2-(Arylalkoxy)-1-Phenylethylamine Derivatives As NK1 Antagonist And Serotonin Reuptake Inhibitors

Abstract

Compounds of the following formula (I) wherein R 1 R 2 , n, Ar 1 and A 2 are as defined in the specification, in vivo-hydrolysable precursors thereof, pharmaceutically acceptable salts thereof, the use in therapy and pharmaceutical compositions and methods of treatment using the same. The example compounds are 1-(2-(naphthylmethoxy)-1-phenylethyl)piperazine derivatives. The compounds are neurokinin 1 (NK 1 ) receptor antagonist and/or serotonin reuptake inhibitors, with medical indications for depression and other disorders.

1 . A compound according to structural diagram I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are independently selected from C 1-6 alkyl or C 1-6 alkenyl, or together with the N to which they are bound, form a heterocycle containing 6, 7 or 8 atoms or such a heterocycle substituted with moieties independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 alkyl substituted with 1, 2 or 3 halo, or amino; wherein said amino is optionally substituted with C 1-4 alkyl, C 1-4 alkoxy or C 1-4 alkyl substituted with 1, 2, or 3 halo; 
 R 4  is hydrogen; 
 n is 0, 1 or 2; 
 Ar 1  is phenyl or phenyl substituted with moieties independently selected from hydrogen, halogen, —S—C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkyl substituted with 1, 2 or 3 halo; and 
 Ar 2  is phenyl, naphthyl, tetralin, or phenyl, naphthyl or tetralin substituted with moieties independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 alkyl substituted with 1, 2 or 3 halo moieties; 
 or an in vivo hydrolysable precursor or a pharmaceutically-acceptable salt thereof. 
 
     
     
         2 . A pharmaceutically-acceptable salt of a compound according to  claim 1  made with an inorganic or organic acid which affords a physiologically-acceptable anion. 
     
     
         3 . A pharmaceutically-acceptable salt of a compound according to  claim 2 , wherein said inorganic or organic acid is selected from hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, sulfamic, para-toluenesulfonic, acetic, citric, lactic, tartaric, malonic, fumaric, ethanesulfonic, benzenesulfonic, cyclohexylsulfamic, salicyclic and quinic acids. 
     
     
         4 . A pharmaceutical composition comprising a compound according to  claim 1 , an in vivo-hydrolysable precursor or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier. 
     
     
         5 . A method of treating a disease condition wherein antagonism of NK 1  receptors in combination with SRI activity is beneficial which method comprises administering to a warm-blooded animal an effective amount of a compound according to  claim 1  or an in vivo-hydrolysable precursor or a pharmaceutically-acceptable salt thereof. 
     
     
         6 . A method of treating a disease condition wherein antagonism of NK 1  receptors is beneficial which method comprises administering to a warm-blooded animal an effective amount of a compound according to  claim 1  or an in vivo-hydrolysable precursor or a pharmaceutically-acceptable salt thereof. 
     
     
         7 . A method of treating a disease condition wherein SRI activity is beneficial with method comprises administering to a warm-blooded animal an effective amount of a compound according to  claim 1  or a in vivo-hydrolysable precursor or a pharmaceutically-acceptable salt thereof. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . A method for treating a disorder or condition selected from hypertension, depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, post partum depression, generalized anxiety disorder, agoraphobia, social phobia, simple phobias, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, anorexia nervosa, bulimia nervosa, obesity, addictions to alcohol, cocaine, heroin, phenobarbital, nicotine or benzodiazepines; cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, dementia, amnestic disorders, age-related cognitive decline, dementia in Parkinson's disease, neuroleptic-induced parkinsonism, tardive dyskinesias, hyperprolactinaemia, vasospasm, cerebral vasculature vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, attention deficit hyperactivity disorder, chronic paroxysmal hemicrania and headache associated with vascular disorders in a mammal, wherein antagonism of the NK 1  receptors and SRI activity is beneficial, comprising administering an effective amount of a compound according to  claim 1  or a pharmaceutically-acceptable salt thereof effective in treating such disorder or condition. 
     
     
         11 . The method according to  claim 5 , wherein said compound is administered in combination with a pharmaceutically-acceptable carrier. 
     
     
         12 . The method according to  claim 6 , wherein said compound is administered in combination with a pharmaceutically-acceptable carrier. 
     
     
         13 . The method according to  claim 7 , wherein said compound is administered in combination with a pharmaceutically-acceptable carrier. 
     
     
         14 . The method according to  claim 10 , wherein said compound is administered in combination with a pharmaceutically-acceptable carrier. 
     
     
         15 . A compound according to structural diagram I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2 , together with the N to which they are bound, form a heterocycle containing 6, 7 or 8 atoms; wherein said heterocycle is optionally substituted with a moiety independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 alkyl substituted with 1, 2 or 3 halo or amino; wherein said amino is optionally substituted with C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 alkyl substituted with 1, 2, or 3 halo; 
 R 4  is hydrogen; 
 n is 1 or 2; 
 Ar 1  is phenyl optionally substituted with a moiety independently selected from hydrogen, halogen, —S—C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 alkyl substituted with 1, 2, or 3 halo; and 
 Ar 2  is naphthyl optionally substituted with a moiety independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 alkyl substituted with 1, 2, or 3 halo; 
 or a pharmaceutically-acceptable salt thereof. 
 
     
     
         16 . A pharmaceutically-acceptable salt of a compound according to  claim 15  made with an inorganic or organic acid which affords a physiologically-acceptable anion. 
     
     
         17 . A pharmaceutically-acceptable salt of a compound according to  claim 16  wherein said inorganic or organic acid is selected from hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, sulfamic, para-toluenesulfonic, acetic, citric, lactic, tartaric, malonic, fumaric, ethanesulfonic, benzenesulfonic, cyclohexylsulfamic, salicyclic, and quinic acids. 
     
     
         18 . A pharmaceutical composition comprising a compound according to  claim 15 , or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier.