AMINO SUBSTITUTED DIARYL[a,d]CYCLOHEPTENE ANALOGS AS MUSCARINIC AGONISTS AND METHODS OF TREATMENT OF NEUROPSYCHIATRIC DISORDERS

Abstract

Disclosed herein are analogs of clozapine and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof; methods of synthesizing the analogs; and methods of using the analogs for treating neuropsychiatric disorders. In some embodiments, the analogs are amino substituted diaryl[a,d]cycloheptenes.

1 . A compound of Formula I or II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
 A is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         X is nitrogen, CH, or CH 2 ; 
         X′ is C or CH, wherein when X′ is C, there is a double bond between X and X′ and wherein when X′ is CH, there is a single bond between X and X′; 
         each Y is separately selected from the group consisting of nitrogen, oxygen, or CH; 
         each W is separately selected from the group consisting of nitrogen, CH, oxygen, or sulfur; 
         each n is separately selected from the group consisting of 0, 1, 2, 3, and 4; 
         m is selected from the group consisting of 1, 2, and 3; 
         each R 1  is separately absent or is separately selected from the group consisting of hydrogen, halogen, amine, optionally substituted C 1-20  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 2-20  alkenyl, optionally substituted C 2-20  alkynyl, optionally substituted C 1-20 -alkoxyalkyl, and optionally substituted aryl and arylalkyl; 
         L is absent or is selected from the group consisting of —NH(CH 2 ) n — and —(CH 2 ) n —; 
         a, b, c, and d are each carbon, 
         e, f, g, and h are each carbon, 
         R 2  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkyloxy, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6 -alkoxyalkyl, optionally substituted C 1-6  alkylthio, perhaloalkyl, CN, COR 10 , CONHR 10 , NHCONHR 10 , SO 2 NHR 10 , SO 2 R 10 , OSO 2 R 10 , heteroalkyl, NO 2 , NHCOR 10 ; 
         R 3 , R 4 , and R 5  are each hydrogen; 
         R 6 , R 8 , and R 9 , are each hydrogen; 
         R 7  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkyloxy, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6 -alkoxyalkyl, optionally substituted C 1-6  alkylthio, perhaloalkyl, CN, COR 10 , CONHR 10 , NHCONHR 10 , SO 2 NHR 10 , SO 2 R 10 , OSO 2 R 10 , heteroalkyl, NO 2 , NHCOR 10 ; 
         Z is selected from the group consisting of NR 11 , oxygen, sulfur, and CH 2 ; 
         R 10  is selected from the group consisting of hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl optionally substituted aryl, optionally substituted arylalkyl, and perhaloalkyl; 
         R 11  is selected from the group consisting of hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, and optionally substituted arylalkyl; and 
         any bond represented by a dashed and solid line represents a bond selected from the group consisting of a carbon-carbon single bond and a carbon-carbon double bond. 
       
     
     
         2 . The compound of  claim 1 , wherein said compound has a structure set forth in Formulas III or IV. 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein R 2  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkyloxy, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, perhaloalkyl, and CN; 
     
     
         5 . The compound of  claim 1 , wherein R 2  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, and optionally substituted C 1-6  alkyloxy. 
     
     
         6 . The compound of  claim 5 , wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. 
     
     
         7 . The compound of  claim 5 , wherein said alkyloxy is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and tert-butoxy. 
     
     
         8 . The compound of  claim 5 , wherein said halogen is selected from the group consisting of fluoro, chloro, and bromo. 
     
     
         9 . The compound of  claim 1 , wherein R 2  is selected from the group consisting of hydrogen, methyl, methoxy, and chloro. 
     
     
         10 . The compound of  claim 1 , wherein R 10  is hydrogen or optionally substituted C 1-6  alkyl. 
     
     
         11 . The compound of  claim 10 , wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. 
     
     
         12 . The compound of  claim 1 , wherein R 7  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkyloxy, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, perhaloalkyl, and CN. 
     
     
         13 . The compound of  claim 1 , wherein R 7  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, perhaloalkyl, CN, SO 2 R 10 , and NO 2 . 
     
     
         14 . The compound of  claim 13 , wherein said perhaloalkyl is perfluoroalkyl. 
     
     
         15 . The compound of  claim 14 . wherein said perfluoroalkyl is trifluoromethyl. 
     
     
         16 . The compound of  claim 1 , wherein R 7  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, and optionally substituted C 1-6  alkyloxy. 
     
     
         17 . The compound of  claim 16 , wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. 
     
     
         18 . The compound of  claim 16 , wherein said halogen is selected from the group consisting of fluoro, chloro, and bromo. 
     
     
         19 . The compound of  claim 1 , wherein R 7  is selected from the group consisting of hydrogen, methyl, chloro, trifluoromethyl, SO 2 CH 3 , CN, and NO 2 . 
     
     
         20 . The compound of  claim 1 , wherein R 7  is selected from the group consisting of hydrogen, methyl, chloro, trifluoromethyl, and CN. 
     
     
         21 . The compound of  claim 1 , wherein R 2  is selected from the group consisting of halogen, C 1-6  alkyl, and C 1-6  alkyloxy and R 7  is selected from the group consisting of halogen, C 1-6  alkyl, and C 1-6  alkyloxy. 
     
     
         22 . The compound of  claim 1 , wherein R 2  is selected from the group consisting of halogen and C 1-6  alkyl and R 7  is selected from the group consisting of halogen and C 1-6  alkyl. 
     
     
         23 . The compound of  claim 1 , wherein R 2  is halogen and R 7  is halogen. 
     
     
         24 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of hydrogen, optionally substituted C 1-6  alkyl, and optionally substituted aryl. 
     
     
         25 . The compound of  claim 24 , wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. 
     
     
         26 . The compound of  claim 1 , wherein R 1  is hydrogen. 
     
     
         27 . The compound of  claim 1 , wherein X is nitrogen. 
     
     
         28 . The compound of  claim 1 , wherein Y is NH. 
     
     
         29 . The compound of  claim 1 , wherein L is absent or is selected from the group consisting of —NHCH 2 —, —NH—, and —CH 2 —. 
     
     
         30 . The compound of  claim 1 , wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and wherein n is selected from the group consisting of 0, 1, and 2. 
       
     
     
         31 . The compound of  claim 1 , wherein Z is oxygen. 
     
     
         32 . The compound of  claim 1 , wherein Z is NH. 
     
     
         33 . The compound of  claim 1 , wherein Z is CH 2 . 
     
     
         34 . The compound of  claim 1 , having the structure of formula (I) wherein:
 A is   
       
         
           
           
               
               
           
         
         L is absent; 
         X is nitrogen; 
         X′ is C; 
         R 1  is hydrogen; 
         R 2  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, and optionally substituted C 1-6 , alkyloxy; 
         R 7  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, perhaloalkyl, CN, SO 2 R 10 , and NO 2 ; 
         R 10  is selected from the group consisting of hydrogen and optionally substituted C 1-6  alkyl; and 
         Z is oxygen, NH, or CH 2 . 
       
     
     
         35 . The compound of  claim 1  selected from the group consisting of:
 8-Bromo-1-chloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine;   1,8-Dichloro-11-(piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine; and   pharmaceutically acceptable salts thereof.   
     
     
         36 . A method of synthesizing a compound of Formula VI, 
       
         
           
           
               
               
           
         
         comprising 
         reacting a compound of Formula VII 
       
       
         
           
           
               
               
           
         
         with a compound of Formula VIII 
       
       
         
           
           
               
               
           
         
         to form a fused ring compound of Formula IX, 
       
       
         
           
           
               
               
           
         
       
       and
 reacting the compound of Formula IX with a compound of Formula X 
 
       
         
           
           
               
               
           
         
       
       to obtain a compound of Formula V,
 wherein
 X is a halogen; 
 R 1  is selected from the group consisting of hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6 -alkoxyalkyl, and optionally substituted aryl and arylalkyl; 
 R 2  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkyloxy, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6 -alkoxyalkyl, optionally substituted C 1-6  alkylthio, perhaloalkyl, CN, COR 10 , CONHR 10 , NHCONHR 10 , SO 2 NHR 10 , SO 2 R 10 ; OSO 2 R 10 , heteroalkyl, NO 2 , NHCOR 10 ; 
 R 3 , R 4 , and R 5  are each hydrogen; 
 R 6 , R 8 , and R 9 , are each hydrogen; 
 R 7  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkyloxy, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6 -alkoxyalkyl, optionally substituted C 1-6  alkylthio, perhaloalkyl, CN, COR 10 , CONHR 10 , NHCONHR 10 , SO 2 NHR 10 , SO 2 R 10 , OSO 2 R 10 , heteroalkyl, NO 2 , NHCOR 10 ; 
 W is selected from the group consisting of nitrogen, CH, oxygen, or sulfur; and 
 n is selected from the group consisting of 0, 1, 2, 3, and 4. 
 
 
     
     
         37 . A combinatorial library of at least 220 dibenzo[b,e][1,4]diazepine[a,d]cycloheptene compounds that can be formed by reacting a compound of Formula VII, 
       
         
           
           
               
               
           
         
       
       with a compound of Formula VIII and 
       
         
           
           
               
               
           
         
       
       a compound of Formula X, 
       
         
           
           
               
               
           
         
         wherein
 X is a halogen; 
 R 1  is selected from the group consisting of hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6 -alkoxyalkyl, and optionally substituted aryl and arylalkyl; 
 R 2  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkyloxy, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6 -alkoxyalkyl, optionally substituted C 1-6  alkylthio, perhaloalkyl, CN, COR 10 , CONHR 10 , NHCONHR 10 , SO 2 NHR 10 , SO 2 R 10 , OSO 2 R 10 , heteroalkyl, NO 2 , NHCOR 10 ; 
 R 3 , R 4 , and R 5  are each hydrogen; 
 R 6 , R 8 , and R 9 , are each hydrogen; 
 R 7  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkyloxy, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6 -alkoxyalkyl, optionally substituted C 1-6  alkylthio, perhaloalkyl, CN, COR 10 , CONHR 10 , NHCONHR 10 , SO 2 NHR 10 , SO 2 R 10 , OSO 2 R 10 , heteroalkyl, NO 2 , NHCOR 10 ; and 
 W is selected from the group consisting of nitrogen, CH, oxygen, or sulfur. 
 
       
     
     
         38 . A combinatorial library of at least 220 dibenzo[b,e][1,4]diazepine[a,d]cycloheptene compounds that can be formed by reacting a compound of Formula VII, 
       
         
           
           
               
               
           
         
       
       with a compound of Formula VIII and 
       
         
           
           
               
               
           
         
       
       a compound of Formula XII, 
       
         
           
           
               
               
           
         
         wherein
 X is a halogen; 
 R 1  is selected from the group consisting of hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6 -alkoxyalkyl, and optionally substituted aryl and arylalkyl; 
 R 2  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkyloxy, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6 -alkoxyalkyl, optionally substituted C 1-6  alkylthio, perhaloalkyl, CN, COR 10 ), CONHR 10 , NHCONHR 10 , SO 2 NHR 10 , SO 2 R 10 , OSO 2 R 10 , heteroalkyl, NO 2 , NHCOR 10 ; 
 R 3 , R 4 , and R 5  are each hydrogen; 
 R 6 , R 8 , and R 9 , are each hydrogen; 
 R 7  is selected from the group consisting of halogen, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkyloxy, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6 -alkoxyalkyl, optionally substituted C 1-6  alkylthio, perhaloalkyl, CN, COR 10 , CONHR 10 , NHCONHR 10 , SO 2 NHR 10 , SO 2 R 10 , OSO 2 R 10 , heteroalkyl, NO 2 , NHCOR 10 ; and 
 W is selected from the group consisting of nitrogen, CH, oxygen, or sulfur. 
 
       
     
     
         39 . A pharmaceutical composition comprising a physiologically acceptable carrier, diluent, or excipient, or a combination thereof; and a compound of  claim 1 . 
     
     
         40 . A method of treating a neuropsychiatric disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         41 . The method of  claim 40 , wherein said neuropsychiatric disorder is selected from the group consisting of schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, appetite disorders, affective disorders, Tourette's Syndrome, drug-induced psychoses, and psychoses secondary to neurodegenerative disorders. 
     
     
         42 . The method of  claim 41 , wherein the affective disorders are selected from major depression, bipolar disorder, and depression with psychotic features. 
     
     
         43 . The method of  claim 41 , wherein the neurodegenerative disorders are selected from Alzheimer's and Huntington's Disease 
     
     
         44 . A method of treating a neuropsychiatric disorder comprising contacting a therapeutically effective amount of a compound of  claim 1  with a patient in need thereof. 
     
     
         45 . The method of  claim 44 , wherein said neuropsychiatric disorder is selected from the group consisting of schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, appetite disorders, affective disorders, Tourette's Syndrome, drug-induced psychoses, and psychoses secondary to neurodegenerative disorders. 
     
     
         46 . The method of  claim 45 , wherein the affective disorders are selected from major depression, bipolar disorder, and depression with psychotic features. 
     
     
         47 . The method of  claim 45 , wherein the neurodegenerative disorders are selected from Alzheimer's and Huntington's Disease 
     
     
         48 . A method of treating cognitive impairment, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         49 . A pharmaceutical composition comprising a compound of  claim 1  and an neuropsychiatric agent. 
     
     
         50 . The composition of  claim 49 , wherein said neuropsychiatric agent is selected from the group consisting of a selective serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, dopamine agonist, muscarinic receptor antagonist, antipsychotic agent, serotonin 2A antagonist, and inverse serotonin 2A agonist. 
     
     
         51 . The composition of  claim 50 , wherein said antipsychotic agent is selected from the group consisting of a phenothiazine, phenylbutylpiperidine, debenzapine, benzisoxidil, and salt of lithium. 
     
     
         52 . The composition of  claim 51 , wherein said phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), and thioridazine (Mellaril®). 
     
     
         53 . The composition of  claim 51 , wherein said phenylbutylpiperidine is selected from the group consisting of haloperidol (Haldol®), and pimozide (Orap®). 
     
     
         54 . The composition of  claim 51 , wherein said debenzapine is selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®) and quetiapine (Seroquel®). 
     
     
         55 . The composition of  claim 51 , wherein said benzisoxidil is selected from the group consisting of risperidone (Resperdal®) and ziprasidone (Geodon®). 
     
     
         56 . The composition of  claim 51 , wherein said salt of lithium is lithium carbonate. 
     
     
         57 . The composition of  claim 50 , wherein said antipsychotic agent is selected from the group consisting of Clozaril, Compazine, Etrafon (Triavil), Geodon, Haldol, Inapsine, Loxitane, Mellaril, Moban, Navane, Orap, Permitil, Prolixin, Phenergan, Reglan, Risperdal, Serentil, Seroquel, Stelazine, Taractan, Thorazine, Trilafon, and Zyprexa. 
     
     
         58 . The composition of  claim 50 , wherein said selective serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, sibutramine, duloxetine, and venlafaxine, and pharmaceutically acceptable salts or prodrugs thereof. 
     
     
         59 . The composition of  claim 50 , wherein said norepinephrine reuptake inhibitor is selected from the group consisting of thionisoxetine and reboxetine. 
     
     
         60 . The composition of  claim 50 , wherein said dopamine agonist is selected from the group consisting of sumatriptan, almotriptan, naratriptan, frovatriptan, rizatriptan, zomitriptan, cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole, and bromocriptine. 
     
     
         61 . The composition of  claim 50 , where in said serotonin 2A antagonist is the compound of Formula XIV, or a related analog thereof: 
       
         
           
           
               
               
           
         
       
     
     
         62 . A method of treating neuropsychiatric disorder in a patient comprising administering to said patient a therapeutically effective amount of a composition of  claim 49 . 
     
     
         63 . A method of treating neuropsychiatric disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of  claim 1  and a therapeutically effective amount of a neuropsychiatric agent. 
     
     
         64 . The method of  claim 63 , wherein said administering step comprises administering said compound of  claim 1  and said neuropsychiatric agent nearly simultaneously. 
     
     
         65 . The method of  claim 63 , wherein said administering step comprises administering one of said compound of  claim 1  and said neuropsychiatric agent first and then administering the other one of said compound of  claim 1  and said neuropsychiatric agent. 
     
     
         66 . The method of  claim 63 , wherein said neuropsychiatric disorder is selected from the group consisting of schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, appetite disorders, affective disorders such as major depression, bipolar disorder, and depression with psychotic features, and Tourette's Syndrome, drug-induced psychoses, psychoses secondary to neurodegenerative disorders such Alzheimer's or Huntington's Disease.