Useful aroyl pyrrole heteroaryl methanones and methanols

Abstract

This invention is directed to aroyl pyrrole heteroaryl methanone and methanol compounds pharmaceutically useful as agents for treating or modulating a central nervous system disorder and methods for treating or modulating a central nervous system disorder.

What is claimed is:  
     
         1 . A compound selected from Formula (I) or Formula (II):  
       
         
           
           
               
               
           
         
       
       wherein 
 A is selected from the group consisting of  
 aryl (optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 alkoxy, hydroxy, hydroxy(C 1-8 )alkyl, hydroxy(C 1-8 )alkoxy, (halo) 1-3 (C 1-8 )alkyl and (halo) 1-3 (C 1-8 )alkoxy) and  
 heteroaryl (optionally substituted on 1 to 4 available carbon atom ring members with a substituent selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 alkoxy, hydroxy, hydroxy(C 1-8 )alkyl, hydroxy(C 1-8 )alkoxy, (halo) 1-3 (C 1-8 )alkyl and (halo) 1-3 (C 1-8 )alkoxy; and, optionally substituted on available nitrogen atom ring members with a substituent selected from the group consisting of C 1-8 alkyl, hydroxy(C 1-8 )alkyl and (halo) 1-3 (C 1-8 )alkyl);  
 B is selected from heteroaryl optionally substituted on 1 to 4 available carbon atom ring members with a substituent selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 alkoxy, hydroxy, hydroxy(C 1-8 )alkyl, hydroxy(C 1-8 )alkoxy, (halo) 1-3 (C 1-8 )alkyl and (halo) 1-3 (C 1-8 )alkoxy; and, optionally substituted on available nitrogen atom ring members with a substituent selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, hydroxy(C 1-8 )alkyl, (halo) 1-3 (C 1-8 )alkyl and oxido;  
 Z is selected from the group consisting of oxo and hydroxy;  
 R 1  is selected from the group consisting of: 
 C 1-8 alkyl {wherein alkyl is optionally substituted on a terminal carbon with one substituent selected from the group consisting of C 1-8 alkoxy, —C(O)— (substituted with one substituent selected from the group consisting of H, OH, C 1-8 alkyl, C 1-8 alkoxy, NH 2 , —NH(C 1-8 )alkyl, —N((C 1-8 )alkyl) 2 ), —NHC(O)— (substituted with one substituent selected from the group consisting of H, OH, C 1-8 alkyl, C 1-8 alkoxy, NH 2 , —NH(C 1-8 )alkyl, —N((C 1-8 )alkyl) 2 ), —OC(O)— (substituted with one substituent selected from the group consisting of H, OH, C 1-8 alkyl, C 1-8 alkoxy, NH 2 , —NH(C 1-8 )alkyl, —N((C 1-8 )alkyl) 2 ), NH 2 , —NH(C 1-8 )alkyl, —N((C 1-8 )alkyl) 2 , —S(C 1-8 )alkyl, —SO 2 (C 1-8 )alkyl, cyano, (halo) 1-3 , hydroxy and nitro},  
 cycloalkyl and aryl {wherein cycloalkyl and aryl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein cycloalkyl and aryl are optionally substituted with one substituent selected from the group consisting of C 1-8 alkyl, (wherein alkyl is optionally substituted on a terminal carbon with one substituent selected from the group consisting of NH 2 , —NH(C 1-8 )alkyl, —N((C 1-8 )alkyl) 2 , cyano, (halo) 1-3 , hydroxy and nitro), C 1-8 alkoxy, NH 2 , —NH(C 1-8 )alkyl and —N((C 1-8 )alkyl) 2 };  
 
 R 2  and R 3  are independently selected from the group consisting of hydrogen, C 1-8 alkyl and halogen;  
 and pharmaceutically acceptable acid addition salts, quaternary ammonium salts and N-oxides thereof.  
 
     
     
         2 . The compound of  claim 1  wherein A is selected from aryl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, hydroxy(C 1-4 )alkyl, hydroxy(C 1-4 )alkoxy, (halo) 1-3 (C 1-4 )alkyl and (halo) 1-3 (C 1-4 )alkoxy; wherein aryl is selected from an aromatic monocyclic ring having six members or an aromatic bicyclic ring having ten members.  
     
     
         3 . The compound of  claim 2  wherein the aryl of A is selected from the group consisting of phenyl and naphthalenyl optionally substituted with 1 to 4 substituents.  
     
     
         4 . The compound of  claim 3  wherein the aryl of A is phenyl optionally substituted with 1 to 4 substituents.  
     
     
         5 . The compound of  claim 2  wherein the aryl substituents of A are independently selected from the group consisting of halogen, C 1-4 alkyl and hydroxy.  
     
     
         6 . The compound of  claim 5  wherein the aryl substituents of A are independently selected from the group consisting of chlorine, fluorine, methyl and hydroxy.  
     
     
         7 . The compound of  claim 6  wherein the aryl substituents of A are independently selected from the group consisting of chlorine, fluorine and methyl.  
     
     
         8 . The compound of  claim 1  wherein A is selected from heteroaryl optionally substituted on 1 to 4 available carbon atom ring members with a substituent selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, hydroxy(C 1-4 )alkyl, hydroxy(C 1-4 )alkoxy, (halo) 1-3 (C 1-4 )alkyl and (halo) 1-3 (C 1-4 )alkoxy; and, optionally substituted on available nitrogen atom ring members with a substituent selected from the group consisting of C 1-4 alkyl, hydroxy(C 1-4 )alkyl and (halo) 1-3 (C 1-4 )alkyl; wherein heteroaryl is selected from an aromatic monocyclic ring having five members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms, an aromatic monocyclic ring having six members of which one, two or three members are a N atom, an aromatic bicyclic ring having nine members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms or an aromatic bicyclic ring having ten members of which one, two or three members are a N atom.  
     
     
         9 . The compound of  claim 8  wherein the heteroaryl of A is selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl and isoquinolinyl optionally substituted on 1 to 4 available carbon atom ring members with a substituent and optionally substituted on available nitrogen atom ring members with a substituent.  
     
     
         10 . The compound of  claim 9  wherein the heteroaryl of A is selected from the group consisting of thienyl, pyridinyl, quinolinyl and isoquinolinyl optionally substituted on 1 to 4 available carbon atom ring members with a substituent and optionally substituted on available nitrogen atom ring members with a substituent.  
     
     
         11 . The compound of  claim 10  wherein the heteroaryl of A is selected from the group consisting of thienyl and pyridinyl optionally substituted on 1 to 4 available carbon atom ring members with a substituent and optionally substituted on available nitrogen atom ring members with a substituent.  
     
     
         12 . The compound of  claim 8  wherein the heteroaryl substituents of A optionally substituted on 1 to 4 available carbon atom ring members are independently selected from the group consisting of halogen and C 1-4 alkyl; and, optionally substituted on available nitrogen atom ring members are selected from C 1-4 alkyl.  
     
     
         13 . The compound of  claim 12  wherein the heteroaryl substituents of A optionally substituted on 1 to 4 available carbon atom ring members are independently selected from the group consisting of chlorine, fluorine and methyl; and, optionally substituted on available nitrogen atom ring members are selected from methyl.  
     
     
         14 . The compound of  claim 1  wherein B is heteroaryl optionally substituted on 1 to 4 available carbon atom ring members with a substituent selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, hydroxy(C 1-4 )alkyl, hydroxy(C 1-4 )alkoxy, (halo) 1-3 (C 1-4 )alkyl and (halo) 1-3 (C 1-4 )alkoxy; and, optionally substituted on available nitrogen atom ring members with a substituent selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, hydroxy(C 1-4 )alkyl, (halo) 1-3 (C 1-4 )alkyl and oxido; wherein heteroaryl is selected from an aromatic monocyclic ring having five members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms, an aromatic monocyclic ring having six members of which one, two or three members are a N atom, an aromatic bicyclic ring having nine members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms or an aromatic bicyclic ring having ten members of which one, two or three members are a N atom.  
     
     
         15 . The compound of  claim 14  wherein the heteroaryl of B is selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl and quinoxalinyl optionally substituted on 1 to 4 available carbon atom ring members with a substituent, as previously described; and, optionally substituted on available nitrogen atom ring members with a substituent, as previously described.  
     
     
         16 . The compound of  claim 15  wherein the heteroaryl of B is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyridinyl, quinolinyl and isoquinolinyl optionally substituted on 1 to 4 available carbon atom ring members with a substituent, as previously described; and, optionally substituted on available nitrogen atom ring members with a substituent, as previously described.  
     
     
         17 . The compound of  claim 16  wherein the heteroaryl of B is selected from the group consisting of thienyl, imidazolyl and pyridinyl optionally substituted on 1 to 4 available carbon atom ring members with a substituent, as previously described; and, optionally substituted on available nitrogen atom ring members with a substituent, as previously described.  
     
     
         18 . The compound of  claim 14  wherein the substituents of B optionally substituted on 1 to 4 available carbon atom ring members are independently selected from the group consisting of halogen and C 1-4 alkyl; and, optionally substituted on a nitrogen atom ring member are selected from oxido.  
     
     
         19 . The compound of  claim 18  wherein the substituents of B optionally substituted on 1 to 4 available carbon atom ring members are independently selected from the group consisting of chlorine and methyl; and, optionally substituted on a nitrogen atom ring member are selected from oxido.  
     
     
         20 . The compound of  claim 1  wherein R 1  is selected from the group consisting of: 
 C 1-4 alkyl {wherein alkyl is optionally substituted on a terminal carbon with one substituent selected from the group consisting of C 1-4 alkoxy, —C(O)— (substituted with one substituent selected from the group consisting of H, OH, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , —NH(C 1-4 )alkyl, —N((C 1-4 )alkyl) 2 ), —NHC(O)— (substituted with one substituent selected from the group consisting of H, OH, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , —NH(C 1-4 )alkyl, —N((C 1-4 )alkyl) 2 ), —OC(O)— (substituted with one substituent selected from the group consisting of H, OH, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , —NH(C 1-4 )alkyl, —N((C 1-4 )alkyl) 2 ), NH 2 , —NH(C 1-4 )alkyl, —N((C 1-4 )alkyl) 2 , —S(C 1-4 )alkyl, —SO 2 (C 1-4 )alkyl, cyano, (halo) 1-3 , hydroxy and nitro},  
 cycloalkyl and aryl {wherein cycloalkyl and aryl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein cycloalkyl and aryl are optionally substituted with one substituent selected from the group consisting of C 1-4 alkyl, (wherein alkyl is optionally substituted on a terminal carbon with one substituent selected from the group consisting of NH 2 , —NH(C 1-4 )alkyl, —N((C 1-4 )alkyl) 2 , cyano, (halo) 1-3 , hydroxy and nitro), C 1-4 alkoxy, NH 2 , —NH(C 1-4 )alkyl and —N((C 1-4 )alkyl) 2 }.  
 
     
     
         21 . The compound of  claim 20  wherein R 1  is selected from C 1-4 alkyl optionally substituted on a terminal carbon with a substituent.  
     
     
         22 . The compound of  claim 20  wherein R 1  is selected from C 1-4 alkyl.  
     
     
         23 . The compound of  claim 21  wherein the optional substituent on the terminal carbon of C 1-4 alkyl is selected from the group consisting of C 1-4 alkoxy, NH 2 , —NH(C 1-4 )alkyl, —N((C 1-4 )alkyl) 2 , cyano, (halo) 1-3 , hydroxy and nitro.  
     
     
         24 . The compound of  claim 1  wherein R 2  and R 3  are independently selected from the group consisting of hydrogen, C 1-4 alkyl and halogen.  
     
     
         25 . The compound of  claim 24  wherein R 2  and R 3  are independently selected from the group consisting of hydrogen and C 1-4 alkyl.  
     
     
         26 . The compound of  claim 25  wherein R 2  and R 3  are independently selected from the group consisting of hydrogen and methyl.  
     
     
         27 . The compound of  claim 1  wherein the compound is selected from Formula (I):  
       
         
           
                 
                 
               
                     
                 
                     
                 
                     
                   Formula (I) 
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                 
               
                   wherein A, B, Z, R 2  and R 3  are dependently selected from 
                 
                   the group consisting of: 
                 
                 
                 
                 
                 
                 
                 
               
                     
                   A 
                   B 
                   Z 
                   R 2   
                   R 3   
                 
                     
                     
                 
                     
                   4-Cl-Ph 
                   4-pyridinyl 
                   O 
                   H 
                   H; 
                 
                     
                   Ph 
                   4-pyridinyl 
                   O 
                   H 
                   H; 
                 
                     
                   4-Me—Ph 
                   4-pyridinyl 
                   O 
                   H 
                   H; 
                 
                     
                   4-Cl—Ph 
                   4-pyridinyl 
                   O 
                   H 
                   H; 
                 
                     
                   4-Cl—Ph 
                   2-pyridinyl 
                   O 
                   H 
                   H; 
                 
                     
                   4-Cl—Ph 
                   4-pyridinyl 
                   OH 
                   H 
                   H; 
                 
                     
                   4-Cl—Ph 
                   1H-imidazol-5-yl 
                   O 
                   H 
                   H; 
                 
                     
                   4-Cl—Ph 
                   1-Me-4-pyridinyl 
                   O 
                   H 
                   H; 
                 
                     
                   4-Cl—Ph 
                   1-oxido-4-pyridinyl 
                   O 
                   H 
                   H; 
                 
                     
                   4-Cl—Ph 
                   1-oxido-4-pyridinyl 
                   OH 
                   H 
                   H; 
                 
                     
                   4-Cl—Ph 
                   4-pyridinyl 
                   OH 
                   CH 3   
                   CH 3 ; 
                 
                     
                   and, 
                 
                     
                   4-Cl—Ph 
                   2-Cl-4-pyridinyl 
                   O 
                   H 
                   H. 
                 
                     
                     
                 
                     
                     
                 
             
                
                
                
                
                
               
            
             
                
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         28 . The compound of  claim 1  wherein the compound is selected from Formula (II):  
       
         
           
                 
                 
               
                     
                 
                     
                 
                     
                   Formula (II) 
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                 
               
                   wherein B, A, R 2  and R 3  are dependently selected from 
                 
                   the group consisting of: 
                 
                 
                 
                 
                 
                 
               
                     
                   B 
                   A 
                   R 2   
                   R 3   
                 
                     
                     
                 
                     
                   2-thienyl 
                   4-pyridinyl 
                   H 
                   H; 
                 
                     
                   3-pyridinyl 
                   4-F—Ph 
                   H 
                   H; 
                 
                     
                   3-pyridinyl 
                   2-naphthalenyl 
                   H 
                   H; 
                 
                     
                   6-Cl-3-pyridinyl 
                   4-Cl—Ph 
                   H 
                   H; 
                 
                     
                   2-pyridinyl 
                   4-F—Ph 
                   H 
                   H; 
                 
                     
                   4-pyridinyl 
                   4-F—Ph 
                   H 
                   H; 
                 
                     
                   and, 
                 
                     
                   3-pyridinyl 
                   4-F—Ph 
                   CH 3   
                   CH 3 . 
                 
                     
                     
                 
                     
                     
                 
             
                
                
                
                
                
               
            
             
                
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         29 . The compound of  claim 1  selected from the group consisting of: 
 [5-(4-Chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]pyridin-4-ylmethanone;  
 (4-Fluorophenyl)-[1-methyl-5-(pyridine-3-carbonyl)-1H-pyrrol-3-yl]methanone Hydrochloride; and,  
 (4-Chlorophenyl)-{4-[hydroxy-(1-oxy-pyridin-4-yl)methyl]-1-methyl-1H-pyrrol-2-yl}methanone.  
 
     
     
         30 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         31 . A pharmaceutical composition made by mixing a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         32 . A process for making a pharmaceutical composition comprising mixing a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         33 . A method for treating or modulating a central nervous system disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         34 . The method of  claim 33  wherein the central nervous system disorder is selected from the group consisting of neuropathic pain, chronic pain, pain, neurological conditions, cardiovascular diseases and other disorders, psychotic disorders, movement disorders, anxiety disorders or neurodegenerative disorders.  
     
     
         35 . The method of  claim 34  wherein neuropathic pain is neuropathic pain resulting from chronic or debilitating conditions (selected from painful diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-stroke pain, multiple sclerosis-associated pain, neuropathies-associated pain (selected from pain as a result of idiopathic neuropathy, post-traumatic neuropathy or mononeuritis), HIV-associated neuropathic pain, cancer-associated neuropathic pain, carpal tunnel-associated neuropathic pain, spinal cord injury-associated pain, complex regional pain syndrome, fibromyalgia-associated neuropathic pain, lumbar and cervical pain, reflex sympathic dystrophy, phantom limb syndrome or other chronic and debilitating condition-associated pain syndromes), sympathetically maintained pain or cluster and migraine headache-associated pain; pain associated with cancer, fibromyalgia, back disorders or migraine and chronic headache, adiposis dolorosa and burn pain, central pain conditions following stroke, thalamic lesions or multiple sclerosis or pain resulting from damage to the peripheral or central nervous system (selected from damage as a result of amputation, paraplegia, herpes or as a result of diabetic polyneuropathy).  
     
     
         36 . The method of  claim 34  wherein chronic pain is chronic pain resulting from inflammation or an inflammatory-related condition, osteoarthritis, rheumatoid arthritis or as sequela to disease, acute injury or trauma and is selected from the group consisting of upper back pain and lower back pain (as a result of systematic, regional or primary spine disease (such as radiculopathy), inflammation or an inflammatory-related condition), bone pain (as a result of osteoarthritis, rheumatoid arthritis, osteoporosis or bone metastases), pelvic pain, spinal cord injury-associated pain, cardiac chest pain, non-cardiac chest pain, central post-stroke pain, myofascial pain, cancer pain, AIDS-related pain, sickle cell pain, geriatric pain or headache-associated pain (selected from chronic or migraine headache), trigeminal neuralgia, temporomandibular joint syndrome, fibromyalgia syndrome, osteoarthritis, rheumatoid arthritis, gout, fibrositis and thoracic outlet syndromes.  
     
     
         37 . The method of  claim 34  wherein neurological conditions are selected from the group consisting of anxiety, convulsions, cyclophrenia, hypotonia, epilepsy, bipolar disorder and unipolar depression.  
     
     
         38 . The method of  claim 37  wherein epilepsy is selected from the group consisting of simple partial seizures, complex partial seizures, secondary generalised seizures and generalized seizures (selected from the group consisting of absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures).  
     
     
         39 . The method of  claim 37  wherein bipolar disorder is selected from the group consisting of bipolar disorder type I, bipolar disorder type II, cyclothymic disorder, rapid cycling, ultradian cycling, bipolar depression, acute mania, mania, mixed mania, hypomania and episodes associated with bipolar disorder.  
     
     
         40 . The method of  claim 34  wherein cardiovascular diseases and other disorders are selected from the group consisting of arrhythmias (selected from cardiac arrhythmia, cardiac infarction or angina pectoris), hypertension, endocrine disorders (selected from acromegaly or diabetes insipidus), tinnitus, muscle spasm, urinary incontinence, diarrhea, pruritus, functional bowel disorders (selected from non-ulcer dyspepsia, non-cardiac chest pain or irritable bowel syndrome), muscular sclerosis, macular degeneration, glaucoma, diseases in which the pathophysiology of the disorder involves excessive or hypersecretory or otherwise inappropriate cellular secretion of an endogenous substance (such as a catecholamine, a hormone or a growth factor) and emesis.  
     
     
         41 . The method of  claim 34  wherein the therapeutically effective amount of the compound of  claim 1  is from about 0.001 mg/kg/day to about 500 mg/kg/day.  
     
     
         42 . The method of  claim 34  further comprising a method for use of a compound of  claim 1  as a local anesthetic for treating or modulating chronic pain comprising topically or subcutaneously administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 1 .  
     
     
         43 . The method of  claim 42  wherein the therapeutically effective amount of the compound of  claim 1  is from about 0.001 mg to about 500 mg.  
     
     
         44 . The method of  claim 42  further comprising a method for use of a compound of  claim 1  as a local anesthetic for prophylactically treating or modulating chronic pain comprising topically or subcutaneously administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 1 .  
     
     
         45 . The method of  claim 44  wherein the therapeutically effective amount of the compound of  claim 1  is from about 0.001 mg to about 500 mg.