The disclosure relates to composition and methods for dosing subjects with oxytocin receptor antagonists to enhance endometrial receptivity and reduce the likelihood of embryo implantation failure in subjects undergoing embryo transfer therapy.

BACKGROUND OF THE INVENTION

Despite recent progress in assisted reproductive technology, the overall effectiveness of even advanced treatments, such as in vitro fertilization (IVF) followed by embryo transfer (IVF/ET) remains relatively low, resulting in an average of about 30% live births per treatment cycle (Andersen et al., Human Reproduction 24:1267-1287 (2009)). Moreover, the embryo implantation success rate tends to decrease with age. Many current treatment strategies to promote successful embryo implantation in a subject undergoing embryo transfer therapy have focused on the inhibition of uterine contractions prior to embryo transfer. Such treatment modalities include the administration of A-adrenergic receptor agonists and non-steroidal anti-inflammatory drugs (NSAIDS), which have not been shown to provide sufficient clinical benefit (Bemabeu 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)). There remains a need for improved treatment procedures and dosing regimens that can be used to promote successful embryo implantation, for instance, by enhancing endometrial receptivity upon embryo transfer in patients undergoing assisted reproductive technology procedures.

SUMMARY OF THE INVENTION

The present disclosure provides methods of dosing a subject undergoing embryo transfer therapy with an oxytocin receptor antagonist, for example, to enhance endometrial receptivity upon embryo implantation, thereby reducing the likelihood of embryo implantation failure and of miscarriage. Oxytocin receptor antagonists that can be used in conjunction with the compositions and methods described herein include substituted pyrrolidin-3-one oxime compounds, such as (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime. Additional examples of oxytocin receptor antagonists that may be used in conjunction with the compositions and methods described herein include epelsiban, retosiban, barusiban, and atosiban, as well as derivatives and variants thereof. Using the compositions and methods described herein, oxytocin antagonists such as the foregoing can be administered to a subject prior to, concurrently with, or after embryo transfer so as to improve endometrial receptivity and reduce the likelihood of embryo implantation failure and miscarriage. The oxytocin antagonist can be administered to the subject in a single dose or in multiple doses, such as doses of varying strength or repeat doses of the same strength. For instance, the oxytocin antagonist may be administered to the subject undergoing embryo transfer in a single high dose or in multiple, lower-strength doses so as to achieve a maximal plasma concentration of the oxytocin antagonist (for instance, of from about 1 μM to about 20 μM, such as from about 1 μM to about 20 μM of a compound represented by formula (I) or (II) as described herein). According to the methods of the disclosure, oxytocin receptor antagonists such as those described herein can be administered to a subject prior to, concurrently with, or after intrauterine transfer of one or more embryos produced ex vivo, for instance, by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) procedures. The one or more embryos may, for example, be produced by fertilization of an ovum derived from the subject that is undergoing the embryo transfer procedure, or may be derived from a donor that is not undergoing the embryo transfer procedure.

The present disclosure is based, in part, on the discovery of doses of oxytocin receptor antagonists, such as compounds of formula (I) (e.g., (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime), that are particularly effective at enhancing endometrial receptivity by multiple modes of action. Particularly, doses of compounds of formula (I), such as (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, have presently 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. Together, the reduced uterine contractile activity and enhanced endometrial perfusion engendered by compounds of formula (I), such as (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, 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.

In a first aspect, the disclosure provides a method of treating a subject undergoing embryo transfer therapy by administering to the subject a therapeutically effective amount of an oxytocin antagonist, such as a compound represented by formula (I)

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or a geometric isomer, enantiomer, diastereomer, racemate, or salt thereof, wherein

n is an integer from 1 to 3;

R¹is selected from the group consisting of hydrogen and C₁-C₆alkyl;

R²is selected from the group consisting of hydrogen, C₁-C₆alkyl, C₁-C₆alkyl aryl, heteroaryl, C₁-C₆alkyl heteroaryl, C₂-C₆alkenyl, C₂-C₆alkenyl aryl, C₁-C₆alkenyl heteroaryl, C₂-C₆alkynyl, C₂-C₆alkynyl aryl, C₂-C₆alkynyl heteroaryl, C₁-C₆cycloalkyl, heterocycloalkyl, C₁-C₆alkyl cycloalkyl, C₁-C₆alkyl heterocycloalkyl, C₁-C₆alkyl carboxy, acyl, C₁-C₆alkyl acyl, C₁-C₆alkyl acyloxy, C₁-C₆alkyl alkoxy, alkoxycarbonyl, C₁-C₆alkyl alkoxycarbonyl, aminocarbonyl, C₁-C₆alkyl aminocarbonyl, C₁-C₆alkyl acylamino, C₁-C₆alkyl ureido, amino, C₁-C₆alkyl amino, sulfonyloxy, C₁-C₆alkyl sulfonyloxy, sulfonyl, C₁-C₆alkyl sulfonyl, sulfinyl, C₁-C₆alkyl sulfinyl, C₁-C₆alkyl sulfanyl, and C₁-C₆alkyl sulfonylamino;

R³is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of oxygen and NR⁴; and

wherein the compound is administered to the subject in an amount of from about 1,500 mg to about 2,700 mg per dose. For example, the compound may be administered to the subject in an amount of from about 1,500 mg to about 2,100 mg per dose, from about 1,550 mg to about 2,050 mg per dose, from about 1,600 mg to about 2,000 mg per dose, from about 1,650 mg to about 1,950 mg per dose, from about 1,700 mg to about 1,900 mg per dose, from about 1,750 mg to about 1,850 mg per dose, from about 1,760 mg to about 1,840 mg per dose, from about 1,770 mg to about 1,830 mg per dose, from about 1,780 mg to about 1,820 mg per dose, from about 1,790 mg to about 1,810 mg per dose, from about 1,791 mg to about 1,809 mg per dose, from about 1,792 mg to about 1,808 mg per dose, from about 1,793 mg to about 1,807 mg per dose, from about 1,794 mg to about 1,806 mg per dose, from about 1,795 mg to about 1,805 mg per dose, from about 1,796 mg to about 1,804 mg per dose, from about 1,797 mg to about 1,803 mg per dose, from about 1,798 mg to about 1,802 mg per dose, or from about 1,799 mg to about 1,801 mg per dose (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in an amount of from about 2,100 mg to about 2,700 mg per dose, from about 2,150 mg to about 2,650 mg per dose, from about 2,200 mg to about 2,600 mg per dose, from about 2,250 mg to about 2,550 mg per dose, from about 2,300 mg to about 2,500 mg per dose, from about 2,350 mg to about 2,450 mg per dose, from about 2,360 mg to about 2,440 mg per dose, from about 2,370 mg to about 2,430 mg per dose, from about 2,380 mg to about 2,420 mg per dose, from about 2,390 mg to about 2,410 mg per dose, from about 2,391 mg to about 2,409 mg per dose, from about 2,392 mg to about 2,408 mg per dose, from about 2,393 mg to about 2,407 mg per dose, from about 2,394 mg to about 2,406 mg per dose, from about 2,395 mg to about 2,405 mg per dose, from about 2,396 mg to about 2,404 mg per dose, from about 2,397 mg to about 2,403 mg per dose, from about 2,398 mg to about 2,402 mg per dose, or from about 2,399 mg to about 2,401 mg per dose (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in an amount of about 1,500 mg, 1,510 mg, 1,520 mg, 1,530 mg, 1,540 mg, 1,550 mg, 1,560 mg, 1,570 mg, 1,580 mg, 1,590 mg, 1,600 mg, 1,610 mg, 1,620 mg, 1,630 mg, 1,640 mg, 1,650 mg, 1,660 mg, 1,670 mg, 1,680 mg, 1,690 mg, 1,700 mg, 1,710 mg, 1,720 mg, 1,730 mg, 1,740 mg, 1,750 mg, 1,760 mg, 1,770 mg, 1,780 mg, 1,790 mg, 1,800 mg, 1,810 mg, 1,820 mg, 1,830 mg, 1,840 mg, 1,850 mg, 1,860 mg, 1,870 mg, 1,880 mg, 1,890 mg, 1,900 mg, 1,910 mg, 1,920 mg, 1,930 mg, 1,940 mg, 1,950 mg, 1,960 mg, 1,970 mg, 1,980 mg, 1,990 mg, 2,000 mg, 2,010 mg, 2,020 mg, 2,030 mg, 2,040 mg, 2,050 mg, 2,060 mg, 2,070 mg, 2,080 mg, 2,090 mg, or 2,100 mg per dose, such as in an amount of about 1,800 mg per dose (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in an amount of about 2,100 mg, 2,110 mg, 2,120 mg, 2,130 mg, 2,140 mg, 2,150 mg, 2,160 mg, 2,170 mg, 2,180 mg, 2,190 mg, 2,200 mg, 2,210 mg, 2,220 mg, 2,230 mg, 2,240 mg, 2,250 mg, 2,260 mg, 2,270 mg, 2,280 mg, 2,290 mg, 2,300 mg, 2,310 mg, 2,320 mg, 2,330 mg, 2,340 mg, 2,350 mg, 2,360 mg, 2,370 mg, 2,380 mg, 2,390 mg, 2,400 mg, 2,410 mg, 2,420 mg, 2,430 mg, 2,440 mg, 2,450 mg, 2,460 mg, 2,470 mg, 2,480 mg, 2,490 mg, 2,500 mg, 2,510 mg, 2,520 mg, 2,530 mg, 2,540 mg, 2,550 mg, 2,560 mg, 2,570 mg, 2,580 mg, 2,590 mg, 2,600 mg, 2,610 mg, 2,620 mg, 2,630 mg, 2,640 mg, 2,650 mg, 2,660 mg, 2,670 mg, 2,680 mg, 2,690 mg, or 2,700 mg per dose, such as in an amount of about 2,400 mg per dose (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in an amount of from about 1,600 mg to about 2,600 mg per dose, such as in an amount of from about 1,610 mg to about 2,590 mg per dose, from about 1,620 mg to about 2,580 mg per dose, from about 1,630 mg to about 2,570 mg per dose, from about 1,640 mg to about 2,560 mg per dose, from about 1,650 mg to about 2,550 mg per dose, from about 1,660 mg to about 2,540 mg per dose, from about 1,670 mg to about 2,530 mg per dose, from about 1,680 mg to about 2,520 mg per dose, from about 1,690 mg to about 2,510 mg per dose, from about 1,700 mg to about 2,500 mg per dose, from about 1,710 mg to about 2,490 mg per dose, from about 1,720 mg to about 2,480 mg per dose, from about 1,730 mg to about 2,470 mg per dose, from about 1,740 mg to about 2,460 mg per dose, from about 1,750 mg to about 2,450 mg per dose, from about 1,760 mg to about 2,440 mg per dose, from about 1,770 mg to about 2,430 mg per dose, from about 1,780 mg to about 2,420 mg per dose, from about 1,790 mg to about 2,410 mg per dose, from about 1,800 mg to about 2,400 mg per dose, from about 1,810 mg to about 2,390 mg per dose, from about 1,820 mg to about 2,380 mg per dose, from about 1,830 mg to about 2,370 mg per dose, from about 1,840 mg to about 2,360 mg per dose, from about 1,850 mg to about 2,350 mg per dose, from about 1,860 mg to about 2,340 mg per dose, from about 1,870 mg to about 2,330 mg per dose, from about 1,880 mg to about 2,320 mg per dose, from about 1,890 mg to about 2,310 mg per dose, from about 1,900 mg to about 2,300 mg per dose, from about 1,910 mg to about 2,290 mg per dose, from about 1,920 mg to about 2,280 mg per dose, from about 1,930 mg to about 2,270 mg per dose, from about 1,940 mg to about 2,260 mg per dose, from about 1,950 mg to about 2,250 mg per dose, from about 1,960 mg to about 2,240 mg per dose, from about 1,970 mg to about 2,230 mg per dose, from about 1,980 mg to about 2,220 mg per dose, from about 1,990 mg to about 2,210 mg per dose, from about 2,000 mg to about 2,200 mg per dose, from about 2,010 mg to about 2,190 mg per dose, from about 2,020 mg to about 2,180 mg per dose, from about 2,030 mg to about 2,170 mg per dose, from about 2,040 mg to about 2,160 mg per dose, from about 2,050 mg to about 2,150 mg per dose, from about 2,060 mg to about 2,140 mg per dose, from about 2,070 mg to about 2,130 mg per dose, from about 2,080 mg to about 2,120 mg per dose, or from about 2,090 mg to about 2,110 mg per dose, such as about 2,100 mg per dose e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In another aspect, the disclosure provides a method of treating a subject undergoing embryo transfer therapy by administering to the subject a therapeutically effective amount of an oxytocin antagonist, such as a compound represented by formula (I)

embedded image

or a geometric isomer, enantiomer, diastereomer, racemate, or salt thereof, wherein

n is an integer from 1 to 3;

R¹is selected from the group consisting of hydrogen and C₁-C₆alkyl;

R³is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of oxygen and NR⁴; and

wherein the compound is administered to the subject in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling from about 1,500 mg to about 2,700 mg. For example, the compound may be administered to the subject in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling from about 1,500 mg to about 2,100 mg, from about 1,550 mg to about 2,050 mg, from about 1,600 mg to about 2,000 mg, from about 1,650 mg to about 1,950 mg, from about 1,700 mg to about 1,900 mg, from about 1,750 mg to about 1,850 mg, from about 1,760 mg to about 1,840 mg, from about 1,770 mg to about 1,830 mg, from about 1,780 mg to about 1,820 mg, from about 1,790 mg to about 1,810 mg, from about 1,791 mg to about 1,809 mg, from about 1,792 mg to about 1,808 mg, from about 1,793 mg to about 1,807 mg, from about 1,794 mg to about 1,806 mg, from about 1,795 mg to about 1,805 mg, from about 1,796 mg to about 1,804 mg, from about 1,797 mg to about 1,803 mg, from about 1,798 mg to about 1,802 mg, or from about 1,799 mg to about 1,801 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling from about 2,100 mg to about 2,700 mg, from about 2,150 mg to about 2,650 mg, from about 2,200 mg to about 2,600 mg, from about 2,250 mg to about 2,550 mg, from about 2,300 mg to about 2,500 mg, from about 2,350 mg to about 2,450 mg, from about 2,360 mg to about 2,440 mg, from about 2,370 mg to about 2,430 mg, from about 2,380 mg to about 2,420 mg, from about 2,390 mg to about 2,410 mg, from about 2,391 mg to about 2,409 mg, from about 2,392 mg to about 2,408 mg, from about 2,393 mg to about 2,407 mg, from about 2,394 mg to about 2,406 mg, from about 2,395 mg to about 2,405 mg, from about 2,396 mg to about 2,404 mg, from about 2,397 mg to about 2,403 mg, from about 2,398 mg to about 2,402 mg, or from about 2,399 mg to about 2,401 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling about 1,500 mg, 1,510 mg, 1,520 mg, 1,530 mg, 1,540 mg, 1,550 mg, 1,560 mg, 1,570 mg, 1,580 mg, 1,590 mg, 1,600 mg, 1,610 mg, 1,620 mg, 1,630 mg, 1,640 mg, 1,650 mg, 1,660 mg, 1,670 mg, 1,680 mg, 1,690 mg, 1,700 mg, 1,710 mg, 1,720 mg, 1,730 mg, 1,740 mg, 1,750 mg, 1,760 mg, 1,770 mg, 1,780 mg, 1,790 mg, 1,800 mg, 1,810 mg, 1,820 mg, 1,830 mg, 1,840 mg, 1,850 mg, 1,860 mg, 1,870 mg, 1,880 mg, 1,890 mg, 1,900 mg, 1,910 mg, 1,920 mg, 1,930 mg, 1,940 mg, 1,950 mg, 1,960 mg, 1,970 mg, 1,980 mg, 1,990 mg, 2,000 mg, 2,010 mg, 2,020 mg, 2,030 mg, 2,040 mg, 2,050 mg, 2,060 mg, 2,070 mg, 2,080 mg, 2,090 mg, or 2,100 mg, such as in an amount of about 1,800 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling about 2,100 mg, 2,110 mg, 2,120 mg, 2,130 mg, 2,140 mg, 2,150 mg, 2,160 mg, 2,170 mg, 2,180 mg, 2,190 mg, 2,200 mg, 2,210 mg, 2,220 mg, 2,230 mg, 2,240 mg, 2,250 mg, 2,260 mg, 2,270 mg, 2,280 mg, 2,290 mg, 2,300 mg, 2,310 mg, 2,320 mg, 2,330 mg, 2,340 mg, 2,350 mg, 2,360 mg, 2,370 mg, 2,380 mg, 2,390 mg, 2,400 mg, 2,410 mg, 2,420 mg, 2,430 mg, 2,440 mg, 2,450 mg, 2,460 mg, 2,470 mg, 2,480 mg, 2,490 mg, 2,500 mg, 2,510 mg, 2,520 mg, 2,530 mg, 2,540 mg, 2,550 mg, 2,560 mg, 2,570 mg, 2,580 mg, 2,590 mg, 2,600 mg, 2,610 mg, 2,620 mg, 2,630 mg, 2,640 mg, 2,650 mg, 2,660 mg, 2,670 mg, 2,680 mg, 2,690 mg, or 2,700 mg, such as in an amount of about 2,400 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling from about 1,600 mg to about 2,600 mg, such as in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling from about 1,610 mg to about 2,590 mg, from about 1,620 mg to about 2,580 mg, from about 1,630 mg to about 2,570 mg, from about 1,640 mg to about 2,560 mg, from about 1,650 mg to about 2,550 mg, from about 1,660 mg to about 2,540 mg, from about 1,670 mg to about 2,530 mg, from about 1,680 mg to about 2,520 mg, from about 1,690 mg to about 2,510 mg, from about 1,700 mg to about 2,500 mg, from about 1,710 mg to about 2,490 mg, from about 1,720 mg to about 2,480 mg, from about 1,730 mg to about 2,470 mg, from about 1,740 mg to about 2,460 mg, from about 1,750 mg to about 2,450 mg, from about 1,760 mg to about 2,440 mg, from about 1,770 mg to about 2,430 mg, from about 1,780 mg to about 2,420 mg, from about 1,790 mg to about 2,410 mg, from about 1,800 mg to about 2,400 mg, from about 1,810 mg to about 2,390 mg, from about 1,820 mg to about 2,380 mg, from about 1,830 mg to about 2,370 mg, from about 1,840 mg to about 2,360 mg, from about 1,850 mg to about 2,350 mg, from about 1,860 mg to about 2,340 mg, from about 1,870 mg to about 2,330 mg, from about 1,880 mg to about 2,320 mg, from about 1,890 mg to about 2,310 mg, from about 1,900 mg to about 2,300 mg, from about 1,910 mg to about 2,290 mg, from about 1,920 mg to about 2,280 mg, from about 1,930 mg to about 2,270 mg, from about 1,940 mg to about 2,260 mg, from about 1,950 mg to about 2,250 mg, from about 1,960 mg to about 2,240 mg, from about 1,970 mg to about 2,230 mg, from about 1,980 mg to about 2,220 mg, from about 1,990 mg to about 2,210 mg, from about 2,000 mg to about 2,200 mg, from about 2,010 mg to about 2,190 mg, from about 2,020 mg to about 2,180 mg, from about 2,030 mg to about 2,170 mg, from about 2,040 mg to about 2,160 mg, from about 2,050 mg to about 2,150 mg, from about 2,060 mg to about 2,140 mg, from about 2,070 mg to about 2,130 mg, from about 2,080 mg to about 2,120 mg, or from about 2,090 mg to about 2,110 mg, such as about 2,100 mg e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses, such as in a single dose) totaling about 1,800 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses, such as in a single dose) totaling about 2,100 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses, such as in a single dose) totaling about 2,400 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In a further aspect, the disclosure provides a method of treating a subject undergoing embryo transfer therapy by administering to the subject a therapeutically effective amount of an oxytocin antagonist, such as a compound represented by formula (I)

embedded image

or a geometric isomer, enantiomer, diastereomer, racemate, or salt thereof, wherein

n is an integer from 1 to 3;

R¹is selected from the group consisting of hydrogen and C₁-C₆alkyl;

R³is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of oxygen and NR⁴; and

wherein the compound is administered to the subject in a single dose (e.g., on the day of the embryo transfer therapy) of from about 1,500 mg to about 2,700 mg. For example, the compound may be administered to the subject in a single dose (e.g., on the day of the embryo transfer therapy) of from about 1,500 mg to about 2,100 mg, from about 1,550 mg to about 2,050 mg, from about 1,600 mg to about 2,000 mg, from about 1,650 mg to about 1,950 mg, from about 1,700 mg to about 1,900 mg, from about 1,750 mg to about 1,850 mg, from about 1,760 mg to about 1,840 mg, from about 1,770 mg to about 1,830 mg, from about 1,780 mg to about 1,820 mg, from about 1,790 mg to about 1,810 mg, from about 1,791 mg to about 1,809 mg, from about 1,792 mg to about 1,808 mg, from about 1,793 mg to about 1,807 mg, from about 1,794 mg to about 1,806 mg, from about 1,795 mg to about 1,805 mg, from about 1,796 mg to about 1,804 mg, from about 1,797 mg to about 1,803 mg, from about 1,798 mg to about 1,802 mg, or from about 1,799 mg to about 1,801 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (I)).

In some embodiments, the compound is administered to the subject in a single dose (e.g., on the day of the embryo transfer therapy) of from about 2,100 mg to about 2,700 mg, from about 2,150 mg to about 2,650 mg, from about 2,200 mg to about 2,600 mg, from about 2,250 mg to about 2,550 mg, from about 2,300 mg to about 2,500 mg, from about 2,350 mg to about 2,450 mg, from about 2,360 mg to about 2,440 mg, from about 2,370 mg to about 2,430 mg, from about 2,380 mg to about 2,420 mg, from about 2,390 mg to about 2,410 mg, from about 2,391 mg to about 2,409 mg, from about 2,392 mg to about 2,408 mg, from about 2,393 mg to about 2,407 mg, from about 2,394 mg to about 2,406 mg, from about 2,395 mg to about 2,405 mg, from about 2,396 mg to about 2,404 mg, from about 2,397 mg to about 2,403 mg, from about 2,398 mg to about 2,402 mg, or from about 2,399 mg to about 2,401 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in a single dose (e.g., on the day of the embryo transfer therapy) of about 1,500 mg, 1,510 mg, 1,520 mg, 1,530 mg, 1,540 mg, 1,550 mg, 1,560 mg, 1,570 mg, 1,580 mg, 1,590 mg, 1,600 mg, 1,610 mg, 1,620 mg, 1,630 mg, 1,640 mg, 1,650 mg, 1,660 mg, 1,670 mg, 1,680 mg, 1,690 mg, 1,700 mg, 1,710 mg, 1,720 mg, 1,730 mg, 1,740 mg, 1,750 mg, 1,760 mg, 1,770 mg, 1,780 mg, 1,790 mg, 1,800 mg, 1,810 mg, 1,820 mg, 1,830 mg, 1,840 mg, 1,850 mg, 1,860 mg, 1,870 mg, 1,880 mg, 1,890 mg, 1,900 mg, 1,910 mg, 1,920 mg, 1,930 mg, 1,940 mg, 1,950 mg, 1,960 mg, 1,970 mg, 1,980 mg, 1,990 mg, 2,000 mg, 2,010 mg, 2,020 mg, 2,030 mg, 2,040 mg, 2,050 mg, 2,060 mg, 2,070 mg, 2,080 mg, 2,090 mg, or 2,100 mg, such as in an amount of about 1,800 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in a single dose (e.g., on the day of the embryo transfer therapy) of about 2,100 mg, 2,110 mg, 2,120 mg, 2,130 mg, 2,140 mg, 2,150 mg, 2,160 mg, 2,170 mg, 2,180 mg, 2,190 mg, 2,200 mg, 2,210 mg, 2,220 mg, 2,230 mg, 2,240 mg, 2,250 mg, 2,260 mg, 2,270 mg, 2,280 mg, 2,290 mg, 2,300 mg, 2,310 mg, 2,320 mg, 2,330 mg, 2,340 mg, 2,350 mg, 2,360 mg, 2,370 mg, 2,380 mg, 2,390 mg, 2,400 mg, 2,410 mg, 2,420 mg, 2,430 mg, 2,440 mg, 2,450 mg, 2,460 mg, 2,470 mg, 2,480 mg, 2,490 mg, 2,500 mg, 2,510 mg, 2,520 mg, 2,530 mg, 2,540 mg, 2,550 mg, 2,560 mg, 2,570 mg, 2,580 mg, 2,590 mg, 2,600 mg, 2,610 mg, 2,620 mg, 2,630 mg, 2,640 mg, 2,650 mg, 2,660 mg, 2,670 mg, 2,680 mg, 2,690 mg, or 2,700 mg, such as in an amount of about 2,400 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in a single dose (e.g., on the day of the embryo transfer therapy) of from about 1,600 mg to about 2,600 mg, such as in a single dose (e.g., on the day of the embryo transfer therapy) of from about 1,610 mg to about 2,590 mg, from about 1,620 mg to about 2,580 mg, from about 1,630 mg to about 2,570 mg, from about 1,640 mg to about 2,560 mg, from about 1,650 mg to about 2,550 mg, from about 1,660 mg to about 2,540 mg, from about 1,670 mg to about 2,530 mg, from about 1,680 mg to about 2,520 mg, from about 1,690 mg to about 2,510 mg, from about 1,700 mg to about 2,500 mg, from about 1,710 mg to about 2,490 mg, from about 1,720 mg to about 2,480 mg, from about 1,730 mg to about 2,470 mg, from about 1,740 mg to about 2,460 mg, from about 1,750 mg to about 2,450 mg, from about 1,760 mg to about 2,440 mg, from about 1,770 mg to about 2,430 mg, from about 1,780 mg to about 2,420 mg, from about 1,790 mg to about 2,410 mg, from about 1,800 mg to about 2,400 mg, from about 1,810 mg to about 2,390 mg, from about 1,820 mg to about 2,380 mg, from about 1,830 mg to about 2,370 mg, from about 1,840 mg to about 2,360 mg, from about 1,850 mg to about 2,350 mg, from about 1,880 mg to about 2,340 mg, from about 1,870 mg to about 2,330 mg, from about 1,880 mg to about 2,320 mg, from about 1,890 mg to about 2,310 mg, from about 1,900 mg to about 2,300 mg, from about 1,910 mg to about 2,290 mg, from about 1,920 mg to about 2,280 mg, from about 1,930 mg to about 2,270 mg, from about 1,940 mg to about 2,260 mg, from about 1,950 mg to about 2,250 mg, from about 1,960 mg to about 2,240 mg, from about 1,970 mg to about 2,230 mg, from about 1,980 mg to about 2,220 mg, from about 1,990 mg to about 2,210 mg, from about 2,000 mg to about 2,200 mg, from about 2,010 mg to about 2,190 mg, from about 2,020 mg to about 2,180 mg, from about 2,030 mg to about 2,170 mg, from about 2,040 mg to about 2,160 mg, from about 2,050 mg to about 2,150 mg, from about 2,060 mg to about 2,140 mg, from about 2,070 mg to about 2,130 mg, from about 2,080 mg to about 2,120 mg, or from about 2,090 mg to about 2,110 mg, such as about 2,100 mg e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in a single dose (e.g., on the day of the embryo transfer therapy) of about 1,800 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (I)).

In some embodiments, the compound is administered to the subject in a single dose (e.g., on the day of the embryo transfer therapy) of about 2,100 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in a single dose (e.g., on the day of the embryo transfer therapy) of about 2,400 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In another aspect, the disclosure features an oxytocin antagonist, such as a compound represented by formula (I), for use in the method described in any of the preceding aspects of the disclosure.

In some embodiments of any of the above aspects of the disclosure, the oxytocin antagonist is administered to the subject prior to transfer of one or more embryos (e.g., one, two, three, or more embryos) to the uterus of the subject. In some embodiments, the administering reduces the likelihood of embryo implantation failure and/or miscarriage.

In another aspect, the disclosure provides a method of treating a subject undergoing embryo transfer therapy by transferring one or more embryos (e.g., one, two, three, or more embryos) to the uterus of the subject, wherein the subject has been previously administered a therapeutically effective amount of an oxytocin antagonist, such as a compound represented by formula (I)

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or a geometric isomer, enantiomer, diastereomer, racemate, or salt thereof, wherein

n is an integer from 1 to 3;

R¹is selected from the group consisting of hydrogen and C₁-C₆alkyl;

R³is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of oxygen and NR⁴; and

wherein the compound is administered to the subject in an amount of from about 1,500 mg to about 2,700 mg per dose. For example, the compound may be administered to the subject in an amount of from about 1,500 mg to about 2,100 mg per dose, 1,550 mg to about 2,050 mg per dose, from about 1,600 mg to about 2,000 mg per dose, from about 1,650 mg to about 1,950 mg per dose, from about 1,700 mg to about 1,900 mg per dose, from about 1,750 mg to about 1,850 mg per dose, from about 1,760 mg to about 1,840 mg per dose, from about 1,770 mg to about 1,830 mg per dose, from about 1,780 mg to about 1,820 mg per dose, from about 1,790 mg to about 1,810 mg per dose, from about 1,791 mg to about 1,809 mg per dose, from about 1,792 mg to about 1,808 mg per dose, from about 1,793 mg to about 1,807 mg per dose, from about 1,794 mg to about 1,806 mg per dose, from about 1,795 mg to about 1,805 mg per dose, from about 1,796 mg to about 1,804 mg per dose, from about 1,797 mg to about 1,803 mg per dose, from about 1,798 mg to about 1,802 mg per dose, or from about 1,799 mg to about 1,801 mg per dose (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in an amount of from about 1,600 mg to about 2,600 mg per dose, such as in an amount of from about 1,610 mg to about 2,590 mg per dose, from about 1,620 mg to about 2,580 mg per dose, from about 1,630 mg to about 2,570 mg per dose, from about 1,640 mg to about 2,560 mg per dose, from about 1,650 mg to about 2,550 mg per dose, from about 1,660 mg to about 2,540 mg per dose, from about 1,670 mg to about 2,530 mg per dose, from about 1,680 mg to about 2,520 mg per dose, from about 1,690 mg to about 2,510 mg per dose, from about 1,700 mg to about 2,500 mg per dose, from about 1,710 mg to about 2,490 mg per dose, from about 1,720 mg to about 2,480 mg per dose, from about 1,730 mg to about 2,470 mg per dose, from about 1,740 mg to about 2,460 mg per dose, from about 1,750 mg to about 2,450 mg per dose, from about 1,760 mg to about 2,440 mg per dose, from about 1,770 mg to about 2,430 mg per dose, from about 1,780 mg to about 2,420 mg per dose, from about 1,790 mg to about 2,410 mg per dose, from about 1,800 mg to about 2,400 mg per dose, from about 1,810 mg to about 2,390 mg per dose, from about 1,820 mg to about 2,380 mg per dose, from about 1,830 mg to about 2,370 mg per dose, from about 1,840 mg to about 2,360 mg per dose, from about 1,850 mg to about 2,350 mg per dose, from about 1,860 mg to about 2,340 mg per dose, from about 1,870 mg to about 2,330 mg per dose, from about 1,880 mg to about 2,320 mg per dose, from about 1,890 mg to about 2,310 mg per dose, from about 1,900 mg to about 2,300 mg per dose, from about 1,910 mg to about 2,290 mg per dose, from about 1,920 mg to about 2,280 mg per dose, from about 1,930 mg to about 2,270 mg per dose, from about 1,940 mg to about 2,260 mg per dose, from about 1,950 mg to about 2,250 mg per dose, from about 1,960 mg to about 2,240 mg per dose, from about 1,970 mg to about 2,230 mg per dose, from about 1,980 mg to about 2,220 mg per dose, from about 1,990 mg to about 2,210 mg per dose, from about 2,000 mg to about 2,200 mg per dose, from about 2,010 mg to about 2,190 mg per dose, from about 2,020 mg to about 2,180 mg per dose, from about 2,030 mg to about 2,170 mg per dose, from about 2,040 mg to about 2,160 mg per dose, from about 2,050 mg to about 2,150 mg per dose, from about 2,060 mg to about 2,140 mg per dose, from about 2,070 mg to about 2,130 mg per dose, from about 2,080 mg to about 2,120 mg per dose, from about 2,090 mg to about 2,110 mg per dose, such as about 2,100 mg per dose e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

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or a geometric isomer, enantiomer, diastereomer, racemate, or salt thereof, wherein

n is an integer from 1 to 3;

R¹is selected from the group consisting of hydrogen and C₁-C₆alkyl;

R³is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of oxygen and NR⁴; and

In some embodiments, the compound is administered to the subject in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling about 1,800 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling about 2,100 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling about 2,400 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In a further aspect, the disclosure provides a method of treating a subject undergoing embryo transfer therapy by transferring one or more embryos (e.g., one, two, three, or more embryos) to the uterus of the subject, wherein the subject has been previously administered a therapeutically effective amount of an oxytocin antagonist, such as a compound represented by formula (I)

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or a geometric isomer, enantiomer, diastereomer, racemate, or salt thereof, wherein

n is an integer from 1 to 3;

R¹is selected from the group consisting of hydrogen and C₁-C₆alkyl;

R³is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of oxygen and NR⁴; and

wherein the compound is administered to the subject in a single dose (e.g., on the day of the embryo transfer therapy) of from about 1,500 mg to about 2,700 mg. For example, the compound may be administered to the subject in a single dose (e.g., on the day of the embryo transfer therapy) of from about 1,550 mg to about 2,050 mg, from about 1,600 mg to about 2,000 mg, from about 1,650 mg to about 1,950 mg, from about 1,700 mg to about 1,900 mg, from about 1,750 mg to about 1,850 mg, from about 1,760 mg to about 1,840 mg, from about 1,770 mg to about 1,830 mg, from about 1,780 mg to about 1,820 mg, from about 1,790 mg to about 1,810 mg, from about 1,791 mg to about 1,809 mg, from about 1,792 mg to about 1,808 mg, from about 1,793 mg to about 1,807 mg, from about 1,794 mg to about 1,806 mg, from about 1,795 mg to about 1,805 mg, from about 1,796 mg to about 1,804 mg, from about 1,797 mg to about 1,803 mg, from about 1,798 mg to about 1,802 mg, or from about 1,799 mg to about 1,801 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In some embodiments, the compound is administered to the subject in a single dose (e.g., on the day of the embryo transfer therapy) of from about 1,600 mg to about 2,600 mg, such as in a single dose (e.g., on the day of the embryo transfer therapy) of from about 1,610 mg to about 2,590 mg, from about 1,620 mg to about 2,580 mg, from about 1,630 mg to about 2,570 mg, from about 1,640 mg to about 2,560 mg, from about 1,650 mg to about 2,550 mg, from about 1,660 mg to about 2,540 mg, from about 1,670 mg to about 2,530 mg, from about 1,680 mg to about 2,520 mg, from about 1,690 mg to about 2,510 mg, from about 1,700 mg to about 2,500 mg, from about 1,710 mg to about 2,490 mg, from about 1,720 mg to about 2,480 mg, from about 1,730 mg to about 2,470 mg, from about 1,740 mg to about 2,460 mg, from about 1,750 mg to about 2,450 mg, from about 1,760 mg to about 2,440 mg, from about 1,770 mg to about 2,430 mg, from about 1,780 mg to about 2,420 mg, from about 1,790 mg to about 2,410 mg, from about 1,800 mg to about 2,400 mg, from about 1,810 mg to about 2,390 mg, from about 1,820 mg to about 2,380 mg, from about 1,830 mg to about 2,370 mg, from about 1,840 mg to about 2,360 mg, from about 1,850 mg to about 2,350 mg, from about 1,860 mg to about 2,340 mg, from about 1,870 mg to about 2,330 mg, from about 1,880 mg to about 2,320 mg, from about 1,890 mg to about 2,310 mg, from about 1,900 mg to about 2,300 mg, from about 1,910 mg to about 2,290 mg, from about 1,920 mg to about 2,280 mg, from about 1,930 mg to about 2,270 mg, from about 1,940 mg to about 2,260 mg, from about 1,950 mg to about 2,250 mg, from about 1,960 mg to about 2,240 mg, from about 1,970 mg to about 2,230 mg, from about 1,980 mg to about 2,220 mg, from about 1,990 mg to about 2,210 mg, from about 2,000 mg to about 2,200 mg, from about 2,010 mg to about 2,190 mg, from about 2,020 mg to about 2,180 mg, from about 2,030 mg to about 2,170 mg, from about 2,040 mg to about 2,160 mg, from about 2,050 mg to about 2,150 mg, from about 2,060 mg to about 2,140 mg, from about 2,070 mg to about 2,130 mg, from about 2,080 mg to about 2,120 mg, or from about 2,090 mg to about 2,110 mg, such as about 2,100 mg e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In another aspect, the disclosure features an oxytocin antagonist, such as a compound represented by formula (I), for use in the method described in any of the preceding aspects of the disclosure.

In some embodiments of any of the above aspects of the disclosure, administration of the oxytocin antagonist reduces the likelihood of embryo implantation failure and/or miscarriage.

In an additional aspect, the disclosure provides a method of treating a subject undergoing embryo transfer therapy by:

a. administering to the subject a therapeutically effective amount of an oxytocin antagonist, such as a compound represented by formula (I)

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or a geometric isomer, enantiomer, diastereomer, racemate, or salt thereof, wherein

n is an integer from 1 to 3;

R¹is selected from the group consisting of hydrogen and C₁-C₆alkyl;

R³is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of oxygen and NR⁴; and

wherein the compound is administered to the subject in an amount of from about 1,500 mg to about 2,700 mg per dose (e.g., in an amount of from about 1,500 mg to about 2,100 mg per dose, from about 1,550 mg to about 2,050 mg per dose, from about 1,600 mg to about 2,000 mg per dose, from about 1,650 mg to about 1,950 mg per dose, from about 1,700 mg to about 1,900 mg per dose, from about 1,750 mg to about 1,850 mg per dose, from about 1,760 mg to about 1,840 mg per dose, from about 1,770 mg to about 1,830 mg per dose, from about 1,780 mg to about 1,820 mg per dose, from about 1,790 mg to about 1,810 mg per dose, from about 1,791 mg to about 1,809 mg per dose, from about 1,792 mg to about 1,808 mg per dose, from about 1,793 mg to about 1,807 mg per dose, from about 1,794 mg to about 1,806 mg per dose, from about 1,795 mg to about 1,805 mg per dose, from about 1,796 mg to about 1,804 mg per dose, from about 1,797 mg to about 1,803 mg per dose, from about 1,798 mg to about 1,802 mg per dose, or from about 1,799 mg to about 1,801 mg per dose, such as an amount of about 1,500 mg, 1,510 mg, 1,520 mg, 1,530 mg, 1,540 mg, 1,550 mg, 1,560 mg, 1,570 mg, 1,580 mg, 1,590 mg, 1,600 mg, 1,610 mg, 1,620 mg, 1,630 mg, 1,640 mg, 1,650 mg, 1,660 mg, 1,670 mg, 1,680 mg, 1,690 mg, 1,700 mg, 1,710 mg, 1,720 mg, 1,730 mg, 1,740 mg, 1,750 mg, 1,760 mg, 1,770 mg, 1,780 mg, 1,790 mg, 1,800 mg, 1,810 mg, 1,820 mg, 1,830 mg, 1,840 mg, 1,850 mg, 1,860 mg, 1,870 mg, 1,880 mg, 1,890 mg, 1,900 mg, 1,910 mg, 1,920 mg, 1,930 mg, 1,940 mg, 1,950 mg, 1,960 mg, 1,970 mg, 1,980 mg, 1,990 mg, 2,000 mg, 2,010 mg, 2,020 mg, 2,030 mg, 2,040 mg, 2,050 mg, 2,060 mg, 2,070 mg, 2,080 mg, 2,090 mg, or 2,100 mg per dose, such as in an amount of about 1,800 mg per dose, or in an amount of from about 2,100 mg to about 2,700 mg per dose, from about 2,150 mg to about 2,650 mg per dose, from about 2,200 mg to about 2,600 mg per dose, from about 2,250 mg to about 2,550 mg per dose, from about 2,300 mg to about 2,500 mg per dose, from about 2,350 mg to about 2,450 mg per dose, from about 2,360 mg to about 2,440 mg per dose, from about 2,370 mg to about 2,430 mg per dose, from about 2,380 mg to about 2,420 mg per dose, from about 2,390 mg to about 2,410 mg per dose, from about 2,391 mg to about 2,409 mg per dose, from about 2,392 mg to about 2,408 mg per dose, from about 2,393 mg to about 2,407 mg per dose, from about 2,394 mg to about 2,406 mg per dose, from about 2,395 mg to about 2,405 mg per dose, from about 2,396 mg to about 2,404 mg per dose, from about 2,397 mg to about 2,403 mg per dose, from about 2,398 mg to about 2,402 mg per dose, or from about 2,399 mg to about 2,401 mg per dose, such as in an amount of about 2,400 mg per dose (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II))); and

b. transferring one or more embryos (e.g., one, two, three, or more embryos) to the uterus of the subject following administration of the oxytocin antagonist.

In another aspect, the disclosure provides a method of treating a subject undergoing embryo transfer therapy by:

a. administering to the subject a therapeutically effective amount of an oxytocin antagonist, such as a compound represented by formula (I)

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or a geometric isomer, enantiomer, diastereomer, racemate, or salt thereof, wherein

n is an integer from 1 to 3;

R¹is selected from the group consisting of hydrogen and C₁-C₆alkyl;

R³is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of oxygen and NR⁴; and

wherein the compound is administered to the subject in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling from about 1,500 mg to about 2,700 mg (e.g., in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling from about 1,500 mg to about 2,100 mg, from about 1,550 mg to about 2,050 mg, from about 1,600 mg to about 2,000 mg, from about 1,650 mg to about 1,950 mg, from about 1,700 mg to about 1,900 mg, from about 1,750 mg to about 1,850 mg, from about 1,760 mg to about 1,840 mg, from about 1,770 mg to about 1,830 mg, from about 1,780 mg to about 1,820 mg, from about 1,790 mg to about 1,810 mg, from about 1,791 mg to about 1,809 mg, from about 1,792 mg to about 1,808 mg, from about 1,793 mg to about 1,807 mg, from about 1,794 mg to about 1,806 mg, from about 1,795 mg to about 1,805 mg, from about 1,796 mg to about 1,804 mg, from about 1,797 mg to about 1,803 mg, from about 1,798 mg to about 1,802 mg, or from about 1,799 mg to about 1,801 mg, such as in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling 1,500 mg, 1,510 mg, 1,520 mg, 1,530 mg, 1,540 mg, 1,550 mg, 1,560 mg, 1,570 mg, 1,580 mg, 1,590 mg, 1,600 mg, 1,610 mg, 1,620 mg, 1,630 mg, 1,640 mg, 1,650 mg, 1,660 mg, 1,670 mg, 1,680 mg, 1,690 mg, 1,700 mg, 1,710 mg, 1,720 mg, 1,730 mg, 1,740 mg, 1,750 mg, 1,760 mg, 1,770 mg, 1,780 mg, 1,790 mg, 1,800 mg, 1,810 mg, 1,820 mg, 1,830 mg, 1,840 mg, 1,850 mg, 1,860 mg, 1,870 mg, 1,880 mg, 1,890 mg, 1,900 mg, 1,910 mg, 1,920 mg, 1,930 mg, 1,940 mg, 1,950 mg, 1,960 mg, 1,970 mg, 1,980 mg, 1,990 mg, 2,000 mg, 2,010 mg, 2,020 mg, 2,030 mg, 2,040 mg, 2,050 mg, 2,060 mg, 2,070 mg, 2,080 mg, 2,090 mg, or 2,100 mg, such as in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling about 1,800 mg, or in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling from about 2,100 mg to about 2,700 mg, from about 2,150 mg to about 2,650 mg, from about 2,200 mg to about 2,600 mg, from about 2,250 mg to about 2,550 mg, from about 2,300 mg to about 2,500 mg, from about 2,350 mg to about 2,450 mg, from about 2,360 mg to about 2,440 mg, from about 2,370 mg to about 2,430 mg, from about 2,380 mg to about 2,420 mg, from about 2,390 mg to about 2,410 mg, from about 2,391 mg to about 2,409 mg, from about 2,392 mg to about 2,408 mg, from about 2,393 mg to about 2,407 mg, from about 2,394 mg to about 2,406 mg, from about 2,395 mg to about 2,405 mg, from about 2,396 mg to about 2,404 mg, from about 2,397 mg to about 2,403 mg, from about 2,398 mg to about 2,402 mg, or from about 2,399 mg to about 2,401 mg, such as in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling about 2,100 mg, 2,110 mg, 2,120 mg, 2,130 mg, 2,140 mg, 2,150 mg, 2,160 mg, 2,170 mg, 2,180 mg, 2,190 mg, 2,200 mg, 2,210 mg, 2,220 mg, 2,230 mg, 2,240 mg, 2,250 mg, 2,260 mg, 2,270 mg, 2,280 mg, 2,290 mg, 2,300 mg, 2,310 mg, 2,320 mg, 2,330 mg, 2,340 mg, 2,350 mg, 2,360 mg, 2,370 mg, 2,380 mg, 2,390 mg, 2,400 mg, 2,410 mg, 2,420 mg, 2,430 mg, 2,440 mg, 2,450 mg, 2,460 mg, 2,470 mg, 2,480 mg, 2,490 mg, 2,500 mg, 2,510 mg, 2,520 mg, 2,530 mg, 2,540 mg, 2,550 mg, 2,560 mg, 2,570 mg, 2,580 mg, 2,590 mg, 2,600 mg, 2,610 mg, 2,620 mg, 2,630 mg, 2,640 mg, 2,650 mg, 2,660 mg, 2,670 mg, 2,680 mg, 2,690 mg, or 2,700 mg, such as in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling about 2,400 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II))); and

b. transferring one or more embryos (e.g., one, two, three, or more embryos) to the uterus of the subject following administration of the oxytocin antagonist.

In a further aspect, the disclosure provides a method of treating a subject undergoing embryo transfer therapy by:

a. administering to the subject a therapeutically effective amount of an oxytocin antagonist, such as a compound represented by formula (I)

embedded image

or a geometric isomer, enantiomer, diastereomer, racemate, or salt thereof, wherein

n is an integer from 1 to 3;

R¹is selected from the group consisting of hydrogen and C₁-C₆alkyl;

R³is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of oxygen and NR⁴; and

wherein the compound is administered to the subject in a single dose (e.g., on the day of the embryo transfer therapy) of from about 1,500 mg to about 2,700 mg (e.g., in a single dose (e.g., on the day of the embryo transfer therapy) of from about 1,500 mg to about 2,100 mg, from about 1,550 mg to about 2,050 mg, from about 1,600 mg to about 2,000 mg, from about 1,650 mg to about 1,950 mg, from about 1,700 mg to about 1,900 mg, from about 1,750 mg to about 1,850 mg, from about 1,760 mg to about 1,840 mg, from about 1,770 mg to about 1,830 mg, from about 1,780 mg to about 1,820 mg, from about 1,790 mg to about 1,810 mg, from about 1,791 mg to about 1,809 mg, from about 1,792 mg to about 1,808 mg, from about 1,793 mg to about 1,807 mg, from about 1,794 mg to about 1,806 mg, from about 1,795 mg to about 1,805 mg, from about 1,796 mg to about 1,804 mg, from about 1,797 mg to about 1,803 mg, from about 1,798 mg to about 1,802 mg, or from about 1,799 mg to about 1,801 mg, such as in a single dose (e.g., on the day of the embryo transfer therapy) of about 1,500 mg, 1,510 mg, 1,520 mg, 1,530 mg, 1,540 mg, 1,550 mg, 1,560 mg, 1,570 mg, 1,580 mg, 1,590 mg, 1,600 mg, 1,610 mg, 1,620 mg, 1,630 mg, 1,640 mg, 1,650 mg, 1,660 mg, 1,670 mg, 1,680 mg, 1,690 mg, 1,700 mg, 1,710 mg, 1,720 mg, 1,730 mg, 1,740 mg, 1,750 mg, 1,760 mg, 1,770 mg, 1,780 mg, 1,790 mg, 1,800 mg, 1,810 mg, 1,820 mg, 1,830 mg, 1,840 mg, 1,850 mg, 1,860 mg, 1,870 mg, 1,880 mg, 1,890 mg, 1,900 mg, 1,910 mg, 1,920 mg, 1,930 mg, 1,940 mg, 1,950 mg, 1,960 mg, 1,970 mg, 1,980 mg, 1,990 mg, 2,000 mg, 2,010 mg, 2,020 mg, 2,030 mg, 2,040 mg, 2,050 mg, 2,060 mg, 2,070 mg, 2,080 mg, 2,090 mg, or 2,100 mg, such as in a single dose (e.g., on the day of the embryo transfer therapy) of about 1,800 mg, or in a single dose (e.g., on the day of the embryo transfer therapy) of from about 2,100 mg to about 2,700 mg, from about 2,150 mg to about 2,650 mg, from about 2,200 mg to about 2,600 mg, from about 2,250 mg to about 2,550 mg, from about 2,300 mg to about 2,500 mg, from about 2,350 mg to about 2,450 mg, from about 2,360 mg to about 2,440 mg, from about 2,370 mg to about 2,430 mg, from about 2,380 mg to about 2,420 mg, from about 2,390 mg to about 2,410 mg, from about 2,391 mg to about 2,409 mg, from about 2,392 mg to about 2,408 mg, from about 2,393 mg to about 2,407 mg, from about 2,394 mg to about 2,406 mg, from about 2,395 mg to about 2,405 mg, from about 2,396 mg to about 2,404 mg, from about 2,397 mg to about 2,403 mg, from about 2,398 mg to about 2,402 mg, or from about 2,399 mg to about 2,401 mg, such as in a single dose (e.g., on the day of the embryo transfer therapy) of about 2,100 mg, 2,110 mg, 2,120 mg, 2,130 mg, 2,140 mg, 2,150 mg, 2,160 mg, 2,170 mg, 2,180 mg, 2,190 mg, 2,200 mg, 2,210 mg, 2,220 mg, 2,230 mg, 2,240 mg, 2,250 mg, 2,260 mg, 2,270 mg, 2,280 mg, 2,290 mg, 2,300 mg, 2,310 mg, 2,320 mg, 2,330 mg, 2,340 mg, 2,350 mg, 2,360 mg, 2,370 mg, 2,380 mg, 2,390 mg, 2,400 mg, 2,410 mg, 2,420 mg, 2,430 mg, 2,440 mg, 2,450 mg, 2,460 mg, 2,470 mg, 2,480 mg, 2,490 mg, 2,500 mg, 2,510 mg, 2,520 mg, 2,530 mg, 2,540 mg, 2,550 mg, 2,560 mg, 2,570 mg, 2,580 mg, 2,590 mg, 2,600 mg, 2,610 mg, 2,620 mg, 2,630 mg, 2,640 mg, 2,650 mg, 2,660 mg, 2,670 mg, 2,680 mg, 2,690 mg, or 2,700 mg, such as in an amount of about 2,400 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II))); and

b. transferring one or more embryos (e.g., one, two, three, or more embryos) to the uterus of the subject following administration of the oxytocin antagonist.

In another aspect, the disclosure features an oxytocin antagonist, such as a compound represented by formula (I), for use in the method described in any of the preceding aspects of the disclosure.

In some embodiments of any of the above aspects of the disclosure, the administering reduces the likelihood of embryo implantation failure and/or miscarriage.

In some embodiments of any of the above aspects of the disclosure, the oxytocin antagonist is administered to the subject from about 1 hour to about 24 hours prior to the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject from about 1 hour to about 12 hours prior the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject from about 12 hours to about 24 hours prior the transfer of the one or more embryos to the subject.

In some embodiments of any of the above aspects of the disclosure, the oxytocin antagonist is administered to the subject from about 1 hour to about 10 hours prior the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject from about 1 hour to about 9 hours prior the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject from about 1 hour to about 8 hours prior the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject from about 1 hour to about 7 hours prior the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject from about 1 hour to about 6 hours prior the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject from about 1 hour to about 5 hours prior the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject from about 1 hour to about 4 hours prior the transfer of the one or more embryos to the subject.

In some embodiments of any of the above aspects of the disclosure, the oxytocin antagonist is administered to the subject from about 2 hours to about 6 hours prior the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject from about 3 hours to about 5 hours prior the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours, or more prior to the transfer of the one or more embryos to the subject.

In some embodiments of any of the above aspects of the disclosure, the oxytocin antagonist is administered to the subject about 4 hours prior to the transfer of the one or more embryos to the subject.

In some embodiments of any of the above aspects of the disclosure, the oxytocin antagonist is administered to the subject prior to embryo transfer in a single dose.

In some embodiments of any of the above aspects of the disclosure, the oxytocin antagonist is administered to the subject prior to embryo transfer (i.e., prior to the transfer of the one or more embryos to the uterus of the subject) in multiple doses (for instance, in multiple periodic doses), such as from 1 to 20 doses, for instance, per 12 hours, per 24 hours, per 36 hours, per 48 hours, per 60 hours, per 72 hours, per 84 hours, per 96 hours, per 108 hours, 120 hours, per 132 hours, per 144 hours, per 156 hours, per 168 hours, or longer, prior to embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject prior to embryo transfer in from 1 to 20 doses per 24 hours, such as 1 dose per 24 hours, 2 doses per 24 hours, 3 doses per 24 hours, 4 doses per 24 hours, 5 doses per 24 hours, 6 doses per 24 hours, 7 doses per 24 hours, 8 doses per 24 hours, 9 doses per 24 hours, 10 doses per 24 hours, 11 doses per 24 hours, 12 doses per 24 hours, 13 doses per 24 hours, 14 doses per 24 hours, 15 doses per 24 hours, 16 doses per 24 hours, 17 doses per 24 hours, 18 doses per 24 hours, 19 doses per 24 hours, 20 doses per 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject prior to embryo transfer in more than 20 doses per 24 hours.

For instance, in some embodiments, the oxytocin antagonist is administered to the subject in from 1 to 10 doses, for example, per 12 hours, per 24 hours, per 36 hours, per 48 hours, per 60 hours, per 72 hours, per 84 hours, per 96 hours, per 108 hours, 120 hours, per 132 hours, per 144 hours, per 156 hours, per 168 hours, or longer, prior to embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject prior to embryo transfer in from 1 to 10 doses per 24 hours, such as 1 dose per 24 hours, 2 doses per 24 hours, 3 doses per 24 hours, 4 doses per 24 hours, 5 doses per 24 hours, 6 doses per 24 hours, 7 doses per 24 hours, 8 doses per 24 hours, 9 doses per 24 hours, 10 doses per 24 hours.

In some embodiments, the oxytocin antagonist is administered to the subject in from 1 to 5 doses, for instance, per 12 hours, per 24 hours, per 36 hours, per 48 hours, per 60 hours, per 72 hours, per 84 hours, per 96 hours, per 108 hours, 120 hours, per 132 hours, per 144 hours, per 156 hours, per 168 hours, or longer, prior to embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in from 10 to 20 doses, for instance, per 12 hours, per 24 hours, per 36 hours, per 48 hours, per 60 hours, per 72 hours, per 84 hours, per 96 hours, per 108 hours, per 120 hours, per 132 hours, per 144 hours, per 156 hours, per 168 hours, or longer, prior to embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in from 10 to 15 doses, for instance, per 12 hours, per 24 hours, per 36 hours, per 48 hours, per 60 hours, per 72 hours, per 84 hours, per 96 hours, per 108 hours, 120 hours, per 132 hours, per 144 hours, per 156 hours, per 168 hours, or longer, prior to embryo transfer.

In some embodiments, the oxytocin antagonist is administered to the subject in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more, doses, for instance, per 12 hours, per 24 hours, per 36 hours, per 48 hours, per 60 hours, per 72 hours, per 84 hours, per 96 hours, per 108 hours, 120 hours, per 132 hours, per 144 hours, per 156 hours, per 168 hours, or longer, prior to embryo transfer.

In some embodiments, the oxytocin antagonist is administered to the subject prior to embryo transfer in up to 7 doses (e.g., 1, 2, 3, 4, 5, 6, or 7 doses) per 24 hours. In some embodiments, the oxytocin antagonist is administered to the subject prior to embryo transfer in 1 dose per 24 hours, such as 1 dose per 24 hours of compound (II), below. In some embodiments, the oxytocin antagonist is administered to the subject prior to embryo transfer in 2 doses per 24 hours, such as 2 doses per 24 hours of compound (II), below. In some embodiments, the oxytocin antagonist is administered to the subject prior to embryo transfer in 3 doses per 24 hours, such as 3 doses per 24 hours of compound (II), below. In some embodiments, the oxytocin antagonist is administered to the subject prior to embryo transfer in 4 doses per 24 hours, such as 4 doses per 24 hours of compound (II), below. In some embodiments, the oxytocin antagonist is administered to the subject prior to embryo transfer in 5 doses per 24 hours, such as 5 doses per 24 hours of compound (II), below. In some embodiments, the oxytocin antagonist is administered to the subject prior to embryo transfer in 6 doses per 24 hours, such as 6 doses per 24 hours of compound (II), below. In some embodiments, the oxytocin antagonist is administered to the subject prior to embryo transfer in 7 doses per 24 hours, such as 7 doses per 24 hours of compound (II), below.

The multiple doses may be administered, for example, starting at from about 1 hour to about 14 days, or more, prior to embryo transfer. In some embodiments, the multiple doses are administered starting at from about 1 hour to about 7 days, or more, prior to embryo transfer. In some embodiments, the multiple doses may be administered starting at from about 1 day to about 14 days prior to embryo transfer. In some embodiments, the multiple doses may be administered starting at from about 3 days to about 11 days prior to embryo transfer. In some embodiments, the multiple doses may be administered starting at from about 1 day to about 7 days prior to embryo transfer. In some embodiments, the multiple doses may be administered starting at from about 2 days to about 5 days prior to embryo transfer. In some embodiments, the multiple doses may be administered starting at from about 3 days to about 4 days prior to embryo transfer. For instance, the multiple doses may be administered starting at 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 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, 29 days, 30 days, or more, prior to embryo transfer to the subject.

In some embodiments, the multiple doses are administered starting at about 2 days prior to embryo transfer.

In some embodiments, the multiple doses are administered starting at about 3 days prior to embryo transfer.

In some embodiments, the multiple doses are administered starting at about 4 days prior to embryo transfer.

In some embodiments, the multiple doses are administered starting at about 5 days prior to embryo transfer.

In some embodiments, the multiple doses are administered starting at about 6 days prior to embryo transfer.

In some embodiments, the multiple doses are administered starting at about 7 days prior to embryo transfer.

In some embodiments, the multiple doses terminate on the day of embryo transfer to the subject. In some embodiments, the multiple doses terminate with a final dose of the oxytocin antagonist that is administered concurrently with (e.g., within 60 minutes of) transfer of the one or more embryos to the subject.

In some embodiments of any of the above aspects of the disclosure, the multiple doses continue following embryo transfer. For instance, the oxytocin antagonist may be administered to the subject in one or more additional doses concurrently with embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses following embryo transfer (for instance, in multiple periodic doses), such as in one or more additional doses administered within about 1 hour to about 1 week, or longer (e.g., within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 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, 29 days, 30 days, or more) following the transfer of the one or more embryos to the subject.

For example, in some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses within about 1 hour to about 24 hours following the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses within about 1 hour to about 12 hours following the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses within from about 12 hours to about 24 hours following the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses within from about 1 hour to about 10 hours following the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses within from about 1 hour to about 9 hours following the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses within from about 1 hour to about 8 hours following the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses within from about 1 hour to about 7 hours following the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses within from about 1 hour to about 6 hours following the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses within from about 1 hour to about 5 hours following the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses within from about 1 hour to about 4 hours following the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses within from about 2 hours to about 6 hours following the transfer of the one or more embryos to the subject. In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses within from about 3 hours to about 5 hours following the transfer of the one or more embryos to the subject.

In some embodiments, the oxytocin antagonist is administered to the subject in one or more additional doses starting at about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, or more, following the transfer of the one or more embryos to the subject.

In some embodiments, the oxytocin antagonist is administered to the subject in multiple additional doses following embryo transfer, such as in from 1 to 20 additional doses, for instance, per 12 hours, per 24 hours, per 36 hours, per 48 hours, per 60 hours, per 72 hours, per 84 hours, per 96 hours, per 108 hours, 120 hours, per 132 hours, per 144 hours, per 156 hours, per 168 hours, or longer, following embryo transfer. In some embodiments, the oxytocin antagonist is additionally administered to the subject following embryo transfer in from 1 to 20 doses per 24 hours, such as 1 dose per 24 hours, 2 doses per 24 hours, 3 doses per 24 hours, 4 doses per 24 hours, 5 doses per 24 hours, 6 doses per 24 hours, 7 doses per 24 hours, 8 doses per 24 hours, 9 doses per 24 hours, 10 doses per 24 hours, 11 doses per 24 hours, 12 doses per 24 hours, 13 doses per 24 hours, 14 doses per 24 hours, 15 doses per 24 hours, 16 doses per 24 hours, 17 doses per 24 hours, 18 doses per 24 hours, 19 doses per 24 hours, 20 doses per 24 hours. In some embodiments, the oxytocin antagonist is additionally administered to the subject following embryo transfer in more than 20 doses per 24 hours.

For instance, in some embodiments, the oxytocin antagonist is administered to the subject in from 1 to 10 additional doses, for instance, per 12 hours, per 24 hours, per 36 hours, per 48 hours, per 60 hours, per 72 hours, per 84 hours, per 96 hours, per 108 hours, 120 hours, per 132 hours, per 144 hours, per 156 hours, per 168 hours, or longer, following embryo transfer. In some embodiments, the oxytocin antagonist is additionally administered to the subject following embryo transfer in from 1 to 10 doses per 24 hours, such as 1 dose per 24 hours, 2 doses per 24 hours, 3 doses per 24 hours, 4 doses per 24 hours, 5 doses per 24 hours, 6 doses per 24 hours, 7 doses per 24 hours, 8 doses per 24 hours, 9 doses per 24 hours, 10 doses per 24 hours.

In some embodiments, the oxytocin antagonist is administered to the subject in from 1 to 5 additional doses, for instance, per 12 hours, per 24 hours, per 36 hours, per 48 hours, per 60 hours, per 72 hours, per 84 hours, per 96 hours, per 108 hours, 120 hours, per 132 hours, per 144 hours, per 156 hours, per 168 hours, or longer, following embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in from 10 to 20 additional doses, for instance, per 12 hours, per 24 hours, per 36 hours, per 48 hours, per 60 hours, per 72 hours, per 84 hours, per 96 hours, per 108 hours, per 120 hours, per 132 hours, per 144 hours, per 156 hours, per 168 hours, or longer, following embryo transfer. In some embodiments, the oxytocin antagonist is administered to the subject in from 10 to 15 additional doses, for instance, per 12 hours, per 24 hours, per 36 hours, per 48 hours, per 60 hours, per 72 hours, per 84 hours, per 96 hours, per 108 hours, 120 hours, per 132 hours, per 144 hours, per 156 hours, per 168 hours, or longer, following embryo transfer.

In some embodiments, the oxytocin antagonist is administered to the subject in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more, additional doses, for instance, per 12 hours, per 24 hours, per 36 hours, per 48 hours, per 60 hours, per 72 hours, per 84 hours, per 96 hours, per 108 hours, 120 hours, per 132 hours, per 144 hours, per 156 hours, per 168 hours, or longer, following embryo transfer.

In some embodiments, the oxytocin antagonist is administered to the subject following embryo transfer in up to 7 additional doses (e.g., 1, 2, 3, 4, 5, 6, or 7 doses) per 24 hours. In some embodiments, the oxytocin antagonist is additionally administered to the subject following embryo transfer in 1 dose per 24 hours, such as 1 additional dose per 24 hours of compound (II), below. In some embodiments, the oxytocin antagonist is additionally administered to the subject following embryo transfer in 2 doses per 24 hours, such as 2 additional doses per 24 hours of compound (II), below. In some embodiments, the oxytocin antagonist is additionally administered to the subject following embryo transfer in 3 doses per 24 hours, such as 3 additional doses per 24 hours of compound (II), below. In some embodiments, the oxytocin antagonist is additionally administered to the subject following embryo transfer in 4 doses per 24 hours, such as 4 additional doses per 24 hours of compound (II), below. In some embodiments, the oxytocin antagonist is additionally administered to the subject following embryo transfer in 5 doses per 24 hours, such as 5 additional doses per 24 hours of compound (II), below. In some embodiments, the oxytocin antagonist is additionally administered to the subject following embryo transfer in 6 doses per 24 hours, such as 6 additional doses per 24 hours of compound (II), below. In some embodiments, the oxytocin antagonist is additionally administered to the subject following embryo transfer in 7 doses per 24 hours, such as 7 additional doses per 24 hours of compound (II), below.

When one or more additional doses of the oxytocin antagonist are administered to the subject following embryo transfer, administration of the oxytocin antagonist may terminate, for instance, within from about 1 hour to about 14 days, or more, following embryo transfer. For instance, administration of the oxytocin antagonist may terminate within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, 96 hours, 108 hours, 120 hours, 132 hours, 144 hours, 156 hours, 168 hours, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 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, 29 days, 30 days, or more, following embryo transfer.

Thus, in some embodiments, the oxytocin antagonist is administered to the subject in additional daily doses following embryo transfer for about 1 day to about 14 days following embryo transfer. In some embodiments, the additional daily doses are administered to the subject for about 3 days to about 11 days following embryo transfer. In some embodiments, the additional daily doses are administered to the subject for 7 days following embryo transfer.

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or a geometric isomer, enantiomer, diastereomer, racemate, or sat thereof, wherein

n is an integer from 1 to 3;

R¹is selected from the group consisting of hydrogen and C₁-C₆alkyl;

R³is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of oxygen and NR⁴; and

wherein the oxytocin antagonist is administered concurrently with transfer of one or more embryos (e.g., one, two, three, or more embryos) to the uterus of the subject.

embedded image

or a geometric isomer, enantiomer, diastereomer, racemate, or salt thereof, wherein

n is an integer from 1 to 3;

R¹is selected from the group consisting of hydrogen and C₁-C₆alkyl;

R³is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of oxygen and NR⁴; and

wherein the oxytocin antagonist is administered concurrently with transfer of one or more embryos (e.g., one, two, three, or more embryos) to the uterus of the subject.

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or a geometric isomer, enantiomer, diastereomer, racemate, or salt thereof, wherein

n is an integer from 1 to 3;

R¹is selected from the group consisting of hydrogen and C₁-C₆alkyl;

R³is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of oxygen and NR⁴; and

wherein the compound is administered to the subject in a single dose (e.g., on the day of the embryo transfer therapy) of from about 1,500 mg to about 2,700 mg (e.g., in a single dose (e.g., on the day of the embryo transfer therapy) of from about 1,550 mg to about 2,050 mg, from about 1,600 mg to about 2,000 mg, from about 1,650 mg to about 1,950 mg, from about 1,700 mg to about 1,900 mg, from about 1,750 mg to about 1,850 mg, from about 1,760 mg to about 1,840 mg, from about 1,770 mg to about 1,830 mg, from about 1,780 mg to about 1,820 mg, from about 1,790 mg to about 1,810 mg, from about 1,791 mg to about 1,809 mg, from about 1,792 mg to about 1,808 mg, from about 1,793 mg to about 1,807 mg, from about 1,794 mg to about 1,806 mg, from about 1,795 mg to about 1,805 mg, from about 1,796 mg to about 1,804 mg, from about 1,797 mg to about 1,803 mg, from about 1,798 mg to about 1,802 mg, or from about 1,799 mg to about 1,801 mg, such as in a single dose (e.g., on the day of the embryo transfer therapy) of about 1,500 mg, 1,510 mg, 1,520 mg, 1,530 mg, 1,540 mg, 1,550 mg, 1,560 mg, 1,570 mg, 1,580 mg, 1,590 mg, 1,600 mg, 1,610 mg, 1,620 mg, 1,630 mg, 1,640 mg, 1,650 mg, 1,660 mg, 1,670 mg, 1,680 mg, 1,690 mg, 1,700 mg, 1,710 mg, 1,720 mg, 1,730 mg, 1,740 mg, 1,750 mg, 1,760 mg, 1,770 mg, 1,780 mg, 1,790 mg, 1,800 mg, 1,810 mg, 1,820 mg, 1,830 mg, 1,840 mg, 1,850 mg, 1,860 mg, 1,870 mg, 1,880 mg, 1,890 mg, 1,900 mg, 1,910 mg, 1,920 mg, 1,930 mg, 1,940 mg, 1,950 mg, 1,960 mg, 1,970 mg, 1,980 mg, 1,990 mg, 2,000 mg, 2,010 mg, 2,020 mg, 2,030 mg, 2,040 mg, 2,050 mg, 2,060 mg, 2,070 mg, 2,080 mg, 2,090 mg, or 2,100 mg, such as in a single dose (e.g., on the day of the embryo transfer therapy) of about 1,800 mg, or in a single dose (e.g., on the day of the embryo transfer therapy) of from about 2,100 mg to about 2,700 mg, from about 2,150 mg to about 2,650 mg, from about 2,200 mg to about 2,600 mg, from about 2,250 mg to about 2,550 mg, from about 2,300 mg to about 2,500 mg, from about 2,350 mg to about 2,450 mg, from about 2,360 mg to about 2,440 mg, from about 2,370 mg to about 2,430 mg, from about 2,380 mg to about 2,420 mg, from about 2,390 mg to about 2,410 mg, from about 2,391 mg to about 2,409 mg, from about 2,392 mg to about 2,408 mg, from about 2,393 mg to about 2,407 mg, from about 2,394 mg to about 2,406 mg, from about 2,395 mg to about 2,405 mg, from about 2,396 mg to about 2,404 mg, from about 2,397 mg to about 2,403 mg, from about 2,398 mg to about 2,402 mg, or from about 2,399 mg to about 2,401 mg, such as in a single dose (e.g., on the day of the embryo transfer therapy) of about 2,100 mg, 2,110 mg, 2,120 mg, 2,130 mg, 2,140 mg, 2,150 mg, 2,160 mg, 2,170 mg, 2,180 mg, 2,190 mg, 2,200 mg, 2,210 mg, 2,220 mg, 2,230 mg, 2,240 mg, 2,250 mg, 2,260 mg, 2,270 mg, 2,280 mg, 2,290 mg, 2,300 mg, 2,310 mg, 2,320 mg, 2,330 mg, 2,340 mg, 2,350 mg, 2,360 mg, 2,370 mg, 2,380 mg, 2,390 mg, 2,400 mg, 2,410 mg, 2,420 mg, 2,430 mg, 2,440 mg, 2,450 mg, 2,460 mg, 2,470 mg, 2,480 mg, 2,490 mg, 2,500 mg, 2,510 mg, 2,520 mg, 2,530 mg, 2,540 mg, 2,550 mg, 2,560 mg, 2,570 mg, 2,580 mg, 2,590 mg, 2,600 mg, 2,610 mg, 2,620 mg, 2,630 mg, 2,640 mg, 2,650 mg, 2,660 mg, 2,670 mg, 2,680 mg, 2,690 mg, or 2,700 mg, such as in a single dose (e.g., on the day of the embryo transfer therapy) of about 2,400 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II))), and

wherein the oxytocin antagonist is administered concurrently with transfer of one or more embryos (e.g., one, two, three, or more embryos) to the uterus of the subject.

In another aspect, the disclosure features an oxytocin antagonist, such as a compound represented by formula (I), for use in the method described in any of the preceding aspects of the disclosure.

In some embodiments of any of the above aspects of the disclosure, the administering reduces the likelihood of embryo implantation failure and/or miscarriage.

In another aspect, the disclosure provides a method of treating a subject undergoing embryo transfer therapy by transferring one or more embryos (e.g., one, two, three, or more embryos) to the uterus of the subject, wherein the subject is concurrently administered a therapeutically effective amount of an oxytocin antagonist, such as a compound represented by formula (I)

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or a geometric isomer, enantiomer, diastereomer, racemate, or salt thereof, wherein

n is an integer from 1 to 3;

R¹is selected from the group consisting of hydrogen and C₁-C₆alkyl;

R³is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of oxygen and NR⁴; and

In another aspect, the disclosure provides a method of treating a subject undergoing embryo transfer therapy by transferring one or more embryos (e.g., one, two, three, or more embryos) to the uterus of the subject, wherein the subject is concurrently administered a therapeutically effective amount of an oxytocin antagonist, such as a compound represented by formula (I)

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or a geometric isomer, enantiomer, diastereomer, racemate, or salt thereof, wherein

n is an integer from 1 to 3;

R¹is selected from the group consisting of hydrogen and C₁-C₆alkyl;

R³is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of oxygen and NR⁴; and

In some embodiments, the compound is administered to the subject in one or more doses (e.g., in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) totaling 1,500 mg, 1,510 mg, 1,520 mg, 1,530 mg, 1,540 mg, 1,550 mg, 1,560 mg, 1,570 mg, 1,580 mg, 1,590 mg, 1,600 mg, 1,610 mg, 1,620 mg, 1,630 mg, 1,640 mg, 1,650 mg, 1,660 mg, 1,670 mg, 1,680 mg, 1,690 mg, 1,700 mg, 1,710 mg, 1,720 mg, 1,730 mg, 1,740 mg, 1,750 mg, 1,760 mg, 1,770 mg, 1,780 mg, 1,790 mg, 1,800 mg, 1,810 mg, 1,820 mg, 1,830 mg, 1,840 mg, 1,850 mg, 1,860 mg, 1,870 mg, 1,880 mg, 1,890 mg, 1,900 mg, 1,910 mg, 1,920 mg, 1,930 mg, 1,940 mg, 1,950 mg, 1,960 mg, 1,970 mg, 1,980 mg, 1,990 mg, 2,000 mg, 2,010 mg, 2,020 mg, 2,030 mg, 2,040 mg, 2,050 mg, 2,060 mg, 2,070 mg, 2,080 mg, 2,090 mg, or 2,100 mg, such as in an amount of about 1,800 mg (e.g., wherein the compound is (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)).

In a further aspect, the disclosure provides a method of treating a subject undergoing embryo transfer therapy by transferring one or more embryos (e.g., one, two, three, or more embryos) to the uterus of the subject, wherein the subject is concurrently administered a therapeutically effective amount of an oxytocin antagonist, such as a compound represented by formula (I)