Corticotropin releasing factor antagonists

Abstract

A pharmaceutical composition for treatment of a disorder or condition the treatment of which can be effected or facilitated by antagonizing Corticotropin Releasing Factor (CRF). The pharmaceutical composition includes a pharmaceutically acceptable carrier and an effective amount to treat the disorder or condition of the following compound: or a pharmaceutically acceptable salt thereof, wherein A, B, Z, R 3 , R 4 , and R 5 are as defined herein.

1 - 28 . (cancelled)  
     
     
         29 . A pharmaceutical composition for the treatment of (a) a disorder or condition the treatment of which can be effected or facilitated by antagonizing CRF or (b) a disorder or condition selected from inflammatory disorders, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception; mood disorders, mood disorders associated with premenstrual syndrome, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; chronic fatigue syndrome; stress-induced headache; cancer; irritable bowel syndrome, Crohn's disease; spastic colon; post operative ileus; ulcer; diarrhea; stress-induced fever; human immunodeficiency virus infections; neurodegenerative diseases; gastrointestinal diseases; eating disorder; hemorrhagic stress; chemical dependencies or addictions; drug or alcohol withdrawal symptoms; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiuretic hormone; obesity; infertility; head trauma; spinal cord trauma; ischemic neuronal damage; excitotoxic neuronal damage; stroke; immune dysfunctions; muscular spasms; urinary incontinence; senile dementia of the Alzheimer's type; multi infarct dementia; amyotrophic lateral sclerosis; hypertension; tachycardia; congestive heart failure; osteoporosis; premature birth; hypoglycemia, and Syndrome X in a mammal or bird, comprising a pharmaceutically acceptable carrier and an amount of the following compound that is effective in the treatment of such disorder or condition:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 A is —CR 7 ;  
 B is —NR 1 R 2 , —CR 1 R 2 R 11 , —C(═CR 2 R 12 )R 1 , —NHCHR 1 R 2 , —OCHR 1 R 2 , —SCHR 1 R 2 , —CHR 2 OR 1 , —CHR 1 OR 2 , —CHR 2 SR 1 , —CHR 2 NR 1 R2, —CHR 1 NHR 2 , —CHR 1 ,N(CH 3 )R 2 , or —NR 12 NR 1 R 2 ;  
 Z is NH, O, S, —N (C 1 -C 2  alkyl)-, —N(C(O)CF 3 ), - or —C(R 13 R 14 )—, wherein R 13  and R 14  are each, independently, hydrogen, trifluoromethyl or methyl, or one of R 13  and R 14  is cyano and the other is hydrogen or methyl, or —C(R 13 R 14 ) is a cyclopropyl group, or Z is nitrogen or CH and forms a five or six membered heterocyclic ring fused with R 5 , which ring optionally comprises two or three further hetero members selected independently from oxygen, nitrogen, NR 12 , and S(O) m , and optionally comprises from one to three double bonds, and is optionally substituted with halo, C 1 -C 4  alkyl, —O(C 1 -C 4  alkyl), NH 2 , NHCH 3 , N(CH 3 ) 2 , CF 3 , or OCF 3 , with the proviso that said ring does not contain any —S—S—, —S—O—, —N—S—, or —O—O— bonds, and does not comprise more than two oxygen or S(O) m  heterologous members;  
 R 1  is C(O)H, C(O)(C 1 -C 6  hydrocarbyl), C(O)(C 1 -C 6  hydrocarbylene)(C 3 -C 8  cyclohydrocarbyl), C(O)(C 3 -C 8  cyclohydrocarbylene )(C 3 -C 8  cyclohydrocarbyl), C(O)(C 1 -C 6  hydrocarbylene)(C 4 -C 8  heterocyclohydrocarbyl ), —C(O)(C 3 -C 8  cyclohydrocarbylene)(C 4 -C 8  heterocyclohydrocarbyl), C 3 -C 8  cyclohydrocarbyl, C 4 -C 8  heterocyclohydrocarbyl, —(C 1 -C 6  hydrocarbylene (C 3 -C 8  cyclohydrocarbyl ),C 3 -C 8  cyclohydrocarbylene)(C 3 -C 8  cyclohydrocarbyl), —(C 1 -C 6 hydrocarbylene)(C 4 -C 8  heterocyclohydrocarbyl), —(C 3 -C 8  cyclohydrocarbylene)(C 4 -C 8  heterocyclohydrocarbyl), or —O-aryl, or —O—(C 1 -C 6  hydrocarbylene)-aryl; wherein said aryl, C 4 -C 8  heterocyclohydrocarbyl, C 1 -C 6  hydrocarbyl, C 3 -C 8  cyclohydrocarbyl, C 3 -C 8  cyclohydrocarbylene, and C 1 -C 6  hydrocarbylene groups may each independently be optionally substituted with from one to six fluoro and may each independently be optionally substituted with one or two substituents R 8  independently selected from the group consisting of C 1 -C 4  hydrocarbyl, —C 3 -C 8  1 cyclohydrocarbyl, hydroxy, chloro, bromo, iodo, CF 3 , —O—(C 1 -C 6  hydrocarbyl), —O—(C 3 -C 5  cyclohydrocarbyl), —O—CO—(C 1 -C 4  hydrocarbyl), —O—CO—NH(C 1 -C 4  hydrocarbyl), —O—CO—N(R 24 )(R 25 ), —N(R 24 )(R 25 ), —S(C 1 -C 4  hydrocarbyl), —S(C 3 -C 5  cyclohydrocarbyl) [−]-N(C 1 -C 4  hydrocarbyl)CO(C 1 -C 4  hydrocarbyl), —NHCO(C 1 -C 4  hydrocarbyl), —COO(C 1 -C 4  hydrocarbyl), —CONH(C 1 -C 4  hydrocarbyl), —CONC 1 -C 4  hydrocarbyl)(C 1 -C 2  hydrocarbyl), CN, NO 2 , —OSO 2 (C 1 -C 4  hydrocarbyl), S + (C 1 -C 6  hydrocarbyl)(C 1 -C 2  hydrocarbyl) I − , —SO(C 1 -C  4  hydrocarbyl) and —SO 2 (C 1 -C 4  hydrocarbyl); and wherein the C 1 -C 6  hydrocarbyl, C 1 -C 6  hydrocarbylene, C 5 -C 8  cyclohydrocarbyl, C 5 -C 8  cyclohydrocarbylene, and C 5 -C 8  heterocyclohydrocarbyl moieties of R 1  may optionally independently contain from one to three double or triple bonds; and wherein the C 1 -C 4  hydrocarbyl moieties and C 1 -C 6  hydrocarbyl moieties of R 8  can optionally independently be substituted with hydroxy, amino, C 1 -C 4  alkyl, aryl, —CH 2 -aryl, C 3 -C 5  cycloalkyl, or —O—(C 1 -C 4  alkyl), and can optionally independently be substituted with firom one to six fluoro, and can optionally contain one or two double or triple bonds; and wherein each heterocyclohydrocarbyl group of R 1  contains from one to three heteromoieties selected from oxygen, S(O) m , nitrogen, and NR 12 ;  
 R 2  is hydrogen, C 1 -C 12  hydrocarbyl, C 3 -C 8  cyclohydrocarbyl, C 4 -C 8  heterocyclohydrocarbyl, —(C 1 -C 6  hydrocarbylene)(C 3 -C 8  cyclohydrocarbyl), —(C 3 -C 8  cyclohydrocarbylene)(C 3 -C 8  cyclohydrocarbyl), —(C 1 -C 6  hydrocarbylene)(C 4 -C 8  heterocyclohydrocarbyl), —(C 3 -C 6  cyclohydrocarbylene)(C 4 -C 8  heterocyclohydrocarbyl), aryl, —(C 1 -C 6  hydrocarbylene)aryl, or —(C 3 -C 8  cyclohydrocarbylene)(aryl); wherein each of the foregoing R 2  groups may optionally be substituted with from one to three substituents independently selected from chloro, fluoro, and C 1 -C 6  alkyl, wherein one of said one to three substituents can further be selected from bromo, iodo, C 1 -C 6  alkoxy, —OH, —O—CO—(C 1 -C 6  alkyl), —O—CO—N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —S (C 1 -C 6  alkyl), —S(O)(C 1 -C 6  alkyl), —S(O) 2 (C 1 -C 6  alkyl), S + (C 1 -C 6  alkyl)(C 1 -C 2  alkyl)I′, CN, and NO 2 ; and wherein the C 1 -C 12  hydrocarbyl, —(C 1 -C 6  hydrocarbylene), and cyclohydrocarbyl gropups of 5-8 carbon atoms, cyclohydrocarbylene groups of 5 to 8 carbon atoms and heterocyclohydrocarbyl groiups of 5 to 8 atoms of R 2  may optionally independently contain from one to three double or triple bonds; and wherein each heterocyclohydrocarbyl group of R 2  contains from one to three heteromoieties selected from oxygen, S(O) m , nitrogen, and NR 12 ;  
 or when R 1  and R 2  are as in —NHCHR 1 R 2 , —OCHR 1 R 2 , —SCHR 1 R 2 , —CHR 1 R 2  or —NR 1 R 2 ,  
 R 1  and R 2  of B may form a saturated 5- to 8-membered ring which may optionally contain one or two double bonds and in which one or two of the ring carbons may optionally be replaced by an oxygen, S(O) m , nitrogen or NR 12 ; and which carbocyclic ring can optionally be substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, C 1 -C 4  alkyl, fluoro, chloro, bromo, iodo, CF 3 , —O—(C 1 -C 4  alkyl), —O—CO—(C 1 -C 4  alkyl), —O—CO—NH(C 1 -C 4  alkyl), —O—CO—N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —NH(C 1 -C 4  alkyl), —N(C 1 -C 2  alkyl)(C 1 -C 4  alkyl), —S(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)CO(C 1 -C 4  alkyl), —NHCO(C 1 -C 4  alkyl),—COO(C 1 -C 4  alkyl), —CONH(C 1 -C 4  alkyl), —CON(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), CN, NO 2 , —OSO 2 (C 1 -C 4  alkyl), —SO(C 1 -C 4  alkyl), and —SO(C 1 -C 4  alkyl), wherein one of said one to three substituents can further be selected from phenyl;  
 R 3  is methyl, ethyl, fluoro, chloro, bromo, iodo, cyano, methoxy, OCF 3 , NH 2 , NH(C 1 -C 2  alkyl), N(CH 3 ) 2 , —NHCOCF 3 , —NHCH 2 CF 3 , S(O) m (C 1 -C 4  alkyl), CONH 2 , —CONHCH 3 , CON(CH 3 ) 2 , —CF 3 , or CH 2 OCH 3 ;  
 R 4  is hydrogen, C 1 -C 4  hydrocarbyl, C 3 -C 5  cycloalkyl, —(C 1 -C 4  hydrocarbylene)(C 3 -C 5  cycloalkyl), —(C 3 -C 5  cycloalkylene)(C 3 -C 6  cycloalkyl), cyano, fluoro, chloro, bromo, iodo, —OR 24  C 1 -C 6  alkoxy, —O— cycloalkyl), —O—(C 1 -C 4  hydrocarbylene)(C 3 -C 5  cycloalkyl), —O—(C 3 -C 5  cycloalkylene)(C 3 -C 5  cycloalkyl), —CH 2 SC(S)O(C 1 -C 4  alkyl), CH 2 OCF 3 , CF 3 , amino, nitro, —NR 24 R 25 , —(C 1 -C 4  hydrocarbylene)-OR 24 , —(C 1 -C 4  hydrocarbylene)Cl, —(C 1 -C 4  hydrocarbylene)NR 24 R 25 , —NHCOR 24 , —NHCONR 24 R 25 , —CH═NOR 24 , —NHNR 24 R 25 , —S(O) m R 24 , —C(O)R 24 , —OC(O)R 24 , —C(O)CN, —C(O)NR 24 R 25 , —C(O)NHNR 24 R 25 , and —COOR 24 , wherein the hydrocarbyl and hydrocarbylene groups of R 4  may optionally independently contain one or two double or triple bonds and may optionally independently be substituted with one or two substituents R 10  independently selected from hydroxy, amino, —NHCOCH 3 , —NHCOCH 2 Cl, —NH(C 1 -C 2  alkyl), —N(C 1 -C 2  alkyl)(C 1 -C 2 alkyl), —COO(C 1 -C 4  alkyl), —COOH, —CO(C 1 -C 4  alkyl), C 1 -C 6  alkoxy, C 1 -C 3  thioalkyl, cyano and nitro, and with one to four substituents independently selected from fluoro and chloro;  
 R 5  is aryl or heteroaryl and is substituted with from one to four substituents R 27  independently selected from halo, C 1 -C 10  hydrocarbyl, —(C 1 -C 4  hydrocarbylene)(C 3 -C 8  cycloalkyl), —(C 1 -C 4  hydrocarbylene)(C 4 -C 8  heterocycloalkyl), —(C 3 -C 8  cycloalkyl), —(C 4 -C 8  heterocycloalkyl), —(C 3 -C 8  cycloalkylene)(C 3 -C 8  cycloalkyl), —(C 3 -C 8  cycloalkylene)(C 4 -C 8  heterocycloalkyl), C 1 -C 4  haloallyl, C 1 -C 4  haloalkoxy, nitro, cyano, —NR 24 R 25 , —NR 24 COR 25 , —NR 24 CO 2 R 26 , —COR 24 , —OR 25 , —CONR 24 R 25 , —CON(OR 22 )R 23 , —CO 2 R 26 , —C═N(OR 22 )R 23 , and —S(O)  m R 23 ; wherein said C 1 -C 10  alkyl, C 3 -C 8  cycloalkyl, (C 1 -C 4  hydrocarbylene), (C 3 -C 8  cycloalkyl), (C 3 -C 8  cycloalkylene), and (C 4 -C 8  heterocycloalkyl) groups can be optionally substituted with from one to three substituents independently selected form C 1 -C 4  alkyl, C 3 -C 8  cycloalkyl, (C 1 -C 4  hydrocarbylene)(C 3 -C 8  cycloalkyl), —(C 3 -C 8  cycloalkylene)(C 3 -C 8  cycloalkyl), C 1 -C 4  haloalkyl, hydroxy, C 1 -C 6  alkoxy, nitro, halo, cyano, —NR 24 R 25 , —NR 24 COR 25 , NR 24 CO 2 R 26 , —COR 24 , —OR 25 , —CONR 24 R 25 , CO 2 R 26 , —CO(NOR 22 )R 25 , and —S(O) m R 23 ; and wherein two adjacent substituents of the R 5  group can optionally form a 5-7 membered ring, saturated or unsaturated, fused to R 5 , which ring optionally can contain one, two, or three heterologous members independently selected from O, S(O) m , and N, but not any —S—S—, —O—O—, —S—O—, or —N—S— bonds, and which ring is optionally substituted with C 1 -C 4  alkyl, C 3 -C 8  cycloalkyl, —(C 1 -C 4  alkylene)(C 3 -C 8  cycloalkyl), —(C 3 -C 8  cyloalkylene)(C 3 -C 8  cycloalkyl), C 1 -C 4  haloalkyl, nitro, halo, cyano —NR 24 R 25 , NR 24 COR 25 , NR 24 CO 2 R 26 , —COR 24 , —OR 25 , —CONR 24 R 25 , CO 2 R 26 , —CO(NOR 26 )R 25 , or —S(O) m R 23 ; wherein one of said one to four optional substituents R 27 , can further be selected from —SO 2 NH(C 1 -C 4  alkyl), —SO 2 NH(C 1 -C 4  alkylene )(C 3 -C 8  cycloalkyl), SO 2 NH(C 3 -C 8  cycloalkyl), —SO 2 NH(C 3 -C 8  cycloalkylene)(C 3 -C 8  cycloalkyl), —SO 2 N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —SO 2 NH 2 , —NHSO 2 (C 1 -C 4  alkyl), —NHSO 2 (C 3 -C 8  cycloalkyl), —NHSO 2 (C 1 -C 4  alkylene)(C 3 -C 8  cycloalkyl), and —NHSO 2 (C 3 -C 8  cycloalkylene)(C 3 -C 8  cycloalkyl); and wherein the hydrocarbyl, and hydrocarbylene groups of R 5  may independently optionally contain one double or triple bond;  
 R 6  is hydrogen, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, —(C 1 -C 6  alkylene)(C 3 -C 8  cycloalkyl), or —(C 3 -C 8  cycloalkylene)(C 3 -C 8  cycloalkyl), wherein said alkyl and cycloalkyl may optionally be substituted with one hydroxy, methoxy, ethoxy or fluoro group;  
 or R 6  and R 4  can together form an oxo (═O) group, or can be connected to form a 3-8 membered carbocyclic ring, optionally containing one to three double bonds, and optionally containing one, two, or three heterologous ring members selected from O, SO m , N, and NR 12 , but not containing any —O—O—, —S—O—, —S—S—, or —N—S— bonds, and further optionally substituted with C 1 - C 4  hydrocarbyl or C 3 -C 6  cycloalkyl, wherein said C 1 -C 4  hydrocarbyl substituent may optionally contain one double or triple bond;  
 R 7  is hydrogen, methyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, —O(C 1 -C 2 ) alkyl), —O(cyclopropyl), —COO(C 1 -C 2  alkyl), —COO(C 3 -C 8  cycloalkyl), —OCF 3 , —CF 3 , —CH 2 OH or CH 2 OCH 3 ;  
 R 11  is hydrogen, hydroxy, fluoro, ethoxy, or methoxy;  
 R 12  is hydrogen or C 1 -C 4  alkyl;  
 R 22  is independently at each occurrence selected from hydrogen, C 1 -C 14  alkyl, C 1 -C 14  haloalkyl, C 3 -C 6  alkenyl, C 3 -C 6  alkynyl, C 3 -C 8  cycloalkyl, (C 3 -C 8  cycloalkylene)(C 3 -C 8  cycloalkyl), and (C 1 -C 4 ) alkylene)(C 3 -C 8  cycloalkyl);  
 R 23  is independently at each occurrence selected from C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 2 -C 8  alkoxyalkyl, C 3 -C 8  cycloalkyl, —(C 1 -C 4  alkylene)(C 3 -C 8  cycloalkyl), —(C 3 -C 8  cycloalkylene)(C 3 -C 8  cycloalkyl), aryl, —(C 1 -C 4  alkylene)aryl, piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, and thiomorpholine;  
 R 24  and R 2 , are independently at each occurrence selected from hydrogen, —C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, —(C 1 -C 4  alkylene)OH, —(C 1 -C 4  alkylene)—O—(C 1 -C 4  alkyl), —(C 1 -C 4  alkylene)—O—(C 3 -C 5  cycloalkyl), C 3 -C 8  cycloalkyl, —(C 1 -C 4  alkylene)(C 3 -C 8  cycloalkyl), —(C 3 -C 8  cycloalkylene)(C 3 -C 8  cycloalkyl), —C 4 -C 8  heterocyclohydrocarbyl, —(C 1 -C 4  alkylene)(C 4 -C 8  heterocyclohydrocarbyll), —(C 3 -C 8  cycloalkylene)(C 4 -C 8  heterocyclohydrocarbyl), aryl, and —(C 1 -C 4  alkylene)(aryl), wherein the —C 4 -C 8  heterocyclohydrocarbyl groups can each independently optionally be substituted with aryl, CH 2 -aryl, or C 1 -C 4  alkyl, and can optionally contain one or two double or triple bonds; or, when R 24  and R 25  are as NR 24 R 25 , —C(O)NR 24 R 25 , —(C 1 -C 4 alkylene)NR 24 R 25 , or —NHCONR 24 R 25 , then NR 24 R 25  may further optionally form a 4 to 8 membered heterocyclic ring optionally containing one or two further hetero members independently selected from S(O) m , oxygen, nitrogen, and NR 12 , and optionally containing from one to three double bonds;  
 R 26  is independently at each occurrence selected from C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 3 -C 8  cycloalkyl, —(C 1 -C 4  alkylene)(C 3 -C 8  cycloalkyl), —(C 3 -C 8  cycloalkylene)(C 3 -C 8  cycloalkyl), aryl, and —(C 1 -C 4  alkylene)(aryl); and  
 wherein each m is independently zero, one, or two,  
 with the proviso that heterocyclohydrocarbylene groups of the compound of formula I, do not comprise any —S—S—, —S—O—, —N—S—, or —O—O— bonds, and do not comprise more than two oxygen or S(O) m  heterologous members.  
 
     
     
         30 . A pharmaceutical composition according to  claim 29  for the treatment of a disorder selected from inflammatory disorders; pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic; phobias; obsessive compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception; mood disorders; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress induced headache; cancer; irritable bowel syndrome, Crohn's disease; spastic colon; human immunodeficiency virus (HIV) infections; neurodegenerative diseases; gastrointestinal diseases; eating disorders; chemical dependencies and addictions; obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage; excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctions; muscular spasms; urinary incontinence; senile dementia of the Alzheimer's type; multi infarct dementia; amyotrophic lateral sclerosis; and hypoglycemia in a mammal.  
     
     
         31 . A pharmaceutical composition as claimed in  claim 29  for treatment of a mood disorder selected from the group consisting of rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies.  
     
     
         32 . A pharmaceutical composition as claimed in  claim 29  for treatment of an inflammatory disorder selected from the group consisting of rheumatoid arthritis and osteoarthritis.  
     
     
         33 . A pharmaceutical composition as claimed in  claim 30  for treatment of depression, selected from the group consisting of major depression, single episode depression, recurrent depression, and child abuse induced depression.  
     
     
         34 . A pharmaceutical composition as claimed in  claim 30  for treatment of neurodegenerative diseases selected from the group consisting of Alzheimer's disease, Parkinson's disease and Huntington's disease.  
     
     
         35 . A pharmaceutical composition as claimed in  claim 30  for treatment of chemical dependencies or addictions, selected from the group consisting of dependencies or addictions to alcohol, cocaine, heroin, benzodiazapines, or other drugs.  
     
     
         36 . A pharmaceutical composition as claimed in  claim 30  for treatment of cerebral ischemia.  
     
     
         37 . A pharmaceutical composition as claimed in  claim 30  for treatment of stress induced immune dysfunctions selected from the group consisting of porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, confinement dysfunction in chicken, sheering stress in sheep, and human animal interaction stress in dogs.  
     
     
         38 . A pharmaceutical composition as claimed in  claim 30  for treatment of fibromyalgia.  
     
     
         39 . A pharmaceutical composition as claimed in  claim 30  for treatment of anorexia or bulimia nervosa.  
     
     
         40 . A pharmaceutical composition as claimed in  claim 30  for treatment of cerebral ischemia selected from cerebral hippocampal ischemia.  
     
     
         41 . A pharmaceutical composition as claimed in  claim 30  for treatment of including social phobia, agoraphobia or specific phobias.  
     
     
         42 . The pharmaceutical composition according to  claim 29  wherein the pain perception is fibromyalgia.  
     
     
         43 . The pharmaceutical composition according to  claim 29  wherein the ischemic neuronal damage is cerebral ischemia.  
     
     
         44 . The pharmaceutical composition according to  claim 30  wherein mood disorder is depression or postpartum depression.  
     
     
         45 . The pharmaceutical composition according to  claim 30  wherein the ischemic neuronal damage is cerebral ischemia.  
     
     
         46 . The pharmaceutical composition according to  claim 30  wherein the mammal is a human.