Benzimidazolidinone derivatives as muscarinic agents

Abstract

Benzimidazolidinone derivative compounds, which increase acetylcholine signaling or effect in the brain, and highly selective muscarinic agonists, particularly for the M 1 and/or M 4 receptor subtypes, pharmaceutical compositions comprising the same, as well as methods of treating psychosis using these compounds are disclosed.

1 . A compound of Formula I 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein:
 X is selected from the group consisting of CH, O, N and S; 
 Z is selected from the group consisting of CH and N; 
 Y is selected from the group consisting of ═O, ═NH and ═S or tautomers thereof; 
 SPU is a spacer unit providing a distance d between Z and N wherein:
 —SPU— is a biradical selected from the group consisting of —(CR 6 R 7 ) n-A-, —(CR   6 R 7 ) p —CH═CH—(CR 6 R 7 ) q —, and —(CR 6 R 7 ) p —C≡C—(CR 6 R 7 ) q — 
 wherein n, p, and q are each individually and independently 3, 4, or 5; and 
 A is absent or an optionally substituted —C 3-8 -cycloalkyl; 
 
 N together with R 1  and R 2  form a heterocyclic ring wherein said heterocyclic ring is piperidine, and wherein the heterocyclic ring is substituted with one or more substituents R 4  independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-8 -alkyl, C 1-8 -heteroalkyl, C 3-8 -cycloalkyl, C 3-8 -heterocyclyl, C 5-10 -aryl, C 5-10 -heteroaryl, C 1-6 -arylalkyl, C 1-6 -heteroarylalkyl, C 1-8 -alkoxy, O—C 2-8 -alkenyl, O—C 2-8 -alkynyl, S—C 1-8 -alkyl, S—C 2-8 -alkenyl, and S—C 2-8 -alkynyl C 1-8 -alkylcarbonyl, C 1-8 -alkoxycarbonyl, C 1-8 -alkylidene, C 2-8 -alkenyl, C 2-8 -alkynyl, C 1-6 -alkyloxyimino, and C 1-6 -alkyloxyamino each of which may be optionally substituted with a substituent R 5 , wherein at least one R 4  is not hydrogen; 
 R 5  is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-8 -alkyl, C 1-8 -heteroalkyl, C 1-8 -alkoxy, C 3-8 -heterocyclyl, C 1-8 -alkylcarbonyl, C 1-8 -alkylidene, C 2-8 -alkenyl and C 2-8 -alkynyl; 
 R X  may be absent or selected from the group consisting of hydrogen, optionally substituted C 1-8 -alkyl, optionally substituted C 3-8 -cycloalkyl, optionally substituted C 2-8 -alkenyl, optionally substituted C 2-8 -alkynyl, CH 2 —N(R 5 )(R 5 ), CH 2 —OR 5 , CH 2 —SR 5 , CH 2 —O—C(═O)R 5 , CH 2 —O—C(═S)R 5 ; 
 R 3  may be present 0-4 times and selected from the group consisting of halogen, hydroxy, optionally substituted C 1-8 -alkyl, C 1-8 -alkoxy, optionally substituted C 1-8 -alkylidene, optionally substituted C 2-8 -alkenyl, optionally substituted C 2-8 -alkynyl optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3-8 -cycloalkyl, optionally substituted C 3-8 -heterocyclyl, and optionally substituted C 1-8 -alkylcarbonyl; and 
 each R 6  and each R 7  is optionally and independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C 1-8 -alkyl, optionally substituted C 1-8 -alkoxy, optionally substituted C 1-8 -heteroalkyl, optionally substituted C 1-8 -alkylidene, optionally substituted C 2-8 -alkenyl, optionally substituted C 2-8 -alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3-8 -cycloalkyl, optionally substituted C 3-8 -heterocyclyl, optionally substituted C 1-6 -arylalkyl, optionally substituted C 5-10 -aryl, optionally substituted C 1-8 -alkylcarbonyl, optionally substituted —C(O)NH-alkyl, optionally substituted —C(O)NH-aryl, optionally substituted —C(O)O-alkyl, optionally substituted —C(O)O-aryl, optionally substituted —OC(O)-alkyl, and optionally substituted —OC(O)-aryl. 
 
   
   
       2 . The compound of  claim 1 , wherein Z is N. 
   
   
       3 . The compound of  claim 2 , wherein X is selected from the group consisting of N, S, and O. 
   
   
       4 . The compound of  claim 3 , wherein —Y is ═O. 
   
   
       5 . The compound of  claim 1 , wherein N(R 1 )R 2  is selected from the group consisting of a piperidine with at least one substituent R 4  in the 2-position, a piperidine with at least one substituent R 4  in the 3-position, and a piperidine with at least one substituent R 4  in the 4-position. 
   
   
       6 . The compound of  claim 5 , wherein N(R 1 )R 2  is a piperidine with at least one substituent R 4  in the 4-position. 
   
   
       7 . The compound of  claim 1 , wherein N(R 1 )R 2  is 
     
       
         
         
             
             
         
       
       wherein each R 4  is independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-8 -alkyl, C 3-8 -cycloalkyl, C 5-10 -aryl, C 1-8 -alkoxy, C 1-8 -heteroalkyl, C 1-8 -alkylcarbonyl, C 1-8 -alkylidene, C 2-8 -alkenyl, C 2-8 -alkynyl, C 1-6 -alkyloxyimino, and C 1-6 -alkyloxyamino each of which may be optionally substituted with a substituent R 5 , wherein at least one R 4  is not hydrogen; and 
       R 5  is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-8 -alkyl, C 1-8 -alkoxy, C 1-8 -alkylidene, C 2-8 -alkenyl and C 2-8 -alkynyl. 
     
   
   
       8 . The compound of  claim 1 , wherein R 4  is selected from the group consisting of hydroxy, C 1-8 -alkyl, C 1-8 -alkoxy, C 1-8 -heteroalkyl, C 3-8 -cycloalkyl, C 1-6 -arylalkyl, C 1-8 -alkylidene, each of which may be optionally substituted with a substituent R 5 . 
   
   
       9 . The compound of  claim 1 , wherein R 4  is selected from the group consisting of hydroxy, C 3-8 -alkyl, C 3-8 -alkoxy, C 5-10 -aryl, and C 3-8 -alkylidene, each of which may be optionally substituted with a substituent R 5  wherein R 5  is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-8 -alkoxy and C 1-8 -alkyl. 
   
   
       10 . The compound of  claim 1 , wherein R 4  is selected from the group consisting of an optionally substituted ethyl, an optionally substituted butyl, an optionally substituted pentyl, an optionally substituted propyloxy, and 3-(C 1-8 -alkyl)-butylidene. 
   
   
       11 . The compound of  claim 1 , wherein:
 X is selected from the group consisting of O, N and S;   Z is N;   Y is ═O or tautomers thereof;   SPU is a spacer unit providing a distance d between Z and N wherein —SPU— is —(CR 6 R 7 ) n -A-, n is 3, and A is absent;   N together with R 1  and R 2  form a piperidine ring substituted with one or more substituents R 4  selected from the group consisting of hydroxy, halogen, C 1-8 -alkyl, C 3-8 -cycloalkyl, C 1-8 -alkoxy, C 1-8 -heteroalkyl, C 1-8 -alkylcarbonyl, C 1-8 -alkylidene, C 2-8 -alkenyl, C 2-8 -alkynyl, C 1-6 -alkyloxyimino, and C 1-6 -alkyloxyamino each of which may be optionally substituted with a substituent R 5 ;   R 5  is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-8 -alkyl, C 1-8 -alkoxy, C 3-8 -heterocyclyl, C 1-8 -alkylcarbonyl, C 1-8 -alkylidene, C 2-8 -alkenyl and C 2-8 -alkynyl;   R X  may be absent or selected from the group consisting of hydrogen, optionally substituted C 1-8 -alkyl;   R 3  may be present 0-4 times and selected from the group consisting of halogen, hydroxy, optionally substituted C 1-8 -alkyl, C 1-8 -alkoxy, optionally substituted C 1-8 -alkylidene, optionally substituted C 2-8 -alkenyl, optionally substituted C 2-8 -alkynyl optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3-8 -cycloalkyl, optionally substituted C 3-8 -heterocyclyl, and optionally substituted C 1-8 -alkylcarbonyl; and   each R 6  and each R 7  is optionally and independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C 1-8 -alkyl, C 1-8 -alkoxy, C 1-8 -heteroalkyl, C 3-8 -cycloalkyl.   
   
   
       12 . A pharmaceutical composition comprising a compound according to  claim 1 , together with pharmaceutically acceptable carriers or excipients. 
   
   
       13 . A method of treating mental disease or disorder in a mammal comprising identifying a mammal in need thereof and administering at least one compound of  claim 1  to said mammal. 
   
   
       14 . The method of  claim 13 , wherein the mental disorder is selected from the group consisting of cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception, depression, sleep disorders, and psychosis. 
   
   
       15 . The method of  claim 13 , wherein the mental disorder is selected from the group consisting of neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Down Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, attention-deficit disorder, and sudden infant death syndrome. 
   
   
       16 . A method of treating a disease or disorder associated with increased intraocular pressure in a mammal comprising identifying a mammal in need thereof and administering at least one compound of  claim 1  to said mammal. 
   
   
       17 . A method of increasing an activity of a cholinergic receptor comprising contacting the cholinergic receptor or a system containing the cholinergic receptor with an effective amount of at least one compound of  claim 1 . 
   
   
       18 . The method of  claim 17 , wherein the compound is a cholinergic agonist. 
   
   
       19 . The method of  claim 18 , wherein the compound is selective for one or both of the M 1  and M 4  muscarinic receptor subtypes. 
   
   
       20 . The method of  claim 19 , wherein the compound further acts as a D 2  antagonist or D 2  inverse agonist. 
   
   
       21 . A method of treating pain in a mammal, comprising administering an effective amount of a compound of  claim 1  to said mammal. 
   
   
       22 . A method of prophylactic or curative treatment of psychosis or alleviation of symptoms of psychosis in a mammal, comprising administering an effective amount of a compound of  claim 1  to said mammal. 
   
   
       23 . A method of modulating the progression or formation of amyloid plaques in an individual susceptible to or affected by Alzheimer's Disease, comprising administering an effective amount of a compound of  claim 1 , said effective amount sufficient to modulate amyloid precursor protein processing.