Compositions and methods for delaying the incidence of labor

Abstract

The invention 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 nifedipine 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. Using the compositions and methods described herein, a subject may be dosed with a PGF2α receptor antagonist and a reduced amount or frequency of nifedipine relative to the amount or frequency of nifedipine that would otherwise be used if the nifedipine were given in the absence of the PGF2α receptor antagonist.

1 - 105 . (canceled) 
     
     
         106 . A method of delaying the onset of delivery in a pregnant human subject, the method comprising administering to the subject a therapeutically effective amount of 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; 
         R 1  is H, carboxy, acyl, alkoxycarbonyl, C 1 -C 5 -alkyl carboxy, C 1 -C 5 -alkyl acyl, C 1 -C 5 -alkyl alkoxycarbonyl, C 1 -C 5 -alkyl acyloxy, C 1 -C 5 -alkyl sulfanyl, C 1 -C 5 -alkyl sulfinyl, C 1 -C 5 -alkyl sulfonyl, C 1 -C 5 -alkyl sulfonyloxy, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 1 -C 6 -alkyl cycloalkyl, C 2 -C 6 -alkenyl aryl, C 2 -C 6 -alkenyl heteroaryl, C 2 -C 6 -alkynyl aryl, C 2 -C 6 -alkynyl heteroaryl, substituted carboxy, substituted acyl, substituted alkoxycarbonyl, substituted C 1 -C 5 -alkyl carboxy, substituted C 1 -C 5 -alkyl acyl, substituted C 1 -C 5 -alkyl alkoxycarbonyl, substituted C 1 -C 5 -alkyl acyloxy, substituted C 1 -C 5 -alkyl sulfanyl, substituted C 1 -C 5 -alkyl sulfinyl, substituted C 1 -C 5 -alkyl sulfonyl, substituted C 1 -C 5 -alkyl sulfonyloxy, substituted C 1 -C 6 -alkyl, substituted C 2 -C 6 -alkenyl, substituted C 2 -C 6 -alkynyl, substituted aryl, substituted heteroaryl, substituted C 3 -C 8 -cycloalkyl, substituted C 1 -C 6 -alkyl aryl, substituted C 1 -C 6 -alkyl heteroaryl, substituted C 1 -C 6 -alkyl cycloalkyl, substituted C 2 -C 6 -alkenyl aryl, substituted C 2 -C 6 -alkenyl heteroaryl, substituted C 2 -C 6 -alkynyl aryl, or substituted C 2 -C 6 -alkynyl heteroaryl; 
         each R 2  is independently C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, substituted C 1 -C 6 -alkyl, substituted C 2 -C 6 -alkenyl, or substituted C 2 -C 6 -alkyny; and 
         n is an integer from 0 to 2, 
         or a pharmaceutically acceptable salt thereof, 
         and wherein the subject is further administered nifedipine in an amount of about 40 mg or less per dose. 
       
     
     
         107 . A method of delaying the onset of delivery in a pregnant human subject, the method comprising administering to the subject a therapeutically effective amount of 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; 
         R 1  is H, carboxy, acyl, alkoxycarbonyl, C 1 -C 5 -alkyl carboxy, C 1 -C 5 -alkyl acyl, C 1 -C 5 -alkyl alkoxycarbonyl, C 1 -C 5 -alkyl acyloxy, C 1 -C 5 -alkyl sulfanyl, C 1 -C 5 -alkyl sulfinyl, C 1 -C 5 -alkyl sulfonyl, C 1 -C 5 -alkyl sulfonyloxy, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 1 -C 6 -alkyl cycloalkyl, C 2 -C 6 -alkenyl aryl, C 2 -C 6 -alkenyl heteroaryl, C 2 -C 6 -alkynyl aryl, C 2 -C 6 -alkynyl heteroaryl, substituted carboxy, substituted acyl, substituted alkoxycarbonyl, substituted C 1 -C 5 -alkyl carboxy, substituted C 1 -C 5 -alkyl acyl, substituted C 1 -C 5 -alkyl alkoxycarbonyl, substituted C 1 -C 5 -alkyl acyloxy, substituted C 1 -C 5 -alkyl sulfanyl, substituted C 1 -C 5 -alkyl sulfinyl, substituted C 1 -C 5 -alkyl sulfonyl, substituted C 1 -C 5 -alkyl sulfonyloxy, substituted C 1 -C 6 -alkyl, substituted C 2 -C 6 -alkenyl, substituted C 2 -C 6 -alkynyl, substituted aryl, substituted heteroaryl, substituted C 3 -C 8 -cycloalkyl, substituted C 1 -C 6 -alkyl aryl, substituted C 1 -C 6 -alkyl heteroaryl, substituted C 1 -C 6 -alkyl cycloalkyl, substituted C 2 -C 6 -alkenyl aryl, substituted C 2 -C 6 -alkenyl heteroaryl, substituted C 2 -C 6 -alkynyl aryl, or substituted C 2 -C 6 -alkynyl heteroaryl; 
         each R 2  is independently C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, substituted C 1 -C 6 -alkyl, substituted C 2 -C 6 -alkenyl, or substituted C 2 -C 6 -alkyny; and 
         n is an integer from 0 to 2, 
         or a pharmaceutically acceptable salt thereof, 
         and wherein the subject is further administered nifedipine in an amount of about 40 mg or less in the first hour of treatment. 
       
     
     
         108 . A method of delaying the onset of delivery in a pregnant human subject, the method comprising administering to the subject a therapeutically effective amount of 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; 
         R 1  is H, carboxy, acyl, alkoxycarbonyl, C 1 -C 5 -alkyl carboxy, C 1 -C 5 -alkyl acyl, C 1 -C 5 -alkyl alkoxycarbonyl, C 1 -C 5 -alkyl acyloxy, C 1 -C 5 -alkyl sulfanyl, C 1 -C 5 -alkyl sulfinyl, C 1 -C 5 -alkyl sulfonyl, C 1 -C 5 -alkyl sulfonyloxy, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 1 -C 6 -alkyl cycloalkyl, C 2 -C 6 -alkenyl aryl, C 2 -C 6 -alkenyl heteroaryl, C 2 -C 6 -alkynyl aryl, C 2 -C 6 -alkynyl heteroaryl, substituted carboxy, substituted acyl, substituted alkoxycarbonyl, substituted C 1 -C 5 -alkyl carboxy, substituted C 1 -C 5 -alkyl acyl, substituted C 1 -C 5 -alkyl alkoxycarbonyl, substituted C 1 -C 5 -alkyl acyloxy, substituted C 1 -C 5 -alkyl sulfanyl, substituted C 1 -C 5 -alkyl sulfinyl, substituted C 1 -C 5 -alkyl sulfonyl, substituted C 1 -C 5 -alkyl sulfonyloxy, substituted C 1 -C 6 -alkyl, substituted C 2 -C 6 -alkenyl, substituted C 2 -C 6 -alkynyl, substituted aryl, substituted heteroaryl, substituted C 3 -C 8 -cycloalkyl, substituted C 1 -C 6 -alkyl aryl, substituted C 1 -C 6 -alkyl heteroaryl, substituted C 1 -C 6 -alkyl cycloalkyl, substituted C 2 -C 6 -alkenyl aryl, substituted C 2 -C 6 -alkenyl heteroaryl, substituted C 2 -C 6 -alkynyl aryl, or substituted C 2 -C 6 -alkynyl heteroaryl; 
         each R 2  is independently C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, substituted C 1 -C 6 -alkyl, substituted C 2 -C 6 -alkenyl, or substituted C 2 -C 6 -alkyny; and 
         n is an integer from 0 to 2, 
         or a pharmaceutically acceptable salt thereof, 
         and wherein the subject is further administered nifedipine in an amount of about 200 mg or less per day. 
       
     
     
         109 . The method of  claim 106 , wherein the compound is represented by formula (VI) 
       
         
           
           
               
               
           
         
         wherein R 6  is hydroxyl, acyl, alkoxycarbonyl, or acyloxy; 
         each R 5  is independently halogen, haloalkyl, cyano, optionally substituted amino, hydroxyl, thiol, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyl, carboxy, ureido, alkyl sulfonyl, aryl sulfonyl, heteroaryl sulfonyl, cycloalkyl sulfonyl, heterocycloalkyl sulfonyl, alkyl sulfanyl, aryl sulfanyl, heteroaryl sulfanyl, cycloalkyl sulfanyl, heterocycloalkyl sulfanyl, alkyl sulfinyl, aryl sulfinyl, heteroaryl sulfinyl, cycloalkyl sulfinyl, heterocycloalkyl sulfinyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted and optionally fused aryl, optionally substituted and optionally fused heteroaryl, optionally substituted and optionally fused cycloalkyl, or optionally substituted and optionally fused heterocycloalkyl; 
         R 4  is halogen, haloalkyl, cyano, optionally substituted amino, hydroxyl, thiol, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyl, carboxy, ureido, alkyl sulfonyl, aryl sulfonyl, heteroaryl sulfonyl, cycloalkyl sulfonyl, heterocycloalkyl sulfonyl, alkyl sulfanyl, aryl sulfanyl, heteroaryl sulfanyl, cycloalkyl sulfanyl, heterocycloalkyl sulfanyl, alkyl sulfinyl, aryl sulfinyl, heteroaryl sulfinyl, cycloalkyl sulfinyl, heterocycloalkyl sulfinyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted and optionally fused aryl, optionally substituted and optionally fused heteroaryl, optionally substituted and optionally fused cycloalkyl, or optionally substituted and optionally fused heterocycloalkyl; 
         i is an integer from 0-3; and 
         x is an integer from 0-5, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         110 . The method of  claim 109 , wherein the compound is represented by formula (VII) 
       
         
           
           
               
               
           
         
         wherein R 7  is H or optionally substituted aminoacyl; 
         each R 5  is independently halogen, haloalkyl, cyano, optionally substituted amino, hydroxyl, thiol, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyl, carboxy, ureido, alkyl sulfonyl, aryl sulfonyl, heteroaryl sulfonyl, cycloalkyl sulfonyl, heterocycloalkyl sulfonyl, alkyl sulfanyl, aryl sulfanyl, heteroaryl sulfanyl, cycloalkyl sulfanyl, heterocycloalkyl sulfanyl, alkyl sulfinyl, aryl sulfinyl, heteroaryl sulfinyl, cycloalkyl sulfinyl, heterocycloalkyl sulfinyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted and optionally fused aryl, optionally substituted and optionally fused heteroaryl, optionally substituted and optionally fused cycloalkyl, or optionally substituted and optionally fused heterocycloalkyl; 
         R 4  is halogen, haloalkyl, cyano, optionally substituted amino, hydroxyl, thiol, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyl, carboxy, ureido, alkyl sulfonyl, aryl sulfonyl, heteroaryl sulfonyl, cycloalkyl sulfonyl, heterocycloalkyl sulfonyl, alkyl sulfanyl, aryl sulfanyl, heteroaryl sulfanyl, cycloalkyl sulfanyl, heterocycloalkyl sulfanyl, alkyl sulfinyl, aryl sulfinyl, heteroaryl sulfinyl, cycloalkyl sulfinyl, heterocycloalkyl sulfinyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted and optionally fused aryl, optionally substituted and optionally fused heteroaryl, optionally substituted and optionally fused cycloalkyl, or optionally substituted and optionally fused heterocycloalkyl; 
         i is an integer from 0-3; and 
         x is an integer from 0-5, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         111 . The method of  claim 106 , the method comprising providing to the subject compound (1). 
       
         
           
           
               
               
           
         
       
     
     
         112 . The method of  claim 106 , wherein the compound is represented by formula (2), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         113 . The method of  claim 112 , wherein the compound is represented by formula (3) 
       
         
           
           
               
               
           
         
       
     
     
         114 . The method of  claim 106 , wherein the nifedipine is administered to the subject in one or more doses per 12 hours, 24 hours, 48 hours, or week. 
     
     
         115 . The method of  claim 114 , wherein a dose of the nifedipine is administered to the subject once every 4 to 12 hours. 
     
     
         116 . The method of  claim 106 , wherein the nifedipine is administered to the subject in an amount of from about 5 mg to about 40 mg per dose. 
     
     
         117 . The method of  claim 116 , wherein the nifedipine is administered to the subject in an amount of from about 10 mg to about 30 mg per dose. 
     
     
         118 . The method of  claim 117 , wherein the nifedipine is administered to the subject in an amount of about 20 mg per dose. 
     
     
         119 . The method of  claim 108 , wherein the nifedipine is administered to the subject in an amount of from about 40 mg to about 120 mg per day. 
     
     
         120 . The method of  claim 106 , wherein the nifedipine is periodically administered to the subject until the subject reaches a gestational age of at least about 34 weeks. 
     
     
         121 . The method of  claim 120 , wherein the nifedipine is periodically administered to the subject until the subject reaches a gestational age of from about 34 weeks to about 40 weeks. 
     
     
         122 . The method of  claim 106 , wherein the nifedipine is administered to the subject orally. 
     
     
         123 . The method of  claim 106 , wherein the subject has a gestational age of from about 24 weeks to about 36 weeks prior to administration of the nifedipine and the compound to the subject. 
     
     
         124 . The method of  claim 106 , wherein the subject exhibits four or more uterine contractions per 30 minutes prior to administration of the nifedipine and the compound to the subject. 
     
     
         125 . A kit comprising a compound represented by formula (2), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and wherein the kit further comprises a package insert instructing a user of the kit to administer the compound to a pregnant human subject in accordance with the method of  claim 106 .