Methods and compositions for the treatment of neuropsychiatric and addictive disorders

Abstract

The present invention relates to methods and compositions for treating neuropathic pain and neuropsychiatric disorders by administering agents that are effective in reducing the effective amount, inactivating, and/or inhibiting the activity of a Na + —K + -2Cl − (NKCC) cotransporter. In certain embodiments, the Na + —K + -2Cl − co-transporter is NKCC1.

1 . A method for treating a disorder in a mammalian subject, comprising administering an effective amount of a composition comprising a Na + K + 2Cl co-transporter antagonist to the subject, wherein the disorder is selected from the group consisting of: addictive disorders, and neuropsychiatric disorders. 
     
     
         2 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist reduces or blocks hypersynchronized neuronal population discharges by non-synaptic effects. 
     
     
         3 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist is a NKCC1 co-transporter antagonist. 
     
     
         4 . The method of  claim 1 , wherein the Na +  K +  Cl co-transporter antagonist is a CNS-targeted NKCC co-transporter antagonist. 
     
     
         5 . The method of  claim 4 , wherein the Na + K + 2Cl co-transporter antagonist is selected from the group consisting of: furosemide; bumetanide; ethacrynic acid; torsemide; azosemide; muzolimine; piretanide; tripamide; and functional analogs and derivatives thereof. 
     
     
         6 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist is selected from the group consisting of: thiazide; and thiazide-like diuretics. 
     
     
         7 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist is a compound selected from the group consisting of the following: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof, wherein 
       R 1  is not present, H, O or S; 
       R 2  is not present, H or when R 1  is O or S, R 2  is selected from the group consisting of hydrogen, alkyl, aralkyl, aryl, alkylaminodialkyl, alkylcarbonylaminodialkyl, alkyloxycarbonylalkyl, alkylcarbonyloxyalkyl, alkylaldehyde, alkylketoalkyl, alkylamide, alkarylamide, arylamide, an alkylammonium group, alkylcarboxylic acid, alkylheteroaryls, alkylhydroxy, a biocompatible polymer such as alkyloxy(polyalkyloxy)alkylhydroxyl, a polyethylene glycol (PEG), a polyethylene glycol ester (PEG ester) and a polyethylene glycol ether (PEG ether), methyloxyalkyl, methyloxyalkaryl, methylthioalkyl and methylthioalkaryl, unsubstituted or substituted, and when R 1  is not present, R 2  is selected from the group consisting of hydrogen, N,N-dialkylamino, N,N-dialkarylamino, N,N-diarylamino, N-alkyl-N-alkarylamino, N-alkyl-N-arylamino, N-alkaryl-N-arylamino, unsubstituted or substituted; 
       R 3  is selected from the group consisting of aryl, halo, hydroxy, alkoxy, and aryloxy, unsubstituted or substituted; and 
       R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkylaminodialkyl, carbonylalkyl, carbonylalkaryl, carbonylaryl and salts thereof, with the following provisos: 
       R 3  of formula I is not unsubstituted aryloxy when R 1  is O and R 2 , R 4  and R 5  are H; 
       R 3  of formula III is not Cl, when R 1  is O and R 2 , R 4  and R 5  are H; 
       R 2  of formula III is not methyl when R 1  is O, R 3  is Cl, and R 4  and R 5  are H; and 
       R 3  of formula V is not unsubstituted aryloxy when R 1  is O and R 2 , R 4  and R 5  are H. 
     
     
         8 . The method of  claim 1 , wherein the compound is selected from the group consisting of bumetanide aldehyde, bumetanide methyl ester, bumetanide cyanomethyl ester, bumetanide ethyl ester, bumetanide isoamyl ester, bumetanide octyl ester, bumetanide benzyl ester, bumetanide dibenzylamide, bumetanide diethylamide, bumetanide morpholinoethyl ester, bumetanide 3-(dimethylaminopropyl)ester, bumetanide N,N-diethylglycolamido ester, bumetanide dimethylglycolamido ester, bumetanide pivaxetil ester, bumetanide propaxetil ester, bumetanide methoxy(polyethyleneoxy) n-1 -ethyl ester, bumetanide benzyltrimethylammonium salt, and bumetanide cetyltrimethylammonium salt. 
     
     
         9 . The method of  claim 7 , wherein the compound is selected from the group consisting of bumetanide methyl thioester, bumetanide cyanomethyl thioester, bumetanide ethyl thioester, bumetanide isoamyl thioester, bumetanide octyl thioester, bumetanide benzyl thioester, bumetanide morpholinoethyl thioester, bumetanide 3-(dimethylaminopropyl)thioester, bumetanide N,N-diethylglycolamide thioester, bumetanide dimethylglycolamide thioester, bumetanide pivaxetil thioester, bumetanide propaxetil thioester, bumetanide methoxy(polyethyleneoxy) n-1 -ethyl thioester, bumetanide thioacid (thiobumetanide), bumetanide benzyltrimethylammonium thioacid salt and bumetanide cetyltrimethylammonium thioacid salt. 
     
     
         10 . The method of  claim 7 , wherein the compound is selected from the group consisting of metastable bumetanide thioacid, bumetanide O-methyl thioester, bumetanide O-cyanomethyl thioester, bumetanide O-ethyl thioester, bumetanide O-isoamyl thioester, bumetanide O-octyl thioester, bumetanide O-benzyl thioester, bumetanide O-(morpholinoethyl)thioester, bumetanide O-[3-(dimethylaminopropyl)]thioester, bumetanide O—(N,N-diethylglycolamido) thioester, bumetanide, O-(dimethylglycolamido) thioester, bumetanide O-pivaxetil thioester, bumetanide O-propaxetil thioester, bumetanide O-[methoxy(polyethyleneoxy) n-1 -ethyl]thioester, bumetanide benzyltrimethylammonium thioacid salt and bumetanide cetyltrimethylammonium thioacid salt. 
     
     
         11 . The method of  claim 7 , wherein the compound is selected from the group consisting of bumetanide thioaldehyde, bumetanide dithioacid, bumetanide methyl dithioester, bumetanide cyanomethyl dithioester, bumetanide ethyl dithioester, bumetanide isoamyl dithioester, bumetanide octyl dithioester, bumetanide benzyl dithioester, bumetanide dibenzylthioamide, bumetanide diethylthioamide, bumetanide morpholinoethyl dithioester, bumetanide 3-(dimethylaminopropyl)dithioester, bumetanide N,N-diethylglycolamido dithioester, bumetanide dimethylglycolamido dithioester, bumetanide pivaxetil dithioester, bumetanide propaxetil dithioester, bumetanide methoxy(polyethyleneoxy) n-1 -ethyl dithioester, bumetanide benzyltrimethylammonium dithioacid salt and bumetanide cetyltrimethylammonium dithioacid salt. 
     
     
         12 . The method of  claim 7 , wherein the compound is selected from the group consisting of furosemide methyl ester, furosemide cyanomethyl ester, furosemide ethyl ester, furosemide isoamyl ester, furosemide octyl ester, furosemide benzyl ester, furosemide morpholinoethyl ester, furosemide 3-(dimethylaminopropyl)ester, furosemide N,N-diethylglycolamido ester, furosemide dimethylglycolamido ester, furosemide pivaxetil ester, furosemide propaxetil ester, furosemide methoxy(polyethyleneoxy) n-1 -ethyl ester, furosemide benzyltrimethylammonium acid salt and furosemide cetyltrimethylammonium acid salt. 
     
     
         13 . The method of  claim 7 , wherein the compound is selected from the group consisting of furosemide thioacid, furosemide S-methyl thioester, furosemide S-cyanomethyl thioester, furosemide S-ethyl thioester, furosemide S-isoamyl thioester, furosemide S-octyl thioester, furosemide S-benzyl thioester, furosemide S-(morpholinoethyl)thioester, furosemide S-[3-(dimethylaminopropyl)]thioester, furosemide S—(N,N-diethylglycolamido) thioester, furosemide S-(dimethylglycolamido) thioester, furosemide S-pivaxetil thioester, furosemide S-propaxetil thioester, furosemide S-[methoxy(polyethyleneoxy) n-1 -ethyl]thioester, furosemide benzyltrimethylammonium thioacid salt, and furosemide cetyltrimethylammonium thioacid salt. 
     
     
         14 . The method of  claim 7 , wherein the compound is selected from the group consisting of metastable furosemide thioacid, furosemide O-methyl thioester, furosemide O-cyanomethyl thioester, furosemide O-ethyl thioester, furosemide O-isoamyl thioester, furosemide O-octyl thioester, furosemide O-benzyl thioester, furosemide O-(morpholinoethyl)thioester, furosemide O-[3-(dimethylaminopropyl)]thioester, furosemide O—(N,N-diethylglycolamido) thioester, furosemide O-(dimethylglycolamido) thioester, furosemide O-pivaxetil thioester, furosemide O-propaxetil thioester, furosemide O-[methoxy(polyethyleneoxy) n-1 -ethyl]thioester, furosemide benzyltrimethylammonium thioacid salt and furosemide cetyltrimethylammonium thioacid salt. 
     
     
         15 . The method of  claim 7 , wherein the compound is selected from the group consisting of furosemide thioaldehyde, furosemide dithioacid, furosemide methyl dithioester, furosemide cyanomethyl dithioester, furosemide ethyl dithioester, furosemide isoamyl dithioester, furosemide octyl dithioester, furosemide benzyl dithioester, furosemide dibenzylthioamide, furosemide diethylthioamide, furosemide morpholinoethyl dithioester, furosemide 3-(dimethylaminopropyl)dithioester, furosemide N,N-diethylglycolamido dithioester, furosemide dimethylglycolamido dithioester, furosemide pivaxetil dithioester, furosemide propaxetil dithioester, furosemide methoxy(polyethyleneoxy) n-1 -ethyl dithioester, furosemide benzyltrimethylammonium dithioacid salt and furosemide cetyltrimethylammonium dithioacid salt. 
     
     
         16 . The method of  claim 7 , wherein the compound is selected from the group consisting of piretanide aldehyde, piretanide methyl ester, piretanide cyanomethyl ester, piretanide ethyl ester, piretanide isoamyl ester, piretanide octyl ester, piretanide benzyl ester, piretanide dibenzylamide, piretanide diethylamide, piretanide morpholinoethyl ester, piretanide 3-(dimethylaminopropyl)ester, piretanide N,N-diethylglycolamide ester, piretanide dimethylglycolamide ester, piretanide pivaxetil ester, piretanide propaxetil ester, piretanide methoxy(polyethyleneoxy) n-1 -ethyl ester, piretanide benzyltrimethylammonium salt and piretanide cetyltrimethylammonium salt. 
     
     
         17 . The method of  claim 7 , wherein the compound is selected from the group consisting of piretanide thioacid, piretanide S-methyl thioester, piretanide S-cyanomethyl thioester, piretanide S-ethyl thioester, piretanide S-isoamyl thioester, piretanide S-octyl thioester, piretanide S-benzyl thioester, piretanide S-(morpholinoethyl)thioester, piretanide S-[3-(dimethylaminopropyl)]thioester, piretanide S—(N,N-diethylglycolamido) thioester, piretanide S-(dimethylglycolamido) thioester, piretanide S-pivaxetil thioester, piretanide S-propaxetil thioester, piretanide S-[methoxy(polyethyleneoxy) n-1 -ethyl]thioester, piretanide benzyltrimethylammonium thioacid salt and piretanide cetyltrimethylammonium thioacid salt. 
     
     
         18 . The method of  claim 7 , wherein the compound is selected from the group consisting of metastable piretanide thioacid, piretanide O-methyl thioester, piretanide O-cyanomethyl thioester, piretanide O-ethyl thioester, piretanide O-isoamyl thioester, piretanide O-octyl thioester, piretanide O-benzyl thioester, piretanide O-(morpholinoethyl)thioester, piretanide O-[3-(dimethylaminopropyl)]thioester, piretanide O—(N,N-diethylglycolamido) thioester, piretanide, O-(dimethylglycolamido) thioester, piretanide O-pivaxetil thioester, piretanide O-propaxetil thioester, piretanide O-[methoxy(polyethyleneoxy) n-1 -ethyl]thioester, piretanide benzyltrimethylammonium thioacid salt and piretanide cetyltrimethylammonium thioacid salt. 
     
     
         19 . The method of  claim 7 , wherein the compound is selected from the group consisting of piretanide thioaldehyde, piretanide dithioacid, piretanide methyl dithioester, piretanide cyanomethyl dithioester, piretanide ethyl dithioester, piretanide isoamyl dithioester, piretanide octyl dithioester, piretanide benzyl dithioester, piretanide dibenzylthioamide, piretanide diethylthioamide, piretanide morpholinoethyl dithioester, piretanide 3-(dimethylaminopropyl)dithioester, piretanide N,N-diethylglycolamido dithioester, piretanide dimethylglycolamido dithioester, piretanide pivaxetil dithioester, piretanide propaxetil dithioester, piretanide methoxy(polyethyleneoxy) n-1 -ethyl dithioester, piretanide benzyltrimethylammonium dithioacid salt and piretanide cetyltrimethylammonium dithioacid salt. 
     
     
         20 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist is a compound of formula VII: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof, wherein 
       R 3  is selected from the group consisting of aryl, halo, hydroxy, alkoxy, and aryloxy, unsubstituted or substituted; 
       R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkylaminodialkyl, carbonylalkyl, carbonylalkaryl, carbonylaryl and salts thereof; 
       R 6  is selected from the group consisting of alkyloxycarbonylalkyl, alkylaminocarbonylalkyl, alkylaminodialkyl, alkylhydroxy, a biocompatible polymer such as alkyloxy(polyalkyloxy)alkylhydroxyl, a polyethylene glycol (PEG), a polyethylene glycol ester (PEG ester) and a polyethylene glycol ether (PEG ether), methyloxyalkyl, methyloxyalkaryl, methylthioalkyl and methylthioalkaryl, unsubstituted or substituted, with the proviso that R 3  is not Cl, when R 4 , R 5  and R 6  are H. 
     
     
         21 . The method of  claim 20 , wherein the compound is selected from the group consisting of tetrazolyl-substituted azosemide, azosemide benzyltrimethylammonium salt and azosemide cetyltrimethylammonium salt. 
     
     
         22 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist is a compound of formula VIII: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof, wherein 
       R 7  is selected from the group consisting of alkyloxycarbonylalkyl, alkylaminocarbonylalkyl, alkylaminodialkyl, alkylhydroxy, a biocompatible polymer such as alkyloxy(polyalkyloxy)alkylhydroxyl, a polyethylene glycol (PEG), a polyethylene glycol ester (PEG ester) and a polyethylene glycol ether (PEG ether), methyloxyalkyl, methyloxyalkaryl, methylthioalkyl and methylthioalkaryl, unsubstituted or substituted; and 
       X″ is a halide or an anionic moiety; or alternatively, X″ is not present. 
     
     
         23 . The method of  claim 22 , wherein the compound is a pyridine-substituted torsemide quaternary ammonium salt. 
     
     
         24 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist modulates extracellular ion composition and chloride gradients in nervous system tissue. 
     
     
         25 . The method of  claim 1 , wherein the composition is delivered orally, sublingually, nasally, transdermally, intravenously, intrathecally, or by inhalation. 
     
     
         26 . The method of  claim 1 , wherein the disorder is a neuropsychiatric disorder selected from the group consisting of: bipolar disorders; anxiety disorders; depression; and schizophrenia. 
     
     
         27 . The method of  claim 1 , wherein the disorder is an anxiety disorder selected from the group consisting of: panic disorder; social anxiety disorder; obsessive compulsive disorder; posttraumatic stress disorder; generalized anxiety disorder; and specific phobia. 
     
     
         28 . The method of  claim 1 , wherein the disorder is an addictive disorder selected from the group consisting of: eating disorders; alcoholism; addiction to narcotics; and smoking. 
     
     
         29 . The method of  claim 1 , wherein the disorder is an eating disorder selected from the group consisting of: obesity; and binge eating.