Aminophenoxyacetamide derivatives and pharmaceutical composition containing thereof

Abstract

The present invention relates to an amiophenoxyacetamide derivative of the formula (I): wherein R 1 to R 4 are, independent from each other, a hydrogen atom or an optionally substituted alkyl group; E 1 is —NR 4 —; and E 2 is an oxygen atom or —NR 10 —; Q is the group —X—Y-Q′, wherein X and Y are connecting bonds or X is an alkylene or alkenylene group and Y is selected from a group comprising C═O, NHC(═O), and C(═O)NH, and Q′ is a hydrogen atom or a phenyl or pyridyl group which may be substituted; and pharmaceutically acceptable salts thereof. The present invention further relates to compositions comprising compounds of the formula (I) and methods of using said compounds for treating cerebral functional disorders and cerebral organic disorders.

1 . An aminophenoxyacetamide derivative represented by the following formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1 , R 2 , R 3  and R 4  are, independent from each other, hydrogen atom or lower alkyl group;  
 R 5 , R 6 , R 7  and R 8  are, independent from each other, hydrogen atom or lower alkyl group;  
 E 1  is group —NR 9 — (in which, R 9  is hydrogen atom or lower alkyl group);  
 E 2  is oxygen atom or group —NR 10 — (in which, R 10  is hydrogen atom or lower alkyl group which may be substituted);  
 Q is a group of —X—Y-Q′, wherein X is a connecting bond, lower alkyl group, lower alkenyl group, or lower alkynyl group; Y is a connecting bond, or a group selected from the groups consisting of C═O, C(═O)NH, NHC(═O), —O—, —S—, CH(OH), —O—CH(OH)— and —O—CH 2 —CH(OH)—, in which hydrogen atom of amido group may be substituted with lower alkyl group; and Q′ is hydrogen atom or a cyclic group selected from the groups consisting of aryl group, heteroaryl group, saturated or unsaturated cyclic hydrocarbon group, and saturated or unsaturated heterocyclic group, wherein one or more of the hydrogen atoms in the cyclic group of Q′ may be substituted;  
 either in the case that X and Y are both connecting bond then Q′ is not hydrogen atom; or in the case that one of X and Y is other than connecting bond then E 2  is the group —O— and all of the groups of R 1 , R 2 , R 3  and R 4  are not hydrogen atom; or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The aminophenoxyacetamide derivative of formula (I) claimed in  claim 1 , wherein X and Y are both connecting bond; or pharmaceutically acceptable salts thereof.  
     
     
         3 . The aminophenoxyacetamide derivative of formula (I) claimed in  claim 1 , wherein, one of X and Y is other than connecting bond and E 2  is the group —O— and all of the groups of R 1 , R 2 , R 3  and R 4  are other than hydrogen atom, wherein X, Y, R 1 , R 2 , R 3  and R 4  are the same as defined above in  claim 1;  or pharmaceutically acceptable salts thereof.  
     
     
         4 . A composition comprising an aminophenoxyacetamide derivative or a pharmaceutically acceptable salt thereof represented by the formula (I) in  claim 1  as an active ingredient.  
     
     
         5 . A composition comprising an aminophenoxyacetamide derivative or a pharmaceutically acceptable salt thereof represented by the formula (I) in  claim 2  as an active ingredient.  
     
     
         6 . A composition comprising an aminophenoxyacetamide derivative or a pharmaceutically acceptable salt thereof represented by the formula (I) in  claim 3  as an active ingredient.  
     
     
         7 . A method for inducing the production of CalbindinD-28K wherein said method comprises administering to a patient a composition according to  claim 4 .  
     
     
         8 . A method for inducing the production of CalbindinD-28K wherein said method comprises administering to a patient a composition according to  claim 5 .  
     
     
         9 . A method for inducing the production of CalbindinD-28K wherein said method comprises administering to a patient a composition according to  claim 6 .  
     
     
         10 . A method for improving or treating cerebral function and/or organic function disorders wherein said method comprises administering to a patient a composition according to  claim 4 .  
     
     
         11 . The method of  claim 10 , wherein said cerebral function disorders are caused by ischemic disorders.  
     
     
         12 . The method of  claim 11 , wherein said ischemic disorders are selected from the group consisting of cerebral infarction, intracerebral hemorrhage and cerebral arteriosclerosis.  
     
     
         13 . The method of  claim 10 , wherein said organic function disorders are selected from the group consisting of senile dementia, cerebral injury, cerebral operation, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.  
     
     
         14 . A method for improving or treating cerebral function and/or organic function disorders wherein said method comprises administering to a patient a composition according to  claim 5 .  
     
     
         15 . The method of  claim 14 , wherein said cerebral function disorders are caused by ischemic disorders.  
     
     
         16 . The method of  claim 15 , wherein said ischemic disorders are selected from the group consisting of cerebral infarction, intracerebral hemorrhage and cerebral arteriosclerosis.  
     
     
         17 . The method of  claim 14 , wherein said organic function disorders are selected from the group consisting of senile dementia, cerebral injury, cerebral operation, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.  
     
     
         18 . A method for improving or treating cerebral function and/or organic function disorders wherein said method comprises administering to a patient a composition according to  claim 6 .  
     
     
         19 . The method of  claim 18 , wherein said cerebral function disorders are caused by ischemic disorders.  
     
     
         20 . The method of  claim 19 , wherein said ischemic disorders are selected from the group consisting of cerebral infarction, intracerebral hemorrhage and cerebral arteriosclerosis.  
     
     
         21 . The method of  claim 18 , wherein said organic function disorders are selected from the group consisting of senile dementia, cerebral injury, cerebral operation, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.  
     
     
         22 . A method for selecting a neuroprotective compound, wherein said method comprises evaluating the activation of receptors for various kinds of physiologically active substances and the phosphorylation of the FGF receptor caused by the induction of CalbindinD-28k production.  
     
     
         23 . The method for selecting a neuroprotective compound according to  claim 22 , wherein said method comprises evaluating the autophosphorylation of the FGF receptor.  
     
     
         24 . The method for selecting a neuroprotective compound according to  claim 22 , wherein said method is performed by evaluating for neuroprotective effect of the physiologically active substance against glutamate-induced neurodegeneration together with one or more of the following tests (i)-(iii): 
 (i) evaluating for antagonism against the neuroprotective effect of the physiologically active substance by treatment with MTA (5-deoxy-5-methyl-thioadenosine), which inhibits autophosphorylation of the FGF receptor, and by treatment with inhibitors of various physiologically active substance receptors, to determine if the neuroprotective effect is due to autophosphorylation of receptors of the FGF receptor;    (ii) evaluating the CalbindinD-28k inducing effect of the physiologically active substance; or    (iii) confirming that the neuroprotective effect of the physiologically active substance is due to its inducing CalbindinD-28k production, by treating with the antisense oligonucleotide of CalbindinD-28k and determining if CalbindinD-28k production is antagonized.    
     
     
         25 . The method according to  claim 22 , wherein said physiological active substance receptors are selected from the group consisting of receptors for neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I/II (IGF-I/II), platelet-derived growth factor (PDGF), and estrogen.  
     
     
         26 . A neuroprotective compound selected by the method according to  claim 22 .  
     
     
         27 . A composition comprising a neuroprotective compound according to  claim 26 .  
     
     
         28 . A method of treating or improving cerebral functional disorders and/or cerebral organic disorders, wherein said method comprises administering the composition according to  claim 27  to a patient in need thereof.  
     
     
         29 . The method according to  claim 28 , wherein said cerebral functional disorders are caused by ischemic disorders.  
     
     
         30 . The method according to  claim 29 , wherein said ischemic disorders are selected from the group consisting of cerebral infarction, intracerebral hemorrhage and cerebral arteriosclerosis.  
     
     
         31 . The method according to  claim 28 , wherein said cerebral organic disorders are selected from the group consisting of senile dementia, cerebral injury, cerebral operation, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.