Patent Publication Number: US-4921863-A

Title: Cyclic amine derivatives

Description:
FIELD OF INDUSTRIAL UTILIZATION 
     The present invention relates to cyclic amine derivatives having excellent medicinal activities. 
     Prior Art: 
     Various medicines for cerebral vascular disorders have been proposed. For example, cerebral vasodilator drugs and cerebral metabolism activators have been used. However, no drug which is drastically effective has been proposed as yet. At present, there is no drug effective particularly for cerebral vascular dementia and intellectual function disorders among the symptoms due to cerebral vascular disorders. 
     OBJECT OF THE INVENTION 
     After intensive investigations made for the purpose of finding a new compound effective for the treatment of various symptoms due to cerebral vascular disorders, particularly mental symptoms, over a long time under the above-mentioned circumstances, the inventors have found quite effective compounds. The present invention has been completed on the basis of this finding. 
     Therefore, an object of the present invention is to provide cyclic amine derivatives and pharmacologically acceptable salts thereof which are effective for the treatment of cerebral vascular disorders such as cerebral stroke, apoplexy, infarction and arteriosclerosis and mental symptoms due to multiple infarct dementia. Another object of the invention is to provide a process for producing said compounds or pharmacologically acceptable salts thereof. Still another object of the invention is to provide medicines containing said compound or a pharmacologically acceptable salt thereof as the active ingredient. 
     Construction and Effect of the Invention: 
     The intended compounds of the present invention are cyclic amine derivatives of the general formula (I) or pharmacologically acceptable salts thereof: ##STR2## 
     wherein A represents a substituted or unsubstituted phenyl, pyridyl or thienyl group, substituted or unsubstituted naphthyl, tetralyl, quinolyl, benzofuranyl, quinazolyl or benzothienyl group or a group of the formula: ##STR3## X represents a group of the formula: ##STR4## 
     n represents an integer of 0 to 4, 
     m represents an integer of 1 to 3, 
     Y represents a carbon or nitrogen atom, 
     Z represents a group of the formula: --CH 2  --, ##STR5## in which R 1  is a hydrogen atom or a lower alkyl, acyl, arylalkyl or heteroarylalkyl group, ##STR6## in which Hal is a halogen atom, ##STR7## in which Hal is a halogen atom, ##STR8## in which Hal is a halogen atom or ##STR9## the symbol &#34;   &#34; between Y and Z represents a single or double bond, 
     the group of the formula: &#34;    Z-B&#34; is bonded with the ring in the above formula at the 3- or 4-position, and 
     B represents a phenyl or naphthyl group which may be substituted with one or two substituents which may be the same or different and which are selected from the group consisting of halogens, lower alkyl groups and lower alkoxy groups. 
     The lower alkyl groups in the above-mentioned definitions of R 1  and B include, for example, straight-chain or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tertbutyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl groups. Among them, methyl and ethyl groups are the most preferred. 
     The lower alkoxy groups in the above-mentioned definition of B are those derived from the abovementioned lower alkyl groups. Preferred examples of them include methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy groups. 
     The substituents of the &#34;substituted or unsubstituted phenyl group &#34;0 and &#34;substituted or unsubstituted naphthyl group&#34; in the definition of A include, for example, the above-defined lower alkyl and alkoxy groups, hydroxyl group, halogen atoms such as fluorine, bromine, iodine and chlorine, phenyl group and heterocyclic groups having nitrogen atom(s) as the hetero atom such as imidazolyl, pyridyl and pyrazolyl groups. Said compounds may have one to three of these substituents. When the compounds have two or more of these substituents, they may be the same or different. 
     The phenyl group may have a methylenedioxy or ethylenedioxy group bonded with two different carbon atoms constituting the phenyl ring in addition to the above-mentioned substituents. Further, the substituted phenyl group includes also a group of the formula: ##STR10## 
     The acyl groups in the definition of R 1  include organic acid residues such as saturated aliphatic, unsaturated aliphatic, carbocyclic and heterocyclic carboxylic acid residues. Examples of them include lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl groups, aroyl groups such as benzoyl, toluoyl and naphthoyl groups and heteroaroyl groups such as furoyl, nicotinoyl and isonicotinoyl groups. 
     The arylalkyl groups in the definition of R 1  include, for example, those derived from substituted or unsubstituted phenyl and naphthyl groups. Typical examples of them include benzyl and phenethyl groups. The substituents in the above definition include, for example, the above-defined lower alkyl and lower alkoxy groups, hydroxyl group and halogen atoms such as fluorine, bromine, iodine and chlorine atoms. 
     Typical examples of the heteroarylalkyl groups include pyridylalkyl groups such as the picolyl group. 
     The halogen atoms include fluorine, chlorine, bromine and iodine atoms. 
     The pharmacologically acceptable salts are ordinary non-toxic salts, for example, inorganic acid salts such as hydrochlorides, hydrobromides, sulfates and phosphates; organic acid salts such as acetates, maleates, tartrates, methanesulfonates, benzenesulfonates and toluenesulfonates; and amino acid salts such as arginine salts, aspartates and glutamates. 
     Production Processes 
     The compounds of the present invention can be produced by various processes. A typical example of these processes comprises: ##STR11## 
     wherein Hal represents a halogen atom and A, X, Y, Z, B, n, m and     Z-B are as defined above. 
     Namely, a halide of the general formula (II) is reacted with a compound of the general formula (III) to obtain an intended compound of the general formula (I). 
     The dehydrohalogenation reaction is carried out by heating in an ordinary manner without using any solvent or in an organic solvent inert to the reaction which is selected from the group consisting of alcoholic solvents such as methanol, ethanol and butanol, benzene, toluene, xylene, tetrahydrofuran, chloroform, carbon tetrachloride and dimethylformamide. Preferred results are obtained when the reaction is carried out in the presence of an inorganic salt such as sodium hydrogencarbonate, potassium carbonate, sodium carbonate or sodium hydroxide or an organic base such as triethylamine, pyridine, pyrimidine or diethylaniline. 
     It is apparent from the pharmacological experiments described below that the compounds of the present invention have excellent pharmacological effects on the central nervous system, particularly a remarkable reparative effect on ischemic cerebral vascular disorders. Therefore, these compounds are useful for relieving, remedying or preventing mental disorders due to the cerebral vascular disorders such as cerebral stroke, apoplexy, infarction, arteriosclerosis and dementias, e.g. multiple infarct dementia. 
     It has been found in toxicity tests effected by using rats that the compounds of the present invention have a high safety and, therefore, the invention is highly valuable also in this regard. 
     According to the toxicity tests of typical compounds of the present invention (see Examples 1 to 12 given below), LD 50  of them was 2,000 to 4,000 mg/kg (oral administration to rats). 
     The compounds of the present invention used as the medicine are given either orally or parenterally. The dose of said compounds is not particularly limited, since it varies depending on the symptoms; age, sex, body weight and sensitivity of the patient; period and intervals of the administration; properties, composition and kind of the medicinal preparation; and varieties of active ingredients. Usually, about 0.1 to 300 mg/day, preferably about 1 to 100 mg/day of the compound is administered 1 to 4 times a day. 
     The compounds of the present invention are used in the form of a medicinal preparation such as an injection, suppository, sublingual tablet, tablet or capsule. 
     In the preparation of the injection, a pH adjustor, buffer, suspending agent, solubilizer, stabilizer, isotonizer, preservative, etc. are added to the active ingredient to form an intravenous, subcutaneous or intramuscular injection by an ordinary method. If necessary, the injection can be freeze-dried by an ordinary method. 
     Examples of the suspending agents include methylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia, tragacanth gum powder, sodium carboxymethylcellulose and polyoxyethylenesorbitan monolaurate. 
     Examples of the solubilizers include polyoxyethylene hardened castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol and ethyl esters of castor oil fatty acids. 
     Examples of the stabilizers include sodium sulfite, sodium metasulfite and ether. Examples of the preservatives include methyl hydroxybenzoate, ethyl hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol. 
    
    
     EXAMPLES 
     Typical examples of the compounds of the present invention will be shown below for facilitating the understanding of the present invention, which by no means limit the scope of the invention. 
     EXAMPLE 1 
     2-{2-[4-(p-Fluorobenzyl)piperidinyl]ethyl}naphthalene hydrochloride: ##STR12## 
     1.05 g of 1-chloro-2-(2-naphthyl)ethane, 1.09 g of 4-(p-fluorobenzyl)piperidine, 0.2 g of potassium iodide and 1.4 g of sodium hydrogencarbonate were refluxed in n-butanol solvent for 5 h. Then, the solvent was filtered out and 100 ml of chloroform was added to the residue. The mixture was washed with water and dried over magnesium sulfate. The oily product thus obtained was purified according to silica gel column chromatography and converted into its hydrochloride by an ordinary method. 
     Yield: 0.45 g 
     Melting point: 244° C. 
     Elementary analysis for C 24  H 26  NF.HCl: 
     
         ______________________________________                                    
           C          H      N                                            
______________________________________                                    
calculated (%)                                                            
             75.08        7.09   3.65                                     
found (%)    75.30        7.32   7.34                                     
______________________________________                                    
 
    
     EXAMPLE 2 
     2-(4-Benzylpiperidinyl)-2&#39;-acetonaphthone hydrochloride: ##STR13## 
     5 g of 2-bromo-2&#39;-acetonaphthone, 3.5 g of 4-benzylpiperidine, 0.2 g of potassium iodine and 5 g of sodium hydrogencarbonate were refluxed in butanol solvent for 4 h. After completion of the reaction, the product was treated by an ordinary process. The oily product thus obtained was purified according to silica gel column chromatography and converted into its hydrochloride, which was then recrystallized from chloroform and ethanol. 
     Yield: 2.1 g 
     Melting point: 233° to 235° C. 
     Elementary analysis for C 24  H 25  NO.HCl: 
     
         ______________________________________                                    
           C          H      N                                            
______________________________________                                    
calculated (%)                                                            
             75.87        6.90   3.69                                     
found (%)    75.67        6.71   3.49                                     
______________________________________                                    
 
    
     EXAMPLE 3 
     2-[4-Bis(4-fluorophenyl)methylene-1-piperidinyl]-2&#39;-acetonaphthone hydrochloride: ##STR14## 
     850 mg of 4-bis(4-fluorophenyl)methylenepiperidine, 700 mg of 2-bromo-2&#39;-acetonaphthone, 20 mg of potassium iodide and 760 mg of sodium hydrogencarbonate were refluxed in n-butanol solvent for 3.5 h. After completion of the reaction, the product was treated by an ordinary process. The obtained oily product was purified according to silica gel column chromatography and converted into its hydrochloride to obtain 510 mg of the intended product. 
     Melting point: 214° to 217° C. 
     Elementary analysis for C 30  H 25  NOF 2 .HCl 
     
         ______________________________________                                    
           C          H      N                                            
______________________________________                                    
calculated (%)                                                            
             73.54        5.35   2.86                                     
found (%)    73.54        5.46   3.03                                     
______________________________________                                    
 
    
     EXAMPLE 4 
     4-(1-Naphthonyl)piperidinyl-3&#39;,4&#39;-dimethylacetophenone hydrochloride: ##STR15## 
     1.9 g of 2-bromo-3&#39;,4&#39;-dimethylacetophenone, 2.0 g of 4-(1-naphthonyl) piperidine, 0.1 g of potassium iodide and 2.1 g of sodium hydrogencarbonate were refluxed in n-butanol solvent for 3 h. After completion of the reaction, the product was treated by an ordinary process. The obtained oily product was purified according to silica gel column chromatography and converted into its hydrochloride to obtain 1.0 g of the intended product. 
     Melting point: 92° to 96° C. (dec.) 
     Elementary analysis for C 26  H 27  NO 2 .HCl: 
     
         ______________________________________                                    
           C          H      N                                            
______________________________________                                    
calculated (%)                                                            
             74.01        6.68   3.32                                     
found (%)    73.79        6.69   3.01                                     
______________________________________                                    
 
    
     EXAMPLE 5 
     1-[3-(p-Fluorobenzoyl)piperidinyl]-2&#39;-acetonaphthone hydrochloride: ##STR16## 
     0.7 g of 1-bromo-2&#39;-acetonaphthone, 0.7 g of 3-(p-fluorobenzoyl)piperidine hydrochloride, 0.05 g of potassium iodide and 0.7 g of sodium hydrogencarbonate were refluxed in n-butanol solvent for 2 h. After completion of the reaction, the product was treated by an ordinary process. The obtained oily product was purified according to silica gel column chromatography and converted into its hydrochloride. 
     Yield: 0.4 g 
     Melting point: 123° to 127° C. (dec.) 
     Elementary analysis for C 24  H 22  NO 2  F.HCl: 
     
         ______________________________________                                    
           C          H      N                                            
______________________________________                                    
calculated (%)                                                            
             69.98        5.63   3.40                                     
found (%)    69.76        5.51   3.18                                     
______________________________________                                    
 
    
     EXAMPLE 6 
     2-[4-(α-Benzyloxy-p-fluorobenzyl)piperidinyl]-2&#39;-acetonaphthone hydrochloride: ##STR17## 
     1.1 g of 2-bromo-2&#39;-acetonaphthone, 1.2 g of 4-(α-benzyloxy-p-fluorobenzyl)piperidine and 4.5 g of sodium hydrogencarbonate were refluxed in ethanol solvent for 3.5 h. After completion of the reaction, the product was treated by an ordinary process. The oily product thus obtained was purified according to silica gel column chromatography and converted into its hydrochloride, which was recrystallized from ethyl acetate/methanol. 
     Yield: 0.6 g 
     Melting point: 115° to 120° C. 
     Elementary analysis for C 31  H 30  NO 2  F.HCl: 
     
         ______________________________________                                    
           C          H      N                                            
______________________________________                                    
calculated (%)                                                            
             76.76        6.44   2.89                                     
found (%)    76.59        6.21   2.68                                     
______________________________________                                    
 
    
     EXAMPLE 7 
     2-[4-(α-Acetoxy-p-fluorobenzyl)piperidinyl]-2&#39;-acetonaphthone hydrochloride ##STR18## 
     5.4 g of 2-bromo-2&#39;-acetonaphthone, 4.6 of 4-(α-hydroxy-p-fluorobenzyl)piperidine and 10 g of sodium hydrogencarbonate were refluxed in ethanol solvent for 2.5 h. After completion of the reaction, the product was treated by an ordinary process. The obtained oily product was purified according to silica gel column chromatography to obtain 5 g of 2-[4-(α-hydroxy-p-fluorobenzyl)piperidinyl]-2&#39;-acetonaphthone; 1 g of this product was stirred together with 1.0 g of acetic anhydride and 0.1 g of dimethylaminopyridine in pyridine solvent at room temperature for 5 h. After completion of the reaction, the oily product was purified according to silica gel column chromatography and converted into its hydrochloride, which was recrystallized from ethyl acetate and methanol. 
     Yield: 1.0 g 
     Melting point: 148° to 152° C. 
     Elementary analysis for C 26  H 26  NO 3  F.HCl: 
     
         ______________________________________                                    
           C          H      N                                            
______________________________________                                    
calculated (%)                                                            
             68.49        5.97   3.07                                     
found (%)    68.24        5.88   3.12                                     
______________________________________                                    
 
    
     EXAMPLE 8 
     4-(4-p-Fluorobenzoyl)piperidinyl-6,7-dimethoxyisoquinoline hydrochloride ##STR19## 
     70 mg of 4-chloromethyl-6,7-dimethoxyisoquinoline was dissolved in 10 ml of dimethyl sulfoxide. 1 ml of triethylamine and 140 mg of 4-(p-fluorobenzoyl) piperidine were added to the solution and the mixture was heated to 80° C. for 1 h. The reaction mixture was dissolved in ethyl acetate, washed with water and dried over magnesium sulfate. The product was purified according to silica gel column chromatography and converted into its hydrochloride. 
     Yield: 80 mg 
     Melting point: 185° to 190° C. 
     Elementary analysis for C 24  H 25  N 2  O 3  F.2HCl: 
     
         ______________________________________                                    
           C          H      N                                            
______________________________________                                    
calculated (%)                                                            
             59.88        5.65   5.82                                     
found (%)    59.78        5.61   5.80                                     
______________________________________                                    
 
    
     EXAMPLE 9 
     4-{2-[4-(p-Fluorobenzoyl)piperidinyl]ethyl}quinazoline hydrochloride ##STR20## 
     2 g of 4-methylquinazoline was dissolved in 20 ml of ethanol. 3.4 g of 4-(p-fluorobenzoyl)piperidine hydrochloride and 1.9 ml of 37% formalin were added to the solution and the mixture was stirred at room temperature for three days. A white precipitate was recovered by filtration and washed with ethanol to obtain the intended product. 
     Yield: 4.4 g 
     Melting point: 135° to 140° C. 
     Elementary analysis for C 22  H 22  N 3  OF.HCl: 
     
         ______________________________________                                    
           C          H      N                                            
______________________________________                                    
calculated (%)                                                            
             66.08        5.79   10.51                                    
found (%)    66.02        5.65   10.44                                    
______________________________________                                    
 
    
     EXAMPLE 10 
     1-(2-Naphthyl)-1-[4-(p-fluorobenzoyl)piperidinyl]-2-diethylaminoethane hydrochloride: ##STR21## 
     1.4 g of 1-(2-naphthyl)-2-diethylaminoethanol was dissolved in 20 ml of dichloromethane. 2.4 ml of triethylamine and 0.9 ml of methanesulfonyl chloride were added to the solution under cooling with ice and the mixture was stirred at room temperature for 4.5 h. A solution of 1.2 g of 4-(p-fluorobenzoyl)piperidine in 25 ml of dioxane was added to the reaction mixture and the obtained mixture was refluxed for 2 h. After completion of the reaction, the product was purified according to silica gel column chromatography and then converted into its hydrochloride. 
     Yield: 1.9 g 
     Melting point: 140° to 145° C. 
     Elementary analysis for C 28  H 33  N 2  OF.2HCl: 
     
         ______________________________________                                    
           C          H      N                                            
______________________________________                                    
calculated (%)                                                            
             66.52        6.97   5.54                                     
found (%)    66.57        6.81   5.38                                     
______________________________________                                    
 
    
     EXAMPLE 11 
     2-[4-(α-Succinimido-p-fluorobenzyl)piperidinyl]-2&#39;-accetonaphthone hydrochloride ##STR22## 
     470 mg of 4-(α-succinimido-p-fluorobenzyl)piperidine was dissolved in 40 ml of ethanol. 410 mg of 2-bromo-2&#39;-acetonaphthone and 420 mg of sodium hydrogencarbonate were added to the solution and the mixture was refluxed for 30 min. After completion of the reaction, the product was treated by an ordinary process. The obtained product was purified according to silica gel column chromatography and converted into its hydrochloride. 
     Yield: 400 mg 
     Melting point: 233° to 237° C. 
     Elementary analysis for C 28  H 27  N 2  O 3  F.HCl: 
     
         ______________________________________                                    
           C          H      N                                            
______________________________________                                    
calculated (%)                                                            
             67.94        5.70   5.66                                     
found (%)    68.13        5.56   5.47                                     
______________________________________                                    
 
    
     EXAMPLE 12 
     2-[4-(p-Fluorobenzoyl)-1-piperidinyl]-2&#39;-acetonaphthone hydrochloride ##STR23## 
     49.7 g of 2-bromo-2&#39;-acetonaphthone, 49.9 g of 4-(p-fluorobenzoyl)piperidine hydrochloride, 0.5 g of potassium iodide and 50.4 g of sodium hydrogencarbonate were added to 500 ml of ethanol and the mixture was refluxed for 2 h. The solvent was distilled off and chloroform was added to the residue. The mixture was washed with water and dried. Chloroform was distilled off and the residue was purified according to silica gel column chromatography to obtain 58.9 g of the crystalline intended product, which was converted into its hydrochloride and recrystallized by an ordinary process to obtain the intended hydrochloride. 
     Melting point: 247° to 248° C. (dec.) 
     Elementary analysis for C 24  H 22  NO 2  F.HCl: 
     
         ______________________________________                                    
           C          H      N                                            
______________________________________                                    
calculated (%)                                                            
             69.98        5.63   3.40                                     
found (%)    69.81        5.51   3.36                                     
______________________________________                                    
 
    
     EXAMPLES 13 to 95 
     Compounds shown in Table 1 were prepared in the same manner as in Examples 1 to 12. 
     
         TABLE 1
  Elementary analysis (%) calculated/found Example No. Structural formula M
 elting point (°C.) Chemical formula C H N
          13
  ##STR24##
  234˜235(dec.) C.sub.21 H.sub.23 N.sub.2 O.sub.2 F.sub.2.HCl
 61.6861.49 5.925.85 6.856.77
  14
 ##STR25##
  216˜218(dec.) C.sub.20 H.sub.22 NO.sub.2 F.HCl 66.0266.16
 6.376.39 3.853.77
  15
 ##STR26##
  228˜229 (dec.) C.sub.20 H.sub.19 NO.sub.2 F.sub.2.HCl 63.2463.11
 5.315.37 3.693.58
  16
 ##STR27##
  223˜224(dec.) C.sub.20 H.sub.21 NOF.sub.2.HCl 65.6665.39 6.066.12 3
 .833.81
  17
 ##STR28##
  225˜226(dec.) C.sub.21 H.sub.24 NO.sub.2.HCl 70.2869.97 7.027.13
 3.903.88
  18
 ##STR29##
  201˜202 C.sub.21 H.sub.27 NO.HCl 72.9272.76 8.168.23 4.054.11  19
  ##STR30##
  233˜235(dec.) C.sub.20 H.sub.20 NO.sub.2 F.HCl 66.3866.27
 5.855.82 3.873.85
  20
 ##STR31##
  244˜245 C.sub.22 H.sub.24 NO.sub.2 F.HCl 67.7767.80 6.466.47
 3.593.57
  21
 ##STR32##
  211˜211.5 C.sub.20 H.sub.23 NO.HCl 72.8272.19 7.337.13 4.254.12
 22
  ##STR33##
  222˜223(dec.) C.sub.20 H.sub. 18 NO.sub.2
  FCl.sub.2.2HCl 55.7555.71 4.444.50 3.253.26
  23
 ##STR34##
  235˜236 C.sub.26 H.sub.23 NOF.sub.2.HCl 70.9870.59 5.505.63
 3.183.34
  24
 ##STR35##
  143˜146 C.sub.26 H.sub.25 NOF.sub.2.HCl 70.6670.43 5.935.91
 3.173.24
  25
 ##STR36##
  65˜69 C.sub.22 H.sub.24 NO.sub.4 F.HCl 62.6362.48 5.97 5.70
 3.393.11
  26
 ##STR37##
  234˜236(dec.) C.sub.22 H.sub.24 NO.sub.4 F.HCl 62.6362.57
 5.975.96 3.323.15
  27
 ##STR38##
  223˜226(dec.) C.sub.19 H.sub.21 N.sub.2 OF.2HCl 59.2359.18
 6.026.11 7.277.02
  28
 ##STR39##
  155˜160(dec.) C.sub.18 H.sub.21 N.sub.2 OF.2HCl 57.9157.80
 6.216.12 7.507.20
  29
 ##STR40##
  220˜225(dec.) C.sub.18 H.sub.19 N.sub.2 OF.2HCl 58.2358.25
 5.705.71 7.557.43
  30
 ##STR41##
  121˜125(dec.) C.sub.22 H.sub.22 N.sub.2 O.HCl 63.0162.91 5.775.73 6
 .686.59
  31
 ##STR42##
  238˜240 C.sub.27 H.sub.20 NO.sub.2 F.HCl 71.4271.13 6.446.29
 3.093.10
  32
 ##STR43##
  173˜174 C.sub.19 H.sub.22 N.sub.2 O.HCl 68.98 68.75 7.016.89
 8.478.26
  33
 ##STR44##
  243˜244 C.sub.18 H.sub.18 NO.sub.2 F.HCl 58.7758.61 5.215.51
 3.813.91
  34
 ##STR45##
  253˜254(dec.) C.sub.26 H.sub.24 NO.sub.2 F.HCl 71.3171.51
 5.756.03 3.203.25
  35
 ##STR46##
  269˜270(dec.) C.sub.23 H.sub.23 N.sub.3 O.sub.2 F.2HCl 59.3659.23 5
 .415.40 9.039.11
  36
 ##STR47##
  182˜184(dec.) C.sub.25 H.sub.25 N.sub.2 O.sub.2 F.HCl 68.1068.31
 5.945.96 6.356.22
  37
 ##STR48##
  232˜234(dec.) C.sub.25 H.sub.25 NO.sub.3.HCl 70.8370.76 6.186.09
 3.303.21
  38
 ##STR49##
  242˜244(dec.) C.sub.24 H.sub.22 NO.sub.2 Cl.HCl 67.3067.22
 5.415.35 3.273.31
  39
 ##STR50##
  253˜255(dec.) C.sub.24 H.sub.24 NOF.HCl 72.4472.40 6.336.38
 3.523.49
  40
 ##STR51##
  199˜200(dec.) C.sub.24 H.sub.29 N.sub.2 OF.2HCl 63.5763.47
 6.896.78 6.186.26
  41
 ##STR52##
  198˜200(dec.) C.sub.24 H.sub.35 N.sub.2 O.sub.3 F.2HCl 60.5860.43 7
 .247.12 5.445.63
  42
 ##STR53##
  209˜210(dec.) C.sub.25 H.sub.24 NO.sub.3 F.HCl 67.9468.01
 5.705.81 3.173.01
  43
 ##STR54##
  195˜196(dec.) C.sub.25 H.sub.24 NOSF.HCl 67.6267.82 6.136.17
 3.152.89
  44
 ##STR55##
  253˜254(dec.) C.sub.22 H.sub.21 NO.sub.4 F.HCl 63.0863.16
 5.295.36 3.343.32
  45
 ##STR56##
  180˜181 C.sub.23 H.sub.24 NO.sub.2 F.HCl 68.73 68.88 6.276.32     3
 3.49.39
  46
 ##STR57##
  209˜210(dec.) C.sub.25 H.sub.24 NO.sub.2 F.HCl 70.4970.40
 5.925.85 3.293.35
  47
 ##STR58##
  266˜267(dec.) C.sub.25 H.sub.34 N.sub.2 O.sub.2.2HCl 64.2364.36
 7.767.72 5.996.11
  48
 ##STR59##
  214˜217(dec.) C.sub.22 H.sub.21 N.sub.2 OF.2HCl 62.7162.77
 5.505.43 6.656.72
  49
 ##STR60##
  260˜263(dec.) C.sub.23 H.sub.23 N.sub.2 OF.2HCl 63.4563.16
 5.795.81 6.436.36
  50
 ##STR61##
  236˜237(dec.) C.sub.25 H.sub.24 NO.sub.2 F.HCl 70.5070.31
 5.925.86 3.293.31
  51
 ##STR62##
  242(dec.) C.sub.25 H.sub.24 NO.sub.2 F.HCl 70.5070.37 5.925.96 3.293.31
  52
 ##STR63##
  237˜238(dec.) C.sub.23 H.sub.22 NOF.HCl 71.9671.88 6.046.12
 3.653.57
  53
 ##STR64##
  231˜232(dec.) C.sub.24 H.sub.24 NO.sub.2 Cl.HCl 69.5769.48
 6.086.16 3.383.42
  54
 ##STR65##
  153˜156 C.sub.24 H.sub.22 NO.sub.2 F.HCl 69.9870.12 5.635.58
 3.403.26
  55
 ##STR66##
  222˜225(dec.) C.sub.25 H.sub.27 NO.HCl 76.2275.93 7.167.33
 3.563.47
  56
 ##STR67##
  250˜253(dec.) C.sub.25 H.sub.25 NO.sub.2.HCl 73.6173.48 6.426.33
 3.433.19
  57
 ##STR68##
  256˜260(dec.) C.sub.24 H.sub.21 NO.sub.2 ClF.HCl 67.4567.18
 5.195.06 3.283.14
  58
 ##STR69##
  246˜248(dec.) C.sub.24 H.sub.24 NO.sub.2 F.HCl 69.6469.61
 6.086.02 3.383.14
  59
 ##STR70##
  250˜254(dec.) C.sub.24 H.sub.24 NO.sub.2 F.HCl 70.9870.96
 6.196.14 3.183.20
  60
 ##STR71##
  223˜226(dec.) C.sub.24 H.sub.22 NO.sub.2 F.HCl 69.9869.86
 5.635.58 3.403.22
  61
 ##STR72##
  272˜274(dec.) C.sub.22 H.sub.27 NOF.HCl 62.8762.69 6.656.54
 6.386.28
  62
 ##STR73##
   214˜217(dec.) C.sub.23 H.sub.25 N.sub.2 O.sub.2 F.HCl 66.2666.13 6
 .296.25 6.726.47
  63
 ##STR74##
  263˜266(dec.) C.sub.23 H.sub.26 NO.sub.2 F.HCl 68.3968.18
 6.746.55 3.473.41
  64
 ##STR75##
  234˜238(dec.) C.sub.21 H.sub.22 N.sub.3 F.3HCl 56.7156.45
 5.665.58 9.459.17
  65
 ##STR76##
  230˜233(dec.) C.sub.21 H.sub.20 N.sub.3 OF.2HCl 59.7359.54
 5.255.13 9.949.78
  66
 ##STR77##
  142˜147 C.sub.24 H.sub.28 NO.sub.2 F.HCl 70.6670.53 6.616.50
 3.173.06
  67
 ##STR78##
   98˜104 C.sub.30 H.sub.29 N.sub.2 O.sub.2 F.2HCl 66.5466.42
 5.775.68 5.175.07
  68
 ##STR79##
  135˜140 C.sub.22 H.sub.22 NO.sub.4 F.HCl 62.9362.69  5.525.41     3
 3.34.17
  69
 ##STR80##
  162˜164 C.sub.25 H.sub.24 NO.sub.2 F 76.3776.03 6.416.40 3.713.56
  70
 ##STR81##
  236˜237(dec.) C.sub.31 H.sub.30 NO.sub.2 F.HCl 73.8673.92
 6.206.21 2.782.78
  71
 ##STR82##
  242˜245 C.sub.24 H.sub.23 NO.sub.2.HCl 73.1873.33 6.146.18
 3.563.66
  72
 ##STR83##
  182˜183 C.sub.25 H.sub.27 NO.sub.2.HCl 73.2573.26 6.886.76
 3.423.24
  73
 ##STR84##
  222˜223 C.sub.24 H.sub.27 N.HCl 78.7778.73 7.117.64 3.833.62  74
  ##STR85##
  246˜246.5 C.sub.24 H.sub.22 NOF.HCl 72.8172.66 5.815.70 3.543.45
 75
  ##STR86##
  243˜244 C.sub.24 H.sub.24 NOF.HCl 72.4472.39 6.336.47 3.523.50
 76
  ##STR87##
  224˜225 C.sub.22 H.sub.20 NO.sub.3 F.HCl 65.7565.79 5.275.26
 3.493.36
  77
 ##STR88##
  206˜207 C.sub.23 H.sub.21 N.sub.2 O.sub.2 F.HCl 66.9066.82
 5.375.36 6.786.80
  78
 ##STR89##
  173˜174 C.sub.24 H.sub.27 NO.sub.2 F.HCl 69.1469.02 6.776.51
 3.363.27
  79
 ##STR90##
   187˜188 C.sub.24 H.sub.23 NOFCl.HCl 66.6766.43 5.595.33 3.243.12
  80
 ##STR91##
  172˜173 C.sub.23 H.sub.25 N.HCl 78.5078.64 7.457.37 3.983.84  81
  ##STR92##
  226˜227 C.sub.24 H.sub.27 N.HCl 78.7678.75 7.457.40 3.833.78  82
  ##STR93##
  274˜275 C.sub.23 H.sub.24 N.sub.2.2HCl 68.4868.52 7.007.02
 6.946.87
  83
 ##STR94##
  249 C.sub.24 H.sub.24 NF.HCl 75.4875.44 6.606.45 3.673.82
  84
 ##STR95##
  203 C.sub.24 H.sub.24 NOF.HCl 72.4472.11 6.336.19 3.523.59
  85
 ##STR96##
  216˜217 C.sub.24 H.sub.27 NO.HCl 75.4775.48 7.397.40 3.673.64  86
  ##STR97##
  239˜241 C.sub.24 H.sub.23 NO.HCl 76.2876.08 6.406.30 3.713.69  87
  ##STR98##
  221˜223 C.sub.22 H.sub.23 NO.sub.2.HCl 71.4471.16 6.546.58
 3.794.03
  88
 ##STR99##
  227˜229 C.sub.28 H.sub.38 NO.sub.2 F.HCl 70.6470.58 8.268.14
 2.942.73
  89
 ##STR100##
  205˜210(dec.) C.sub.24 H.sub.24 NOF.HCl 72.4472.41 6.336.19
 3.523.41
  90
 ##STR101##
  195˜197(dec.) C.sub.25 H.sub.26 NOF.HCl 72.8972.83 6.606.54
 3.403.37
  91
 ##STR102##
   oily C.sub.19 H.sub.19 N.sub.2 O.sub.2 F.2HCl 57.1556.78 5.305.14
 7.026.87
  92
 ##STR103##
  233.5˜235 C.sub.24 H.sub.25 NO.HCl.1/4H.sub.2 O 74.9874.90
 6.956.92 3.643.69
  93
 ##STR104##
  oily C.sub.24 H.sub.23
  NOFCl.HCl 66.6766.39 5.595.62 3.243.24
 
    
     The examples of pharmacological experiments of the compounds of the present invention will be given below: 
     EXPERIMENTAL EXAMPLE 1 
     Effect of Protecting Ischemic Brain 
     Carotid arteries of both sides of ICR mice 6 to 8 weeks old) were exposed under halothane anesthesia and ligated. The mice thus treated had stroke symptoms such as jumping, rolling and convulsion and almost all of them died within 24 h. 
     The compound of the present invention was administered orally to the mice one hour before the ligation and the survival time (maximum: 6 h) was examined as an index of the effect of protecting the ischemic brain. In this experiment, the compound was used in the form of a 5% suspension in acacia and a 5% acacia solution was given to the control group. 
     The results are shown in Table 2. It is apparent that the compounds of the present invention had a life-prolonging effect, while the average survival time of the control group was 149.9 min. 
     
                       TABLE 2                                                     
______________________________________                                    
Effect of protecting ischemic brain                                       
                             Average survival                             
          Dose               time                                         
          (mg/kg,   Number   (min)                                        
Compound used                                                             
          p.o.)     of cases (average ± S.E.)                          
                                        %                                 
______________________________________                                    
Control group                                                             
          --        26       149.9 ± 25.8                              
                                        100                               
Compound of                                                               
           3        10       213.7 ± 52.3                              
                                        143                               
Example 12                                                                
          10        10       181.4 ± 43.6                              
                                        121                               
          30         9       191.1 ± 54.3                              
                                        128                               
Compound of                                                               
          10         7       150.4 ± 57.6                              
                                        100                               
Example 73                                                                
          30         6       275.2 ± 58.2                              
                                        184                               
Compound of                                                               
           3        10       143.3 ± 39.6                              
                                         96                               
Example 74                                                                
          10         7       205.1 ± 43.6                              
                                        137                               
          30         7       194.2 ± 49.7                              
                                        130                               
______________________________________                                    
 
    
     EXPERIMENTAL EXAMPLE 2 
     Effect of Remedying Learning Disorder After Ischemia 
     Common carotid arteries on both sides of Mongolian gerbils (17 to 21 weeks old) were clipped with Skoville clamps without anesthesia and the clamps were removed after 5 min to realize a short period of ischemia. Twenty-four hours after the removal of the clamps, these animals were subjected to learning and memory tests were conducted after an additional 24 h. 
     The learning and memory functions were examined by the passive avoidance method with a modification of a device reported by Jarvik and Kopp in &#34;Psychological Reports&#34;, 21, 221 to 224 (1967). The device had two chambers, i.e. a well-lighted chamber A and a dark chamber B. In the tests, the animals were placed in the well-lighted chamber A and an electric current (A.C., 1.6 mA) was applied to a grid on the floor of the dark chamber B for 5 min when they entered the chamber B. 
     On the next day, the animals subjected to the learning were placed in the chamber A and the time (latent time) which had elapsed before they entered the chamber B was measured. The upper limit of the latent time was set at 300 sec. 
     The compound was administered in the form of a 5% suspension in acacia orally one hour before causing the ischemia. A 5% acacia solution was administered to the control group. 
     The results are shown in Table 3. The average latent time of the normal (pseudo-operation) group was 246.5 sec and that of the control group was as short as 71.5 sec. Namely, the learning and memory functions of them were damaged by the 5-min ischemia. When the compounds of the present invention were administered to the control group, the latent time was elongated again, namely the learning disorder after the ischemia was remedied. 
     
                       TABLE 3                                                     
______________________________________                                    
Effects of remedying learning                                             
disorder after ischemia                                                   
                            Latent time                                   
          Dose              (sec)    Recovery*                            
          (mg/kg,  Number   (average ±                                 
                                     ratio                                
Compound used                                                             
          p.o.)    of cases S.E.)    (%)                                  
______________________________________                                    
Normal group                                                              
          --       65       246.5 ± 10.9                               
                                     100                                  
Control group                                                             
          --       62        71.5 ± 11.7                               
                                      0                                   
Compound of                                                               
           3       22       168.8 ± 23.0                               
                                     56                                   
Example 12                                                                
          10       24       196.8 ± 22.3                               
                                     72                                   
          30       11       196.3 ± 37.0                               
                                     71                                   
Compound of                                                               
          10        8       193.1 ± 35.3                               
                                     69                                   
Example 73                                                                
          30        7        80.1 ± 28.2                               
                                      5                                   
Compound of                                                               
           3       13       110.2 ± 29.0                               
                                     22                                   
Example 74                                                                
          10       24       123.2 ± 24.3                               
                                     30                                   
          30       21       129.2 ± 23.8                               
                                     33                                   
______________________________________                                    
 *The recovery ratio was calculated according to the following formula for
 each latent time:                                                        
 ##STR105##                                                               
 
    
     EXPERIMENTAL EXAMPLE 3 
     Effect of Protecting Cells From Disorder After Ischemia 
     Carotid arteries on both sides of Mongolian gerbils were blocked to realize cerebral ischemia for 5 min. As a result, the nerve cells in the CAI region of the hippocampus disappeared extensively [Karino, T.: Brain Res., 239, 57 to 69 (1982)]. 
     The compound of the present invention was administered orally to them, while a 5% acacia suspension was administered to the control group. After one hour, the ischemia was realized for 5 min. After one week, the animal was perfused and fixed with 4% neutral formalin transcardially. The treated sample was embedded in paraffin and cut to obtain slices having a thickness of 3 μm. The slices were dyed with hematoxylin-eosin and the number of the nerve cells in the CAI region of the hippocampus of each slice was counted. 
     The results are shown in Table 4. The nerve cell density in the CAI region of the hippocampus was 287/mm in the normal (pseudo-operation) group and that of the control group was as small as 21/mm. Namely, a serious disapperance of the cell was caused by the 5-min ischemia. On the other hand, when the compound of the present invention was administered, the nerve cell density was increased to prove the effect thereof in protecting the cells from the disorder. 
     
                       TABLE 4                                                     
______________________________________                                    
Effect of protecting the cells                                            
from disorder after ischemia                                              
                                Nerve cell                                
          Dose         Number   density                                   
Compound used                                                             
          (mg/kg, p.o.)                                                   
                       of cases (number/mm)                               
______________________________________                                    
Normal group                                                              
          --            6       287 ± 6                                
Control group                                                             
          --           16       21 ± 10                                
Compound of                                                               
           3            8       62 ± 26                                
Example 12                                                                
          10           10       75 ± 32                                
          30           10       83 ± 32                                
Compound of                                                               
          10            7       69 ± 21                                
Example 73                                                                
          30            5       49 ± 8                                 
Compound of                                                               
          30            8       62 ± 5                                 
Example 74                                                                
______________________________________