Serotonergic agents for treating sexual dysfunction

Abstract

Methods and compositions are provided for treating sexual dysfunction, e.g., sexual dysfunction associated with drug treatment, using 5-HT 1A receptor antagonists.

1 . A method for treating sexual dysfunction associated with drug treatment in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound that is a 5-HT 1A  antagonist.  
     
     
         2 . The method of  claim 1 , wherein the drug treatment is antidepressant drug treatment, antipsychotic drug treatment, or anticonvulsant drug treatment.  
     
     
         3 . The method of  claim 1 , wherein the compound is a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable acid addition salt thereof wherein: 
 A is alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups,  
 Z is oxygen or sulfur,  
 R is H or lower alkyl,  
 R 1  is a mono or bicyclic aryl or heteroaryl radical,  
 R 2  is a mono or bicyclic heteroaryl radical, and  
 R 3  is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl, heteroaryl(lower)alkyl, a group of formula —NR 4 R 5  [where R 4  is hydrogen, lower alkyl, aryl or aryl(lower)alkyl and R 5  is hydrogen, lower alkyl, —CO(lower)alkyl, aryl, —Coaryl, aryl(lower)alkyl, cycloalkyl, or cycloalkyl-(lower)alkyl or R 4  and R 5  together with the nitrogen atom to which they are both attached represent a saturated hytrocyclic ring which may contain a further heteroatom], or a group of formula OR 6  [where R 6  is lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl or heteroaryl(lower)alkyl].  
 
     
     
         4 . The method of  claim 3 , wherein the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof.  
     
     
         5 . The method of  claim 1 , wherein the compound is (R)-4-cyano-N-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]propyl}-N-pyridin-2-yl-benzamide or a pharmaceutically acceptable acid addition salt thereof (Example compound 1), N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (Example compound 2) or a pharmaceutically acceptable acid addition salt thereof, or (R)-N-(2-methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide (Example compound 3) or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         6 . The method of  claim 1 , wherein the drug is a selective serotonin reuptake inhibitor (SSRI).  
     
     
         7 . The method of  claim 6 , wherein the SSRI is fluoxetine, citolopram, escitalopram oxalate, fluvoxamine maleate, paroxetine, or sertraline.  
     
     
         8 . The method of  claim 1 , wherein the drug is a tricyclic antidepressant.  
     
     
         9 . The method of  claim 8 , wherein the tricyclic antidepressant is desipramine, amitriptiyline, amoxipine, clomipramine, doxepin, imipramine, nortriptyline, protriptyline, or trimipramine.  
     
     
         10 . The method of  claim 1 , wherein the drug is an aminoketone class compound.  
     
     
         11 . The method of  claim 10 , wherein the aminoketone class compound is bupropion.  
     
     
         12 . The method of  claim 1 , wherein the drug is a monoamine oxidase inhibitor (MAOI).  
     
     
         13 . The method of  claim 12 , wherein the monoamine oxidase inhibitor is phenelzine.  
     
     
         14 . The method of  claim 1 , wherein the drug is a serotonin and norepinepherine reuptake inhibitor (SNRI).  
     
     
         15 . The method of  claim 14 , wherein the SNRI is venlafaxine, nefazodone, milnacipran, or duloxetine.  
     
     
         16 . The method of  claim 1 , wherein the drug is a norepinephrine reuptake inhibitor (NRI).  
     
     
         17 . The method of  claim 16 , wherein the drug is reboxetine.  
     
     
         18 . The method of  claim 1 , wherein the drug is a partial 5-HT 1A  agonist.  
     
     
         19 . The method of  claim 18 , wherein the drug is buspirone.  
     
     
         20 . The method of  claim 1 , wherein the drug is a 5-HT 2A  receptor antagonist.  
     
     
         21 . The method of  claim 20 , wherein the drug is nefazodone.  
     
     
         22 . The method of  claim 1 , wherein the drug is a typical antipsychotic drug.  
     
     
         23 . The method of  claim 1 , wherein the drug is an atypical antipsychotic drug.  
     
     
         24 . The method of  claim 1 , wherein the drug is an aliphatic phethiazine, a piperazine phenothiazine, a butyrophenone, a substituted benzamide, a thioxanthine.  
     
     
         25 . The method of  claim 1 , wherein the drug is phenobarbital, phenyloin, primidone, or carbamazepine.  
     
     
         26 . The method of  claim 2 , wherein the patient is being treated with at least two drugs that are antidepressant drugs, antipsychotic drugs, anticonvulsant drugs, or a combination thereof.  
     
     
         27 . The method of  claim 1 , wherein the method comprises oral delivery of the compound.  
     
     
         28 . The method of  claim 1 , wherein the method comprises delivery of a sustained release compound.  
     
     
         29 . The method of  claim 1 , wherein the sexual dysfunction comprises a deficiency in penile erection.  
     
     
         30 . A method of improving sexual function in a patient in need thereof, the method comprising administering to the patient a pharmaceutically effective amount of a compound that is a 5-HT 1A  antagonist.  
     
     
         31 . The method of  claim 30 , wherein the compound is a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable acid addition salt thereof, wherein 
 A is alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups,  
 Z is oxygen or sulfur,  
 R is H or lower alkyl,  
 R 1  is a mono or bicyclic aryl or heteroaryl radical,  
 R 2  is a mono or bicyclic heteroaryl radical, and 
 R 3  is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl, heteroaryl(lower)alkyl, a group of formula —NR 4 R 5  [where R 4  is hydrogen, lower alkyl, aryl or aryl(lower)alkyl and R 5  is hydrogen, lower alkyl, —CO(lower)alkyl, aryl, —Coaryl, aryl(lower)alkyl, cycloalkyl, or cycloalkyl-(lower)alkyl or R 4  and R 5  together with the nitrogen atom to which they are both attached represent a saturated hytrocyclic ring which may contain a further heteroatom], or a group of formula OR 6  [where R 6  is lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl or heteroaryl(lower)alkyl]; a compound of formula (III)  
                     
 wherein R 1  is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable acid addition salts thereof, or formula (IV)  
                     
 wherein, Ra and Rb are each hydrogen or methyl and Rc is' hydrogen, halo or C 1-4 alkyl; or a pharmaceutically acceptable acid addition salt thereof.  
 
 
     
     
         32 . The method of  claim 30 , wherein the compound is Example compound 1, Example compound 2, or Example compound 3.  
     
     
         33 . A pharmaceutical composition for treating sexual dysfunction associated with drug treatment, the composition comprising a compound of formula (I), formula (III), or formula (IV).  
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein the drug is an antidepressant, an antipsychotic, or an anticonvulsant.  
     
     
         35 . The pharmaceutical composition of  claim 33 , wherein the compound is effective for ameliorating sexual dysfunction in an animal model of sexual dysfunction associated with drug treatment.  
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein the animal model of sexual dysfunction is an antidepressant drug-induced model of sexual dysfunction.  
     
     
         37 . A package comprising a 5-HT 1A  antagonist and instructions, wherein the instructions comprise instructions for treating sexual dysfunction.  
     
     
         38 . The package of  claim 37 , wherein the instructions are for treating sexual dysfunction associated with drug treatment.  
     
     
         39 .- 50 . (canceled)