Acylamino cyclopropane derivatives

Abstract

This invention relates to novel acylamino cyclopropane derivatives, processes for their preparation, pharmaceutical compositions containing them and their use as modulators of dopamine D3 receptors and for the treatment of anxiety, psychosis, substance abuse, Parkinson's disease, sexual dysfunction, and other central nervous system disorders.

1 . A compound of the formula  
       
         
           
           
               
               
           
         
         wherein D, E, F, G, L, T, W, X, Y and Z are each, independently, N or CH;  
         U is CR 8  or N when U is single bonded to both carbons adjacent to it in the nitrogen containing ring of which it is a member, and U is C when U is double bonded to one of the carbons that is adjacent to it in the nitrogen containing ring of which it is a member;  
         A is (CH 2 )m wherein m is zero, one or two; R 1  and R 2  are selected, independently, from hydrogen, (C 1 -C 6 ) alkyl optionally substituted with from one to seven fluorine atoms, cyano, —OR 9 , and —CONHR 10 ;  
         or R 1  and R 2 , together with carbon atoms of the cyclopropyl ring to which they are attached, form a five or six membered saturated or unsaturated monocyclic ring containing from zero to four heteroatoms, wherein said heteroatoms are selected, independently, from oxygen, sulfur and nitrogen, with the proviso that there can not be two adjacent ring oxygen atoms, and wherein said ring can be optionally substituted with from one to three substituents independently selected from (C 1 -C 4 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 4 ) alkoxy optionally substituted with from one to three fluorine atoms, cyano, nitro, halo, hydroxy, amino, (C 1 -C 4 ) alkylamino, di[(C 1 -C 6 )alkyl] amino, (C 1 -C 4 ) amidoamino and (C 1 -C 4 ) alkanoyl;  
         or one of R 1  and R 2  forms, together with R 7,  a five or six membered saturated or unsaturated monocyclic ring containing from zero to four heteratoms, wherein said heteroatoms are selected, independently, from oxygen, sulfur and nitrogen, with the proviso that there can not be two adjacent ring oxygen atoms, and wherein said ring can be optionally substituted with from one to three substituents independently selected from (C 1 -C 4 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 4 ) alkoxy optionally substituted with from one to three fluorine atoms, cyano, nitro, halo, hydroxy, amino, (C 1 -C 4 ) alkylamino, di[(C 1 -C 6 )alkyl] amino, (C 1 -C 4 ) amidoamino and (C 1 -C 4 ) alkanoyl;  
         R 3  and R 4  are selected, independently, from hydrogen, halo, (C 1 -C 6 ) alkyl optionally substituted with from one to seven fluorine atoms, cyano, hydroxy, —CONHR 11 , —OR 12 , —NR 13 R 14  and —COR 15 :  
         or one of R 3  and R 4  forms, together with R 7,  a five or six membered aromatic or nonaromatic ring containing from one to four heteroatoms, wherein said heteroatoms are selected, independently, from oxygen, sulfur and nitrogen, with the proviso that there can not be two adjacent ring oxygen atoms, and wherein said ring can be optionally substituted with from one to three substituents independently selected from (C 1 -C 4 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 4 ) alkoxy optionally substituted with from one to three fluorine atoms, cyano, nitro, halo, hydroxy, amino, (C 1 -C 4 ) alkylamino, di[(C 1 -C 6 )alkyl] amino, (C 1 -C 4 ) amidoamino and (C 1 -C 4 ) alkanoyl;  
         R 5  and R 6  are selected, independently, from hydrogen, halo, (C 1 -C 6 ) alkyl optionally substituted with from one to seven chlorine atoms, cyano, hydroxy, —CONHR 16 , —OR 17 , —NR 18 R 19 , and —COR 20 ;  
         R 7  is hydrogen, (C 1 -C 6 )alkyl optionally substituted with from one to seven fluorine atoms, or aryl selected from phenyl and naphthyl, wherein said aryl can be optionally substituted with from one to three substituents independently selected from (C 1 -C 4 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 4 ) alkoxy optionally substituted with from one to three fluorine atoms, cyano, nitro, halo, hydroxy, amino, (C 1 -C 4 ) alkylamino, di[(C 1 -C 6 )alkyl] amino, (C 1 -C 4 ) amidoamino and (C 1 -C 4 ) alkanoyl;  
         or R 7  can form a ring with R 1  or R 2 , as described in the above definition of R 1  and R 2 ;  
         or R 7  can form a ring with R 3  or R 4 , as described in the above definition of R 3  and R 4 ;  
         R 8  is selected from hydrogen, cyano, (C 1 -C 6 ) alkyl optionally substituted with from one to seven fluorine atoms, —OR 9 , and —CONHR 10 ;  
         R 9 , R 10 ,R 11 , R 12 , R 13 ,R 14 , R 16 R 17 , R 18  and R 19  are selected, independently, from hydrogen, (C 1 -C 6 )alkyl optionally substituted with from one to seven fluorine atoms, aryl and heteroaryl, wherein said aryl is selected from phenyl and naphthyl and said heteroaryl is selected from four to six membered monocyclic aromatic rings containing from one to four heteroatoms (nonlimiting examples of such rings are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl and pyrazolyl) and eight to twelve membered bicyclic aromatic rings containing from one to five heteroatoms, wherein said heteroatoms are selected, independently, from oxygen, sulfur and nitrogen, with the proviso that there can not be two adjacent ring oxygen atoms, and wherein said aryl and heteroaryl rings can optionally be substituted one or more substitituents, preferably with from zero to two substituents, independently selected from (C 1 -C 4 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 4 ) alkoxy optionally substituted with from one to three fluorine atoms, cyano, nitro, halo, hydroxy, amino, (C 1 -C 4 ) alkylamino, di[(C 1 -C 6 )alkyl] amino, (C 1 -C 4 ) amidoamino and (C 1 -C 4 ) alkanoyl;  
         R 15  and R 20  are selected, independently, from NHR 21  and the group of radicals listed in the definition of R 9  through R 19 ; and  
         R 21  is selected from the group of radicals listed in the definition of R 9  through R 19 ;  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         2 . A compound according to  claim 1 , wherein U is nitrogen.  
     
     
         3 . A compound according to  claim 1 , wherein both R 1  and R 2 are hydrogen.  
     
     
         4 . A compound according to  claim 1 , wherein R 1  and R2 are selected, independently, from hydrogen and (C 1 -C 6 )alkyl.  
     
     
         5 . A compound according to  claim 1  wherein U is carbon.  
     
     
         6 . A compound according to  claim 1  wherein U is —CH.  
     
     
         7 . A compound according to  claim 1  wherein U is —C—CN.  
     
     
         8 . A compound according to  claim 1  wherein U is —C—(C 1 -C 6 )alkyl wherein the alkyl moiety may optionally be substituted with from one to seven fluorine atoms.  
     
     
         9 . A compound according to  claim 1  wherein U is —COR 9 .  
     
     
         10 . A compound according to  claim 1  wherein U is —C—CONHR 10 .  
     
     
         11 . A compound according to  claim 1  wherein U is —C—CN.  
     
     
         12 . A compound according to  claim 1  which is in the Z (cis) configuration with respect to the cyclopropyl ring.  
     
     
         13 . A compound according to  claim 1  wherein m is zero or two, in the case where m is two forming an azabicyclic ring system bridged either diagonally or directly across the ring system.  
     
     
         14 . A compound according to  claim 1  wherein R 1  and R 2  are selected, independently, from hydrogen, methyl, cyano, trifluoromethyl and trifluoromethoxy.  
     
     
         15 . A pharmaceutical composition for treating a disorder or condition selected from psychotic (e.g., psychosis, schizophrenia, schizo-affective disorders, psychotic depression, mania, paranoid and delusional disorders), anxiety-related disorders (e.g., generalized anxiety disorder, post traumatic stress disorder, panic disorder, obsessive-compulsive disorder and phobias, including social phobia), mood disorders (e.g., cyclothymia, dysthymia, major depressive disorder, premenstrual syndrome, premenstrual dysphoric disorder, bipolar disorder, seasonal affective disorder), Parkinson's disease, hypertension, hypotension, urinary incontinence, chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, nicotine, benzodiazepines, phenobarbitol), sexual dysfunction (e.g., premature ejaculation, male erectile dysfunction) and movement disorders (e.g., drug induced and neurodegeneration based dyskinesias) in a mammal, comprising an amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier.  
     
     
         16 . A method of treating a disorder or condition selected from psychotic (e.g., psychosis, schizophrenia, schizo-affective disorders, psychotic depression, mania, paranoid and delusional disorders), anxiety-related disorders (e.g., generalized anxiety disorder, post traumatic stress disorder, panic disorder, obsessive-compulsive disorder and phobias, including social phobia), mood disorders (e.g., cyclothymia, dysthymia, major depressive disorder, premenstrual syndrome, premenstrual dysphoric disorder, bipolar disorder, seasonal affective disorder), Parkinson's disease, hypertension, hypotension, urinary incontinence, chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, nicotine, benzodiazepines, phenobarbitol), sexual dysfunction (e.g., premature ejaculation, male erectile dysfunction) and movement disorders (e.g., drug induced and neurodegeneration based dyskinesias) in a mammal, comprising administering to said mammal an amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.  
     
     
         17 . A pharmaceutical composition for treating a disorder or condition selected from psychotic (e.g., psychosis, schizophrenia, schizo-affective disorders, psychotic depression, mania, paranoid and delusional disorders), anxiety-related disorders (e.g., generalized anxiety disorder, post traumatic stress disorder, panic disorder, obsessive-compulsive disorder and phobias, including social phobia), mood disorders (e.g., cyclothymia, dysthymia, major depressive disorder, premenstrual syndrome, premenstrual dysphoric disorder, bipolar disorder, seasonal affective disorder), Parkinson's disease, hypertension, hypotension, urinary incontinence, chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, nicotine, benzodiazepines, phenobarbitol), sexual dysfunction (e.g., premature ejaculation, male erectile dysfunction) and movement disorders (e.g., drug induced and neurodegeneration based dyskinesias) in a mammal, comprising a dopamine D3 receptor binding modulating amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
     
     
         18 . A method of treating a disorder or condition selected from psychotic (e.g., psychosis, schizophrenia, schizo-affective disorders, psychotic depression, mania, paranoid and delusional disorders), anxiety-related disorders (e.g., generalized anxiety disorder, post traumatic stress disorder, panic disorder, obsessive-compulsive disorder and phobias, including social phobia), mood disorders (e.g., cyclothymia, dysthymia, and major depressive disorder, premenstrual syndrome, premenstrual dysphoric disorder, bipolar disorder, seasonal affective disorder), Parkinson's disease, hypertension, hypotension, urinary incontinence, chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, nicotine, benzodiazepines, phenobarbitol), sexual dysfunction (e.g., premature ejaculation, male erectile dysfunction) and movement disorders (e.g., drug induced and neurodegeneration based dyskinesias) in a mammal, comprising administering to said mammal a D3 receptor binding modulating effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         19 . A pharmaceutical composition for treating a disorder or condition, treatment of which can be effected or facilitated by modulating binding activity at the dopamine D3 receptor, in a mammal, including a human, comprising an amount of a compound according to  claim 1  that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier.  
     
     
         20 . A method of treating a disorder or condition, treatment of which can be effected or facilitated by modulating binding activity at the dopamine D3 receptor, in a mammal, including a human, comprising administering to said mammal an amount of a compound according to  claim 1  that is effective in treating such disorder or condition.  
     
     
         21 . A pharmaceutical composition for treating a disorder or condition, treatment of which can be effected or facilitated by modulating binding activity at the dopamine D3 receptor, in a mammal, including a human, comprising a D3 receptor binding modulating effective amount of a compound according to  claim 1 , and a pharmaceutically acceptable carrier.  
     
     
         22 . A method of treating a disorder or condition, treatment of which can be effected or facilitated by modulating binding activity at the dopamine D3 receptor, in a mammal, including a human, comprising administering to said mammal a D3 receptor binding modulating effective amount of a compound according to  claim 1 .  
     
     
         23 . A method according to  claim 16  wherein the disorder or condition being treated is a psychotic disorder or condition.  
     
     
         24 . A method according to  claim 16  wherein the disorder or condition being treated is n anxiety-related disorder.  
     
     
         25 . A method according to  claim 16  wherein the disorder or condition being treated is a movement disorder.  
     
     
         26 . A method according to  claim 16  wherein the disorder or condition being treated is Parkinson's disease.  
     
     
         27 . A method according to  claim 16  wherein the disorder or condition being treated is a urinary incontinence.  
     
     
         28 . A method according to  claim 16  wherein the disorder or condition being treated is a hypertension.  
     
     
         29 . A method according to  claim 16  wherein the disorder or condition being treated is hypotension.  
     
     
         30 . A method according to  claim 16 , wherein the disorder or condition being treated is a chemical dependency or addiction.  
     
     
         31 . A method according to  claim 16 , wherein the disorder or condition being treated is a behavioral dependency or addiction.  
     
     
         32 . A method according to  claim 16 , wherein the disorder or condition being treated is a mood disorder.