Abstract:
A condensed heterocyclic compound having the formula (I): ##STR1## wherein A and B are both carbonyl groups of one thereof represents a methylene group and the other represents a carbonyl group; Z represents an oxygen atom, a sulfur atom, a substituted or unsubstituted nitrogen atom, or a methylene group; n is an integer of 2 to 6; and R represents a group having the following formula: ##STR2## wherein R 1  represents a hydrogen atom or a hydroxyl group; R 2  represents a substituted or unsubstituted phenyl or 2-pyridyl group or salts thereof. 
     The compounds according to the present invention exhibit a strong affinity to the σ-receptor and are useful as psychopharmaceuticals.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to a condensed heterocyclic compound and a psychopharmaceutical composition containing the same. 
     The condensed heterocyclic compounds and salts thereof according to the present invention show activities specific to the σ-receptor, and therefore, are effective as remedies for treating psychoneurosis. 
     2. Description of the Related Art 
     The principal conventionally developed remedies for treating psychosis are D 2  -receptor antagonists such as butyrophenone derivatives represented by Haloperidol, phenothiazine, and thioxanthine, owing to the presence of dopamine in the brain. 
     Nevertheless, many cases have been known which cannot be improved by the use of these D 2  -receptor antagonists, and it is known that the use thereof is accompanied by side-effects such as extrapyramidal tract disorders. Accordingly, there is a need for the development of a specific remedy for treating psychosis, which is not accompanied by side-effects. 
     In this connection, it recently has been proved that the σ-receptor, which is a subtype of the opioid receptor, is closely involved in the development of various symptoms of psychosis, and remedies have been developed for treating psychosis based on the σ-receptor antagonism, as represented by Rimcazole and BMY 14802 having the following structures, respectively. ##STR3## 
     Nevertheless, the antipsychotic effect of these Rimicazole and BMY 14802 is inferior to those of existing remedies such as Haloperidol, and as a cause thereof, it is considered that the σ-receptor antagonism thereof is inferior to those of existing remedies such as Haloperidol. 
     SUMMARY OF THE INVENTION 
     Accordingly, the objects of the present invention are to eliminate the above-mentioned disadvantages of the prior art and to provide a novel compound having a strong affinity to the σ-receptor and a low affinity to the D 2  -receptor and a psychopharmaceutical composition containing the same. 
     Other objects and advantages of the present invention will be apparent from the following description. 
     In accordance with the present invention, there is provided a condensed heterocyclic compound having the formula (I): ##STR4## wherein A and B are both carbonyl groups or one thereof represents a methylene group and the other represents a carbonyl group; Z represents an oxygen atom, a sulfur atom, an unsubstituted or substituted imino group, or a methylene group; n is an integer ranging from 2 to 6; and R represents a group having the following formula: ##STR5## wherein R 1  represents a hydrogen atom or a hydroxyl group; R 2  represents a substituted or unsubstituted phenyl or 2-pyridyl group or salts thereof as well as a psychotropic drug containing the same as an effective component. 
     In accordance with the present invention, there is also provided a psychopharmaceutical composition comprising the above-mentioned a condensed heterocyclic compound having the formula (I) or a pharmacologically acceptable salt thereof, as an effective component, and a carrier therefor. 
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The present inventors conducted intensive studies into the developing of a pharmaceutically active compound having a stronger affinity for the σ-receptor and a lower affinity for the D 2  -receptor, and thus a higher selectivity to the σ-receptor, and as a result, found that the compounds having the above-mentioned formula (I) and salts thereof show a strong affinity for the σ-receptor and a low affinity for the D 2  -receptor, and thus completed the present invention. 
     The typical examples of the substituent in the substituted imino group in the formula (I) of the compounds according to the present inventions are C 1-5  alkyl group (for example, methyl, ethyl, propyl, butyl and pentyl group), aryl group (for example, phenyl, benzyl and phenethyl group) and heterocyclic group (for example, pyridyl group). 
     The preferable compound (I) according to the present invention are 4-(4-(4-phenyl)-1-piperidnyl) butyl-2,3,4,5-tetrahydro-1,4-benzodiazepine-3,5-dione (A,B=carbonyl group, Z=imino group, n=4, R=piperidinyl group, R 1  =hydrogen atom, R 2  =phenyl group), 4-(5-(4-phenyl)-1-piperidinyl)pentyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one (A=carbonyl group, B=methylene group, Z=oxygen atom, n=5, R=piperidinyl group, R 1  =hydrogen atom, R 2  =phenyl group) and 2-(5-(4-(chlorophenyl)-1-piperidinyl)pentyl-1,3,4,5-tetrahydro-2-benzazepine-1,3-dione (A,B=carbonyl group, Z=methylen group, n=5, R=piperidinyl group, R 1  =hydrogen atom, R 2  =4-chlorophenyl group). 
     The compounds having the above-mentioned formula (I) according to the present invention can be prepared, for example, by the following methods: 
     1) Preparation of Intermediate Compounds (II): ##STR6## wherein A, B, Z and n are the same as defined above and X and Y may be the same or different and each represents a halogen atom. 
     2) Preparation of Final Compounds: 
     
         (II)+RH (V) →(I) 
    
     (wherein R is the same as defined above). 
     More specifically, a compound represented by the following general formula (Ia): ##STR7## i.e., a compound of the formula (I), wherein A is a carbonyl group, B is a methylene group and Z is an oxygen atom, can be prepared by forming a compound having the following formula (III): ##STR8## according to the method disclosed in the article of G. S. Sidhu, G. Thyagarajan and U. T. Bhalerao (J. Chem. Soc. (C), 1966, p. 969), reacting same with a dibromoalkane to form a compound having the formula (IV): ##STR9## and then condensing the resulting compound with an amine derivative of the formula (V) in the usual manner. 
     A compound having the following general formula (Ib): ##STR10## i.e., a compound of the formula (I) wherein A is a methylene group, B is a carbonyl group and Z is an oxygen atom, can be prepared by forming a compound having the following formula (VI): ##STR11## according to the method disclosed in the article of Kost. A. N., Stankevicius, A. (Khim. Geterotsiki. Soedin., 1971, 7 (9), p. 1288), reacting it with a dibromoalkane to give a compound having the following general formula (VII) ##STR12## and then condensing the resulting compound with an amine derivative (V) in a usual manner. A compound having the following general formula (Ic): ##STR13## i.e., a compound of the formula (I) wherein A and B each represents a carbonyl group and Z is an oxygen atom, can be prepared by forming a compound having the following formula (VIII): ##STR14## according to the method disclosed in the article of A. Cattaneo, P. Galimberti, M. Melandri (Boll. Chim. Farm., 1963, 102, p. 541), reacting it with a dibromoalkane to give a compound having the following general formula (IX) ##STR15## and then condensing the resulting compound with an amine derivative (V) in a usual manner. 
     The compound having the general formula (I) and pharmacologically acceptable salts thereof (such as hydrochlorides, sulfates, nitrates, hydrobromides, phosphates, methanesulfonates, p-toluenesulfonates, acetates, oxalates, malonates, succinates, tartrates, maleates, fumarates, lactates, citrates and malates) according to the present invention can be administered alone, or if necessary and desirable, in combination with other commonly pharmacologically acceptable additives such as carriers, excipients and diluents in desired shapes such as tablets, capsules, powder, liquids, injectable liquids, and suppositories through oral or parenteral routes. Examples of such carriers or diluents are polyvinylpyrrolidone, gum arabic, gelatin, sorbit, cyclodextrin, tragacanth, magnesium stearate, talc, polyethylene glycol, polyvinyl alcohol, silica, lactose, crystalline cellulose, sugar, starches, potassium phosphate, vegetable oils, calcium carboxymethyl cellulose, sodium laurylsulfate, water, ethanol, glycerin, mannitol, and syrup. 
     The concentration of the compound of the formula (I) in the pharmaceutical composition is not restricted, but is generally from 1 to 100% by weight, preferably 10 to 90% by weight. Moreover, the dose thereof is not critical, but is generally from 0.01 to 1,000 mg/day/man, preferably 0.1 to 500 mg/day/man. The frequency of the administration is usually 1 to 3 times per day. 
    
    
     EXAMPLES 
     The present invention will now be further illustrated by, but is by no means limited to, the following Reference Examples, Examples and Test Examples. 
     REFERENCE EXAMPLE 1 Preparation of 4-(5-bromopentyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one ##STR16## 
     In 20 ml of dimethylformamide (DMF) was dissolved 100 mg of 2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one, and the solution then ice-cooled. Then, to the resulting solution were added 0.251 ml (3 equivalents) of 1,5-dibromopentane and 29.4 mg (1.2 equivalent) of a 60% sodium hydride oil dispersion, and the mixture was stirred for one hour with ice-cooling. The reaction solution was poured into a citric acid aqueous solution and extracted with ethyl acetate, and the ethyl acetate phase was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was then concentrated and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (8:2)) to give 124 mg (yield: 65.0%) of the title compound. 
     REFERENCE EXAMPLE 2 Preparation of 4-(5-bromopentyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-one ##STR17## 
     In 20 ml of DMF was dissolved 100 mg of 2,3,4,5-tetrahydro-1,4-benzoxazepin-3-one and the solution then ice-cooled. Then, to the resulting solution were added 0.125 ml (1.5 equivalent) of 1,5-dibromopentane and 29.4 mg (1.2 equivalent) of a 60% sodium hydride oil dispersion and the mixture was stirred for 1.5 hour with ice-cooling. Thereafter, the reaction solution was reacted and/or treated and purified in the same manner as in Reference Example 1 to give 133 mg (yield: 69.5%) of the title compound. 
     REFERENCE EXAMPLE 3 Preparation of 4-(5-bromopentyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine-3,5-dione ##STR18## 
     In 20 ml of DMF was dissolved 102 mg of 2,3,4,5-tetrahydro-1,4-benzothiazepine-3,5-dione and the solution then ice-cooled. Then, to the resulting solution were added 0.116 ml (1.5 equivalent) of 1,5-dibromopentane and 27.4 mg (1.2 equivalent) of a 60% sodium hydride oil dispersion and the mixture was stirred for 2 hours with ice-cooling. Thereafter, the reaction solution was reacted and/or treated and purified in the same manner as in Reference Example 1 to give 79.2 mg (yield: 42.4%) of the title compound. 
     REFERENCE EXAMPLE 4 Preparation of 4-(5-bromopentyl)-2,3,4,5-tetrahydro-1,4-benzodiazepine-3,5-dione ##STR19## 
     In 10 ml of dimethylformamide (DMF) was dissolved 100 mg of 2,3,4,5-tetrahydro-1,4-benzodiazepine-3,5-dione and the solution then ice-cooled. Then, to the resulting solution were added 0.116 ml (1.5 equivalent) of 1,5-dibromopentane and 27.3 mg (1.2 equivalent) of a 60% sodium hydride oil dispersion and the mixture was stirred for 2 hours with ice-cooling. The reaction solution was poured into ice-cooled water containing citric acid, made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The ethyl acetate phase was then washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The product was purified in the same manner as in Reference Example 1 to give 97.5 mg (yield: 52.8%) of the title compound. 
     REFERENCE EXAMPLE 5 Preparation of 2-(5-bromopentyl)-1,3,4,5-tetrahydro-2-benzazepine-1,3-dione ##STR20## 
     In 20 ml of DMF was dissolved 100 mg of 1,3,4,5-tetrahydro-2-benzazepine-1,3-dione and the solution then ice-cooled. Then, to the resulting solution were added 0.117 ml (1.5 equivalent) of 1,5-dibromopentane and 27.4 mg (1.2 equivalent) of a 60% sodium hydride oil dispersion and the mixture was stirred for 1.5 hour with ice-cooling. Thereafter, the reaction solution was reacted and/or treated and purified in the same manner as in Reference Example 1 to give 109 mg (yield: 58.9%) of the title compound. 
     Physical data of the compounds prepared in Reference Examples 1 to 5 are summarized in Table 1. 
     
                                           TABLE I__________________________________________________________________________Ref. Ex. No.  m.p. IR (cm.sup.-1)             NMR (δ ppm)    Mass__________________________________________________________________________1      Oily 2930          2870             1.48-1.96(m, 6H)     HiMs  product       1640          1600             3.43(t, 2H, J=6.6Hz), 3.50(t, 2H, J=5.3Hz)                                  Calcd. 311.0520       1470          1420             3.60-3.65(m. 2H)     Obsd. 311.0504       1360          1320             4.37(t, 2H, J=5.3Hz)       1285          1210             7.00(d. 1H, J=7.9Hz)       1110          1045             7.16(t, 1H, J=7.9Hz)        875           805             7.41(dt, 1H, J=2.0Hz &amp; 7.9Hz)        790           760             7.80(dd, 1H, J=2.0Hz &amp; 7.9Hz)        7052      Oily 2930          2870             1.38-1.92(m, 6H)     HiMs  product       1670          1640             3.37(t, 2H, J=6.6Hz) Calcd. 311.0520       1580          1495             3.55(t, 2H, J=7.3Hz) Obsd. 311.0536       1460          1435             4.47(s, 2H)       1350          1310             4.69(s, 2H)       1230          1220             7.03-7.33(m, 4H)       1195          1115       1055          1025        845           760        7003      Oily 2920          2850             1.43-1.95(m, 6H)     HiMs  product       1690          1640             3.40(t, 2H, J=6.6Hz) Calcd. 341.0084       1580          1455             3.68(s, 2H)          Obsd. 341.0074       1430          1330             4.00(t, 2H, J=7.3Hz)       1290          1260             7.37-7.49(m, 3H)       1220          1105             8.16-8.20(m, 1H)       1080           950        910           780        740           6854      65-66° C.       3350          2940             1.39-1.92(m, 6H)     HiMs       2860          1700             3.78(t, 2H, J=6.6Hz) Calcd. 324.0472       1620          1495             3.87-3.92(m, 2H)     Obsd. 324.0424       1430          1395             3.90(d, 2H, J=4.6Hz)4.87(t, 1H, J=4.6Hz)       1360          1320             6.79(d. 1H, J=7.9Hz)       1240          1155             6.95(dd, 1H, J=7.3Hz &amp; 7.9Hz)       1125          1105             7.35(ddd, 1H, J=1.3Hz &amp; 7.3Hz &amp; 7.9Hz)       1020           980             8.25(dd, 1H, J=1.3Hz &amp; 7.9Hz)        860           785        755           7005      Oily 2950          2860             1.48-1.97(m, 6H)     HiMs  product       1700          1645             2.99(s, 4H)          Calcd. 323.0520       1600          1455             3.40-3.45(m, 2H)     Obsd. 323.0472       1340          1315             4.00(t, 2H, J=7.3Hz)       1265          1240             7.16(d, 1H, J=7.3Hz)       1210          1115             7.33-7.48(m, 2H)       1040           890             7.96(dd, 1H, J=1.3Hz &amp; 7.9Hz)        795            755        710__________________________________________________________________________ 
    
     REFERENCE EXAMPLE 6 Preparation of 4-(4-bromobutyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one ##STR21## 
     The same procedures as used in Reference Example 1 were repeated except that 1,4-dibromobutane was substituted for 1,5-dibromopentane to give the title compound. 
     REFERENCE EXAMPLE 7 Preparation of 4-(4-bromobutyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-one ##STR22## 
     The same procedures as used in Reference Example 2 were repeated except that 1,4-dibromobutane was substituted for 1,5-dibromopentane to give the title compound. 
     REFERENCE EXAMPLE 8 Preparation of 4-(4-bromobutyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-3,5-dione ##STR23## 
     The same procedures as used in Reference Example 1 were repeated except that 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione was substituted for 2,3,4,5-tetrahydro-1,4-benzoxazepin-3-one to give the title compound. 
     REFERENCE EXAMPLE 9 Preparation of 4-(4-bromobutyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine-3,5-dione ##STR24## 
     The same procedures as used in Reference Example 3 were repeated except that 1,4-dibromobutane was substituted for 1,5-dibromopentane to give the title compound. 
     REFERENCE EXAMPLE 10 Preparation of 4-(4-bromobutyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine-3,5-dione ##STR25## 
     The same procedures as used in Reference Example 4 were repeated except that 1,4-dibromobutane was substituted for 1,5-dibromopentane to give the title compound. 
     REFERENCE EXAMPLE 11 Preparation of 1-methyl-4-(4-bromobutyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine-3,5-dione ##STR26## 
     The same procedures as used in Reference Example 10 were repeated except that 1-methyl-2,3,4,5-tetrahydro-1,4-benzodiazepine-3,5-dione was substituted for 2,3,4,5-tetrahydro-1,4-benzothiazepine-3,5-dione to give the title compound. 
     REFERENCE EXAMPLE 12 Preparation of 2-(4-bromobutyl)-1,3,4,5-tetrahydro-2-benzazepine-1,3-dione ##STR27## 
     The same procedures as used in Reference Example 5 were repeated except that 1,4-dibromobutane was substituted for 1,5-dibromopentane to give the title compound. 
     REFERENCE EXAMPLE 13 Preparation of 4-(5-bromopentyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione ##STR28## 
     The same procedures as used in Reference Example 8 were repeated except that 1,5-dibromopentane was substituted for 1,4-dibromobutane to give the title compound. 
     EXAMPLE 1 Synthesis of 4-(4-(4-phenyl)-1-piperidinyl)butyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one ##STR29## 
     In 10 ml of dioxane was dissolved 49.8 mg of the compound obtained in Reference Example 6, 80.8 mg (3 equivalents) of 4-phenylpiperidine was added to the resulting solution, and the mixture was stirred at 110° C. for 3 hours with heating. The dioxane was distilled off, an aqueous solution of sodium hydrogen carbonate was added thereto, and the resulting solution was extracted with methylene chloride. The methylene chloride phase was washed with water, dried over anhydrous magnesium sulfate, and then filtered. The resulting filtrate was concentrated and the residue obtained was subjected to silica gel column chromatography (developing solution : ethyl acetate) to give 56.3 mg (yield: 89.1%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 2 Synthesis of 4-(4-(4-(4-chlorophenyl)-1-piperidinyl)butyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one ##STR30## 
     In 110 ml of dioxane was dissolved 61.3 mg of the compound prepared in Reference Example 6, then 121 mg (3 equivalents) of 4-(4-chlorophenyl)piperidine was added thereto, and the resulting mixture was stirred at 110° C. for 3 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 76.9 mg (yield: 90.6%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 3 Synthesis of 4-(4-(4-hydroxy-4-phenyl)-1-piperidinyl)butyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one ##STR31## 
     In 10 ml of dioxane was dissolved 119 mg of the compound prepared in Reference Example 6, then 212 mg (3 equivalents) of 4-hydroxy-4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 100° C. for 2 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 153 mg (yield: 97.2%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 4 Synthesis of 4-(4-(4-phenyl)-1-piperidinyl)butyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one ##STR32## 
     In 10 m l of dioxane was dissolved 20 mg of the compound prepared in Reference Example 7, then 32.5 mg (3 equivalents) of 4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 100° C. for 5 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 17.9 mg (yield: 70.5%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 5 Synthesis of 4-(4-(4-chlorophenyl)-1-piperidinyl)butyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-one ##STR33## 
     In 7 ml of dioxane 30.5 mg of the compound prepared in Reference Example 7, then 60 mg (3 equivalents) of 4-(4-chlorophenyl)piperidine was added thereto, and the resulting mixture was stirred at 110° C. for 4 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 21.7 mg (yield: 51.4%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 6 Synthesis of 4-(4-(4-hydroxy-4-phenyl)-1-piperidinyl)butyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-one ##STR34## 
     In 10 ml of dioxane was dissolved 45.0 mg of the compound prepared in Reference Example 7, then 80.3 mg (3 equivalents) of 4-hydroxy-4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 110° C. for 4 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 58.3 mg (yield: 98.0%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 7 Synthesis of 4-(4-(4-(4-chlorophenyl)-4-hydroxy)-1-piperidinyl)-butyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-one ##STR35## 
     In 8 ml of dioxane was dissolved 47.0 mg of the compound prepared in Reference Example 7, then 100 mg (3 equivalents) of 4-(4-chlorophenyl)-4-hydroxypiperidine was added thereto, and the resulting mixture was stirred at 120° C. for 3 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 61.2 mg (yield: 90.5%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 8 Synthesis of 4-(4-(4-phenyl)-1-piperidinyl)butyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione ##STR36## 
     In 40 ml of dioxane was dissolved 1.30 g of the compound prepared in the Reference Example 8, 966 mg (1.5 equivalent) of 4-phenylpiperidine and 1.10 g (2 equivalents) of anhydrous potassium carbonate were added to the resulting solution, and the mixture was refluxed for 16 hours. The dioxane was distilled off under a reduced pressure, water and ethyl acetate were added to the resulting residue to perform a liquid-liquid separation, the ethyl acetate phase was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under a reduced pressure. The residue was developed with ethyl acetate-hexane (9:1) using silica gel column chromatography to give 1.52 g (yield: 96.8%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 9 Synthesis of 4-(4-(4-(4-chlorophenyl)-1-piperidinyl)butyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione ##STR37## 
     In 8 ml of dioxane was dissolved 20 mg of the compound prepared in Reference Example 8, then 37.6 mg (3 equivalents) of 4-(4-chlorophenyl)piperidine was added thereto, and the resulting mixture was stirred at 110° C. for 6 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 19.1 mg (yield: 69.7%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 10 Synthesis of 4-(4-(4-hydroxy-4-phenyl)-1-piperidinyl)butyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione ##STR38## 
     In 10 ml of dioxane was dissolved 114 mg of the compound prepared in Reference Example 8, then 194 mg (3 equivalents) of 4-hydroxy-4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 120° C. for 3 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 148 mg (yield: 99.0%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 11 Synthesis of 4-(4-(4-(4-chlorophenyl)-4-hydroxy-l-piperidinyl)butyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione ##STR39## 
     In 10 ml of dioxane was dissolved 48.7 mg of the compound prepared in Reference Example 8, then 99.0 mg (3 equivalents) of 4-(4-chlorophenyl)-4-hydroxypiperidine was added thereto, and the resulting mixture was stirred at 120° C. for 6 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 58.0 mg (yield: 83.9%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 12 Synthesis of 4-(4-(4-phenyl-1,2,3,6-tetrahydro)-1-pyridyl)butyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione ##STR40## 
     In 10 ml of dioxane was dissolved 218 mg of the compound prepared in Reference Example 8, then 318 mg (2.9 equivalents) of 4-phenyl-1,2,3,6-tetrahydropyridine was added thereto, and the resulting mixture was refluxed for 20 hours. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 50 mg (yield: 18.2%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 13 Synthesis of 4-(4-(4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl)butyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione ##STR41## 
     In 10 ml of dioxane was dissolved 50 mg of the compound prepared in Reference Example 8, then 93.0 mg (3 equivalents) of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine was added thereto, and the resulting mixture was stirred at 110° C. for 7 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 23.0 mg (yield: 33.7%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 14 Synthesis of 4-(4-(4-(2-pyridyl)-1-piperidinyl)butyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione ##STR42## 
     In 20 ml of dioxane was dissolved 326 mg of the compound obtained in Reference Example 8, 552 mg (2 equivalents) of 4-(2-pyridyl)piperidine.trifluoroacetate and 2.76 g (20 equivalents) of anhydrous potassium carbonate were added thereto, and the resulting mixture was refluxed for 8 hours. The dioxane was distilled off under a reduced pressure, a 0.5 N aqueous solution of sodium hydroxide was added to the resulting residue, the product was extracted with ethyl acetate, the ethyl acetate phase was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under a reduced pressure. The residue obtained was subjected to silica gel column chromatography (developing solution: methylene chloride-methanol (9:1) to give 270 mg (yield: 68.5%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from ethanol-ether. 
     EXAMPLE 15 Synthesis of 4-(4-(4-hydroxy-4-(2-pyridyl)-1-piperidinyl)butyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione ##STR43## 
     In 20 ml of dioxane was dissolved 326 mg of the compound obtained in Reference Example 8, 873 mg (3 equivalents) of 4-hydroxy-4-(2-pyridyl)piperidine.trifluoroacetate and 2.76 g (20 equivalents) of anhydrous potassium carbonate were added thereto, and the resulting mixture was refluxed for 3 days. The same procedures for reaction and treatment as used in Example 8 were repeated and the resulting residue was subjected to silica gel column chromatography (developing solution: methylene chloride-methanol (10:1)) to give 270 mg (yield: 66.0%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from ethanol-ether. 
     EXAMPLE 16 Synthesis of 4-(4-(4-(2-pyridyl)-1,2,3,6-tetrahydro-1-pyridyl)butyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione ##STR44## 
     In 20 ml of dioxane was dissolved 260 mg of the compound obtained in Reference Example 8, 411 mg (1.9 equivalent) of 4-(2-pyridyl)-1,2,3,6-tetrahydropyridine.trifluoroacetate and 2.07 g (19 equivalents) of anhydrous potassium carbonate were added thereto, and the resulting mixture was refluxed for 23 hours. The dioxane was distilled off under a reduced pressure, ethyl acetate and conc. aqueous ammonia were added to the resulting residue to separate into solutions, the ethyl acetate phase was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under a reduced pressure. The residue obtained was purified in the same manner as used in Example 8 to give 179 mg (yield: 57.0%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from ethanol-ether. 
     EXAMPLE 17 Synthesis of 4-(4-(4-phenyl)-1-piperidinyl)butyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-3,5-dione ##STR45## 
     In 5 ml of dioxane was dissolved 27.0 mg of the compound prepared in Reference Example 9, then 41.5 mg (3 equivalents) of 4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 110° C. for 3.5 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 15.7 mg (yield: 46.3%) of the title compound. The maleate of this compound was obtained by converting the compound into maleate in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 18 Synthesis of 4-(4-(4-phenyl)-1-piperidinyl)butyl-2,3,4,5-tetrahydro- 1,4-benzodiazepine-3,5-dione ##STR46## 
     In 5ml of dioxane was dissolved 16.3 mg of the compound prepared in Reference Example 10, then 25.4 mg (3 equivalents) of 4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 110° C. for 4 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 16.9 mg (yield: 62.2%) of the title compound. The hydrochloride and fumarate of this compound were obtained by converting the compound into hydrochloride and fumarate in the usual manner, and then recrystallizing the salts from methylene chloride-ether. 
     EXAMPLE 19 Synthesis of 4-(4-(4-chlorophenyl)-1-piperidinyl)butyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-3,5-dione ##STR47## 
     In 10 ml of dioxane was dissolved 33.0 mg of the compound prepared in Reference Example 10, then 31.1 mg (1.5 equivalent) of 4-(4-chlorophenyl)piperidine and 22.0 mg (1.5 equivalent) of potassium carbonate were added thereto, and the resulting mixture was stirred at 110° C. for 21 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 29.3 mg (yield: 65.0%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 20 Synthesis of 4-(4-(4-hydroxy-4-phenyl)-1-piperidinyl)butyl-2,3,4,5-tetrahydro-1,4-benzodiazepine-3,5-dione ##STR48## 
     In 10 ml of dioxane was dissolved 44.8 mg of the compound prepared in Reference Example 10, then 76.5 mg (3 equivalents) of 4-hydroxy-4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 100° C. for 4 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 51.7 mg (yield: 88.2%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 21 Synthesis of 1-methyl-4-(4-(4-phenyl) -1-piperidinyl)butyl-2,3,4,5-tetrahydro-1,4-benzodiazepine-3,5-dione ##STR49## 
     In 10 ml of dioxane was dissolved 56.9 mg of the compound prepared in Reference Example 11, then 62.0 mg (2.2 equivalents) of 4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 110° C. for 12 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 66.6 mg (yield: 93.9%) of the title compound. The fumarate of this compound was obtained by converting the compound into fumarate in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 22: Synthesis of 2-(4-(4-phenyl)-1-piperidinyl)butyl-1,3,4,5-tetrahydro-2-benzazepine-1,3-dione ##STR50## 
     In 5 ml of dioxane was dissolved 19.7 mg of the compound prepared in Reference Example 12, then 30.7 mg (3 equivalents) of 4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 110° C. for 4 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 21.9 mg (yield: 88.3%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 23 Synthesis of 2-(4-(4-(4-chlorophenyl)-1-piperidinyl)butyl)-1,3,4,5-tetrahydro-2-benzazepine-1,3-dione ##STR51## 
     In 10 ml of dioxane was dissolved 20.0 mg of the compound prepared in Reference Example 12, then 18.9 mg (1.5 equivalents) of 4-(4-chlorophenyl)piperidine and 13.3 mg (1.5 equivalent) of potassium carbonate were added thereto, and the resulting mixture was stirred at 110° C. for 21 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 19.9 mg (yield: 72.5%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 24 Synthesis of 2-(4-(4-phenyl)-1-piperidinyl)butyl-1,3,4,5-tetrahydro-2-benzazepine-1,3-dione ##STR52## 
     In 10ml of dioxane was dissolved 53.5 mg of the compound prepared in Reference Example 12, then 91.8 mg (3 equivalents) of 4-hydroxy-4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 110° C. for 4 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 68.6 mg (yield: 98.0%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 25 Synthesis of 2-(4-(4-(4-chlorophenyl)-4-hydroxy)-1-piperidinyl)butyl-1,3,4,5-tetrahydro-2-benzazepine-1,3-dione ##STR53## 
     In 10 ml of dioxane was dissolved 39.0 mg of the compound prepared in Reference Example 12, then 79.8 mg (3 equivalents) of 4-(4-chlorophenyl)-4-hydroxypiperidine was added thereto, and the resulting mixture was stirred at 120° C. for 5 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 52.0 mg (yield: 93.8%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 26 Synthesis of 4-(5-(4-phenyl)-1-piperidinyl)pentyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one ##STR54## 
     In 10 ml of dioxane was dissolved 80.0 mg of the compound prepared in Reference Example 1, then 95 mg (2.2 equivalents) of 4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 100° C. for 6 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 94.8 mg (yield: 93.4%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 27 Synthesis of 4-(5-(4-(4-chlorochenyl)1-piperidinyl)pentyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one ##STR55## 
     In 10 ml of dioxane was dissolved 64.5 mg of the compound prepared in Reference Example 1, then 116 mg (3 equivalents) of 4-(4-chlorophenyl)piperidine was added thereto, and the resulting mixture was stirred at 110° C. for 6 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 86.3 mg (yield: 99.0%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 28 Synthesis of 4-(5-(4-phenyl)-1-piperidinyl)pentyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-one ##STR56## 
     In 10 ml of dioxane was dissolved 65.0 mg of the compound prepared in Reference Example 2, then 96.0 mg (3 equivalents) of 4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 110° C. for 8 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 49.0 mg (yield: 60.0%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 29 Synthesis of 4-(5-(4-(4-chlorophenyl)1-piperidinyl)pentyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-one ##STR57## 
     In 10 ml of dioxane was dissolved 65.2 mg of the compound prepared in Reference Example 2, then 123 mg (3 equivalents) of 4-(4-chlorophenyl)piperidine was added thereto, and the resulting mixture was stirred at 110° C. for 6 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 46.7 mg (yield: 52.4%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 30 Synthesis of 4-(5-(4-phenyl)-1-piperidinyl)pentyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione ##STR58## 
     In 10 ml of dioxane was dissolved 40.0 mg of the compound prepared in Reference Example 13, then 62.0 mg (3 equivalents) of 4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 100° C. for 3  hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 39.8 mg (yield: 79.2%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 31 Synthesis of 4-(5-(4-(4-chlorophenyl)-1-piperidinyl)pentyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione ##STR59## 
     In 20 ml of dioxane was dissolved 100 mg of the compound prepared in Reference Example 13, then 173 mg (3 equivalents) of 4-(4-chlorophenyl)piperidine was added thereto, and the resulting mixture was stirred at 110° C. for 7 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 123 mg (yield: 92.0%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 32 Synthesis of 4-(5-(4-phenyl)-1-piperidinyl)pentyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-3,5-dione ##STR60## 
     In 5 ml of dioxane was dissolved 30.5 mg of the compound prepared in Reference Example 3, then 29.0 mg (2.2 equivalents) of 4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 110° C. for 24 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 33.4 mg (yield: 88.0%) of the title compound. The maleate and fumarate of this compound was obtained by converting the compound into maleate and fumarate in the usual manner, and then fumarate was recrystallized from ether-hexane. 
     EXAMPLE 33 Synthesis of 4-(5-(4-(4-phenyl)-1-piperidinyl)pentyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine-3,5-dione ##STR61## 
     In 10 ml of dioxane was dissolved 44.0 mg of the compound prepared in Reference Example 3, then 57.7 mg (2.2 equivalents) of 4-(4-chlorophenyl)piperidine was added thereto, and the resulting mixture was stirred at 110° C. for 30 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 37.5 mg (yield: 63.1%) of the title compound. The maleate of this compound was obtained by converting the compound into maleate in the usual manner. 
     EXAMPLE 34 Synthesis of 4-(5-(4-phenyl)-1-piperidinyl)pentyl-2,3,4,5-tetrahydro-1,4-benzodiazepine-3,5-dione ##STR62## 
     In 5 ml of dioxane was dissolved 57.8 mg of the compound prepared in Reference Example 4, then 86.0 mg (3 equivalents) of 4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 100° C. for 8 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 70.8 mg (yield: 98.3%) of the title compound. The fumarate of this compound was obtained by converting the compound into fumarate in the usual manner, and then recrystallizing the salt from acetone-ether. 
     EXAMPLE 35 Synthesis of 4-(5-(4-(4-chlorophenyl)-1-piperidinyl)pentyl)-2,3,4,5-tetrahydro-1,4-benzodiazepine-3,5-dione ##STR63## 
     In 5 ml of dioxane was dissolved 40.9 mg of the compound prepared in Reference Example 4, then 61.5 mg (2.5 equivalents) of 4-(4-chlorophenyl)piperidine was added thereto, and the resulting mixture was stirred at 100° C. for 12 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 49.9 mg (yield: 90.2%) of the title compound. The fumarate of this compound was obtained by converting the compound into fumarate in the usual manner, and then recrystallizing the salt from acetone-ether. 
     EXAMPLE 36 Synthesis of 2-(5-(4-phenyl)-1-piperidinyl)pentyl-1,3,4,5-tetrahydro-2-benzazepine-1,3-dione ##STR64## 
     In 8 ml of dioxane was dissolved 44.0 mg of the compound prepared in Reference Example 5, then 48.2 mg (2.2 equivalents) of 4-phenylpiperidine was added thereto, and the resulting mixture was stirred at 110° C for 6 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 46.6 mg (yield: 85.0%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     EXAMPLE 37 Synthesis of 2-(5-(4-(4-chlorophenyl)-1-piperidinyl)pentyl)-1,3,4,5-tetrahydro-2-benzazepine-1,3-dione ##STR65## 
     In 10 ml of dioxane was dissolved 61.2 mg of the compound prepared in Reference Example 5, then 111 mg (3 equivalents) of 4-(4-chlorophenyl)piperidine was added thereto, and the resulting mixture was stirred at 110° C. for 7 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 66.7 mg (yield: 79.6%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether. 
     The physical data of the compounds prepared in Examples 1 to 37 are summarized in Table II. 
     
                                           TABLE II__________________________________________________________________________Ex. No.m.p.    IR (cm.sup.-1)              NMR (δppm)      Elemental Analysis__________________________________________________________________________ 1   202-205° C.        2920           2750              1.59-1.78(m, 6H), 1.82-1.86(m, 2H)                                    HCl salt 1/4 H.sub.2 O(HCl salt)        1630           1600              2.02-2.09(m, 2H), 2.42-2.54(m, 3H)                                        C  H  N        1465           1450              3.05-3.09(m, 2H), 3.51(t, 2H, J=5.3Hz)                                    Calc.                                        68.72                                           7.57                                              6.68        1410           1360              3.62-3.67(m, 2H), 4.38(t, 2H, J=5.3Hz)                                    Obsd.                                        68.98                                           7.53                                              6.74        1280           1205              7.00(d, 1H, J=7.9Hz)        1100           1040              7.16-7.32(m, 6H)         800            755              7.40(ddd, 1H, J=1.3Hz&amp;7.3Hz&amp;7.9Hz)         695  7.80(dd, 1H, J=1.3Hz&amp;7.9Hz) 2   205-207° C.        2920           2740              1.57-1.81(m, 8H), 1.96-2.06(m, 2H)                                    HCl salt 3/4 H.sub.2 O(HCl salt)        1635           1600              2.38-2.50(m, 3H), 3.00-3.04(m, 2H)                                        C  H  N        1465           1410              3.46(t, 2H, J=5.3Hz)  Calc.                                        62.26                                           6.86                                              6.05        1370           1310              3.58- 3.63(m, 2H)     Obsd.                                        62.12                                           6.56                                              6.02        1280           1205              4.34(t, 2H, J=5.3Hz)        1105           1080              6.97(d, 1H, J=7.9Hz)        1040           1005              7.09-7.40(m, 6H)         820            800              7.77(dd, 1H, J=1.3Hz&amp;7.9Hz)         755            695 3   192-194° C.        3350           2930              1.50-1.82(m, 6H), 2.23-2.38(m, 2H)                                    HCl salt 1/4 H.sub.2 O(HCl salt)        2820           1625              2.55-2.68(m, 4H)          C  H  N        1470           1420              3.51(t, 2H, J=5.3Hz)  Calc.                                        66.19                                           7.29                                              6.43        1380           1305              3.66(t, 2H, J=6.6Hz)  Obsd.                                        66.08                                           7.42                                              6.42        1280           1210              4.38(t, 2H, J=5.3Hz)7.00(d, 1H, J=8.6Hz)        1120           1040              7.16(dd, 1H, J=7.3Hz&amp;7.9Hz)         980            800              7.30-7.44(m, 4H)         760            730              7.52(d, 2H, J=7.3Hz)         695  7.79(dd, 1H, J=1.3Hz&amp;7.3Hz) 4   189-190° C.        2920           2750              1.44-1.59(m, 4H), 1.71-1.78(m, 4H)                                    HCl salt 1/4 H.sub.2 O(HCl salt)        1660           1630              1.93-2.02(m, 2H), 2.31-2.45(m, 3H)                                         C H  N        1570           1485              2.93-2.97(m, 2H), 3.48-3.53(m, 2H)                                    Calc.                                        68.72                                           7.57                                              6.68        1470           1430              4.43(s, 2H), 4.62(s, 2H)                                    Obsd.                                        68.71                                           7.44                                              6.71        1340           1300              6.95-7.00(m, 2H)        1220           1185              7.09-7.25(m, 7H)        1115           1050        1015            750         690 5   167-169° C.        2920           2750              1.48-1.64(m, 4H), 1.72-1.80(m, 4H)                                    HCl salt(HCl salt)        1660           1575              1.97-2.04(m, 2H), 2.36-2.49(m, 3H)                                        C  H  N        1485           1450              2.97-3.02(m, 2H), 3.52-3.57(m, 2H)                                    Calc.                                        64.14                                           6.73                                              6.23        1340           1300              4.47(s, 2H)           Obsd.                                        64.00                                           7.02                                              6.15        1220           1190              4.67(s, 2H)        1120           1090              6.99-7.25(m, 8H)        1050           1010         820            755         690 6   176-179° C.        3350           2920              1.56-1.81(m, 6H), 2.32-2.34(m, 2H)                                    HCl salt 1/2 H.sub.2 O(HCl salt)        2810           1650              2.57-2.65(m, 4H), 2.90-2.94(m, 2H)                                        C  H  N        1570           1485              3.59(t, 2H), J= 6.6Hz)                                    Calc.                                        65.51                                           7.33                                              6.37        1440           1345              4.51(s, 2H), 4.70(s, 2H)                                    65.80                                        7.38                                           6.43        1300           1220              7.02-7.07(m, 2H)        1185           1125              7.18-7.53(m, 7H)        1040           1020         755            695 7   182-184° C.        3350           2920              1.48-1.74(m, 6H)      HCl salt(HCl salt)        2800           1640              2.09-2.20(m, 2H)          C  H  N        1485           1460              2.39-2.50(m, 4H)      Calc.                                        61.93                                           6.50                                              6.02        1430           1360              2.78-2.82(m, 2H)      Obsd.                                        61.66                                           6.45                                              5.98        1300           1220              3.55-3.60(m, 2H)        1190           1125              4.50(s, 2H), 4.70(s, 2H)        1090           1040              7.02-7.46(m, 8H)        1010            910         820            755         730            695 8   174-176° C.        2940           2800              1.52-1.83(m, 8H),     HCl salt 3/4 H.sub.2 O(HCl salt)        2770           1705              2.04(m, 2H)               C  H  N        1650           1600              2.40(t, 2H, J=7.3Hz)  Calc.                                        65.15                                           6.94                                              6.33        1490           1460              2.48(m, 1H), 3.04(d, 2H, J=11.2Hz)                                    Obsd.                                        65.00                                           6.56                                              6.25        1290           1210              4.02(t, 2H, J=7.9Hz), 4.75(s, 2H)        1110           1060              7.08(dd, 1H, J=1.3Hz&amp;7.9Hz)        1040            760              7.15-7.31(m, 6H)         700  7.51(m, 1H)              8.16(dd, 1H, J=1.3Hz&amp;7.9Hz) 9   202-204° C.        2910           2750              1.55-1.83(m, 8H), 1.98-2.08(m, 2H)                                    HCl salt(HCl salt)        1700           1645              2.38-2.51(m, 3H)          C  H  N        1600           1480              3.02-3.07(m, 2H), 4.01(t, 2H, J=7.3Hz)                                    Calc.                                        62.20                                           6.09                                              6.05        1440           1360              4.75(s, 2H), 7.08-7.30(m, 6H)                                    Obsd.                                        62.51                                           6.36                                              5.96        1330           1290              7.51(ddd, 1H, J=1.3Hz&amp;7.9Hz&amp;8.6Hz)        1210           1120              8.17(dd, 1H, J=1.3Hz&amp;7.9Hz)        1080           1005         815            780         760            69010   151-153° C.        3350           2930              1.47-1.79(m, 6H)      HCl salt 1/4 H.sub.2 O(HCl salt)        2800           1700              2.14-2.25(m, 2H), 2.41-2.51(m, 4H)                                        C  H  N        1640           1600              2.64-2.88(m, 2H)      Calc.                                        64.13                                           6.62                                              6.23        1480           1445              3.99-4.05(m, 2H)      Obsd.                                        64.32                                           6.77                                              6.26        1360           1335              4.76(s, 2H)        1290           1215              7.10(d, 1H, J=7.9Hz)        1040            955              7.21-7.55(m, 7H)         815            755              8.17(dd, 1H, J=1.7Hz&amp;7.9Hz)         69511   186-188° C.        3300           2900              1.44-1.75(m, 6H),     HCl salt(HCl salt)        2750           1695              2.05-2.20(m, 2H)          C  H  N        1640           1600              2.35-2.55(m, 4H)      Calc.                                        60.13                                           5.89                                              5.84        1475           1445              2.78-2.90(m, 2H), 3.98-4.03(m, 2H)                                    Obsd.                                        59.98                                           5.82                                              5.79        1360           1330              4.76(s, 2H)        1285           1205              7.08(d, 1H, J=7.9Hz)        1115           1080              7.21-7.54(m, 6H)        1035            820              8.15(dd, 1H, J=1.3Hz&amp;7.9Hz)         76012   141-145° C.        2550           1710              1.60-1.78(m, 4H)      Mass(HCl salt)        1640           1480              2.50(t, 2H), J=7.9Hz), 2.57(m, 2H)                                    HiMs                                        (free base)        1450           1300              2.70(t, 2H, J=5.3Hz), 3.14(m, 2H)                                    Calc.                                        390.1942        1220           1120              4.03(t, 2H, J=7.9Hz), 4.75(s, 2H)                                    Obsd.                                        390.1943              6.05(m, 1H), 7.09(dd, 1H, J=1.3Hz&amp;7.9Hz)              7.20-7.40(m, 6H)              7.51(m, 1H)              8.16(dd, 1H, J=1.3Hz&amp;7.9Hz)13   155-158° C.        2880           2750              1.49-1.70(m, 4H)      HCl salt 1/4 H.sub.2 O(HCl salt)        1700           1640              2.41-2.45(m, 4H), 2.61-2.65(m, 2H)                                        C  H  N        1600           1480              3.06-3.08(m, 2H), 3.92-3.98(m, 2H)                                    Calc.                                        60.30                                           5.89                                              5.84        1440           1335              4.68(s, 2H), 5.96-5.98(m, 2H)                                    Obsd.                                        60.03                                           5.66                                              5.87        1290           1215              7.02(d, 1H, J=7.9Hz)        1120           1090              7.14-7.47(m, 6H)        1040            820              8.09(dd, 1H, J=1.3Hz&amp;8.4Hz)         76014   167-170° C.        2940           1705              1.57-2.12(m, 10H),    Mass(HCl salt)        1650           1600              2.42(t, 2H, J=7.3Hz), 2.71(m, 1H)                                    HiMs                                        (free base)        1480           1460              3.06(d, 2H, J=11.9Hz), 4.02(t, 2H, J=7.9Hz)                                    Calc.                                        393.2051        1440           1300              4.76(s, 2H), 7.09(dd, 1H, J=1.3Hz, &amp;7.9Hz)                                    Obsd.                                        393.2057        1220           1130              7.12-7.23(m, 3H), 7.51(m, 1H)        1040            760              7.61(m, 1H), 8.16(dd, 1H, J=1.3Hz&amp;7.9Hz)              8.51(dd, 1H, J=1.3Hz&amp;4.0Hz)15   188-190° C.        3300           2950              1.56-1.77(m, 6H), 1.94(br, s, 1H)                                    Mass(HCl salt)        2820           1705              2.11(dt, 2H, J=4.6Hz&amp;12.5Hz)                                    HiMs                                        (free base)        1650           1600              2.47-2.57(m, 4H), 2.88(m, 2H)                                    Calc.                                        409.2000        1490           1460              4.02(t, 2H, J=7.9Hz), 4.76(s, 2H)                                    Obsd.                                        409.2004        1440           1300              7.09(dd, 1H, J=1.3Hz&amp;7.9Hz)        1220           1130              7.18-7.24(m, 2H), 7.40(d, 1H, J=7.9Hz)        1050            790              7.51(m, 1H), 7.71(m, 1H)              8.16(dd, 1H, J=1.3Hz&amp;7.9Hz)              8.51(d, 1H, J=4.6Hz)16   172-175° C.        2920           2800              1.55-1.75(m, 4H), 2.52(t, 2H, J=7.9Hz)                                    Mass(HCl salt)        1700           1650              2.65-2.75(m, 4H), 3.22(m, 2H)                                    HiMs                                        (free base)        1600           1580              4.03(t, 2H, J=7.3Hz), 4.75(s, 2H)                                    Calc.                                        391.1893        1480           1460              6.62(s, 1H), 7.07-7.14(m, 2H)                                    Obsd.                                        391.1881        1450           1430              7.23(m, 1H), 7.36(d, 1H, J=8.6Hz)        1370           1290              7.51(m, 1H), 7.62(m, 1H)        1220           1120              8.16(dd, 1H, J=1.3Hz&amp;7.9Hz)        1040            760              8.55(d, 1H, J=4.0Hz)17   103-105° C.        2920           2750              1.51-1.83(m, 8H)      Maleate(Maleate)        1695           1635              1.98-2.07(m, 2H)           C H  N        1580           1440              2.37-2.50(m, 3H), 3.01-3.06(m, 2H)                                    Calc.                                        64.10                                           6.15                                              5.34        1430           1350              3.68(s, 2H), 4.03(t, 2H, J=7.2Hz)                                    Obsd.                                        63.76                                           6.35                                              5.22        1320           1265              7.16-7.49(m, 8H)        1110           1085              8.17-8.21(m, 1H)         780            740         69518   153-155° C.        3250           2920              1.40-1.63(m, 4H), 1.66-1.75(m, 4H)                                    HCl salt H.sub.2 O(Fumarate)        2850           1685              1.89-1.98(m, 3H), 2.92-2.96(m, 2H)                                        C  H  N        1630           1600              3.83(d, 2H, J=4.6Hz), 3.83-3.89(m, 2H)                                    Calc.                                        64.63                                           7.23                                              9.42        1485           1425              4.77(t, 1H)           Obsd.                                        64.92                                           7.09                                              9.36        1360           1315              6.70(d, 1H, J=7.9Hz)        1285           1150              6.87(dd, 1H, J=7.3Hz&amp;7.9Hz)        1120           1010              7.08-7.30(m, 6H)         970            780              8.18(dd, 1H, J=1.3Hz&amp;7.9Hz)         740            69019   Undeterminable        3300           2920              1.49-1.81(m, 8H), 1.95-2.04(m, 2H)                                    HCl salt H.sub.2 Obecause of        2750           1690              2.31-2.49(m, 3H), 2.98-3.03(m, 2H)                                        C  H  Nhygroscopicity        1635           1600              3.90(d, 2H, J=4.6Hz), 3.93(t, 2H, J=7.3Hz)                                    Calc.                                        60.00                                           6.50                                              8.75(HCl salt)        1485           1425              4.91(t, 1H, J=4.6Hz)  Obsd.                                        59.76                                           6.70                                              8.62        1360           1315              6.78(d, 1H, J=7.9Hz)        1290           1120              6.94(dd, 1H, J=7.2Hz&amp;7.9Hz)        1085           1005              7.12-7.37(m, 5H)         970            820              8.25(dd, 1H, J=1.3Hz&amp;7.9Hz)         780            745         69520   203-205° C.        3300           2930              1.41-1.76(m, 6H), 2.10-2.22(m, 2H)                                    HCl salt 1/2 H.sub.2 O(HCl salt)        2800           1685              2.38-2.46(m, 4H), 2.78-2.82(m, 2H)                                        C  H  N        1625           1600              3.91(d, 2H, J=4.6Hz), 3.49(t, 2H, J=6.6Hz)                                    Calc.                                        63.63                                           6.90                                              9.28        1480           1420              4.75(t, 1H, J=4.6Hz)  Obsd.                                        63.21                                           6.79                                              9.18        1360           1315              6.78(d, 1H, J=7.9Hz)        1290           1120              6.95(dd, 1H, J=7.3Hz&amp;8.6Hz),        1035            970              7.23-7.38(m, 4H)         775            745              7.51(d, 2H, J=7.2Hz)         690  8.26(dd, 1H, J=1.3Hz&amp;8.6Hz),21   153-155° C.        2910           2750              1.51-1.81(m, 6H)      Fumarate 1/2 H.sub.2 O(Fumarate)        1690           1630              1.95-2.07(m, 2H), 2.37(t, 2H, J=7.2Hz)                                        C  H  N        1595           1490              2.37-2.53(m, 1H), 2.98-3.02 (m, 2H)                                    Calc.                                        65.64                                           6.84                                              7.92        1430           1360              3.22(s, 3H), 3.85(s, 2H)                                    Obsd.                                        65.49                                           6.88                                              7.94        1325           1260              3.89-3.94(m, 2H)        1240           1190              6.91-6.98(m, 2H)        1100           1070              7.18-7.46(m, 6H)         995            775              8.32(d, 1H, J=7.9Hz)         745            69522   175-177° C.        2920           2730              1.47-1.78(m, 8H)      HCl salt 1/2 H.sub.2 O(HCl salt)        1690           1635              1.92-2.02(m, 2H), 2.32-2.43(m, 3H)                                        C  H  N        1595           1485              2.92(s, 4H), 2.92-3.01(m, 2H)                                    Calc.                                        68.87                                           7.40                                              6.43        1440           1305              3.93-3.98(m, 2H)      Obsd.                                        69.13                                           7.23                                              6.43        1265           1180              7.08-7.37(m, 8H)        1100            745              7.89(dd, 1H, J=1.3Hz&amp;7.9Hz)         69023   180-182° C.        2920           2750              1.55-1.81(m, 8H)      HCl salt(HCl salt)         1690           1640              1.99-2.08(m, 2H), 2.39-2.50(m, 3H)                                        C  H  N        1595           1490              2.99-3.07(m, 6H)      Calc.                                        65.07                                           6.55                                              6.07        1440           1370              3.99-4.05(m, 2H)      Obsd.                                        65.01                                           6.62                                              6.14        1335           1310              7.13-7.47(m, 7H)        1270           1180              7.96(dd, 1H, J=1.3Hz&amp;7.9Hz)        1100           1005         885            820         750            71024   201-202° C.        3350           2930              1.52-1.79(m, 6H)      HCl salt 1/4 H.sub.2 O(HCl salt)        2800           1690              2.14-2.25(m, 2H), 2.41-2.51(m, 4H)                                        C  H  N        1640           1600              2.83-2.88(m, 2H), 3.00(s, 4H)                                    Calc.                                        67.10                                           7.10                                              6.26        1490           1440              4.00-4.05(m, 2H)      Obsd.                                        67.22                                           7.07                                              6.27        1380           1300              7.17(d, 1H, J=7.3Hz)        1265           1180              7.25-7.54(m, 7H)        1105           1040              7.96(d, 1H, J=7.9Hz)         960            790         755            69525   186-188° C.        3400           2920              1.49-1.75(m, 6H)      HCl salt(HCl salt)        2800           1690              2.09-2.20(m, 2H), 2.40-2.48(m, 4H)                                        C  H  N        1640           1600              2.84-2.96(m, 2H), 2.99(s, 4H)                                    Calc.                                        62.89                                           6.33                                              5.87        1480           1440              4.03(t, 2H, J=7.3Hz)  Obsd.                                        62.39                                           6.25                                              5.82        1340           1315              7.16(d, 1H, J=7.3Hz)        1270           1185              7.29-7.46(m, 6H)        1110           1040              7.96(d, 1H, J=7.9Hz)        1010            960         820            790         75026   178-180° C.        3300           2920              1.39-1.72(m, 6H), 1.83-1.90(m, 4H)                                    HCl salt 1/2 H.sub.2 O(HCl salt)        2860           2750              2.06-2.15(m, 2H), 2.39-2.55(m, 3H)                                        C  H  N        1630           1600              3.07-3.15(m, 2H)      Calc.                                        68.55                                           7.82                                              6.40        1460           1420              3.50(t, 2H, J=5.3Hz)  Obsd.                                        69.00                                           7.65                                              6.41        1370           1315              3.60-3.65(m, 2H), 4.38(t, 2H, J=5.3Hz)        1280           1210              7.00(d, 1H, J=8.7Hz)        1105           1040              7.12-7.43(m, 7H),         980            800              7.80(dd, 1H ,J=2.0Hz&amp;7.9Hz)         755            69527   180-181° C.        2900           2740              1.33-1.52(m, 2H), 1.53-1.88(m, 8H)                                    HCl salt(HCl salt)        1635           1600              2.02-2.10(m, 2H), 2.36-2.54(m, 3H)                                        C  H  N        1460           1410              3.06-3.10(m, 2H)      Calc.                                        64.79                                           6.96                                              6.04        1360           1310              3.50(t, 2H, J=5.3Hz), 3.62(t, 2H, J=7.2Hz)                                    Obsd.                                        64.64                                           6.93                                              6.03        1280           1205              4.38(t, 2H, J=5.3Hz), 7.00(d, 1H, J=7.9Hz)        1085           1040              7.13-7.27(m, 5H),         820            755              7.40(dt, 1H, J=1.3Hz&amp;7.9Hz)         690  7.81(dd, 1H, J=1.3Hz&amp;7.9Hz)28   161-163° C.        2920           2730              1.26-1.40(m, 2H), 1.49-1.70(m, 4H)                                    HCl salt 1/4 H.sub.2 O(HCl salt)        1660           1630              1.78-1.89(m, 4H), 2.00-2.10(m, 2H)                                        C  H  N        1485           1450              2.33-2.39(m, 2H)      Calc.                                        69.27                                           7.79                                              6.46        1340           1300              2.47-2.53(m, 1H)      Obsd.                                        69.30                                           7.61                                              6.49        1220           1185              3.02-3.10(m, 2H)        1105           1050              3.55(t, 2H, J=7.3Hz), 4.49(s, 2H)        1020            750              4.69(s, 2H), 7.03-7.32 (m, 9H)         69529   144-148° C.        2900           2850              1.25-1.36(m, 2H), 1.49-1.69(m, 4H)                                    HCl salt 1/2 H.sub. 2 O(HCl salt)        2750           1660              1.70-1.82(m, 4H), 1.97-2.09(m, 2H)                                        C  H  N        1575           1480              2.32-2.37(m, 2H)      Calc.                                        63.56                                           7.04                                              5.93        1440           1340              2.41-2.51(m, 1H), 3.03-3.07(m, 2H)                                    Obsd.                                        63.38                                           6.86                                              5.91        1300           1215              3.52-3.58(m, 2H)        1185           1080              4.49(s, 2H), 4.69(s, 2H)        1045           1020              7.03-7.32(m, 8H),         815            745         69030   176-178° C.        2920           2750              1.33-1.72(m, 6H)      HCl salt 1/4 H.sub.2 O(HCl salt)        1700           1645              1.74-1.85(m, 4H), 1.98-2.06(m, 2H)                                        C  H  N        1600           1480              2.35-2.40(m, 2H), 2.45-2.51(m, 1H)                                    Calc.                                        67.10                                           7.10                                              6.26        1445           1370              3.03-3.07(m, 2H), 3.96-4.01(m, 2H)                                    Obsd.                                        67.16                                           7.09                                              6.28        1335           1290              4.76(s, 2H)        1215           1115              7.09(d, 1H, J=7.9Hz)        1060           1040              7.16-7.33(m, 6H)         985            815              7.51(dt, 1H, J=1.3Hz&amp;7.9Hz)         755            695              8.17(dd, 1H, J=1.3Hz&amp;7.9Hz)31   166-168° C.        2910           2740              1.35-1.44(m, 2H)      HCl salt(HCl salt)        1700           1645              1.48-1.83(m, 8H)          C  H  N        1600           1475              1.96-2.05(m, 2H), 2.33-2.39(m, 2H)                                    Calc.                                        62.89                                           6.33                                              5.87        1440           1360              2.42-2.52(m, 1H), 3.02-3.06(m, 2H)                                    Obsd.                                        63.02                                           6.32                                              5.86        1325           1290              3.95-4.01(m, 2H), 4.76(s, 2H)        1210           1115              7.08-7.27(m, 6H),        1085           1035              7.51(dt, 1H, J=1.3Hz&amp;7.9Hz)         815            760              8.16(dt, 1H, J=1.3Hz&amp;7.9Hz)         69032   124-128° C.        2930           2750              1.31-1.50(m, 2H)      Fumarate 1/2 H.sub.2 O(Fumarate)        1695           1640              1.51-1.84(m, 8H), 1.94-2.07(m, 2H)                                        C  H  N        1580           1490              2.35(t, 2H), J=7.9Hz), 2.45-2.52(m, 1H)                                    Calc.                                        63.60                                           6.44                                              5.12        1430           1350              3.02-3.06(m, 2H)      Obsd.                                        63.73                                           6.41                                              5.11        1320           1255              3.68(s, 2H), 4.00(t, 2H, J=7.9Hz)        1230           1085              7.16-7.47(m, 8H)         985            780              8.17-8.21(m, 1H),         740            69533   Oily product        2920           2750              1.33-1.47(m, 2H)      Maleate(Maleate)        1690           1630              1.50-1.85(m, 8H), 1.91-2.04(m, 2H)                                        C  H  N        1580           1490              2.35(t, 2H, J=7.3Hz)  Calc.                                        60.77                                           5.80                                              4.89        1460           1430              2.39-2.52(m, 1H), 3.01-3.05(m, 2H)                                    Obsd.                                        60.26                                           5.88                                              4.78        1320           1255              3.68(s, 2H), 3.97-4.02(m, 2H)        1230           1085              7.13-7.49(m, 7H)        1010            985              8.19(dd, 1H, J=1.9Hz&amp;7.9Hz)         820            780         740            68534   183-184° C.        3250           2900              1.33-1.39(m, 2H), 1.52-1.84(m, 8H)                                    Fumarate 1/2 H.sub.2 O(Fumarate)        2750           1685              1.98-2.07(m, 2H), 2.33-2.38(m, 2H)                                        C  H  N        1630           1600              2.45-2.48(m, 1H), 3.02-3.07(m, 2H)                                    Calc.                                        65.64                                           6.84                                              7.92        1485           1425              3.91(d, 2H, J=4/6Hz), 3.90-3.93(m, 2H)                                    Obsd.                                        65.24                                           6.63                                              7.72        1350           1310              4.71(t, 1H, J=4.6Hz), 6.77(d, 1H, J=7.9Hz)        1290           1230              6.95(t, 1H, J=7.9Hz),        1150           1110              7.19-7.37(m, 6H)         970            745              8.26(dd, 1H, J=1.3Hz&amp;7.9Hz)         69035    171-173° C.        3250           2900              1.25-1.39(m, 2H), 1.49-1.84(m, 8H)                                    Fumarate(Fumarate)        2750           1695              1.95-2.05(m, 2H), 2.31-2.37(m, 2H)                                        C  H  N        1640           1605              2.37-2.51(m, 1H), 3.01-3.05(m, 2H)                                    Calc.                                        62.64                                           6.16                                              7.56        1490           1430              3.87-3.92(m, 4H)      Obsd.                                        62.29                                           6.17                                              7.56        1360           1320              4.70-4.73(m, 1H), 6.77(d, 1H, J=8.6Hz)        1240           1120              6.94(t, 1H, J=7.9Hz)        1090            980              7.13-7.37(m, 5H)         825            750              8.26(d, 1H, J=7.9Hz)36   151-152° C.        2920           2750              1.33-1.44(m, 2H), 1.50-1.84(m, 8H)                                    HCl salt 1/4 H.sub.2 O(HCl salt)        1695           1640              1.98-2.07(m, 4H), 2.37(t, 2H, J=7.9Hz)                                        C  H  N        1600           1445              2.43-2.53(m, 1H), 2.99(s, 4H)                                    Calc.                                        70.10                                           7.58                                              6.29        1335           1310              3.03-3.07(m, 2H)      Obsd.                                        70.26                                           7.49                                              6.29        1240           1180              4.00(t, 2H, J=7.3Hz)        1090            980              7.15-7.44(m, 8H)         885            750              7.97(dd, 1H, J=1.3Hz&amp;7.3Hz)         695 37  175-178° C.        2920           2750              1.35-1.44(m, 2H)      HCl salt(HCl salt)        1690           1640              1.53-1.84(m, 8H)          C  H  N        1595           1485              1.97-2.05(m, 2H), 2.34-2.40(m, 2H)                                    Calc.                                        65.68                                           6.78                                              5.89        1440           1335              2.43-2.51(m, 1H), 2.99(s, 4H)                                    Obsd.                                        65.60                                           6.95                                              5.84        1310           1240              3.03-3.07(m, 2H)        1180           1085              3.97-4.02(m, 2H)        1005            980              7.13-7.45(m, 7H)         880            820              7.97(dd, 1H, J=1.3Hz&amp;7.9Hz)         750            705__________________________________________________________________________ 
    
     The pharmacological test results will now be explained. 
     (I) AFFINITY TO σ-receptor 
     The affinities of the present compounds to the δ-receptor were determined according to a method described in the &#34;Molecular Pharmacology,&#34; Vol. 32, 772-784 (1987). 
     That is, 50 mM of a Tris-HCl (pH=7.7) buffer solution was added to all of the cerebra, other than the cerebellum, of Wistar male rats, followed by homogenizing for 30 minutes in a Polytson.sup.® and then centrifugally separating same at 35000 G for 10 minutes. To the resultant precipitate was added the same buffer solution as used above, and the homogenizing and the centrafugalization were repeated. This procedure was repeated once more, and to the final precipitate was added a 50 mM Tris -HCl (pH=8.0) buffer solution and the receptor having a binding capability. In the binding experiments, 3nM [ 3  H] propyl-3-(3-hydroxyphenyl) piperidine (i.e., [ 3  H]3PPP) was used, and as a non-specific ligand, 1 μM haloperidol was used. After incubation at 25° C. for 90 minutes, the bound ligand was recovered by filtration and the determination was carried out. The filter used was a Whatmen GF/B filter treated with 0.5% polyethylene imine. 
     All of the present compounds exhibit strong activities on the order of μM or less. The receptor binding capabilities of the typical compounds are shown in Table III. 
     
                       TABLE III______________________________________Affinity to δ-ReceptorExample No.    IC.sub.50 (nM)______________________________________ 1             14.2 2             11.7 4             9.22 5             18.7 8             6.61 9             4.7312             12.114             17.817             4.0018             14.119             16.121             13.722             3.7423             6.4026             10.927             10.628             8.0229             10.330             4.7331             7.8232             3.9533             17.636             3.6237             8.91______________________________________ 
    
     (II) Inhibitory Activity Against Locomotor Hyperactivity Induced by Anfoneric Acid 
     The inhibitory activity against locomotor hyperactivity induced by amfoneric acid of the present compounds were determined according to a method described in the &#34;Journal of Pharmacology &amp; Experimental Therapeuties,&#34; Vol. 239, 124-131 (1986) by R. T. Matthews et al. 
     That is, to a ddy male mouse having a body weight of about 25g, were simultaneously administered amfoneric acid (2.5 mg/kg, subcutaneous administration) and the present compound (intraperitoneal administration), and the amount of movement was determined using an apparatus for determining the amount of movement of a mouse. The amount of movement was determined over 100 minutes, and the test of significance thereof was effected for the total count number for 100 minutes by a Manwhitnee test. The value was indicated as the inhibition rate based, as a control, upon the group to which 2.5 mg/kg of amfoneric acid was subcutaneously administered. 
     The results are shown in Table IV. 
     
                       TABLE IV______________________________________Inhibitory activity against locomotorhyperativity induced by anfoneric acid        Inhibition Rate (%)Example No.  (mg/kg Intraperitoneal administration)______________________________________ 8           73%* (30)18           90%** (10), 65%* (1)19           53%* (10)22           52%* (10)26           65%** (10)29           60%** (10)30           70%* (30)37           74%* (10)Control BMY14802        51%* (30)______________________________________ *0.05 &gt; P &gt; 0.01 **0.01 &gt; P &gt; 0.001 
    
     (III) Catalepsy 
     To ddy male mice having a body weight of about 25 g was intraperitoneally administered the present compound and the catalepsy was determined after 30, 60, 90, and 120 minutes therefrom. The score of the catalepsy was as follows. 
     The forelegs of the mouse were placed on an aupper edge of a 5.5 cm height box and the time until the more fulled its forelegs down from the box or the mouse jumped up onto the top of the box was measured and the score was determined based upon the following standard. 
     
         ______________________________________Score       Condition______________________________________0           15 sec or less1           more than 15 sec but less than 30 sec2           more than 30 sec but less than 60 sec3           more than 60 sec______________________________________ 
    
     The results are evaluated based upon the determined score as follows. 
     
         ______________________________________Evaluation      Score______________________________________-               less than 1+               more than 1 but less than 2++              more than 2 but less than 3______________________________________ 
    
     The results of the typical compounds are shown in Table V. 
     
                       TABLE V______________________________________Catalepsy       CatalepsyExample No. (mg/kg Intraperitoneal administration)______________________________________ 8          - (30)18          - (10)19          - (20)21          - (30)26          - (30)29          - (30)30          - (30)31          - (30)37          - (30)Control     ++ (0.1)(Haloperidol)______________________________________