Methods of managing conditioned fear with neurokinin receptor antagonists

Abstract

This disclosure relates to managing conditioned fear and conditions induced by experiencing or witnessing an extreme traumatic event using neurokinin receptor antagonists. In certain embodiments, the disclosure relates to methods of treating or preventing conditioned fear comprising administering an effective about neurokinin 3 receptor antagonist to a subject in need thereof. In certain embodiments, the subject is diagnosed with Post-Traumatic Stress Disorder.

1 .- 8 . (canceled) 
     
     
         9 . A method of treating Post-Traumatic Stress Disorder (PTSD), the method comprising administering to a subject diagnosed with PTSD an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or salts or derivatives thereof, wherein:
 X is CH 2 , or C═O; 
 Z is CH 2  or O; 
 y is 2 or 3; 
 Ar is a phenyl mono- or di-substituted with a halogen atom; 
 R 1  is a phenyl or benzoyl that is un-substituted or substituted once or twice with one or two substituents independently chosen from a halogen atom, a (C 1 -C 4 )alkyl and a (C 1 -C 4 )alkoxy; 
 R 2  is a pyridyl, a phenyl that is un-substituted or substituted once or twice with one or two substituents independently chosen from a halogen atom, a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy, a trifluoromethyl group and a trifluoromethoxy group; a benzyl that is un-substituted or substituted on the phenyl once or twice with one or two substituents independently chosen from a halogen atom, a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy, a trifluoromethyl group and a trifluoromethoxy group; a heterocyclyl chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine or perhydroazepine when R 3  represents a cyano or a group —CONR 11 R 12 ; 
 R 3  is (C 1 -C 4 ) alkyl; (C 1 -C 4 ) alkylcarbonyl; cyano; —(CH 2 ) q —OH; —(CH 2 ) q —O—(C 1 -C 4 )alkyl; —(CH 2 ) q —O—CO—R 4 ; —(CH 2 ) q —O—CO—NH—(C 1 -C 4 )alkyl; —NR 5 R 6 ; —NR 7 COR 8 ; —(CH 2 ) q —NR 7 COR 8 ; —(CH 2 ) q —NR 7 COOR 9 ; —(CH 2 ) q —NR 7 SO 2 R 10 ; —(CH 2 ) q —NR 7 CONR 11 R 12 ; —CH 2 NR 13 R 14 ; —CH 2 —CH 2 NR 13 R 14 ; —COOH; —COO—(C 1 -C 4 ) alkyl; —CONR 11 R 12 ; —CH 2 —COOH; —CH 2 —COO—(C 1 -C 4 )alkyl; —CH 2 —CONR 11 R 12 ; —O—CH 2 CH 2 OR 15 ; —NR 7 COCOR 16 ; —CONR 7 —NR 17 R 18 ; 
 
       
         
           
           
               
               
           
         
       
       or 
       
         
           
           
               
               
           
         
         q is 0, 1 or 2; 
         R 4  is a (C 1 -C 4 )alkyl, a (C 3 -C 7 )cycloalkyl that is un-substituted or substituted with one or more methyl groups, a phenyl, or a pyridyl; 
         R 5  is a hydrogen atom or a (C 1 -C 4 )alkyl; 
         R 6  is a hydrogen atom, a (C 1 -C 4 )alkyl, a (C 3 -C 7 )cycloalkylmethyl, a benzyl or a phenyl; or R 5  and R 6 , together with the nitrogen atom to which they are attached, constitute a heterocycle chosen from azetidine, pyrrolidine, piperidine, morpholine thiomorpholine, perhydroazepine or piperazine that is un-substituted or substituted in position 4 with a (C 1 -C 4 )alkyl; 
         R 7  is a hydrogen atom or a (C 1 -C 4 )alkyl; 
         R 8  is a hydrogen atom, a (C 1 -C 4 )alkyl, a vinyl, a phenyl, a benzyl, a pyridyl, or a (C 3 -C 7 )cycloalkyl that is un-substituted or substituted with one or more methyl groups, a furyl, a thienyl, a pyrrolyl, an imidazolyl; 
         or R 7  and R 8  together represent a group —(CH 2 ) p —; 
         p is 3 or 4; 
         R 9  is a (C 1 -C 4 ) alkyl or a phenyl; 
         or R 7  and R 9  together represent a group —(CH 2 ) n —; 
         n is 2 or 3; 
         R 10  is a (C 1 -C 4 ) alkyl or an amino that is free or substituted with one or two (C 1 -C 4 )alkyls, a phenyl that is un-substituted or substituted one or more times with a substituent chosen from: a halogen atom, a (C 1 -C 4 )alkyl, a trifluoromethyl, a hydroxyl, a (C 1 -C 4 )alkoxy, a carboxyl, a (C 1 -C 4 )alkoxycarbonyl, a (C 1 -C 4 )alkylcarbonyloxy, a cyano, a nitro, an amino that is free or substituted with one or two (C 1 -C 4 )alkyls, the said substituents being identical or different; 
         R 11  is a hydrogen or a (C 1 -C 4 ) alkyl; 
         R 12  is a hydrogen, a (C 1 -C 4 ) alkyl, a (C 3 -C 7 )cycloalkyl, a (C 3 -C 7 )cycloalkylmethyl, a hydroxyl, a (C 1 -C 4 )alkoxy, a benzyl or a phenyl; or R 11  and R 12 , together with the nitrogen atom to which they are attached, constitute a heterocycle chosen from azetidine, pyrrolidine, piperidine, morpholine thiomorpholine and perhydroazepine; 
         or R 7  and R 12  together represent a group —(CH 2 ) m —; 
         m is 2 or 3; 
         R 13  is a hydrogen atom or a (C 1 -C 4 )alkyl; 
         R 14 is a hydrogen atom, a (C 1 -C 4 )alkyl, a (C 3 -C 7 )cycloalkylmethyl or a benzyl; 
         R 15  is a hydrogen atom; a (C 1 -C 4 )alkyl; a formyl; a (C 1 -C 4 )alkylcarbonyl; 
         R 16  is a (C 1 -C 4 )alkoxy; 
         R 17  and R 18  each independently is a hydrogen atom or a (C 1 -C 4 )alkyl; or alternatively R 17  and R 18 , together with the nitrogen atom to which they are attached, constitute a heterocycle chosen from pyrrolidine, piperidine and morpholine; 
         R 19  is a hydrogen atom or a (C 1 -C 4 )alkyl; 
         R 20  is a hydrogen atom or a (C 1 -C 4 ) alkyl; and 
         R 21  is a hydrogen atom, a (C 1 -C 4 ) alkyl, a formyl or a (C 1 -C 4 )alkylcarbonyl. 
       
     
     
         10 . The method of  claim 9 , wherein X is CH 2 , Z is CH 2 , Ar represents a phenyl disubstituted with a halogen atom, y is 3, and R 1  is benzoyl. 
     
     
         11 . The method of  claim 9 , wherein the compound of Formula I is administered in combination with a second active agent comprising an anti-depressant. 
     
     
         12 . The method of  claim 11 , wherein the second active agent is sertraline, paroxetine, fluoxetine, citalopram, baclofen, modafinil, eszopiclone, hydrocortisone, varenicline, dexamethasone or combinations thereof. 
     
     
         13 . The method of  claim 9 , wherein the effective amount is a daily dose of about 25 mg per day. 
     
     
         14 . The method of  claim 13 , wherein the daily dose is between 10 and 40 mg per day. 
     
     
         15 . The method of  claim 9 , wherein the compound of Formula I is administered within an hour of or within a day of experiencing a traumatic event. 
     
     
         16 . The method of  claim 9 , wherein the compound of Formula I is administered at the time of or within an hour of psychotherapy, cognitive behavioral therapy, exposure therapy, cognitive restructuring, or stress inoculation training. 
     
     
         17 . The method of  claim 9 , wherein the compound of Formula I is 3-hydroxy-2-phenyl-N-(1-phenylpropyl)quinoline-4-carboxamide. 
     
     
         18 . The method of  claim 9 , wherein the compound of Formula I is 3-methyl-2-phenyl-N-(1-phenylpropyl) quinoline-4-carboxamide.