Tetrahydroquinazoline-2,4-diones and therapeutic uses thereof

Abstract

The present invention relates to tetrahydroquinazoline-2,4-diones derivatives of the formula (I): pharmaceutically acceptable salts thereof, wherein A is (CH 2 ) n where n is equal to 0, 1 or 2; U is CH 2 , NH, or NR 3 , R 1 and R 2 are selected independently from H, (C 1 -C 6 )alkyl, Cl, F, CN, nitro, CF 3 , —NHC(O)R 6 and —OR 7 , or R 1 and R 2 , together with the atoms to which they are attached, form a carbocyclic or heterocyclic five- or six-membered ring, R 3 is selected from the group consisting of H, (C 1 -C 6 ) m alkyl, C(═O)-(C 1 -C 6 )alkyl, where m=1 or 2; R 4 and R 5 are selected from H, (C 1 -C 6 )alkyl, Cl, F, —CF 3 , —CN, —NHC(═O)R 6 , —OR 7 , a 5-to 7-membered aryl or heteroaryl ring, where m, R 6 and R 7 are as defined above; and R 6 and R 7 are selected independently from H, (C 1 -C 6 )alkyl or a 5- to 7-membered aryl or heteroaryl ring; V is CH, CR 3 , or N; W is CH 2 , C(O), or S(O) 2 ; X is C or N; and Y is CH, CR 1 , CR 2 , or N. The invention also relates to pharmaceutical compositions containing the same and to methods of use thereof, including in the inhibition of serotonin reuptake, the inhibition of the binding of 5-HT 2A serotonin receptors and the treatment of diseases, conditions or disorders of the central nervous system. Further, the present invention is also directed to methods for the preparation of 4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-propyl-1,2,3,4-tetrahydroquinazoline-2,4-dione compounds and intermediates useful therefor.

What is claimed is:  
     
         1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 A is (CH 2 ) n  where n is equal to 0, 1 or 2, with the proviso that when n is 0 there is no bridging group A;  
 U is NH or NR 3 ,  
 R 1  and R 2  are selected independently from H, (C 1 -C 6 )alkyl, Cl, F, CN, nitro, CF 3 , —NHC(O)R 6  and —OR 7 ,  
 R 3  is selected from the group consisting of (C 1 -C 6 ) m alkyl, C(═O)-(C 1 -C 6 )alkyl, where m=1 or 2;  
 R 4  and R 5  are selected from H, (C 1 -C 6 )alkyl, Cl, F, —CF 3 , —CN, —NHC(═O)R 6 , —OR 7 , a 5- to 7-membered aryl or heteroaryl ring, where m, R 6  and R 7  are as defined above; and  
 R 6  and R 7  are selected independently from H, (C 1 -C 6 )alkyl or a 5- to 7-membered aryl or heteroaryl ring;  
 V is CH, CR 3 , or N;  
 W is CH 2  or C(O);  
 X is C;  
 Y is CH, CR 1 , or CR 2 , where R 1  and R 2  are as defined above.  
 
     
     
         2 . A compound according to  claim 1  wherein A is (CH 2 ) n  where n is equal to 1 or 2; and pharmaceutically acceptable salts thereof.  
     
     
         3 . A compound according to  claim 1  wherein n is equal to zero and there is no bridging group A; W is C(═O); X is C; Y is C; V is CH or N; and pharmaceutically acceptable salts thereof.  
     
     
         4 . A compound according to  claim 1  wherein n is equal to zero; W is C(═O); X is C; Y is C; V is CH or N; U is NH, and R 1 , R 2 , R 4 , R 5  are independently chosen from the group consisting of hydrogen, halo, —CF 3 , nitro, (C 1 -C 6 )alkyl, hydroxy or methoxy; and pharmaceutically acceptable salts thereof.  
     
     
         5 . A compound according to  claim 1  wherein n is equal to zero and there is no bridging group A; W is C(═O); X is C; Y is C; V is CH; U is NH, and R 1 , R 2 , R 4 , R 5  are independently chosen from the group consisting of hydrogen, halo, —CF 3 , nitro, methyl, hydroxy or methoxy; and pharmaceutically acceptable salts thereof.  
     
     
         6 . A compound according to  claim 1  selected from the group consisting of: 
 3-{3-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridinyl-1-yl]-propyl}-6-methyl-1H-quinazoline-2,4-dione;  
 3-{3-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridinyl-1-yl]-propyl}-8-methoxy-1H-quinazoline-2,4-dione;  
 3-{3-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridinyl-1-yl]-propyl}-8-chloro-1H-quinazoline-2,4-dione; and  
 5-Methyl-3-[3-(4-m-tolyl-3,6-dihydro-2H-pyridin-1-yl)-propyl]-1H-quinazoline-2,4-dione;  
 3-{3-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-propyl}-5-fluoro-1H-quinazoline-2,4-dione;  
 3-{3-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-propyl}-6-fluoro-1H-quinazoline-2,4-dione;  
 3-{3-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-propyl}-7-fluoro-1H-quinazoline-2,4-dione;  
 3-{3-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-propyl}-6,7-difluoro-1H-quinazoline-2,4-dione; 
 and pharmaceutically acceptable salts thereof.  
 
 
     
     
         7 . A method for preparing a compound of formula (I):  
       
         
           
           
               
               
           
         
         wherein:  
         A is (CH 2 ) n  where n is equal to 0, 1 or 2, with the proviso that when n is 0 there is no bridging group A;  
         U is NH or NR 3 ,  
         R 1  and R 2  are selected independently from H, (C 1 -C 6 )alkyl, Cl, F, CN, nitro, CF 3 , —NHC(O)R 6  and —OR 7 ,  
         R 3  is selected from the group consisting of (C 1 -C 6 ) m alkyl, C(═O)-(C 1 -C 6 )alkyl, where m=1 or 2;  
         R 4  and R 5  are selected from H, (C 1 -C 6 )alkyl, Cl, F, —CF 3 , —CN, —NHC(═O)R 6 , —OR 7 , a 5- to 7-membered aryl or heteroaryl ring, where m, R 6  and R 7  are as defined above;  
         R 6  and R 7  are selected independently from H, (C 1 -C 6 )alkyl or a 5- to 7-membered aryl or heteroaryl ring;  
         V is CH 2  CR 3 , or N;  
         W is CH 2  or C(O);  
         X is C;  
         Y is CH, CR 1 , or CR 2 ;  
         comprising the step of allowing a compound of formula (AII):  
         
           
             
             
                 
                 
             
           
         
         wherein U, W, X, Y, R 1  and R 2  are as defined above, to react with a compound of formula (BI):  
         
           
             
             
                 
                 
             
           
         
         wherein A, V, R 4  and R 5  are as defined above.  
       
     
     
         8 . The method according to  claim 7  wherein U is NH; V is CH or N; W is carbonyl; X is C; n is 0 and there is no bridging group A; and Y is C.  
     
     
         9 . The method according to  claim 7  wherein n is 1 or 2.  
     
     
         10 . A method for the preparation of a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is (CH 2 ) n  where n is equal to 0, 1 or 2 with the proviso that when n is 0 there is no bridging group A;  
 U is CH 2  or NH,  
 R 1  and R 2  are selected independently from H, (C 1 -C 6 )alkyl, Cl, F, CN, nitro, —CF 3 , —NHC(O)R 6  and —OR 7 , or R 1  and R 2 , together with the atoms to which they are attached, form a carbocyclic or heterocyclic five- or six-membered ring,  
 R 3  is selected from the group consisting of (C 1 -C 6 ) m alkyl, —C(═O)-(C 1 -C 6 )alkyl, where m=1 or 2;  
 R 4  and R 5  are selected from H, (C 1 -C 6 )alkyl, Cl, F, —CF 3 , —CN, —NHC(═O)R 6 , —OR 7 , a 5- to 7-membered aryl or heteroaryl ring, where m, R 6  and R 7  are as defined above; and  
 R 6  and R 7  are selected independently from H, (C 1 -C 6 )alkyl or a 5- to 7-membered aryl or heteroaryl ring;  
 V is CH, CR 3 , or N;  
 W is CH 2 , C(O), or S(O) 2 ;  
 X is C or N;  
 Y is CH, CR 1 , CR 2 , or N;  
 comprising the step of allowing a compound of formula (CI)  
                     
 wherein U, V, W, X, Y, R 1 , R 2 , R 4  and R 5  are as defined above and “Lower alkyl” is (C 1 -C 6 )alkyl;  
 to undergo an internal ring closure reaction.  
 
     
     
         11 . The method according to  claim 10  further comprising the step of allowing a compound of formula (AIII)  
       
         
           
           
               
               
           
         
         wherein U′ is CH or N,  
         W is CH 2 , C(O), or S(O) 2 ;  
         X is C or N;  
         Y is CH, CR 1 , CR 2 , or N;  
         R 1  and R 2  are selected independently from H, (C 1 -C 6 )alkyl, Cl, F, CN, nitro, CF 3 , —NHC(O)R 6  and —OR 7 , or R 1  and R 2 , together with the atoms to which they are attached, form a carbocyclic or heterocyclic five- or six-membered ring,  
         where R 6  and R 7  are selected independently from H, (C 1 -C 6 )alkyl or a 5- to 7-membered aryl or heteroaryl ring;  
         to react with a compound of formula (BII)  
         
           
             
             
                 
                 
             
           
         
         A is (CH 2 ) n  where n is equal to 0, 1 or 2;  
         R 4  and R 1  are selected from H, (C 1 -C 6 )alkyl, Cl, F, —CF 3 , —CN, —NHC(═O)R 6 , —OR 7 , a 5- to 7-membered aryl or heteroaryl ring, where m, R 6  and R 7  are as defined above and V is CH, CR 3 , or N, and R 3  is selected from the group consisting of H, (C 1 -C 6 ) m alkyl, C(═O)-(C 1 -C 6 )alkyl, where m=1 or 2.  
       
     
     
         12 . The method according to  claim 10  wherein U is NH; V is CH or N; W is carbonyl; X is C; n is 0 and there is no bridging group A; and Y is C.  
     
     
         13 . The method according to  claim 11  wherein U is NH; U′ is N; V is CH or N; W is carbonyl; X is C; n is 0 and there is no bridging group A; and Y is C.  
     
     
         14 . The method according to  claim 10  where n is 1 or 2.  
     
     
         15 . The method according to  claim 11  where n is 1 or 2.  
     
     
         16 . A method for the preparation of a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is (CH 2 ) n  where n is equal to 0, 1 or 2;  
 U is CH 2  or NH,  
 R 1  and R 2  are selected independently from H, (C 1 -C 6 )alkyl, Cl, F, CN, nitro, —CF 3 , —NHC(O)R and —OR 7 , or R 1  and R 2 , together with the atoms to which they are attached, form a carbocyclic or heterocyclic five- or six-membered ring,  
 R 4  and R 5  are selected from H, (C 1 -C 6 )alkyl, Cl, F, —CF 3 , —CN, —NHC(═O)R 6  —OR 7 , a 5- to 7-membered aryl or heteroaryl ring, where m, R 6  and R 7  are as defined above; and  
 R 6  and R 7  are selected independently from H, (C 1 -C 6 )alkyl or a 5- to 7-membered aryl or heteroaryl ring;  
 V is CH, CR 3 , or N; where R 3  is selected from the group consisting of (C 1 -C 6 ) m alkyl, —C(═O)-(C 1 -C 6 )alkyl, where m=1 or 2;  
 W is CH 2 , C(O), or S(O) 2 ;  
 X is C or N;  
 Y is CH, CR 1 , CR 2 , or N;  
 comprising the step of (a) allowing a compound of formula (DIII):  
                     
 wherein X, Y, R 1 , and R 2  are as defined above; to react with a 3-halopropylisocyanate, wherein halo is bromo, iodo or chloro to form a compound of formula (GI):  
                     
 (b) allowing the product of step (a) to undergo a double ring closure reaction to form a compound of formula (FI):  
                     
 wherein U′ is CH or N; and X, Y, W, R 1  and R 2  are defined above; and  
 (c) allowing the product of step (b) to react with a compound of formula (BI):  
                     
 wherein A, V, R 4  and R 5  are defined above; or a salt thereof.  
 
     
     
         17 . The method according to  claim 16  wherein U is NH; U′ is N; V is CH or N; W is carbonyl; X is C; n is 0 and there is no bridging group A; and Y is C.  
     
     
         18 . The method according to  claim 16  wherein n is 1 or 2.  
     
     
         19 . A method of inhibiting serotonin reuptake or 5-HT 2A  serotonin receptor binding in the central nervous system of a mammal comprising the administration to the mammal a serotonin receptor binding-inhibiting effective amount or a serotonin reuptake-inhibiting effective amount of a compound of  claim 1 .  
     
     
         20 . A method of treating a mammal for a disease, condition or disorder of the central nervous system, said method comprising the administration to the mammal a therapeutically effective amount of a compound of  claim 1 .  
     
     
         21 . The method according to  claim 20  wherein the disease, condition or disorder of the central nervous system is selected from the group consisting of aggression disorder; anxiety disorder selected from the group consisting of panic attack, agoraphobia, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder and acute stress disorder; cognitive disorder selected from the group consisting of amnestic disorders, deliriums, dementias, and cognitive disorders not otherwise specified; emesis; epilepsy; food behavior disorder selected from anorexia nervosa and bulimia, headache disorder selected from the group consisting of migraine, cluster and vascular headaches; learning disorder selected from attention deficit disorder and attention deficit/hyperactivity disorder; obesity; psychotic condition selected from the group consisting of schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and psychotic disorders not otherwise specified; sleep disorder selected from the group consisting of primary sleep disorders, sleep disorders related to another mental disorder, sleep disorders due to a general medical condition and sleep disorders not otherwise specified; sexual behavior disorder; substance-abuse disorder selected from the group consisting of alcohol-related disorders, amphetamine-related disorders, caffeine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen-related disorders, inhalant-related disorders, nicotine-related disorders, opioid-related disorders, phencyclidine-related disorders, sedative-related disorders, hypnotic-related disorders, anxiolytic-related disorders and polysubstance-related disorder and vision disorders including glaucoma  
     
     
         22 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         23 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a serotonin reuptake-inhibiting effective amount or a serotonin binding-inhibiting effective amount of the compound of  claim 1 .  
     
     
         24 . A compound of the formula (GI)  
       
         
           
           
               
               
           
         
         U is CH 2  or NH,  
         R 1  and R 2  are selected independently from H, (C 1 -C 6 )alkyl, Cl, F, CN, nitro, —CF 3 , —NHC(O)R 6  and —OR 7 , or R 1  and R 2 , together with the atoms to which they are attached, form a carbocyclic or heterocyclic five- or six-membered ring,  
         W is CH 2 , C(O), or S(O) 2 ;  
         X is C or N;  
         Y is CH, CR 1 , CR 2 , or N.  
       
     
     
         25 . A compound according to  claim 24  wherein halo is chloro, U is NH, W is carbonyl, X is C, Y is CH, and R 1  is chloro and R 2  is hydrogen.  
     
     
         26 . A compound according to  claim 24  which is  
       
         
           
           
               
               
           
         
       
     
     
         27 . A compound of formula (FI):  
       
         
           
           
               
               
           
         
         wherein U′ is CH or N;  
         R 1  and R 2  are selected independently from H, (C 1 -C 6 )alkyl, Cl, F, CN, nitro, —CF 3 , —NHC(O)R 6  and —OR 7 , or R 1  and R 2 , together with the atoms to which they are attached, form a carbocyclic or heterocyclic five- or six-membered ring,  
         W is CH 2 , C(O), or S(O) 2 ;  
         X is C or N;  
         Y is CH, CR 1 , CR 2 , or N.  
       
     
     
         28 . A compound according to  claim 27  wherein U′ is N; R 1  is chloro and R 2  is hydrogen; W is carbonyl; X is C; and Y is CH.  
     
     
         29 . A compound according to  claim 27  which is