US 2024/0024294 A1Published application

Compositions and methods for the treatment or prevention of preterm labor

AssigneeXoma (US) LLC

InventorJean-Pierre GOTTELAND

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Abstract

The disclosure provides compositions and methods for delaying the onset of delivery in a pregnant subject, such as a pregnant human subject, that is undergoing or at risk of undergoing preterm labor at a gestational age of from about 24 weeks to about 34 weeks. Using the compositions and methods described herein, such subjects may be administered atosiban in combination with a prostaglandin F2α (PGF2α) antagonist. Exemplary PGF2α receptor antagonists that may be used for the treatment or prevention of preterm labor as described herein include 1,3-thiazolidine-2-carboxamide compounds, such as (3S)-3-({[(2S)-3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}-amino)-3-(4-fluorophenyl)propyl L-valinate or a pharmaceutically acceptable salt thereof (e.g., (3S)-3-({[(2S)-3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}-amino)-3-(4-fluorophenyl)propyl L-valinate hydrochloride). The compositions and methods described herein provide various clinical benefits. Delivery at an early gestational age is a leading cause of perinatal mortality. By delaying labor in pregnant human patients at an early gestational age, the compositions and methods of the disclosure provide unborn infants with additional time to develop vital organs and tissue systems, thereby significantly improving the likelihood of survival following delivery. The compositions and methods described herein may be used to delay the onset of delivery by one or more hours, days, or weeks, for example, so as to enable pregnant subjects to reach a gestational age at which parturition is substantially safer.

Claims153

Dependent claims

A method of delaying the onset of delivery in a pregnant human subject, the method comprising administering to the subject therapeutically effective amounts of atosiban and a compound represented by formula (I)

wherein ring Ar is an optionally fused, optionally substituted aryl group or an optionally fused, optionally substituted heteroaryl group;
ring Cy is an optionally fused, optionally substituted aryl group, optionally fused, optionally substituted heteroaryl group, optionally fused, optionally substituted cycloalkyl group, or an optionally fused, optionally substituted heterocycloalkyl group;
R1 is H, carboxy, acyl, alkoxycarbonyl, C1-C5-alkyl carboxy, C1-C5-alkyl acyl, C1-C5-alkyl alkoxycarbonyl, C1-C5-alkyl acyloxy, C1-C5-alkyl sulfanyl, C1-C5-alkyl sulfinyl, C1-C5-alkyl sulfonyl, C1-C5-alkyl sulfonyloxy, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, C3-C8-cycloalkyl, C1-C6-alkyl aryl, C1-C6-alkyl heteroaryl, C1-C6-alkyl cycloalkyl, C2-C6-alkenyl aryl, C2-C6-alkenyl heteroaryl, C2-C6-alkynyl aryl, C2-C6-alkynyl heteroaryl, substituted carboxy, substituted acyl, substituted alkoxycarbonyl, substituted C1-C5-alkyl carboxy, substituted C1-C5-alkyl acyl, substituted C1-C5-alkyl alkoxycarbonyl, substituted C1-C5-alkyl acyloxy, substituted C1-C5-alkyl sulfanyl, substituted C1-C5-alkyl sulfinyl, substituted C1-C5-alkyl sulfonyl, substituted C1-C5-alkyl sulfonyloxy, substituted C1-C6-alkyl, substituted C2-C6-alkenyl, substituted C2-C6-alkynyl, substituted aryl, substituted heteroaryl, substituted C3-C8-cycloalkyl, substituted C1-C6-alkyl aryl, substituted C1-C6-alkyl heteroaryl, substituted C1-C6-alkyl cycloalkyl, substituted C2-C6-alkenyl aryl, substituted C2-C6-alkenyl heteroaryl, substituted C2-C6-alkynyl aryl, or substituted C2-C6-alkynyl heteroaryl;
each R2 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, substituted C1-C6-alkyl, substituted C2-C6-alkenyl, or substituted C2-C6-alkynyl;
and
n is an integer from 0 to 2,
or a pharmaceutically acceptable salt thereof,
wherein the compound is administered to the subject in an amount of from about 250 mg to about 2,500 mg per dose.

5 more elements

A method of treating or preventing preterm labor in a pregnant human subject, the method comprising administering to the subject therapeutically effective amounts of atosiban and a compound represented by formula (I)

wherein ring Ar is an optionally fused, optionally substituted aryl group or an optionally fused, optionally substituted heteroaryl group;
ring Cy is an optionally fused, optionally substituted aryl group, optionally fused, optionally substituted heteroaryl group, optionally fused, optionally substituted cycloalkyl group, or an optionally fused, optionally substituted heterocycloalkyl group;
R1 is H, carboxy, acyl, alkoxycarbonyl, C1-C5-alkyl carboxy, C1-C5-alkyl acyl, C1-C5-alkyl alkoxycarbonyl, C1-C5-alkyl acyloxy, C1-C5-alkyl sulfanyl, C1-C5-alkyl sulfinyl, C1-C5-alkyl sulfonyl, C1-C5-alkyl sulfonyloxy, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, C3-C8-cycloalkyl, C1-C6-alkyl aryl, C1-C6-alkyl heteroaryl, C1-C6-alkyl cycloalkyl, C2-C6-alkenyl aryl, C2-C6-alkenyl heteroaryl, C2-C6-alkynyl aryl, C2-C6-alkynyl heteroaryl, substituted carboxy, substituted acyl, substituted alkoxycarbonyl, substituted C1-C5-alkyl carboxy, substituted C1-C5-alkyl acyl, substituted C1-C5-alkyl alkoxycarbonyl, substituted C1-C5-alkyl acyloxy, substituted C1-C5-alkyl sulfanyl, substituted C1-C5-alkyl sulfinyl, substituted C1-C5-alkyl sulfonyl, substituted C1-C5-alkyl sulfonyloxy, substituted C1-C6-alkyl, substituted C2-C6-alkenyl, substituted C2-C6-alkynyl, substituted aryl, substituted heteroaryl, substituted C3-C8-cycloalkyl, substituted C1-C6-alkyl aryl, substituted C1-C6-alkyl heteroaryl, substituted C1-C6-alkyl cycloalkyl, substituted C2-C6-alkenyl aryl, substituted C2-C6-alkenyl heteroaryl, substituted C2-C6-alkynyl aryl, or substituted C2-C6-alkynyl heteroaryl;
each R2 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, substituted C1-C6-alkyl, substituted C2-C6-alkenyl, or substituted C2-C6-alkynyl;
and
n is an integer from 0 to 2,
or a pharmaceutically acceptable salt thereof,
wherein the compound is administered to the subject in an amount of from about 250 mg to about 2,500 mg per dose.

5 more elements

A method of preventing labor prior to cesarean delivery in a pregnant human subject, the method comprising administering to the subject therapeutically effective amounts of atosiban and a compound represented by formula (I)

wherein ring Ar is an optionally fused, optionally substituted aryl group or an optionally fused, optionally substituted heteroaryl group;
ring Cy is an optionally fused, optionally substituted aryl group, optionally fused, optionally substituted heteroaryl group, optionally fused, optionally substituted cycloalkyl group, or an optionally fused, optionally substituted heterocycloalkyl group;
R1 is H, carboxy, acyl, alkoxycarbonyl, C1-C5-alkyl carboxy, C1-C5-alkyl acyl, C1-C5-alkyl alkoxycarbonyl, C1-C5-alkyl acyloxy, C1-C5-alkyl sulfanyl, C1-C5-alkyl sulfinyl, C1-C5-alkyl sulfonyl, C1-C5-alkyl sulfonyloxy, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, C3-C8-cycloalkyl, C1-C6-alkyl aryl, C1-C6-alkyl heteroaryl, C1-C6-alkyl cycloalkyl, C2-C6-alkenyl aryl, C2-C6-alkenyl heteroaryl, C2-C6-alkynyl aryl, C2-C6-alkynyl heteroaryl, substituted carboxy, substituted acyl, substituted alkoxycarbonyl, substituted C1-C5-alkyl carboxy, substituted C1-C5-alkyl acyl, substituted C1-C5-alkyl alkoxycarbonyl, substituted C1-C5-alkyl acyloxy, substituted C1-C5-alkyl sulfanyl, substituted C1-C5-alkyl sulfinyl, substituted C1-C5-alkyl sulfonyl, substituted C1-C5-alkyl sulfonyloxy, substituted C1-C6-alkyl, substituted C2-C6-alkenyl, substituted C2-C6-alkynyl, substituted aryl, substituted heteroaryl, substituted C3-C8-cycloalkyl, substituted C1-C6-alkyl aryl, substituted C1-C6-alkyl heteroaryl, substituted C1-C6-alkyl cycloalkyl, substituted C2-C6-alkenyl aryl, substituted C2-C6-alkenyl heteroaryl, substituted C2-C6-alkynyl aryl, or substituted C2-C6-alkynyl heteroaryl;
each R2 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, substituted C1-C6-alkyl, substituted C2-C6-alkenyl, or substituted C2-C6-alkynyl;
and
n is an integer from 0 to 2,
or a pharmaceutically acceptable salt thereof,
wherein the compound is administered to the subject in an amount of from about 250 mg to about 2,500 mg per dose.

5 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/037,007Filed 16 Nov 2021
Priority: 16 Nov 2020
Published: 25 Jan 2024
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

A61K 31/426
Thiazoles: 1,3-Thiazoles
A61K 31/401
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: proline; Derivatives…
A61K 38/095
Peptides having 5 to 11 amino acids: oxytocins; Vasopressins; Related peptides
A61P 5/12
Of the posterior pituitary hormones, e.g. oxytocin, ADH: for decreasing, blocking or antagonising the activity of the posterior pituitary hormones

Family

Application63/114,233Us provisional application · filed 16 Nov 2020
US 2024/0024294 A1This patent

From the US filing history. Foreign family members aren’t listed.

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