Compounds with high monoamine transporter affinity

Abstract

Featured compounds have high monoamine transport affinity and are characterized by one of the following two general formulas set out above. The compounds bind selectively or non-selectively to monoamine transporters. The compounds are useful to treat various medical indications including attention deficit hyperactivity disorder (ADHD), Parkinson's disease, cocaine addiction, smoking cessation, weight reduction, obsessive-compulsive disorder, various forms of depression, traumatic brain injury, stroke, and narcolepsy.

1 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     WHERE:  
     * indicates a chiral center, and each chiral center, independently, may be R, S, or R/S;  
     —X≡CH 2 R 1 ; —CHR 1 R 5 ; —CR 1 ═O; —CR 6 ═O; —O—R 1 ; —SR 1 ; —SOR 6 ; —SO 2 R 6 ; —SO 2 NHR 1 ; or —CH═CR 1 R 5  and where: 
 a. —R 1  and —R 5  are independently selected from: —H; —CH 3 ; —CH 2 CH 3 ; or —CH 2 (CH 2 ) m CH 3 , where m=0, 1, 2, or 3; 
 PROVIDED THAT, when X≡O—R 1 , then R 1  # H; and  
 
 b. —R 6  is selected from: —OH; —OCH 3 ; —NHR 1 ; —O-alkyl; —O-alkenyl; —O-alkynyl; —O-allyl; —O-iodoallyl; -alkyl; -alkenyl; -alkynyl; -allyl; -isopropyl; and -isobutyl;.  
 —Ar=either  
 a) phenyl substituted at any two positions with R 3a  and R 3b , where R 3a  and R 3b  are as defined in options “I.” or “II.”, below; or  
 b) 1-napththyl or 2-naphthyl, substituted at any two positions with R 3a , and R 3b  where R 3a  and R 3b  are as defined in option “I.”, below); 
 OPTION I for R 3a , and R 3b  (phenyl or naphthyl substitutions)  
 —R 3a  and —R 3b  are independently selected from: —H; —Br; —Cl; —I; —F; —OH; —OCH 3 ; —CF 3 ; —NO 2 ; —NH 2 ; —CN; —NHCOCH 3 , —C(CH 3 ) 3 , —(CH 2 ) q CH 3  where q=0-6; —COCH 3 ; —F (at the 2, 3 or 4 position), —Cl (at the 2, 3 or 4 position); —I (at the 2, 3 or 4 position); alkyl; alkenyl; alkenyl; allyl; iospropyl; isobutyl; alkyl; -alkylN 2 S 2 chelator; -alkylN 2 S 2 Tc chelator; or COR 7 , where R 7  is defined below; 
 OR  
 
 OPTION II. for R 3a  and R 3b  (phenyl substitutions)  
 —R 3a  and —R 3b  as a pair are independently selected from the following pairs: 3,4-diCl; 3,4,diOH; 3,4-diOAc; 3,4-diOCH 3 ; 3-OH, 4-Cl; 3-OH, 4-F; 3-Cl, 4-OH; or 3-F, 4-OH;  
 n=0 or 1;  
 —R 2 =—H; —COOCH 3 ; —COR 7 ; -alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl; -isoxazole; -oxadiazole; -oxazole; -alkylN 2 S 2  chelator-; —O-alkylN 2 S 2  chelator; -alkylN 2 S 2 Tc chelator; —O-alkylN 2 S 2 Tc chelator; where,  
 
 —R 7  is=—NHR 5 ; morpholinyl; piperidinyl; —CH 3 ; —CH 2 CH 3 ; —CH 2 (CH 2 ) r CH 3  where r=0, 1, 2, or 3; alkyl; alkenyl; alkynyl; allyl; isopropyl; iodoallyl; O-iodoallyl; -isobutyl; —CH 2 SO 2 ; -alkylN 2 S 2  chelator; -alkylN 2 S 2 Tc chelator; O-alkylN 2 S 2  chelator; or —O-alkylN 2 S 2 Tc chelator; and 
 —R 8  is=-alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl; -isoxazole; -oxadiazole; -oxazole; -alkylN 2 S 2  chelator —O-alkylN 2 S 2  chelator; -alkylN 2 S 2 Tc chelator; or —O-alkylN 2 S 2 Tc chelator;  
 R 4a  and R 4b  are independently selected from:  
 
 —H; —Br; —Cl; —I; —F; —OH; —OCH 3 ; —CF 3 ; —NO 2 ; —NH 2 ; —CN; —NHCOCH 3 , —C(CH 3 ) 3 , —(CH 2 ) q CH 3  where q=0-6; —COCH 3 ; —F (at the 2, 3 or 4 position), —Cl (at the 2, 3 or 4 position); —I (at the 2, 3 or 4 position); alkyl; alkenyl; alkynyl; allyl; iospropyl; isobutyl; alkyl; -alkylN 2 S 2 ; -alkylN 2 S 2 Tc; and COR 7 , where R 7  is defined above;  
 or  
 R 4a  and R 4b  are selected as a pair from the following pairs:  
 3,4-diCl; 3,4-diOH; 3,4-diOAc; 3,4-diOCH 3 ; 3-OH, 4-Cl; 3-OH, 4-F; 3-Cl, 4-OH; and 3-F, 4-OH.  
 
   
   
       2 . The compound of  claim 1  in which n=0.  
   
   
       3 . The compound of  claim 1  or  claim 2  in which X≡O—R 1 .  
   
   
       4 . The compound of  claim 3  in which —R 1 ═—CH 3 .  
   
   
       5 . The compound of  claim 1  in which Ar=1- or 2-naphthyl, substituted at any two positions with R 3a , and R 3b , where R 3a  and R 3b  are as defined in option “I.”, above.  
   
   
       6 . The compound of  claim 5  in which R 3a  and R 3b  are both —H.  
   
   
       7 . The compound of  claim 1  in which Ar=phenyl substituted at any two positions with R 3a , and R 3b .  
   
   
       8 . The compound of  claim 7  in which R 3a , and R 3b  are independently selected from —H and —Cl.  
   
   
       9 . The compound of  claim 8  in which R 3a , and R 3b  are both —Cl.  
   
   
       10 . (canceled)  
   
   
       11 . A compound having the formula A, B, or C:  
     
       
         
         
             
             
         
       
     
     Where:  
     n is 0, 1, 2, or 3; 
 >X is >CH 2 ; >CHY, >C(Y,Z); >C═O; >O; >S; >SO; >SO 2 ; >NSO 2 ; >NSO 2 R 3 ; or >C═CYZ; where Y and Z are independently selected from H; Br; Cl; I; F; OH; OCH 3 ; CF 3 ; NO 2 ; NH 2 ; CN; NHCOCH 3 ; N(CH 3 ) 2 ; (CH 2 ) n CH 3 , where m=0-6; COCH 3 ; alkyl alkenyl, alkynyl, allyl, isopropyl, isobutyl;  
 —Ar=either  
 a) phenyl substituted at any two positions with R 1a  and R 1b , where R 1a  and R 1b  are as defined in options “I.” or “II.”, below; or  
 b) 1-napththyl or 2-naphthyl, substituted at any two positions with R 1a  and R 1b  where R 1a  and R 1b  are as defined in option “I.”, below);  
 OPTION I for R 1a , and R 1b  (phenyl or naphthyl substitutions)  
 —R 1a  and —R 1b  are independently selected from: —H; —Br; —Cl; —I; —F; —OH; —OCH 3 ; —CF 3 ; —NO 2 ; —NH 2 ; —CN; —NHCOCH 3 , —C(CH 3 ) 3 , —(CH 2 ) q CH 3  where q=0-6; —COCH 3 ; —F (at the 2, 3 or 4 position), —Cl (at the 2, 3 or 4 position); —I (at the 2, 3 or 4 position); alkyl; alkenyl; alkynyl; allyl; iospropyl; isobutyl; alkyl; -alkylN 2 S 2  chelator; -alkylN 2 S 2 Tc chelator; or COR 4 , where R 4  is defined below; 
 OR  
 OPTION II. for R 1a , and R 1b  (phenyl substitutions)  
 
 —R 1a  and —R 1b  as a pair are independently selected from the following pairs: 3,4-diCl; 3,4,diOH; 3,4-diOAc; 3,4-diOCH 3 ; 3-OH, 4-Cl; 3-OH, 4-F; 3-Cl, 4-OH; or 3-F, 4-OH;  
 —R 2 =—COOCH 3 ; —COR 4 ; -alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl; -isoxazole; -oxadiazole; -oxazole; -alkylN 2 S 2  chelator; —O-alkylN 2 S 2  chelator; -alkylN 2 S 2 Tc chelator; —O-alkylN 2 S 2 Tc chelator; or  
                     
 where,  
 —R 4  is=—NHR 5 ; morpholinyl; piperidinyl; —CH 3 ; —CH 2 CH 3 ; —CH 2 (CH 2 ),CH 3  where r=0, 1, 2, or 3; alkyl; alkenyl; alkynyl; allyl; isopropyl; iodoallyl; O-iodoallyl; -isobutyl; —CH 2 SO 2 ; -alkylN 2 S 2  chelator; -alkylN 2 S 2 Tc chelator; O-alkylN 2 S 2  chelator; or —O-alkylN 2 S 2 Tc chelator; and  
 —R 5  is=-alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl; -isoxazole; -oxadiazole; -oxazole; -alkylN 2 S 2  chelator; —O-alkylN 2 S 2  chelator; -alkylN 2 S 2 Tc chelator; —O-alkylN 2 S 2 Tc chelator, and  
 R 9  and R 10  are independently ═H, CH 3 , CH 2 CH 3 , (CH 2 ) r CH 3 , (CH 2 ) r C 6 H 3 YZ, isopropyl, isobutyl, CH═CH—(CH 2 ) r CH 3 , CH 2 CH═CH(CH 2 ) r CH 3 , (CH 2 ) s CH═CH(CH 2 ) r CH 3 , C═C(CH 2 ) r CH 3 , CH 2 C═C(CH 2 ) r CH 3 , where r=0-6 and s=0-6 and Y and Z are independently ═H, F, Cl, Br, I, OH, OR, CH 3 , CF 3 , amino, NO 2 .  
 
   
   
       12 . The compound of  claim 11  in which X=O.  
   
   
       13 . The compound of  claim 11  in which n=1.  
   
   
       14 . The compound of  claim 11  in which X═C.  
   
   
       15 . The compound of  claim 11  in which X═C and n=0.  
   
   
       16 . The compound of  claim 11  in which the compound has formula A.  
   
   
       17 . The compound of  claim 16  in which R 2  is selected from —COR 4  or —COOCH 3 .  
   
   
       18 . The compound of  claim 16  in which —Ar=phenyl substituted at any two positions with R 1a  and R 1b .  
   
   
       19 . The compound of  claim 18  in which R 1a  and R 1b  are independently selected from —H and —Cl.  
   
   
       20 . The compound of  claim 19  in which R 1a  and R 1b  are each —Cl.  
   
   
       21 . (canceled)  
   
   
       22 . A compound selected from compounds α-Cyclohexyl(3,4-dichlorobenzyl)cyanide and 2,2-(3,4-Dichlorophenyl)cyclohexyl acetic acid methyl ester.  
   
   
       23 . A compound selected from compounds α-cyclopentyl-3,4-dichlorobenzylcyanide and a-cyclopentyl-3,4-dichlorophenylcyclohexyl acetic acid methyl ester.  
   
   
       24 . The compound of  claim 11  in which R 2 = 
     
       
         
         
             
             
         
       
     
   
   
       25 . A method for treating a patient by administering to the patient a compound according to  claim 1  or  claim 11  in a dose effective to inhibit a monoamine transporter.  
   
   
       26 . A method of treating a medical condition comprising administering to a patient a compound according to  claim 1  or  claim 11 , said medical condition being attention deficit hyperactivity disorder (ADHD), Parkinson's disease, cocaine addiction, smoking cessation, weight reduction, obsessive-compulsive disorder, various forms of depression, traumatic brain injury, stroke, and narcolepsy.  
   
   
       27 . A method of making a medicament for treating attention deficit hyperactivity disorder (ADHD), Parkinson's disease, cocaine addiction, smoking cessation, weight reduction, obsessive-compulsive disorder, various forms of depression, traumatic brain injury, stroke, and narcolepsy, said method comprising formulating a compound according to  claim 1  or  claim 11  into said medicament.  
   
   
       28 . A method of treating a medical condition comprising administering to a patient a compound according to  claim 1  or  claim 11 , said medical condition being depression and related disorders, seasonal affective disorders, sexual dysfunction, sexual behavior disorders, attention deficit hyperactivity disorder, learning deficit, senile dementia, disorders involving the release of acetylcholine, including memory deficits, dementia of aging, AIDS-dementia, senile dementia, pseudodementia, presenile dementia), autism, mutism, cognitive disorders, dyslexia, tardive dyskinesia, hyperkinesia, anxiety, panic disorders, paranoia, post-traumatic syndrome, social phobia, other phobias, psychosis, bipolar disorder and other psychiatric or clinical disfunctions, mania, manic depression, schizophrenia (deficient form and productive form) and acute or chronic extrapyramidal symptoms induced by neuroleptic agents, obsessive compulsive disorders (OCD), chronic fatigue syndrome, for enhancing alertness, attention, arousal and vigilance, narcolepsy, disorders of sleep, jet-lag, obesity, bulimic and other eating disorders, anorexia nervosa, cocaine and other drug addiction or misuse, alcoholism, tobacco abuse, neurological disorders including epilepsy, traumatic brain injury, treatment of neurodegenerative diseases, including Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis, Gilles de la Tourette's syndrome, the treatment of mild, moderate or even severe pain of acute, chronic or recurrent character, as well as pain caused by migraine, postoperative pain, and phantom limb pain, disorders linked to decreased transmission of serotonin in mammals, including Ganser's syndrome, migraine headache, pre-menstrual syndrome or late luteal phase syndrome, and peripheral neuropathy.  
   
   
       29 . A pharmaceutical composition comprising a compound according to  claim 1  or  claim 11  mixed with a pharmaceutically acceptable carrier.  
   
   
       30 . A method of visualizing monoamine transport activity comprising exposing cells to a compound according to  claim 1  or  claim 11 , and visualizing the presence of the compound.  
   
   
       31 . A method according to  claim 30  in which the compound is labeled to aid visualization.  
   
   
       32 . The method of  claim 31  in which the label is a radiolabel.  
   
   
       33 . The method of  claim 31  in which the method is diagnostive of a medical indication involving monoamine transport.  
   
   
       34 . The method of  claim 33  in which the medical indication is depression and related disorders, seasonal affective disorders, sexual dysfunction, sexual behavior disorders, attention deficit hyperactivity disorder, learning deficit, senile dementia, disorders involving the release of acetylcholine, including memory deficits, dementia of aging, AIDS-dementia, senile dementia, pseudodementia, presenile dementia), autism, mutism, cognitive disorders, dyslexia, tardive dyskinesia, hyperkinesia, anxiety, panic disorders, paranoia, post-traumatic syndrome, social phobia, other phobias, psychosis, bipolar disorder and other psychiatric or clinical disfunctions, mania, manic depression, schizophrenia (deficient form and productive form) and acute or chronic extrapyramidal symptoms induced by neuroleptic agents, obsessive compulsive disorders (OCD), chronic fatigue syndrome, for enhancing alertness, attention, arousal and vigilance, narcolepsy, disorders of sleep, jet-lag, obesity, bulimic and other eating disorders, anorexia nervosa, cocaine and other drug addiction or misuse, alcoholism, tobacco abuse, neurological disorders including epilepsy, traumatic brain injury, treatment of neurodegenerative diseases, including Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis, Gilles de la Tourette's syndrome, the treatment of mild, moderate or even severe pain of acute, chronic or recurrent character, as well as pain caused by migraine, postoperative pain, and phantom limb pain, disorders linked to decreased transmission of serotonin in mammals, including Ganser's syndrome, migraine headache, pre-menstrual syndrome or late luteal phase syndrome, and peripheral neuropathy.