Method of treating nausea, vomiting, retching or any combination thereof

Abstract

The invention relates to a method of treating nausea, vomiting, retching or any combination thereof in a subject in need of treatment. The method comprises administering to a subject in need of treatment a therapeutically effective amount of a compound that has 5-HT 3 receptor antagonist activity and NorAdrenaline Reuptake Inhibitor (NARI) activity. The invention further relates to a method of treating nausea, vomiting, retching or any combination thereof in a subject in need thereof, comprising coadministering to said subject a first amount of a 5-HT 3 antagonist and a second amount of a NARI, wherein the first and second amounts together comprise a therapeutically effective amount or are each present in a therapeutically effective amount. In addition, the method of the invention comprises administering a NARI alone.

What is claimed is:  
     
         1 . A method of treating nausea, vomiting, retching or any combination thereof in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula I:  
       
         
           
           
               
               
           
         
         wherein, R 1  and R 2  independently represent hydrogen, halogen or a C 1 -C 6  alkyl group; or R 1  and R 2  together with the carbon atom to which they are attached form a cycloalkylene group having 5 to 6 carbon atoms;  
         R 3  and R 4  independently represent hydrogen or a C 1 -C 6  alkyl group;  
         R 5  is hydrogen, C 1 -C 6  alkyl,  
         
           
             
             
                 
                 
             
           
         
         or —C(O)—NH—R 6  
 wherein m is an integer from about 1 to about 3, X is halogen and R 6  is a C 1 -C 6  alkyl group; and  
 
         Ar is a substituted or unsubstituted phenyl, 2-thienyl or 3-thienyl group; and  
         n is 2 or 3; or a pharmaceutically acceptable salt thereof.  
       
     
     
         2 . The method of  claim 1 , wherein the the nausea, vomiting, retching or any combination thereof is caused by an anesthetic, radiation, a cancer chemotherapeutic agent, a toxic agent, an odor, a medicine, pregnancy or motion.  
     
     
         3 . The method of  claim 2 , wherein the medicine is selected from the group consisting of an analgesic, an antibiotic, an antifungal or a serotonin reuptake inhibitor.  
     
     
         4 . The method of  claim 1 , wherein the nausea, vomiting, retching or any combination thereof is caused by a condition which is associated with vertigo.  
     
     
         5 . The method of  claim 1 , wherein the nausea, vomiting, retching or any combination thereof is caused by headache.  
     
     
         6 . The method of  claim 1 , wherein the nausea, vomiting, retching or any combination thereof is caused by a malady of the gastrointestinal (GI) tract.  
     
     
         7 . The method of  claim 1 , wherein the subject is a human.  
     
     
         8 . The method of  claim 1 , wherein for the compound of Formula I, R 1  is a C 1 -C 6  alkyl group and Ar is a substituted phenyl.  
     
     
         9 . The method of  claim 8 , wherein the substituted phenyl group is substituted with a halogen.  
     
     
         10 . The method of  claim 1 , wherein for the compound of Formula I, n is 2, R 1  is a C 1 -C 6  alkyl group and Ar is a substituted phenyl.  
     
     
         11 . The method of  claim 10 , wherein the substituted phenyl group is substituted with a halogen and R 1  is a methyl group.  
     
     
         12 . The method of  claim 1 , wherein for the compound of Formula I, R 1  is a C 1 -C 6  alkyl group or a halogen and Ar is an unsubstituted phenyl.  
     
     
         13 . The method of  claim 12 , wherein R 2  is hydrogen or a C 1 -C 6  alkyl group.  
     
     
         14 . The method of  claim 1 , wherein for the compound of Formula I, n is 2, R 1  is a C 1 -C 6  alkyl group and Ar is an unsubstituted phenyl.  
     
     
         15 . The method of  claim 14 , wherein R 2  is hydrogen or a C 1 -C 6  alkyl group.  
     
     
         16 . A method of treating nausea, vomiting, retching or any combination thereof in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound represented by Formula II:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         17 . The method of  claim 16 , wherein the the nausea, vomiting, retching or any combination thereof is caused by an anesthetics, radiation, a cancer chemotherapeutic agent, a toxic agent, an odor, a medicine, pregnancy or motion.  
     
     
         18 . The method of  claim 16 , wherein the nausea, vomiting, retching or any combination thereof is caused by a condition which is associated with vertigo.  
     
     
         19 . The method of  claim 16 , wherein the nausea, vomiting, retching or any combination thereof is caused by headache.  
     
     
         20 . The method of  claim 16 , wherein the nausea, vomiting, retching or any combination thereof is caused by a malady of the gastrointestinal (GI) tract.  
     
     
         21 . The method of  claim 16 , wherein the subject is a human.  
     
     
         22 . A method for treating nausea, vomiting, retching or any combination thereof in a subject in need thereof comprising administering to said subject: 
 a) a first amount of a 5-HT 3  receptor antagonist; and    b) a second amount of a noradrenaline reuptake inhibitor wherein the first and second amounts together comprise a therapeutically effective amount.    
     
     
         23 . The method of  claim 22 , wherein the the nausea, vomiting, retching or any combination thereof is caused by an anesthetic, radiation, a cancer chemotherapeutic agent, a toxic agent, an odor, a medicine, pregnancy or motion.  
     
     
         24 . The method of  claim 22 , wherein the medicine is selected from the group consisting of an analgesic, an antibiotic, an antifungal or a serotonin reuptake inhibitor.  
     
     
         25 . The method of  claim 22 , wherein the nausea, vomiting, retching or any combination thereof is caused by a condition which is associated with vertigo.  
     
     
         26 . The method of  claim 22 , wherein the nausea, vomiting, retching or any combination thereof is caused by headache.  
     
     
         27 . The method of  claim 22 , wherein the nausea, vomiting, retching or any combination thereof is caused by a malady of the gastrointestinal (GI) tract.  
     
     
         28 . The method of  claim 22 , wherein the subject is a human.  
     
     
         29 . The method of  claim 22 , wherein the 5-HT 3  receptor antagonist is selected from the group consisting of indisetron, YM-114 ((R)-2,3-dihydro-1-[(4,5,6,7-tetrahydro-1H-benzimidazol-5-yl-)carbonyl]-1H-indole), granisetron, talipexole, azasetron, bemesetron, tropisetron, ramosetron, ondansetron, palonosetron, lerisetron, alosetron, N-3389, zacopride, cilansetron, E-3620 ([3(S)-endo]-4-amino-5-chloro-N-(8-methyl-8-azabicyclo[3.2.1-]oct-3-yl-2[(1-methyl-2-butynyl)oxy]benzamide), lintopride, KAE-393, itasetron, zatosetron, dolasetron, (±)-zacopride, (±)-renzapride, (−)-YM-060, DAU-6236, BIMU-8 and GK-128 [2-[2-methylimidazol-1-yl)methyl]-benzo[ƒ]thiochromen-1-one monohydrochloride hemihydrate].  
     
     
         30 . The method of  claim 29 , wherein the 5-HT 3  receptor antagonist is selected from the group consisting of indisetron, granisetron, azasetron, bemesetron, tropisetron, ramosetron, ondansetron, palonosetron, lerisetron, alosetron, cilansetron, itasetron, zatosetron, and dolasetron.  
     
     
         31 . The method of  claim 22 , wherein the noradrenaline reuptake inhibitor is selected from the group consisting of venlafaxine, duloxetine, buproprion, milnacipran, reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.  
     
     
         32 . The method of  claim 31 , wherein the noradrenaline reuptake inhibitor is selected from the group consisting of reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.  
     
     
         33 . A method for treating nausea, vomiting, retching or any combination thereof in a subject in need thereof comprising administering to said subject: 
 a) a therapeutically effective amount of a 5-HT 3  receptor antagonist; and    b) a therapeutically effective amount of a noradrenaline reuptake inhibitor.    
     
     
         34 . The method of  claim 33 , wherein the the nausea, vomiting, retching or any combination thereof is caused by an anesthetic, radiation, a cancer chemotherapeutic agent, a toxic agent, an odor, a medicine, pregnancy or motion.  
     
     
         35 . The method of  claim 33 , wherein the medicine is selected from the group consisting of an analgesic, an antibiotic, an antifungal or a serotonin reuptake inhibitor.  
     
     
         36 . The method of  claim 33 , wherein the nausea, vomiting, retching or any combination thereof is caused by a condition which is associated with vertigo.  
     
     
         37 . The method of  claim 33 , wherein the nausea, vomiting, retching or any combination thereof is caused by headache.  
     
     
         38 . The method of  claim 33 , wherein the nausea, vomiting, retching or any combination thereof is caused by a malady of the gastrointestinal (GI) tract.  
     
     
         39 . The method of  claim 33 , wherein the subject is a human.  
     
     
         40 . The method of  claim 33 , wherein the 5-HT 3  receptor antagonist is selected from the group consisting of indisetron, YM-114 ((R)-2,3-dihydro-1-[(4,5,6,7-tetrahydro-1H-benzimidazol-5-yl-)carbonyl]-1H-indole), granisetron, talipexole, azasetron, bemesetron, tropisetron, ramosetron, ondansetron, palonosetron, lerisetron, alosetron, N-3389, zacopride, cilansetron, E-3620 ([3(S)-endo]-4-amino-5-chloro-N-(8-methyl-8-azabicyclo[3.2.1-]oct-3-yl-2[(1-methyl-2-butynyl)oxy]benzamide), lintopride, KAE-393, itasetron, zatosetron, dolasetron, (±)-zacopride, (±)-renzapride, (−)-YM-060, DAU-6236, BIMU-8 and GK-128 [2-[2-methylimidazol-1-yl)methyl]-benzo[ƒ]thiochromen-1-one monohydrochloride hemihydrate].  
     
     
         41 . The method of  claim 40 , wherein the 5-HT 3  receptor antagonist is selected from the group consisting of indisetron, granisetron, azasetron, bemesetron, tropisetron, ramosetron, ondansetron, palonosetron, lerisetron, alosetron, cilansetron, itasetron, zatosetron, and dolasetron.  
     
     
         42 . The method of  claim 33 , wherein the noradrenaline reuptake inhibitor is selected from the group consisting of venlafaxine, duloxetine, buproprion, milnacipran, reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.  
     
     
         43 . The method of  claim 42 , wherein the noradrenaline reuptake inhibitor is selected from the group consisting of reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.  
     
     
         44 . A method of treating nausea, vomiting, retching or any combination thereof in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a noradrenaline reuptake inhibitor, wherein the noradrenaline reuptake inhibitor characterized by the substantial absence of anticholinergic effects.  
     
     
         45 . The method of  claim 44 , wherein the the nausea, vomiting, retching or any combination thereof is caused by an anesthetic, radiation, a cancer chemotherapeutic agent, a toxic agent, an odor, a medicine, pregnancy or motion.  
     
     
         46 . The method of  claim 45 , wherein the medicine is selected from the group consisting of an analgesic, an antibiotic, an antifungal or a serotonin reuptake inhibitor.  
     
     
         47 . The method of  claim 44 , wherein the nausea, vomiting, retching or any combination thereof is caused by a condition which is associated with vertigo.  
     
     
         48 . The method of  claim 44 , wherein the nausea, vomiting, retching or any combination thereof is caused by headache.  
     
     
         49 . The method of  claim 44 , wherein the nausea, vomiting, retching or any combination thereof is caused by a malady of the gastrointestinal (GI) tract.  
     
     
         50 . The method of  claim 44 , wherein the subject is a human.  
     
     
         51 . The method of  claim 44 , wherein the noradrenaline reuptake inhibitor is selected from the group consisting of venlafaxine, duloxetine, buproprion, milnacipran, reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.  
     
     
         52 . The method of  claim 51 , wherein the noradrenaline reuptake inhibitor is selected from the group consisting of reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.  
     
     
         53 . A pharmaceutical composition comprising: 
 a) a first amount of a 5-HT 3  receptor antagonist; and    b) a second amount of a noradrenaline reuptake inhibitor.    
     
     
         54 . The pharmaceutical composition of  claim 53 , further comprising a pharmaceutically acceptable carrier.  
     
     
         55 . The pharmaceutical composition of  claim 53 , wherein the 5-HT 3  receptor antagonist is selected from the group consisting of indisetron, YM-114 ((R)-2,3-dihydro-1-[(4,5,6,7-tetrahydro-1H-benzimidazol-5-yl-)carbonyl]-1H-indole), granisetron, talipexole, azasetron, bemesetron, tropisetron, ramosetron, ondansetron, palonosetron, lerisetron, alosetron, N-3389, zacopride, cilansetron, E-3620 ([3(S)-endo]-4-amino-5-chloro-N-(8-methyl-8-azabicyclo[3.2.1-]oct-3-yl-2[(1-methyl-2-butynyl)oxy]benzamide), lintopride, KAE-393, itasetron, zatosetron, dolasetron, (±)-zacopride, (±)-renzapride, (−)-YM-060, DAU-6236, BIMU-8 and GK-128 [2-[2-methylimidazol-1-yl)methyl]-benzo[ƒ]thiochromen-1-one monohydrochloride hemihydrate].  
     
     
         56 . The pharmaceutical composition of  claim 55 , wherein the 5-HT 3  receptor antagonist is selected from the group consisting of indisetron, granisetron, azasetron, bemesetron, tropisetron, ramosetron, ondansetron, palonosetron, lerisetron, alosetron, cilansetron, itasetron, zatosetron, and dolasetron.  
     
     
         57 . The pharmaceutical composition of  claim 53 , wherein the noradrenaline reuptake inhibitor is selected from the group consisting of venlafaxine, duloxetine, buproprion, milnacipran, reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline; oxaprotiline, levoprotiline, viloxazine and atomoxetine.  
     
     
         58 . The pharmaceutical composition of  claim 53 , wherein the noradrenaline reuptake inhibitor is selected from the group consisting of reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.  
     
     
         59 . A method for processing a claim under a health insurance policy submitted by a claimant seeking reimbursement for costs associated with treatment of nausea, vomiting, retching or any combination thereof, wherein said treatment comprises coadministering to a subject a first amount of a 5-HT 3  receptor antagonist and a second amount of a noradrenaline reuptake inhibitor, wherein the first and second amounts together comprise a therapeutically effective amount comprising: 
 a) reviewing said claim;    b) determining whether said treatment is reimbursable under said insurance policy; and    c) processing said claim to provide partial or complete reimbursement of said costs.    
     
     
         60 . The method of  claim 59 , wherein the nausea, vomiting, retching or any combination thereof is caused by an anesthetic, radiation, a cancer chemotherapeutic agent, a toxic agent, an odor, a medicine, pregnancy or motion.  
     
     
         61 . The method of  claim 60 , wherein the medicine is selected from the group consisting of an analgesic, an antibiotic, an antifungal or a serotonin reuptake inhibitor.  
     
     
         62 . The method of  claim 59 , wherein the nausea, vomiting, retching or any combination thereof is caused by a condition which is associated with vertigo.  
     
     
         63 . The method of  claim 59 , wherein the nausea, vomiting, retching or any combination thereof is caused by headache.  
     
     
         64 . A method of  claim 59 , wherein the nausea, vomiting, retching or any combination thereof is caused by a malady of the gastrointestinal (GI) tract.  
     
     
         65 . A method for processing a claim under a health insurance policy submitted by a claimant seeking reimbursement for costs associated with treatment of nausea, vomiting, retching or any combination thereof, wherein said treatment comprises coadministering to a subject a therapeutically effective amount of a 5-HT 3  receptor antagonist and a therapeutically effective amount of a noradrenaline reuptake inhibitor comprising: 
 a) reviewing said claim;    b) determining whether said treatment is reimbursable under said insurance policy; and    c) processing said claim to provide partial or complete reimbursement of said costs.    
     
     
         66 . The method of  claim 65 , wherein the nausea, vomiting, retching or any combination thereof is caused by an anesthetic, radiation, a cancer chemotherapeutic agent, a toxic agent, an odor, a medicine, pregnancy or motion.  
     
     
         67 . The method of  claim 66 , wherein the medicine is selected from the group consisting of an analgesic, an antibiotic, an antifungal or a serotonin reuptake inhibitor.  
     
     
         68 . The method of  claim 65 , wherein the nausea, vomiting, retching or any combination thereof is caused by a condition which is associated with vertigo.  
     
     
         69 . The method of  claim 65 , wherein the nausea, vomiting, retching or any combination thereof is caused by headache.  
     
     
         70 . The method of  claim 65 , wherein the nausea, vomiting, retching or any combination thereof is caused by a malady of the gastrointestinal (GI) tract.