Piperidine derivatives and anti-platelet agents containing the same

Abstract

The present invention relates to a novel serotonin antagonist and an anti-platelet agent, more particularly, a serotonin antagonist and an anti-platelet agent which potently and specifically inhibit the serotonin 2 receptor with low adverse side effect.

What is claimed as new and is desired to be secured by Letters Patent of the United States is:  
     
         1 . A method of treating or preventing a disease caused by seretonin comprising administering effective amount of a piperidine derivative of general formula (I) or pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein A 1  represents an unsubstituted or substituted pyridyl, piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazinyl group, a substituted alkyl group having from 1 to 8 carbon atoms, a substituted cycloalkyl group having from 4 to 8 carbon atoms, or an unsubstituted or substituted alkoxyl group having 1 to 8 carbon atoms, 
 X 1  is a hydrogen atom or a halogen atom,  
 Y 1  is —CONH—, —NHCO—, —CONHCH 2 —, —(CH 2 ) n or —COO—,  
 wherein n is an integer of from 0 to 4, and  
 Z 1  is —CH═CH—, —S—CH 2 —, —S— or —CH 2 —CH 2 —.  
 
     
     
         2 . The composition of  claim 1 , wherein A 1  has a substituent and said substituent is 
 R 1 —CO— or                          wherein R 1  is a hydrogen atom, an alkyl or alkoxyl group having from 1 to 6 carbon atoms, an amino group which may be substituted by an alkyl group having from 1 to 6 carbon atoms, or an acylaminoalkyl group having from 1 to 6 carbon atoms, and    R 2  and R 3 , which may be the same or different, each represents a hydrogen atom, an alkyl, acyl or alkoxycarbonyl group having from 1 to 6 carbon atoms, or an aminocarbonyl group which may be substituted by an alkyl group having from 1 to 6 carbon atoms.    
     
     
         3 . The method of  claim 1 , wherein said substituent on A 1  is formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl, N-formyl-β-alanyl, N-acetyl-β-alanyl, N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl, N-ethyl-N-formyl or N-ethyl-N-acetyl.  
     
     
         4 . The method of  claim 1 , wherein Y 1  is a —CONH—.  
     
     
         5 . The method of  claim 1 , wherein Z 1  is a —CH═CH—.  
     
     
         6 . The method of  claim 1 , wherein the piperidine derivative is 1-formyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide.  
     
     
         7 . A method of treating or preventing platelet aggregation comprising administering an effective amount of a piperidine derivative of the formula (I) or a salt thereof or an active ingredient of a pharmaceutical composition:  
       
         
           
           
               
               
           
         
       
       wherein A 1  represents an unsubstituted or substituted pyridyl, piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazinyl group, a substituted alkyl group having from 1 to 8 carbon atoms, a substituted cycloalkyl group having from 4 to 8 carbon atoms, or an unsubstituted or substituted alkoxyl group having 1 to 8 carbon atoms, 
 X 1  is a hydrogen atom or a halogen atom,  
 Y 1  is —CONH—, —NHCO—, —CONHCH 2 —, —(CH 2 ) or —COO—,  
 wherein n is an integer of from 0 to 4, and  
 Z 1  is —CH═CH—, —S—CH 2 —, —S— or —CH 2 —CH 2 —.  
 
     
     
         8 . The method of  claim 7 , wherein the piperidine derivative is 1-formyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide.  
     
     
         9 . A piperidine derivative represented by the general formula (II) or a salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein A 2  represents an unsubstituted or substituted piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazinyl group, a substituted alkyl group having from 1 to 8 carbon atoms, a substituted cycloalkyl group having from 4 to 8 carbon atoms, or an unsubstituted or substituted alkoxyl group having 1 to 8 carbon atoms, 
 wherein suitable substituents include:  
 R 4 —CO— or  
                     
 wherein R 4  represents an alkyl or alkoxyl group having from 1 to 6 carbon atoms, an amino group which may be substituted by an alkyl group having from 1 to 6 carbon atoms, or an acylaminoalkyl group having from 1 to 6 carbon atoms.  
 R 1  and R 6 , which may be the same or different, each represents a hydrogen atom, an alkyl, acyl or alkoxycarbonyl group having from 1 to 6 carbon atoms, or an aminocarbonyl group which may be substituted by an alkyl group having from 1 to 6 carbon atoms, and  
 X 2  is a hydrogen atom or a halogen atom,  
 Y 2  is —CONH—, —NHCO—, —CONHCH 2 —, —(CH 2 ) n — or —COO—,  
 wherein n is an integer of from 0 to 4, and  
 Z 2  is —CH═CH—, —S—CH 2 —, —S— or —CH 2 —CH 2 —.  
 
     
     
         10 . The piperidine derivative of  claim 9 , wherein A 2  is substituted with a substituent selected from the group consisting of acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl, N-formyl-β-alanyl, N-acetyl-β-alanyl, N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl, N-ethyl-N-formyl, and N-ethyl-N-acetyl.  
     
     
         11 . The piperidine derivative of  claim 9 , wherein Y 2  is a group —CONH—.  
     
     
         12 . The piperidine derivative of  claim 9 , wherein Z 2  is a group —CH═CH—.  
     
     
         13 . A compound selected from the group consisting of 1-methoxycarbonyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)1-piperidinyl))ethylisonipecotamide, 
 N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,    1-acetyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,    1-t-butoxycarbonyl-N-(2-(4-(5H-dibenzo[[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide,    1-carbamoyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,    1-(N,N-dimethylcarbamoyl)-N-(2(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide,    1-(N-acetylglycyl)-N-(2-(4(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide,    N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidinyl)) ethylpipecolamide,    N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethyl-(N-acetyl)pipecolamide,    1-formyl-4-((2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylcarbamoyl)piperazine,    N-(2-1(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethyl-4-aminocyclohexanecarboxamide,    N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethyl-4-acetylaminocyclohexanecarboxamide,    N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethyl-4-(1-t-butoxycarbonylamino)cyclohexanecarboxamide,    4-5H-dibenzo[a,d]cyclohepten-5-ylidene))1-2-ethoxycarbonylamino)ethyl)piperidine,    4-(5H-dibenzo[a,d]cyclohepten-5-ylidene-1-(2-t-butoxycarbonylamino)ethyl)piperidine,    N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-1-(1-amino)cyclohexanecarboxamide,    N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethyl-1-(1-acetylamino)cyclohexanecarboxamide,    N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-1-(1-t-butoxycarbonylamino) cyclohexanecarboxamide,    N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-1-(formylamino)cyclohexanecarboxamide,    N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-1-(1-N,N-dimethylcarbamoylamino) cyclohexanecarboxamide,    N-(2-(4-(5Hdibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-aminobutyramide,    N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidinyl)) ethyl-4-formylaminobutyramide,    N-(2-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-acetylaminobutyramide,    N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-t-butoxycarbonylaminobutyramide,    N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-(N,N-dimethylcarbamoylamino) butyramide,    N-(2(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-(N-methylamino)butyramide,    N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-(N-methyl-t-butoxycarbonylamino) butyramide,    1-formyl-N-(3-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))propylisonipecotamide,    4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1(3-t-butoxycarbonyl aminopropyl)piperidine,    1-(3-aminopropyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine,    1-formyl-isonipecotic acid 2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethyl ester,    1-(2-aminoethyl)-4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine,    4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-t-butoxycarbonylamino)ethyl)piperidine,    1-formyl-N-(2-(4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,    1-(2-aminoethyl)-4-(9-thioxanthinidene)piperidine,    4-(9-thioxanthinidene)-1-((2-t-butoxycarbonylamino)ethyl) piperidine,    1-formyl-N-(2-(4-(9-thioxanthinidene)piperidinyl)) ethylisonipecotamide,    1-formyl-N-(2(4-(11-H-dibenzo[b,e]thiepin-2-fluoro-11-ylidene)-1-piperidinyl))ethylisonipecotamide,    1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)butyl)morpholine,    1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5ylidene)-1-piperidinyl)butyl)thiomorpholine,    1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)pentyl)morpholine,    1-(4-(4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)butyl)piperidine and    1-(4-(4-(9-thioxanthilidene)piperidinyl)butyl)morpholine.