Benztropine compounds and uses thereof

Abstract

Disclosed are benztropine analogs having the formula (I) in which Ar is a C 6 -C 20 monocyclic aryl group or a C 10 -C 20 bicyclic aryl group or a heteroaryl, heterocyclic, or arylheterocyclic group having 2 to 12 carbon atoms and one or more heteroatoms selected from the group consisting of N, O, S, P, and any combination thereof; m=1 to 5; n=1 to 3; and R 1 to R 4 are as described in the specification; or a pharmaceutically acceptable salt or solvate thereof; pharmaceutical compositions and use thereof, e.g., in treating mental disorders.

1 .- 44 . (canceled) 
     
     
         45 . A compound of the formula (I): 
       
         
           
           
               
               
           
         
       
       in which:
 R 1  is selected from the group consisting of hydrogen, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 6 -C 20  aryl C 1 -C 12  alkyl, C 5 -C 20  heteroaryl C 1 -C 12  alkyl, C 1 -C 12  aminoalkyl, C 1 -C 12  alkoxy C 1 -C 12  alkyl, C s -C 20  heterocycloalkyl C 1 -C 12  alkyl, C 1 -C 12  alkylsulfonyl, C 2 -C 12  alkylcarbonyl, (N(C 6 -C 20  aryl)amido)C 1 -C 12  alkyl, (N(C 1 -C 12  alkyl)amido)C 1 -C 12  alkyl, (N(C 6 -C 20  aryl)amido)C 2 -C 12  alkylcarbonyl, (N(C 1 -C 12  alkyl)amido)C 2 -C 12  alkylcarbonyl, C 1 -C 12  alkylamido C 6 -C 20  aryl, and a polymer; 
 R 2  and R 3  are each independently selected from the group consisting of hydrogen, halo, C 1 -C 12  alkyl, C 1 -C 12  alkoxyl, nitro, cyanato, isocyanato, thiocyanato, amino, halo C 1 -C 12  alkyl, hydroxyl, trihalo C 1 -C 12  alkyl, and any combination thereof; 
 m=1 to 5; n=1 to 3; 
 R 4  is selected from the group consisting of hydroxyl, carboxyl, C 1 -C 12  alkyl, C 1 -C 12  alkoxyl, C 2 -C 12  carboxyalkyl, C 2 -C 12  alkyloxycarbonyl, C 6 -C 20  aryloxycarbonyl, C 6 -C 20  aryl C 2 -C 12  alkyloxycarbonyl, C 2 -C 12  alkyloxycarbonyl C 1 -C 12  alkyl, C 6 - C 20  aryl, C 6 -C 20  aryl C 2 -C 12  alkylcarbonyloxy C 1 -C 12  alkyl, C 1 -C 12  alkylsulfonyl, C 1 -C 12  hydroxyalkyl, formyl, C 2 -C 12  formylalkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkyloxycarbonyl C 2 -C 12  alkenyl, and C 2 -C 12  alkynyl; and 
 Ar is a C 6 -C 20  monocyclic aryl group or a C 10 -C 20  bicyclic aryl group; 
 wherein any of R 1 , R 2 , R 3 , and R 4  other than hydrogen, halo, hydroxyl, nitro, cyanato, isocyanato, and thiocyanato may be further substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyanato, isocyanato, thiocyanato, amino, C 1 -C 12  alkyl, amido, nitro, methoxyl, CF 3 , azido, C 2 -C 12  alkylcarbonylamino, C 1 -C 12  alkylamino, C 2 -C 12  alkylcarbonyl, and any combination thereof; 
 or a pharmaceutically acceptable salt thereof, with the provisos that: 
 (a) if Ar is phenyl, m=n=1, R 1  is CH 3 , and R 4  is β-COOCH 3 , R 2  and R 3  are not simultaneously hydrogen, R 2  and R 3  are not simultaneously 4-halo or R 2  and R 3  are not simultaneously 4-methyl; 
 (b) if Ar is phenyl, m=n=1, R 1  is H, and R 4  is β-COOCH 3 , R 2  and R 3  are not hydrogen or halo; 
 (c) if Ar is phenyl, m=1, n=2, R 1  is H, R 4  is β-COOCH 3 , and R 2  is H, both R 3  are not hydroxyl or both R 3  are not C 1 -C 12  alkoxyl, 
 (d) if Ar is phenyl, m=n=1, R 1  is CH 3 , and R 2  and R 3  are 4-fluoro, R 4  is not COOC 2 H 5 , CO 2 CH(CH 3 ) 2 , CO 2 CH 2 Ph, CO 2 CH 2 CH 2 Ph, CO 2 CH 2 CH 2 Ph-4′-NO 2 , CO 2 CH 2 CH 2 Ph-4′-NH 2 , CO 2 CH 2 CH 2 Ph-3′-I, 4′-NH 2 , CO 2 CH 2 CH 2 Ph-3′-I, 4′-N 3 , or CO 2 CH 2 CH 2 Ph-4′-NCS where R 4  has β-configuration; 
 (e) if Ar is phenyl, m=n=1, R 1  is CH 3 , R 4  is β-COOCH 3 , and R 2  is hydrogen, R 3  is not 4-halo or 4-methyl; 
 (f) if Ar is phenyl, m=1, n=2, R 1  is CH 3 , R 4  is β-COOCH 3 , and R 2  is hydrogen, R 3  is not hydroxyl, alkoxyl, or methylcarbonyloxy; and 
 (g) if R 1  is C 6 -C 20  aryl C 1 -C 12  alkyl, optionally substituted with halo, R 4  is β-COOCH 3 , and m=n=1, R 2  and R 3  are not simultaneously 4-halo. 
 
     
     
         46 . The compound or salt of  claim 45 , wherein the compound is of Formula II: 
       
         
           
           
               
               
           
         
       
     
     
         47 . The compound or salt of  claim 46 , wherein R 3  is fluoro or chloro. 
     
     
         48 . The compound or salt of  claim 46 , wherein m=n=1. 
     
     
         49 . The compound or salt of  claim 46 , wherein Ar is selected from the group consisting of phenyl, naphthyl, and biphenyl. 
     
     
         50 . The compound or salt of  claim 46 , wherein R 1  is selected from the group consisting of hydrogen, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 6 -C 20  aryl-C 1 -C 12  alkyl, C 1 -C 12  aminoalkyl, C 5 -C 20  heterocycloalkyl-C 1 -C 12  alkyl, and (N(C 6 -C 20 -aryl)amido)C 1 -C 12  alkyl. 
     
     
         51 . The compound or salt of  claim 50 , wherein R 1  is selected from the group consisting of methyl, ethyl, propyl, butyl, allyl, phenylbutyl, 2-aminoethyl, [2-(1H-indol-3-yl)-ethyl]-, and 3-[(N-phenyl)amidopropyl]. 
     
     
         52 . The compound or salt of  claim 46 , wherein R 4  is selected from the group consisting of hydroxyl, carboxyl, C 1 -C 12  alkyl, C 1 -C 12  alkoxyl, C 2 -C 12  carboxyalkyl, C 2 -C 12  alkyloxycarbonyl C 1 -C 12  alkyl, C 6 -C 20  aryl, C 6 -C 20  aryl C 2 -C 12  alkylcarbonyloxy C 1 -C 12  alkyl, C 1 -C 12  alkylsulfonyl, C 1 -C 12  hydroxyalkyl, formyl, C 2 -C 12  formylalkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkyloxycarbonyl C 2 -C 12  alkenyl, and C 2 -C 12  alkynyl. 
     
     
         53 . The compound or salt of  claim 52 , wherein:
 Ar is phenyl;   R 1  is selected from the group consisting of hydrogen, 2-propyl, (CH 2 ) p CH 3 , CH 2 CF 3 , CH 2 (CH 2 ) p OH, CH 2 (CH 2 ) p O(CH 2 ) q CH 3 , CH 2 CH═CHX, 2-(1-piperidinyl)ethyl, 2-(4-morpholinyl)ethyl, or (CH 2 ) p C 6 H 4 X, wherein X is selected from the group consisting of H, halo, hydroxyl, methoxyl, CF 3 , nitro, amino, cyanato, NHCOCH 3 , N(CH 3 ) 2 , (CH 2 ) p CH 3 , C(O)CH 3 , and C(CH 3 ) 3 ;   p=0-6;   q=0-4; and   at least one of R 2  and R 3  is selected from the group consisting of C 1 -C 12  alkyl, C 2 -C 12  alkoxyl, nitro, cyanato, isocyanato, thiocyanato, amino, halo C 1 -C 12  alkyl, and trihalo C 1 -C 12  alkyl.   
     
     
         54 . The compound or salt of  claim 46 , wherein:
 m=n=1;   Ar is phenyl;   R 1  is selected from the group consisting of hydrogen, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 6 -C 20  aryl-C 1 -C 12  alkyl, C 1 -C 12  aminoalkyl, C 5 -C 20  heterocycloalkyl-C 1 -C 12  alkyl, and (N(C 6 -C 20 -aryl)amido)C 1 -C 12  alkyl;   R 2  and R 3  are halo; and   R 4  is selected from the group consisting of methyloxycarbonyl, ethyloxycarbonyl, hydroxymethyl, formyl, methyloxycarbonylethenyl, methyloxycarbonylethyl, ethenyl, 4-nitrophenylpropylcarbonyloxymethyl, and 4-aminophenylpropylcarbonyloxymethyl.   
     
     
         55 . The compound or salt of  claim 54 , wherein R 1  is selected from the group consisting of hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 6 -C 10  aryl-C 1 -C 6  alkyl, C 1 -C 6  aminoalkyl, C 5 -C 10  heterocycloalkyl-C 1 -C 6  alkyl, and (N(C 6 -C 10 -aryl)amido)C 1 -C 6  alkyl. 
     
     
         56 . The compound or salt of  claim 55 , wherein R 1  is selected from the group consisting of methyl, n-butyl, allyl, phenylbutyl, 2-aminoethyl, [2-(1H-indol-3-yl)-ethyl]-, and 3-[(N- phenyl)amidopropyl]. 
     
     
         57 . The compound or salt of  claim 54 , wherein R 2  and R 3  are chloro. 
     
     
         58 . The compound or salt of  claim 54 , wherein R 2  and R 3  are fluoro. 
     
     
         59 . The compound or salt of  claim 54 , wherein R 4  is methyloxycarbonyl or ethyloxycarbonyl. 
     
     
         60 . The compound or salt of  claim 54 , wherein:
 m=n=1;   Ar is phenyl;   R 1  is selected from the group consisting of hydrogen, methyl, n-butyl, allyl, phenylbutyl, 2-aminoethyl, [2-(1H-indol-3-yl)-ethyl]-, and 3-[(N-phenyl)amidopropyl];   R 2  and R 3  are 4-fluoro or 4-chloro; and   R 4  is selected from the group consisting of hydroxymethyl, formyl, methyloxycarbonylethenyl, methyloxycarbonylethyl, ethenyl, 4-nitrophenylpropylcarbonyloxymethyl, and 4-aminophenylpropylcarbonyloxymethyl.   
     
     
         61 . The compound or salt of  claim 60 , wherein R 1  is methyl. 
     
     
         62 . The compound or salt of  claim 45 , wherein the compound is selected from the group consisting of S-(+)-2β-carboethoxy-3α-[bis(4-chlorophenyl)methoxy]tropane, S-(−)-2β-carboethoxy-3α-[bis(4-chlorophenyl)methoxy]tropane, and S-(±)-2β-carboethoxy-3α-[bis(4-chlorophenyl)methoxy]tropane. 
     
     
         63 . A pharmaceutical composition comprising a compound or salt of  claim 45  and a pharmaceutically acceptable carrier. 
     
     
         64 . A method of treating a patient for a mental disorder comprising administering to the patient an effective amount of a compound or salt of  claim 45 . 
     
     
         65 . The method of  claim 64 , wherein the mental disorder is selected from the group consisting of conduct disorders, alcohol addiction, tobacco addiction, nicotine addiction, drug addiction, sleep disorders, inhalation disorders, obesity, Parkinsonism, female and male orgasmic disorders, female and male sexual arousal disorders, hypoactive sexual desire disorder, and anxiety, stress and/or depression disorders. 
     
     
         66 . The method of  claim 65 , wherein the Parkinsonism is Parkinson's disease. 
     
     
         67 . A method of selectively imaging cocaine binding sites of the central nervous system of a patient, the method comprising administering to the central nervous system of the patient a compound or salt of  claim 45  and detecting the binding of that compound or salt to the central nervous system tissue. 
     
     
         68 . A method of detecting or monitoring Parkinsonism in a patient, the method comprising administering to the patient a detectably labeled compound or salt of  claim 45  and detecting the binding of that compound or salt to the central nervous system tissue. 
     
     
         69 . A method of increasing attention relative to an untreated control in a mammal comprising administering to the mammal an effective amount of a compound of the formula (III): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is C 1 -C 12  alkyl or C 2 -C 12  alkenyl; and 
 R 2  and R 3  are each independently hydrogen or halo. 
 
     
     
         70 . A method of reducing the effect of nicotine by at least 50% in a mammal comprising administering to the mammal an effective amount of a compound of the formula (III): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is C 1 -C 12  alkyl or C 2 -C 12  alkenyl; and 
 R 2  and R 3  are each independently hydrogen or halo. 
 
     
     
         71 . A method of reducing food intake in a mammal comprising administering to the mammal an effective amount of a compound of the formula (III): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is C 1 -C 12  alkyl or C 2 -C 12  alkenyl; and 
 R 2  and R 3  are each independently hydrogen or halo.