Teirahydropyridine derivatives

Abstract

The present invention relates to tetrahydropyridine derivatives which have high affinity and specificity to .sigma. receptors, whereby these compounds are thought to be effective for treatment of some psychoses.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel tetrahydropyridine derivatives with psychotropic activities.

2. Prior Art

Antidopamine agents such as haloperidol (U.S. Pat. No. 3,438,991) are used as an antipsychotic agent. Adverse reactions in the extrapyramidal tract such as delayed dyskinesia are caused by them during long-term therapy. Recently, safer drugs, rimcazole (JP. Pat. Publn. No. 55-64,585) and BMY 148021 (GB Patent No. 2,155,925), which show high affinity to .sigma. receptors but low affinity to dopamine receptors, have been developed as psychotropic drugs. On the other hand, the existence of a binding site of dextromethorphan (DM) in the central nervous system has been reported (J. Musacchio, M. Klein and L. J. Santiago, The Journal of Pharmacology and Therapeutics 247 (2), 424 (1988), High Affinity Dextromethorphan Binding Sites in Guinea Pig Brain; Further Characterization and Allosteric Interactions). DM, which is one of the most popular antitussives, is thought to be effective for ischemic encephalopathy (F. C. Tortella, M. Pellicano and N. G. Bowery, Trips, 10(12), 501 (1989), Dextromethophan and neuromodulation: old drug coughs up new activities). It is also thought that the property of .sigma. receptors, which is labeled with [3H]3PPP adopted in the present invention, resembles that of the DM binding site (J. M. Musacchio, M. Klein and P. D. Cano 11, Life Sciences, 45, 1721 (1989), Dextromethorphan and Sigma Ligands: Common Sites but Diverse Effects).

SUMMARY OF THE INVENTION

This invention relates to novel tetrahydropyridine derivatives with psychotropic activities. Furthermore, these compounds have high affinity and specificity to .sigma. receptors, whereby they are thought to be effective for some psychoses such as depression, mania, and acute and chronic schizophrenia, and cerebral ischemic disease.

DETAILED DESCRIPTION

The present invention relates to compounds of the formula: ##STR1## wherein Ar is phenyl or thienyl which may have identically or differently one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, substituted or unsubstituted phenyl, trifluoromethyl, and hydroxy; n is an integer of from 2 to 6; R is hydroxy or a group of the formula: ##STR2## wherein R.sup.1 is hydrogen or lower alkyl; R.sup.2 and R.sup.3 each is hydrogen or lower alkyl or taken together with the adjacent nitrogen atom may form a 5- or 6-membered heterocyclic group, which may be condensed with a benzene ring, where the heterocyclic group may have identically or differently have 1 to 3 substituents selected from the group consisting of lower alkyl, halogen, oxo, pyrimidine, and substituted or unsubstituted phenyl; R.sup.4 is NH, O, or a single bond; X.sup.1 and X.sup.2 each is hydrogen, lower alkyl, halogen, or hydroxy; p and q each is an integer of 0 or 1, excluding the case where p is 0 when q is 1, or a pharmaceutically acceptable acid addition salt thereof.

In this specification, the term "lower alkyl" refers to a straight or branched chain C.sub.1 to C.sub.6 alkyl including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 2-methylbutyl, n-hexyl, isohexyl and the like.

The term "lower alkoxy" refers to C.sub.1 to C.sub.6 alkoxy including methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.

The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

"Substituted phenyl" means phenyl substituted by one or more substituents, of which examples are hydroxy, lower alkyl, lower alkoxy, and halogen.

The "5- or 6-membered heterocyclic group" may contain one or more additional heteroatoms including oxygen, sulfur, and nitrogen atoms, and examples of the 5- or 6-membered heterocyclic group are isothiazole, pyrazole, pyridine, pyrimidine, imidazole, and isoxazole, preferably, pyrrolidine, piperidine, piperazine, imidazolidine, thiomorpholine, morpholine, pyrazolidine, and the like. The above mentioned heterocyclic group may be condensed with a benzene ring at any position. Further they may have identically or differently 1 to 3 substituents selected from the group consisting of lower alkyl, halogen, oxo, pyrimidine, and substituted or unsubstituted phenyl.

Pharmaceutically acceptable acid addition salts include mineral acid salts such as hydrochloride, sulfate, nitrate, and phosphate, and organic acid salts such as acetate, fumarate, citrate, tartarate, maleate, and oxalate, most preferably hydrochloride, maleate and oxalate.

The compounds of this invention can be prepared by the following method. ##STR3##

METHOD A

Step 1

The compound (II) is reacted with the compound of the formula:

R(CH.sub.2)nY (VI) wherein R, Y, and n each has the same meaning as defined above in an appropriate organic solvent, if necessary in the presence of a base to prepare the compound (III).

The reaction is performed at a temperature of from 50.degree. to 200.degree. C., preferably from 85.degree. to 120.degree. C., for 1-15 hours, especially for 5-10 hours.

Organic solvents which may be used are alcohols such as methanol and ethanol, ethers such as diethylether and tetrahydrofuran, dimethylformamide, acetonitrile and the like, most preferably dimethylformamide.

As the base, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, pyridine, triethylamine, and the like may be used.

Step 2

The compound (III) is subjected to dehydration in an organic solvent in the presence of the acid to prepare the compound (Ia).

The reaction is performed at a temperature of from 0.degree. to 120.degree. C., preferably at room temperature for 1-96 hours, especially for 3-72 hours.

The same organic solvent as mentioned in Step 1 may be used.

The acid includes hydrochloride, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid.

METHOD B

Step 1

The compound (II) is reacted with the compound of the formula:

Z.sup.1 (CH.sub.2)nY (VII) wherein Z.sup.1, Y, and n each has the same meaning as defined above in an organic solvent in the presence of a base to prepare the compound (IV).

The reaction is performed at 10.degree.-150.degree. C., preferably from room temperature to 110.degree. C., for 1-20 hours, especially for 3-7 hours.

The same organic solvent and the base as mentioned Method A (step 1) may be used.

The compound (VII) means phthalimide butylbromide, 3-bromo-1-chloropropane and the like.

Step 2

The compound (IV) is reacted with the compound of the formula:

RH (VIII) wherein R has the same meaning as defined above in an organic solvent, if necessary in the presence of a base to prepare the compound (III).

The reaction is performed at 80.degree.-200.degree. C., preferably at 100.degree.-130.degree. C., for 1-24 hours, especially for 2-7 hours.

The same organic solvent and the base as mentioned Step 1 may be used.

Step 3

The compound (III) is subjected to dehydration in the same manner as Method A (step 2) to prepare the compound (Ia). Each condition is the same as Method A (step 2).

METHOD C

Step 1

The compound (II) is reacted with the compound of the formula:

HO(CH.sub.2)nY (IX) wherein Y and n each has the same meaning as defined above, preferably in the presence of the base to prepare the compound (IV).

The reaction is performed at 50.degree.-200.degree. C., preferably at 120.degree.-150.degree. C., for 3-20 hours, especially for 5-9 hours.

Step 2

The compound (IV) is reacted with a chloride of a nonmetal element to prepare the compound (V).

The reaction is performed at 0.degree.-100.degree. C., preferably at room temperature, for 1-48 hours, especially for 2-24 hours.

The chloride includes sulfur chloride, thionylchloride, hydrochloride, carbon tetrachloride, and the like.

Step 3

The compound (V) is reacted with RH (VIII) to prepare the compound (III).

The reaction is performed at 0.degree.-100.degree. C., preferably from room temperature to 50.degree. C. for 1-96 hours, preferably for 3-72 hours.

Step 4

The compound (III) is subjected to dehydration in the same manner as Method A (step 2) to prepare the compound (Ia).

METHOD D

Step 1

The compound (II) is reacted with N-protected-.beta.-alanine, in the presence of a condensing agent such as 1,3-dicyclohexylcarbodiimide, and 1-hydroxybenzotriazole in an appropriate organic solvent to prepare the compound (IV).

The reaction is performed at a temperature of from 10.degree. to 150.degree. C., preferably from room temperature to 70.degree. C., for 1-20 hours, especially for 3-7 hours.

The same organic solvent as mentioned in METHOD A (Step 1) may be used.

Step 2

The compound (IV) is reacted in an appropriate solvent to remove the amino-protecting group. Then the obtained compound is subjected to a reduction reaction in the presence of a reductant.

The former reaction is performed at a temperature of from 10.degree. to 150.degree. C., preferably from room temperature to 70.degree. C., for 1-20 hours, especially for 3-7 hours.

The same organic solvent as mentioned in METHOD A (Step 1) may be used, most preferably trifluoroacetic acid.

The latter reduction reaction is performed in an ordinary method in the presence of the reductant such as lithium aluminium hydride, hydro iodide, hydrogen sulfide, and sodium iodide at a temperature of from 0.degree. to 100.degree. C., preferably room temperature, for 1 to 7 hours, especially for 2 to 4 hours.

Step 3

The compound (V) is reacted with RH (VIII) to prepare the compound (Ia).

The reaction is performed at a temperature of from 50.degree. to 200.degree. C., preferably from 100.degree. to 130.degree. C., for 30 minutes to 5 hours, especially for 1-3 hours.

The compound of the present invention can be administered orally or parenterally. For example, the compound of the present invention may be orally administered in the form of tablets, powders, capsules, and granules, or liquid form such as syrup or elixir, and parenterally in the form of injection of an aqueous or oily suspension.

These preparations can be prepared in a conventional manner by using excipients, binders, lubricants, aqueous or oily solubilizers, emulsifier, suspending agents, and the like. And further additives such as preservatives and stabilizers can be used.

The dosages may be varied depending upon the administration route, age, weight and condition of the patient, and the kind of disease of the but is usually 5-1000 mg/day, preferably 20-200 mg/day through the oral route, and 1-500 mg/day, preferably 5-50 mg/day through the parenteral route in a single or divided doses.

The present invention is illustrated by the following examples and reference examples, which are not to be considered as limiting.

The abbreviations used in the examples and reference examples have the following meanings.

Me: methyl, Et: ethyl, t-Bu: tert-butyl, iPr: isopropyl, Ph: phenyl, Ts: tosyl DMF: dimethylformamide, aq.: aqueous.

EXAMPLE 1

1-[3-{4-(3,4-dichlorophenyl)-1,2,5,6-tetrahydropyridin-1-yl}-propylcarbamoyl]-2-oxopyrrolidine (Ia-1) ##STR4##

(1) A solution of 3.0 g of 4-hydroxy-4-(3,4-dichlorophenyl)piperidine (II-1) and 2.50 g of 1-{(3-chloropropyl)carbamoyl-2-oxopyrrolidine in 35 ml of DMF is stirred at 105.degree.-110.degree. C. for 6 hours in the presence of 2.74 g of NaI and 4.22 g of K.sub.2 CO.sub.3 (reaction condition 1). The reaction mixture is poured into ice-water, and the solution is extracted with ethyl acetate. The organic layer is washed with water, dried over MgSO.sub.4 and concentrated under reduced pressure. The obtained oily substance is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol (15/1-10/1 v/v) to prepare 4.20 g of the objective compound (III-1) as colorless needles.

mp.: 135.5.degree.-137.0.degree. C.

Anal Calcd. (%) for C.sub.19 H.sub.25 N.sub.3 O.sub.3 Cl.sub.2 : C, 54.90; H, 6.10; N, 10.16; Cl, 17.21. Found: C, 55.08; H, 6.08; N, 10.14; Cl, 17.11.

IR (CHCl.sub.3): 3600, 3320, 1712, 1680, 1545, 1489, 1470.

NMR (CDCl.sub.3) .delta.(200 MHz): 1.682 (dd, J.sub.1 =12 Hz, J.sub.2 =2 Hz, 2H); 1.772 (quint, J=7 Hz, 2H); 2.042 (quint, J=8 Hz, 2H); 2.062 (s, 1H); 2.191 (td, J.sub.1 =13 Hz, J.sub.2 =4 Hz, 2H); 2.409 (t, J=11 Hz, 2H); 2.497 (t, J=7 Hz, 2H); 2.628 (t, J=8 Hz, 2H); 2.837 (dd, J.sub.1 =11 Hz, J.sub.2 =2 Hz, 2H); 3.394 (q, J=6 Hz, 2H); 3.854 (t, J=7 Hz, 2H); 7.393, 7.401, 7.716 (sx3, 3H).

(2) A solution of 2.77 g of the compound (III-1) and 1.60 g of p-toluenesulfonic acid in 300 ml of toluene refluxed for 48 hours to separate water as azeotropic mixture of toluene. After removal of the solvent, the residue is dissolved in ethyl acetate and washed with aq.NaOH and water. The solution is dried over Na.sub.2 SO.sub.4 and concentrated under reduced pressure. The oily residue is subjected to column chromatography with silica gel, eluting with ethyl acetate-methylene chloride/methanol (20/1 v/v) to prepare 2.26 g (Yield: 89.3%) of the objective compound (Ia-1) as an oil. The maleate is recrystallized from i-PrOH to prepare 2.50 g colorless needles. mp. 135.5.degree.-136.5.degree. C.

Anal Calcd. (%) for C.sub.19 H.sub.23 N.sub.3 O.sub.2 Cl.sub.2.C.sub.4 H.sub.4 O.sub.4 : C, 53.84; H, 5.32; N, 8.18; Cl, 13.93. Found: C, 53.91; H, 5.31; N, 8.20; Cl, 13.84.

IR (Nujol) cm.sup.-1: 3310, 1713, 1680, 1625, 1580, 1550 (sh), 1518, 1485, 1455.

NMR (CDCl.sub.3) .delta.(200 MHz): 1.829 (quint, J=7 Hz, 2H); 2.039 (quint, J=8 Hz, 2H); 2.50.about.2.55 (m, 4H); 2.612 (t, J=8 Hz, 2H); 2.714 (t, J=6 Hz, 2H); 3.171 (q, J=3.3 Hz, 2H); 3.398 (q, J=7 Hz, 2H); 3.874 (t, J=7 Hz, 2H); 6.100 (quint, J=2 Hz, 1H); 7.224 (dd, J.sub.1 =8 Hz, J.sub.2 =2 Hz, 1H); 7.397 (d, J=8 Hz, 1H); 7.463 (d, J=2 Hz, 2H); 8.513 (brs, 1H).

EXAMPLE 2-16

The reaction is performed in the same manner as Example 1 to prepare the compound (Ia). The reaction conditions are shown in table 1 and 2, and physical constants of the compound (III) are shown in table 3 and those of the compound (Ia) are shown in table 4.

TABLE 1__________________________________________________________________________(Step 1) ##STR5##Ex. (II) DMF K.sub.2 CO.sub.3 NaI reaction eluent g (%)No. X = R(CH.sub.2).sub.n Y (VI) (ml) (g) (g) condition(1) condition compd.__________________________________________________________________________ No.2 CF.sub.3 (p) 2.50 g (II-2) ##STR6## 25 2.28 2.29 105-110 7 hr. CH.sub.2 Cl.sub.2 /MeOH = 3.89 (92.2) (III-2)3 n-Pr(p) 2.25 g (II-3) ##STR7## 20 2.85 2.31 105 5 hr. CH.sub.2 Cl.sub.2 /MeOH = 2.98 (74.6) (III-3)4 Et(p) 3.00 g (II-4) ##STR8## 30 4.04 3.28 105 7 hr. CH.sub.2 Cl.sub.2 /MeOH = 4.10 (75.2) (III-4)5 Ph(p) 4.76 g (II-5) ##STR9## 57 5.19 4.22 105 24 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1- 10/1 7.31 (92.3) (III-5)6 t-Bu(p) 6.0 g (II-6) ##STR10## 60 7.11 5.78 105 10 hr. CH.sub.2 Cl.sub.2 /MeOH = 8.36 (81.0) (III-6)7 n-Pr(p) 1.95 g (II-3) ##STR11## 30 2.46 2.0 105.degree. C. 9 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1.about.10/1 2.0 (65.0) (III-7)8 t-Bu(p) 1.98 g (II-6) ##STR12## 20 1.35 1.10 100.degree. C. 2.6 hr. CH.sub.2 Cl.sub.2 /MeOH = 19/1-9/1 0.853 (46.9) (III-8)9 CF.sub.3 (p) 2.33 g (II-2) ##STR13## 30 2.62 2.14 100-105.degree. C. 8.5 CH.sub.2 Cl.sub.2 /MeOH = 20/1-10/1 2.46 (65.0) (III-9)10 Ph 930 mg (II-5) ##STR14## 11 1.015 0.825 105.degree. C. 5 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH = 128/16/1-32/6/1 0.616 (41.0) (III-10)11 t-Bu(p) 844 mg (II-6) ##STR15## 11 1.00 0.813 100.degree. C. 5.5 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH = 128/16/1-64/8/1 0.830 (57.3) (III-11)12 CF.sub.3 (m) 2.5 g (II-7) ##STR16## 25 2.76 2.25 100-105.degree. C. 5.5 CH.sub.2 Cl.sub.2 /MeOH = 3.8 (90.2) (III-12)13 CF.sub.3 (p) 527 mg (II-2) ##STR17## 7 0.59 -- 105.degree. C. 7 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1-10/1 0.82 (86.0) (III-13)14 t-Bu(p) 2.03 g (II-6) ##STR18## 20 2.40 1.95 105.degree. C. 7.5 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1-7/1 2.99 (82.8) (III-14)15 Me(p) 1.07 g (II-8) ##STR19## 26 1.61 1.31 95.degree. C. 7 hr. CH.sub.2 Cl.sub.2 /MeOH = 19/1-9/1 0.477 (24.8) (III-15)16 t-Bu(p) 980 mg (II-6) ##STR20## 20 1.16 0.94 105.degree. C. 6.5 hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1-5/1 1.69 (92.6) (III-16)__________________________________________________________________________ TABLE 2__________________________________________________________________________(Step 2)starting eluenting condition productmaterial acid solvent (ml) reflux time (2) (g)__________________________________________________________________________(III-2) TsOH.H.sub.2 O toluene (280) 48 hr. ethyl acetate- Ia-24.24 g (3.90 g) dichloro- CH.sub.2 Cl.sub.2 /MeOH = 20/1 2.26 g ethane (70)(III-3) CF.sub.3 COOH -- 10 hr. toluene/ethyl Ia-32.52 g (25 ml) acetate = 1/1 2.22 g CH.sub.2 Cl.sub.2 /MeOH = 20/1(III-4) CF.sub.3 COOH -- 10 hr. ethyl acetate- Ia-44.10 g (35 ml) CH.sub.2 Cl.sub.2 /MeOH = 3.41 g 30/1-20/1(III-5) CF.sub.3 COOH -- 9 hr. CH.sub.2 Cl.sub.2 /MeOH = Ia-52.73 g (30 ml) 30/1-20/1 2.40 g(III-6) CF.sub.3 COOH -- 4 hr. ethyl acetate- Ia-62.08 g (25 ml) CH.sub.2 Cl.sub.2 /MeOH = 1.90 g 30/1-20/1 (95.6)(III-7) CF.sub.3 COOH -- 7.5 hr. toluene/ethyl- Ia-72.67 g (30 ml) ethyl acetate = 1/1- 0.24 g ethyacetate (59.8)(III-8) CF.sub.3 COOH -- 1.8 hr. toluene/acetone = 2/1 Ia-80.822 g (2 ml) CH.sub.2 Cl.sub.2 /MeOH = 9/1 0.697 g (88.8)(III-9) CF.sub.3 COOH -- 24.5 hr. toluene/ethyl Ia-92.27 g (25 ml) acetate = 1/1 1.13 g CH.sub.2 Cl.sub.2 /MeOH = (52.1) 20/1-10/1 (III-10) CF.sub.3 COOH -- 1 hr. CH.sub.2 Cl.sub.2 /MeOH = 9/1 Ia-10*0.766 g (10 ml) 0.572 g (60.5) (III-11) CF.sub.3 COOH -- 1 hr. CH.sub.2 Cl.sub.2 /MeOH = 9/1 Ia-11*0.914 g (10 ml) 0.854 g (75.4) (III-12) CF.sub.3 COOH -- 23 hr. toluene/ethyl Ia-123.42 g (35 ml) acetate = 1/1 3.15 g CH.sub.2 Cl.sub.2 /MeOH = 20/1 (96.0) (III-13) CF.sub.3 COOH -- 72 hr. toluene/ethyl Ia-133.45 g (45 ml) acetate = 1/1 2.96 g CH.sub.2 Cl.sub.2 /MeOH = 20/1 (89.4) (III-14) CF.sub.3 COOH -- 5 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1 Ia-142.82 g (35 ml) 2.62 g (97.0) (III-15) CF.sub.3 COOH -- 3 hr. toluene/acetone = 2/1 Ia-150.544 g (1 ml) (room 0.313 g temperature) (59.6) (III-16) CF.sub.3 COOH -- 4 hr. toluene/ethyl Ia-161.50 g (20 ml) acetate = 1/1 1.40 g CH.sub.2 Cl.sub.2 /MeOH = (97.4) 20/1-10/1__________________________________________________________________________ *maleate TABLE 3__________________________________________________________________________Compd. mp. (.degree.C.) Anal. Calcd. (%)No. (solvent) Found (%) IR (cm.sup.-1) NMR (.delta.)__________________________________________________________________________III-2 151.5-152.5 C.sub.20 H.sub.26 N.sub.3 O.sub.3 F.sub.3 : (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- C, 57.92(58.10) 3600, 3310, 1713 1.712(d-d, J.sub.1 =12Hz, J.sub.2 =2Hz, 2H); 1.776(quintJ= 7Hz, 2H); 2.026 Et.sub.2 O) H, 6.26(6.34) 1680, 1605, 1510 (quint, J=7Hz, 2H); 2.046(s, 1H); 2.210(t-d, J.sub.1 =13Hz, J.sub.2 =4Hz, 2H); N, 10.15(10.16) 1489 2.432(t-d, J.sub.1 =11Hz, J.sub.2 =2Hz, 2H; 2.490(t, J=7Hz, 2H); 2.601 F, 13.57(13.79) (t, J=8Hz, 2H); 2.838(d-d J.sub.1 =11Hz, J.sub.2 =2Hz, 2H); 7.595(d, J=8Hz, 2H); 7.679(d, J=8Hz, 2H); 8.619(brs, 1H)III-3 96.0-97.0 C.sub.22 H.sub.33 N.sub.3 O.sub.3 : (CHCl.sub.3) (CDCl.sub.3) (ethyl- C, 67.84(68.18) 3600, 3320, 1713 1.634(sextet, J=7Hz, 2H); 1.70.about.1.85(m, 4H); 2.018(quint, J=8Hz, acetate- H, 8.41(8.58) 1680, 1602, 1547 2H); 2.185(t-d, J.sub.1 =13Hz, J.sub.2 =4Hz, 2H); 2.38.about. 2.64(m, 8H); 7.160 Et.sub.2 O N, 10.74(10.84) 1490, 1460 (d, J=8Hz, 2H); 7.343(d, J=8Hz, 2H); 8.551(brs, 1H)III-4 84.0-85.5 (CHCl.sub.3) (CDCl.sub.3) 3600, 3320, 1713 1.235(t, J=8Hz, 3H); 1.72.about.1.83(m, 4H); 2.022(quint, J=7Hz, 2H); 1680, 1545 2.191(t-d, J.sub.1 =13Hz, J.sub.2 =4Hz, 2H); 2.4.about.2.7(m, 8H); 2.819(d-d, J.sub.1 = 12Hz, J.sub.2 =1Hz, 2H); 3.375(q, J=6Hz, 2H); 3.848(t, J=7Hz, 2H); 7.186 (d, J=8Hz, 2H); 7.442(d, J=8Hz, 2H); 8.555(brs, 1H)III-5 155.5-156.5 C.sub.25 H.sub.31 N.sub.3 O.sub.3. (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- 1/5H.sub.2 O 3600, 3320, 1713 1.84.about.1.73(m, 4H); 2.014(quint, J=8Hz, 2H); 2.247(t-d, J.sub.1 =14Hz, Et.sub.2 O) C, 70.50(70.63) 1682, 1545 J.sub.2 =4Hz, 2H); 2.458(t-d, J.sub.1 =14Hz, J.sub.2 =1H, 2H); 2.507(t, J=7Hz, 2H); H, 7.46(7.82) 2.595(t, J=8Hz, 2H); 2.853(d, J=11Hz, 2H); 3.386(q, J=6Hz, N, 9.65(9.88) 2H); 3.846(t, J=7Hz, 2H); 7.25.about.7.65(m, 9H); 8.577 (brs, 1H)III-6 149.5-150.5 C.sub.23 H.sub.35 N.sub.3 O.sub.3 (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- C, 68.48(68.80) 3600, 3320, 1713 1.303(s, 9H); 1.521(s, 1H); 1.738(d-d, J.sub.1 =11Hz, J.sub.2 =3Hz, 2H; Et.sub.2 O) H, 8.69(8.79) 1680, 1543 1.793(quint, J=8Hz, 2H); 2.022(quint, J=7Hz, 2H); 2.195(t-d, J.sub.1 = N, 10.39(10.46) 13Hz, J.sub.2 =4Hz, 2H); 2.39.about.2.53(m, 4H); 2.593(t, J=8Hz, 2H); 2.823 (d, J=11Hz, 2H); 3.375(q, J=7Hz, 2H); 3.851(t, J=7Hz, 2H); 7.38, 7.43(ABq, J=9Hz, 4H); 8.543(brs, 1H)III-7 161.0.about.162.5 C.sub.22 H.sub.33 N.sub.2 O.sub.3 Cl. (Nujol) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- 1/3H.sub.2 O 3310, 2640, 2560 0.939(t, J=7Hz, 3H); 1.630(sextet, J=7Hz, 2H); 1.781(d, J=12Hz, ethyl- C, 63.46(63.68) 1730, 1680 2H); 1.87-2.10(m, 4H); 2.246(t-d, J.sub.1 =12Hz, J.sub.2 =3Hz, 2H); 2.50- acetate) H, 8.02(8.18) 2.68(m, 8H); 2.920(d, J=12Hz, 2H); 2.957(t, J=7Hz, 2H); 3.804 H, 6.83(6.75) (t, J=7Hz, 2H); 7.156, 7.406(ABq, J=8Hz, 4H) F, 7.98(8.54)III-8 207.0-210.0 C.sub.23 H.sub.34 N.sub.2 O.sub.3 : (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- C, 63.73(71.47) 3663, 3598, 3345 1.299(s, 9H); 1.960(d, J= 14Hz, 2H); 1.95-2.13(m, 4H); 2.17-2.35 Et.sub.2 O- H, 8.09(8.87) 2630, 2460, 2410 (m, 2H); 2.606(t, J=8Hz, 2H); 2.694(t-d, J.sub.1 =14Hz, J.sub.2 =2Hz, 2H); n-hexane) N, 7.31(7.25) 1740, 1692, 1611 2.95-3.10(m, 4H); 3.25-3.45(m, 4H); 3.800(t, J=7Hz, 2H); 7.368, 1509, 1471, 1460 7.441(ABq, J=8Hz, 4H)III-9 147.0.about.148.0 C.sub.26 H.sub.25 N.sub.2 O.sub.3 F.sub.3. (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- 1/5H.sub.2 O 3600, 1738, 1693 1.715(d-d, J.sub.1 =14Hz, J.sub.2 =2Hz, 2H); 1.878(s, 1H); 1.898(quint, J=8 Et.sub.2 O) C, 59.79(59.75) 1620 Hz, 2H); 2.021(quint, J=8Hz, 2H); 2.152(t-d, J.sub.1 =14Hz, J.sub.2 =4Hz, 2H); H, 6.27(6.97) 2.451(t-d, J.sub.1 =15Hz, J.sub.2 =2Hz, 2H); 2.482(t, J=8Hz, 2H); 2.584 N, 6.79(6.37) (t, J=8Hz, 2H); 2.862(d, J=15Hz, 2H); 2.936(t, J=7Hz, 2H); 3.794 F, 14.26(14.18) (t, J=7Hz, 2H); 7.579, 7.627(ABq, J=8Hz, 4H)III-10 225.0.about.228.0 C.sub.25 H.sub.33 N.sub.3 O.sub.2. (Nujol) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- 1/10H.sub.2 O 3300, 3055, 3030 1.775(quint, J=7Hz, 2H); 1.845(d, J=14Hz, 2H); 1.89-1.96(m, 4H); MeOH-- C, 73.25(73.35) 2810, 2770, 2670 2.171(t-d, J.sub.1 =13Hz, J.sub.2 =4Hz, 2H); 2.52-2.63(m, 4H); 2.900(d, Et.sub.2 O) H, 8.26(8.18) 1606, 1528, 1487 J=12Hz, 2H); 3.25-3.38(m, 4H); 7.30-7.70(m, 9H) N, 10.21(10.27) 1471, 1456, 1448III-11 138.5.about.140.5 C.sub.23 H.sub.37 N.sub.3 O.sub.2. (Nujol) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- 2/5H.sub.2 O 3350, 3150, 1631 1.322(s, 9H); 1.76-1.94(m, 8H); 2.262(t-d, J.sub.1 =14Hz, J.sub.2 =4Hz, 2H); Et.sub.2 O) C, 70.07(69.98) 1542, 1509, 1485 2.50-2.65(m, 4H); 2.951(d, J=11Hz, 2H); 3.30-3.39(m, 4H); H, 9.54(9.65) 1460, 1441, 1388 5.738(brs, 1H); 7.378, 7.418(ABq, J=8Hz, 4H) N, 10.66(10.64)III-12 113.5.about.114.5 C.sub.20 H.sub.26 N.sub.3 O.sub.3 F.sub.3 : (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- C, 57.90(58.10) 3600, 3320, 1713 1.715(d-d, J.sub.1 =12Hz, J.sub.2 =2Hz, 2H); 1.780(quintJ=7Hz, 2H); 2.000 Et.sub.2 O) H, 6.26(6.34) 1680, 1545, 1490 (s, 1H); 2.027(quint, J=7Hz, 2H); 2.253(t-d, J.sub.1 =13Hz, J.sub.2 =4Hz, 2H); N, 10.14(10.16) 1385, 1332 2.442(d, J=12Hz, 2H); 2.504(t, J=7Hz, 2H); 2.606(t, J=8Hz, 2 F, 13.49(13.79) H); 2.854(d-d, J.sub.1 =11Hz, J.sub.2 =3Hz, 2H); 3.394(quint, J=7Hz, 2H); 3.850(t, J=7Hz, 2H); 7.474(d, J=7Hz, 1H); 7.492(t, J=7Hz, 1H); 7.746(d, J=7Hz, 1H); 7.871(s, 1H); 8.678(brs, 1H)III-13 oil -- -- (CDCl.sub.3) 1.30-1.44(m, 2H); 1.584(quint.times.2, J=7Hz, 4H); 1.747(d, J=12Hz, 2H); 2.022(quint, J=7Hz, 2H); 2.216(t-d, J.sub.1 =13Hz, J.sub.2 =4Hz, 2H); 2.41-2.49(m, 4H); 2.600(t, J=8Hz, 2H); 2.773(d, J=11Hz, 2H); 3.292 (q, J=7Hz, 2H); 3.837(t, J=7Hz, 2H); 7.598, 7.662(ABq, J=9 Hz, 4H); 8.428(brs, 1H)III-14 153.0.about.154.0 C.sub.24 H.sub.37 N.sub.3 O.sub.3 : (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- C, 69.29(69.36) 3600, 3280, 1702 1.319(s, 9H); 1.623(s, 1H); 1.71-1.86(m, 8H); 2.190(t-d, J.sub.1 =13 Et.sub.2 O) H, 8.93(8.97) (sh), 1697, 1645 Hz, J.sub.2 =4Hz, 2H); 2.39-2.58(m, 6H); 2.824(d, J=11Hz, 2H); 3.375 N, 10.14(10.11) 1530, 1480, 1460 (q, J=7Hz, 2H); 3.75-3.82(m, 2H); 7.463, 7.372(ABq, J=9Hz, 4H); 1400 9.479(brs, 1H)III-15 .about.180 -- -- (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- 1.782(d-d, J.sub.1 =14Hz, J.sub.2 =2Hz, 2H); 1.90-2.12(m, 6H); 2.275(t-d, Et.sub.2 O) J.sub.1 =14Hz, J.sub.2 =2Hz, 2H); 2.330(s, 3H); 2.600(t, J=8Hz, 4H); 2.965 (t, J=7Hz, 4H); 3.810(t, J=7Hz, 2H); 7.163, 7.394(ABq, J=8Hz, 4H)III-16 129.0.about.130.5 C.sub.28 H.sub.41 N.sub.3 O. (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- 1/3H.sub.2 O 3600, 1602, 1580 1.661(s, 1H); 1.77-1.94(m, 4H); 2.285(t-d, J.sub.1 =13Hz, J.sub.2 =2Hz, 2H); Et.sub.2 O) C, 76.08(76.15) 1505(sh), 1495, 2.460(t, J=7Hz, 2H); 2.53-2.65(m, 6H); 3.18-3.24(m, 2H); H, 9.41(9.51) 1470, 1460(sh), 6.80-7.48(m, 9H) N, 9.63(9.51) 1455, 1400, 1380__________________________________________________________________________ TABLE 4__________________________________________________________________________Compd. mp. (.degree.C.) Anal Calcd. (%)No. (solvent) Found (%) IR (cm.sup.-1) NMR (.delta.)__________________________________________________________________________Ia-2 187.0-188.5 C.sub.20 H.sub.24 N.sub.3 O.sub.2 F.sub.3.C.sub.2 H.sub.2 O.sub.4 (CHCl.sub.3) (CDCl.sub.3 --CD.sub.3 OD= 1/5) (oxalate) C, 54.45 (54.43) 3290, 2600 (br), 2.00.about.2.20(m, 4H); 2.620(t, J=8Hz, 2H); 2.98.about.2.87(brs, (i-PrOH) H, 5.38 (5.40) 1710, 1685, 1615 2H); 3.292(t, J=8Hz, 2H); 3.451(t, J=7Hz, 2H); 3.556(t, N, 8.76 (8.66) 1550, 1460 J=6Hz, 2H); 3.819(t, J=7Hz, 2H); 3.977(d, J=3Hz, F, 12.26 (11.74) 2H); 6.239(t, J=3Hz, 1H); 7.646(s, 4H)Ia-3 162.0-162.5 C.sub.26 H.sub.35 N.sub.3 O.sub.6 : (Nujol) (CDCl.sub.3) (maleate) C, 64.23 (64.31) 3330, 1705 (s), 0.935(t, J=7Hz, 3H); 1.629(sextet, J=7Hz, 2H); (i-PrOH) H, 7.23 (7.27) 1695, 1620, 1575 1.828(quint, J=7Hz, 2H); 2.015(quint, J=7Hz, 2H); N, 8.54 (8.65) 1528 2.49.about.2.64(m, 8H); 2.706(t, J=6Hz, 2H); 3.158(q, J=3Hz, 2H); 3.387(q, J=7Hz, 2H); 3.858(t, J=7Hz, 2H); 6.032(quint, J=2Hz, 1H); 7.117(d, J=8Hz, 2H); 7.302(d, J=8Hz, 2H); 8.486(brs, 1H)Ia-4 86.0-87.0 C.sub.21 H.sub.29 N.sub.3 O.sub.2 (CHCl.sub.3) (CDCl.sub.3) (ether) C, 70.97 (70.95) 3220, 1713, 1682 1.227(t, J=7Hz, 3H); 1.824(quint, J=7Hz, 2H); H, 8.11 (8.22) 1545, 1488, 1460 2.015(quint, J=7Hz, 2H); 2.527(t, J=8Hz, 2H); N, 11.97 (11.82) 2.561(brs, 2H); 2.591(t, J=8Hz, 2H); 2.629(q, J=8Hz, 2H); 3.150(q, J=3Hz, 2H); 3.386(q, J=7Hz, 2H); 3.856(t, J=7Hz, 2H); 6.017(quint, J=2Hz, 1H); 7.141(d, J=8Hz, 2H); 7.310(d, J=8Hz, 2H); 8.490(brs, 1H)Ia-5 144.0-146.0 C.sub.25 H.sub.29 N.sub.3 O.sub.2 (CHCl.sub.3) (CDCl.sub.3) (decom. point) C, 74.32 (74.41) 3320, 1702, 1680 1.840(quint, J=7Hz, 2H); 2.019(quint, J=8Hz, 2H); (ethyl acetate) H, 7.21 (7.24) 1600, 1545, 1485 2.555(t, J=8Hz, 2H); 2.584(br, 2H); 2.596(t, J=8Hz, N, 10.49 (10.41) 2H); 2.733(t, J=6Hz, 2H); 3.190(q, J=3Hz, 2H); 3.398(q, J=7Hz, 2H); 3.863(t, J=7Hz, 2H); 6.128(quint, J=3Hz, 1H); 7.26.about.7.63(m, 9H); 8.504(brs, 1H)Ia-6 173.0-174.0 C.sub.23 H.sub.33 N.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4 (NUjol) (CDCl.sub.3)(free) (decom.) C, 64.68 (64.91) 3320, 1712, 1690 1.314(s, 9H); 1.837(quint, J=7Hz, 2H); 2.022(quint, (maleate) H, 7.48 (7.46) 1620, 1580, 1543 J=7Hz, 2H); 2.5.about.2.6(m, 6H); 2.717(t, J=6Hz, 2H); (i-PrOH--MeOH) N, 8.38 (8.41) 3.169(q, J=3Hz, 2H); 3.387(q, J=6Hz, 2H); 6.023(q, J=2Hz, 1H); 7.332(s, 4H); 8.496(brs, 1H)Ia-7 190.0-191.0 C.sub.20 H.sub.24 N.sub.3 O.sub.2 F.sub.3.C.sub.2 H.sub.2 O.sub.4 (Nujol) (CDCl.sub.3) (oxalate) C, 64.39 (64.85) 2500, 1732, 1725 0.935(t, J=7Hz, 3H); 1.629(sextet, J=8Hz, 2H); (MeOH) H, 7.27 (7.26) (sh), 1685, 1610 1.978(sextet, J=7Hz, 2H); 1.989(sextet, J=7Hz, 2H); N, 6.12 (6.30) (br) 2.52-2.60(m, 8H); 2.745(t, J=6Hz, 2H); 2.973(t, J=7Hz, 2H); 3.195(q, J=3Hz, 2H); 3.795(t, J=7Hz, 2H); 6.022(quint, J=2Hz, 1H); 7.120, 7.299(ABq, J=8Hz, 4H)Ia-8 96.0-97.0 C.sub.23 H.sub.32 N.sub.2 O.sub.2 : (CHCl.sub.3) (CDCl.sub.3) (Et.sub.2 O-n-hexane) C, 75.23 (74.96) 1737, 1692, 1508 1.317(s, 9H); 1.962(sextet, J=6Hz, 2H); 1.996(sextet, H, 8.73 (8.75) 1482, 1459, 1427 J=6Hz, 2H); 2.570(q, J=8Hz, 6H); 2.721(t, J=5Hz, N, 7.65 (7.60) 1364 2H); 2.972(t, J=7Hz, 2H); 3.174(q, J=3Hz, 2H); 3.801(t, J=7Hz, 2H); 6.031(quint, J=2Hz, 1H); 7.331(s, 4H)Ia-9 149.5-150.5 C.sub.20 H.sub.23 N.sub.2 O.sub.2 F.sub.3 (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 --Et.sub.2 O) C, 63.17 (63.15) 1738, 1692, 1615 1.964(sextet, J=7Hz, 2H); 2.001(sextet, J=7Hz, 2H); H, 6.09 (6.09) 1477, 1365, 1325 2.538(q, J=8Hz, 6H); 2.745(t, J=6Hz, 2H); 2.980(t, N, 7.38 (7.36) J=7Hz, 2H); 3.207(q, J=3Hz, 2H); 3.803(t, J=7Hz, F, 15.06 (14.98) 2H); 6.160(quint, J=3Hz, 1H); 7.472, 7.565(ABq, J=8Hz, 4H)Ia-10 164.0-166.0 C.sub.25 H.sub.31 N.sub.3 O.C.sub.4 H.sub. (Nujol).4 (CD.sub.3 OD) (malenate) C, 68.89 (68.89) 3403, 3037, 2330 1.88-2.06(m, 4H); 2.951(brs, 2H); 3.20-3.40(m, 6H); (MeOH--Et.sub.2 O) H, 6.97 (6.98) 1700, 1640, 1578 3.557(brs, 2H); 3.959(brs, 2H); 6.220(s, 1H); 6.248(s, N, 8.30 (8.31) 1537, 1498, 1457 2H); 7.30-7.70(m, 9H)Ia-11 138.0-140.0 C.sub.23 H.sub.35 N.sub.3 O.C.sub.4 H.sub.4 O.sub.4.1/5H.sub .2 O (Nujol) (CD.sub.3 OD) (malenate) C, 66.16 (66.29) 3522, 3362, 2718 1.316(s, 9H); 1.87-2.08(m, 6H); 2.896(brs, 2H); (MeOH--Et.sub.2 O) H, 8.21 (8.12) 2350, 1701, 1630 3.22-3.36(m, 8H); 3.526(brs, 2H); 3.918(brs, 2H); N, 8.82 (8.59) 1579, 1524, 1498 6.117(quint, J=3Hz, 1H); 6.245(s, 2H); 7.414(s, 4H)Ia-12 128.0-129.0 C.sub.20 H.sub.24 N.sub.3 O.sub.2 F.sub.3.C.sub.4 H.sub.4 O.sub.4 (Nujol) (CDCl.sub.3) (malenate) C, 56.35 (56.36) 3300, 2300 (br), 1.831(quint, J=7Hz, 2H); 2.027(quint, J=8Hz, 2H); (i-PrOH--MeOH) H, 5.55 (5.52) 1710, 1638, 1625 2.51-2.65(m, 6H); 2.729(t, J=6Hz, 2H); 3.186(q, N, 8.21 (8.22) 1570, 1530, 1500 J=3Hz, 2H); 3.397(q, J=7Hz, 2H); 3.865(t, J=7Hz, F, 11.08 (11.14) 1460, 1445 2H); 6.145(quint, J=2Hz, 1H); 7.41-7.63(m, 4H); 8.517(brs, 1H)Ia-13 128.0-129.5 C.sub.22 H.sub.28 N.sub.3 O.sub.2 F.sub.3.C.sub.2 H.sub.2 O.sub.4.1/2PrOH (Nujol) (CDCl.sub.3) (oxalate) C, 56.18 (56.35) 3510, 3310, 1708 1.35-1.47(m, 2H); 1.613(quint.times.2 , J=7Hz, 4H); (MeOH-i-PrOH) H, 6.23 (6.39) 1690, 1680, 1615 2.025(quint, J=8Hz, 2H); 2.44-2.65(m, 6H); N, 7.70 (7.73) 1537, 1480, 1460 2.716(t, J=5Hz, 2H); 3.181(q, J=3Hz, 2H); 3.312(q, F, 10.22 (10.49) J=6Hz, 2H); 3.862(t, J=7Hz, 2H); 6.157(quint, J=2Hz, 1H); 7.472, 7.563(ABq, J=8Hz, 4H); 8.419(brs, 1H)Ia-14 185.0-186.5 C.sub.24 H.sub.35 N.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4 (Nujol) (CDCl.sub.3) (malenate) C, 65.53 (65.48) 3285, 1695, 1648 1.312(s, 9H); 1.77-1.88(m, 6H); 2.49-2.56(m, 6H); (MeOH) H, 7.62 (7.65) 1620, 1580, 1523 2.704(t, J=6Hz, 2H); 3.160(q, J=3Hz, 2H); 3.380(q, N, 8.24 (8.18) 1477, 1460, 1450 J=7Hz, 2H); 3.75-3.82(m, 2H); 6.026(quint, J=2Hz, 1H); 7.328(s, 4H); 9.444(brs, 1H)Ia-15 109.5-110.0 C.sub.20 H.sub.26 N.sub.2 O.sub.2 (CHCl.sub.3) (CDCl.sub.3) (Et.sub.2 O-n-hexane) C, 73.79 (73.59) 1738, 1692, 1512 1.939(quint, J=7Hz, 2H); 2.007(quint, J=7Hz, 2H); H, 8.08 (8.03) 1485, 1460, 1430 2.328(s, 3H); 2.49-2.63(m, 4H); 2.713(t, J=5Hz, 2H); N, 8.55 (8.58) 1367 2.969(t, J=7Hz, 2H); 3.153(q, J=3Hz, 2H); 3.794(t, J=7Hz, 2H); 6.018(quint, J=2Hz, 1H); 7.115, 7.280(ABq, J=8Hz, 4H)Ia-16 105.0-106.0 C.sub.28 H.sub.39 N.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4 (Nujol) (CDCl.sub.3) (malenate) C, 66.49 (66.54) 1710, 1622, 1598 1.315(s, 9H); 1.78-1.84(m, 8H); 2.43-2.75(m, 8H); (i-PrOH--Et.sub.2 O) H, 7.26 (7.29) 1575, 1495(sh), 3.16-3.25(m, 6H); 6.043(quint, J=2Hz, 1H); 210.0-212.5 N, 6.59 (6.47) 1480, 1462, 1450 6.80-7.34(m, 9H) (MeOH) 1385, 1360__________________________________________________________________________

EXAMPLE 17

1-[4-{4-(4-trifluoromethylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}-butylcarbamoyl]-2-oxopyrrolidine (Ia-17) ##STR21##

(1) A solution of 2.00 g of 4-hydroxy-4-(4-trifluoromethylphenyl)piperidine (II-2) and 2.42 g of phthalimido butyl bromide in 20 ml of DMF in the presence of 2.26 g of K.sub.2 CO.sub.3 is stirred at 105.degree. C. for 6 hours. The reaction mixture is poured into ice-water, and the solution is extracted with ethyl acetate. The organic layer is washed with water, dried over Na.sub.2 SO.sub.4 and concentrated under reduced pressure. The obtained residue is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol (20/1 v/v). The purified substance is recrystallized from methylene chloride/ether to prepare 3.0 g of the compound (IV-1). mp. 139.0.degree.-140.5.degree. C.

Anal Calcd. (%) for C.sub.24 H.sub.25 N.sub.2 O.sub.3 F.sub.3 : C, 64.23; H, 5.73; N, 6.10; F, 12.98. Found: C, 64.57; H, 5.64; N, 6.27; F, 12.77.

IR (CHCl.sub.3): 3590, 1772, 1713, 1618, 1470, 1440, 1409(sh), 1389.

NMR (CDCl.sub.3) (200 MHz) .delta.:1.52-1.80 (m, 6H); 1.843 (s, 1H); 2.152 (td, J.sub.1 =13 Hz, J.sub.2 =4 Hz, 2H); 2.37-2.50 (m, 4H); 2.838 (dd, J.sub.1 =9 Hz, J.sub.2 =2 Hz, 2H); 3.728 (t, J=7 Hz, 2H); 7.613, 7.640 (ABq, J=9 Hz, 4H) 7.7-7.9 (m, 4H).

(2) A solution of 2.56 g of the compound (IV-1) and 424 mg of hydrazine hydrate in 25 ml of ethanol is refluxed for 3 hours. After the excess agent is distilled off under reduced pressure, the residue is mixed with 1.15 g of 1-phenoxycarbonyl-2-oxopyrrolidine and heated at 105.degree. C. for 1.5 hours. The reaction mixture is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol=20/1-10/1 v/v. The obtained material is recrystallized from methylene chloride-ether to prepare 1.76 g (Yield: 73.5%) of the objective compound (III-17) as colorless needles. mp. 150.5.degree.-152.0.degree. C.

Anal Calcd. (%) for C.sub.21 H.sub.28 N.sub.3 O.sub.3 F.sub.3 : C, 58.78; H, 6.51; N, 9.75; F, 13.56. Found: C, 59.01; H, 6.60; N, 9.83; F, 13.33.

IR (CHCl.sub.3): 3590, 3320, 1713, 1680, 1618, 1545, 1489, 1460, 1409, 1385, 1328.

NMR (CDCl.sub.3): 1.57-1.63 (m, 4H); 1.743 (d, J=12 Hz, 2H); 2.019 (quint, J=7 Hz, 2H); 2.189 (td, J.sub.1 =13 Hz, J.sub.2 =4 Hz, 2H); 2.341 (s, 1H); 2.42-2.55 (m, 4H); 2.595 (t, J=8 Hz, 2H); 2.862 (dd, J.sub.1 =10 Hz, J.sub.2 =2 Hz, 2H); 3.311 (q, J=6 Hz, 2H); 3.822 (t, J=7 Hz, 2H); 7.591, 7.653 (ABq, J=9 Hz, 4H); 8.438 (brs, 1H)

(3) A solution of 1.40 g of the compound (III-17) in 20 ml of trifluoro acetic acid is refluxed for 72 hours. After removal of the excess reagent, the residue is poured into sodium hydroxide, and the solution is extracted with ethyl acetate. The organic layer is dried over MgSO.sub.4 and concentrated under reduced pressure. The oily residue is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol (20/1 v/v) and recrystallized from i-PrOH-ether to prepare 1.31 g (Yield: 97.7%) of the objective compound (Ia-17) as needles.

mp. 136.0.degree.-136.5.degree. C.

Anal Calcd. (%) for C.sub.21 H.sub.26 N.sub.3 O.sub.2 F.sub.3 : C, 61.87; H, 6.49; N, 10.26; F, 13.87. Found: C, 61.60; H, 6.40; N, 10.26; F, 13.92.

IR (CHCl.sub.3): 3310, 1713, 1680, 1615, 1545, 1487, 1458, 1385, 1327.

NMR (CDCl.sub.3) (200 MHz) .delta.:1.55-1.67 (m, 4H); 2.031 (quint, J=8 Hz, 2H); 2.47-2.65 (m, 6H); 2.725 (t, J=5 Hz, 2H); 3.190 (q, J=3 Hz, 2H); 3.344 (q, J=6 Hz, 2H); 3.857 (t, J=8 Hz, 2H); 6.154 (quint, J=2 Hz, 1H); 7.471, 7.564 (ABq, J=8 Hz, 4H); 8.436 (brs, 1H).

EXAMPLE 18

1-[N-propyl-N-[3-{4-(4-t-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}-propylcarbamoyl]]-2-oxopyrrolidine (Ia-18) ##STR22##

(1) A solution of 2.00 g of the compound (II-6) and 1.42 g of 3-bromo-1-chloropropane in 30 ml of DMF is stirred in the presence of 2.37 g of K.sub.2 CO.sub.3 at room temperature for 3.5 hours. The reaction mixture is poured into ice-water, and the solution is extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure to prepare 1.32 g of the compound (IV-2).

(2) A solution of 0.5 g of the compound (IV-2) and 0.44 ml of n-propyl in 1 ml of DMF is heated at 105.degree. C. for 2 hours under stirring. The mixture is concentrated, and the residue is poured into aq.NaOH. The solution is extracted with methylene chloride, the organic layer is dried over MgSO.sub.4 under reduced pressure. The oily residue is mixed with 310 mg of 1-phenoxycarbonyl-2-oxopyrrolidine and reacted at 115.degree. C. for 2 hours. The reaction mixture is dissolved into methylene chloride, washed with aq.NaOH and aq.NaCl in order, dried over Na.sub.2 SO.sub.4, and concentrated under reduced pressure. The oily residue is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol (20/1-10/1 v/v) to prepare 500 mg (Yield: 70.0%) of the compound (III-18) as an oil.

IR (CHCl.sub.3): 3595, 1720, 1665, 1605, 1517, 1465(sh), 1460, 1425, 1400, 1375.

NMR (CDCl.sub.3): 0.889 (t, J=7 Hz, 3H); 1.316 (s, 9H); 1.594 (q, J=8 Hz, 2H); 1.74-1.89 (m, 4H); 2.076 (quint, J=7 Hz, 2H); 2.207 (t, J=15 Hz, 2H); 2.435 (t, J=8 Hz, 2H); 2.48-2.60 (m, 4H); 2.80-2.90 (m, 2H); 3.317 (t, J=4 Hz, 2H); 3.421 (t, J=4 Hz, 2H); 3.712 (t, J=7 Hz, 2H); 7.368, 7.436 (ABq, J=8 Hz, 4H)

(3) A solution of 1.40 g of the compound (III-17) in 15 ml of trifluoroacetic acid is refluxed for 2.5 hours. The solution is concentrated, and the residue is poured into aq.NaOH. The solution is extracted with ethyl acetate, and the organic layer is dried over MgSO.sub.4 and concentrated under reduced pressure. The oily residue is subjected to column chromatography with silica gel, eluting with toluene/ethyl acetate (1/1 v/v) to prepare 1.07 g (Yield: 80%) of the objective compound (Ia-18) as an oil.

mp. 158.5.degree.-159.5.degree. C. (dec.).

Anal Calcd. (%) for C.sub.26 H.sub.39 N.sub.3 O.sub.2.C.sub.2 H.sub.2 O.sub.4.1/2H.sub.2 O: C, 64.38; H, 8.11; N, 8.05. Found: C, 64.10; H, 8.07; N, 8.01.

IR (Nujol): 3420, 2720, 2590, 2500, 1715, 1692, 1675(sh), 1610(br), 1515, 1460.

NMR (CD.sub.3 OD) (200 MHz) .delta.:0.894 (t, J=7 Hz, 3H); 1.312 (s, 9H); 1.618 (q, J=7 Hz, 2H); 2.117 (quint, J=7 Hz, 4H); 2.458 (t, J=8 Hz, 2H); 2.872 (brs, 2H); 3.28-3.37 (m, 4H); 3.49-3.56 (m, 4H); 3.695 (t, J=7 Hz, 2H); 3.932 (brs, 2H); 6.089 (quint, J=2 Hz, 1H); 7.402 (s, 4H).

EXAMPLE 19

1-[3-{4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propyl]pyrrolidine (Ia-19) ##STR23##

(1) A mixture of 10.061 g of the compound (II-6) and 5.41 ml of 3-chloro-1-propanol is stirred at 140.degree. C. for 6 hours in the presence of 12.03 ml of Et.sub.3 N. The reaction mixture is recrystallized from methylene chloride-ether-n-hexane to prepare 9.357 g (Yield: 74.0%) of the compound (IV-3). mp. 122.5.degree.-123.5.degree. C.

Anal Calcd. (%) for C.sub.18 H.sub.29 NO.sub.2.1/10H.sub.2 O C,73.72; H,9.93; N,4.82. Found: C,73.73; H,10.04; N,4.78.

IR (CHCl.sub.3) cm.sup.-1 : 3600, 3225, 1509, 1472, 1437, 1424, 1399, 1372 (sh), 1366.

NMR (CDCl.sub.3) .delta.:1.31 (s, 9H); 1.62-1.85 (m, 4H); 2.119 (td, J.sub.1 =13 Hz, J.sub.2 =4 Hz, 2H); 2.507 (td, J.sub.1 =12 Hz, J.sub.2 =2 Hz, 2H); 2.707 (t, J=6 Hz, 2H); 2.973 (d, J=11 Hz, 2H); 3.829 (t, J=6 Hz, 2H); 7.367, 7.417 (ABq, J=8 Hz, 4H).

(2) A mixture of 10.568 g of the compound (IV-3) and 26.4 ml of thionyl chloride is stirred at room temperature overnight. Excess reagent is distilled off under reduced pressure, and the residue is poured into aq.Na.sub.2 CO.sub.3. The solution is extracted with methylene chloride, and the organic layer is dried over MgSO.sub.4 and concentrated. The residue is subjected to column chromatography with silica gel, eluting with toluene/acetone (8/1-6/1 v/v) and recrystallized from n-hexane to prepare 2.167 g (Yield: 20.5%) of the compound (V-1) as colorless crystals.

Anal Calcd. (%) for C.sub.18 H.sub.26 NCl: C, 73.86; H, 9.08; N, 4.96; Cl, 12.35. Found: C, 74.07; H, 8.98; N, 4.80; Cl, 12.15.

IR (CHCl.sub.3): 1640, 1610, 1510, 1470, 1390, 1380.

NMR (CDCl.sub.3): 1.315 (s, 9H); 2.041 (quint, J=7 Hz, 2H); 2.50-2.66 (m, 4H); 2.714 (t, J=5 Hz, 2H); 3.169 (q, J=3 Hz, 2H); 3.638 (t, J=7 Hz, 2H); 6.032 (quint, J=3H, 1H); 7.334 (s, 4H).

(3) A mixture of 621 mg of the compound (V-1) and 1.78 ml of pyrrolidine is stirred at room temperature for 72 hours. The excess reagent is distilled off, and the residue is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol/ammonia (128/16/1 v/v) to prepare 675 mg of the compound (Ia-19) as an oil, which is crystallized as maleate and recrystallized from methanol to give 800 mg (yield: 67.3%) of colorless plates. mp. 190.0.degree.-191.0.degree. C. (dec.).

Anal Calcd. (%) for C.sub.22 H.sub.34 N.sub.2 O.sub.2.C.sub.4 H.sub.4 O.sub.4 : C, 64.74; H, 7.58; N, 5.11. Found: C, 64.50; H, 7.58; N, 5.01.

IR (Nujol): 2355, 1711, 1620, 1577, 1543, 1479(sh), 1461, 1378.

NMR (CD.sub.3 OD) .delta.:1.314 (s, 9H); 2.122 (quint, J=3 Hz, 2H); 2.20-2.37 (m, 2H); 2.907 (brs, 2H); 3.30-3.43 (m, 6H); 3.567 (t, J=6 Hz, 2H); 3.949 (brs, 2H); 6.129 (brs, 1H); 6.269 (s, 2H); 7.416 (s, 4H).

EXAMPLE 20

1-[3-{4-(4-trifluoromethyl)-1,2,5,6-tetrahydropyridin-1-yl}-propyl]pyrrolidine (Ia-20) ##STR24##

(1) A mixture of 5.00 g of the compound (II-2) and 2.22 ml of 3-chloro-1-propanol is stirred in the presence of 4.27 ml of Et.sub.3 N at 140.degree. C. for 8 hours. The mixture is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol/ammonium=64/8/1-32/6/1 v/v. The obtained purified substance is recrystallized from ether-n-hexane to prepare 5.155 g (Yield: 75.7%) of the compound (IV-4). mp. 116.0.degree.-116.5.degree. C.

Anal Calcd. (%) for C.sub.15 H.sub.20 NO.sub.2 F.sub.3 : C, 59.31; H, 6.59; N, 4.69; F, 18.70. Found: C, 59.40; H, 6.65; N, 4.62; F, 18.79.

IR (Nujol): 3335, 3075, 2773, 1617, 1462, 1436, 1407, 1378.

NMR (CDCl.sub.3) .delta.:1.73-1.83 (m, 4H); 2.119 (td, J.sub.1 =13 Hz, J.sub.2 =4 Hz, 2H); 2.494 (td, J.sub.1 =12 Hz, J.sub.2 =3 Hz, 2H); 2.716 (t, J=6 Hz, 2H); 3.009 (d-d, J.sub.1 =12 Hz, J.sub.2 =2 Hz, 2H); 3.836 (t, J=6 Hz, 2H); 7.612 (s, 4H).

(2) The compound (IV-4) 4.892 g is treated in the same manner as Example 19(2) to prepare 3.357 g of the compound (V-2) as an oil.

IR (CHCl.sub.3): 1608, 1453, 1439, 1399, 1368(sh), 1319.

NMR (CDCl.sub.3): 2.036 (quint, J=7 Hz, 3H); 2.54-2.62 (m, 2H); 2.636 (t, J=7 Hz, 2H); 2.733 (t, J=6 Hz, 2H); 3.192 (q, J=3 Hz, 2H); 3.635 (t, J=7 Hz, 2H); 6.152 (quint, J=2 Hz, 1H); 7.466, 7.562 (ABq, J=8 Hz, 4H).

(3) A mixture of 1.05 g of the compound (V-2) and 1.44 ml of pyrrolidine is stirred at room temperature for 32.5 hours, and the reaction mixture is treated in the same manner as Example 19 (3) to prepare 1.15 g (Yield: 98.2%) of the objective compound (Ia-20) as crystals. The malenate is recrystallized from methanol to prepare 1.04 g (Yield: 98.2%) of colorless needles. mp. 175.0-178.0 (dec.).

Anal. Calcd. (%) for C.sub.19 H.sub.25 N.sub.2 F.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4 C, 57.92; H, 5.74; N, 4.97; F, 10.05. Found: C, 56.84; H, 5.83; N, 4.91; F, 9.99.

IR (Nujol): 2590, 2360, 2160, 1711, 1620, 1560, 1535(sh), 1483, 1458, 1378, 1359.

NMR (CD.sub.3 OD): 2.119 (quint, J=3 Hz, 4H); 2.20-2.37 (m, 2H); 2.92 7 (brs, 2H); 3.28-3.50 (m, 8H); 3.566 (t, J=6 Hz, 2H); 3.971 (q, J=2 Hz, 2H); 6.266 (s, 4H); 6.295 (brs, 1H); 7.681 (s, 4H).

EXAMPLE 21

1-[3-{4-(4-methylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propyl]pyrrolidine (Ia-21) ##STR25##

(1) A mixture of 10.20 g of the compound (II-8) and 5.51 ml of 3-chloro-1-propanol is stirred in the presence of 11 ml of Et.sub.3 N at 140.degree. C. for 5.5 hours. The reaction mixture is recrystallized from methylene chloride-ether to prepare 8.51 g (Yield: 64.0%) of the compound (IV-5). mp. 110.5.degree.-111.5.degree. C.

Anal Calcd. (%) for C.sub.15 H.sub.23 NO.sub.2 : C, 72.01; H, 9.25; N, 5.58. Found: C, 72.25; H, 9.30; N, 5.62.

IR (CHCl.sub.3): 3597, 3220, 1513, 1470, 1452, 1437, 1423, 1397.

NMR (CDCl.sub.3) .delta.:1.67-1.81 (m, 4H); 2.087 (td, J.sub.1 =13 Hz, J.sub.2 =4 Hz, 2H); 2.337 (s, 3H); 2.479 (td, J.sub.1 =15 Hz, J.sub.2 =3 Hz, 2H); 2.693 (t, J=6 Hz, 2H); 2.952 (d, J=11 Hz, 2H); 3.828 (t, J=5 Hz, 2H); 7.168, 7.372 (ABq, J=8 Hz, 4H).

(2) A solution of 12.82 g of the compound (IV-5) in 38 ml of trifluoroacetic acid is refluxed for 3.1 hours. The reaction mixture is concentrated, and the residue is poured into aq.NaHCO.sub.3. The mixture is extracted with ethyl acetate, and the organic layer is dried over MgSO.sub.4 and concentrated under reduced pressure. The oily substance is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol/NH.sub.4 OH (128/16/1 v/v). A mixture of 870 mg of the product and 8.01 ml of thionyl chloride is stirred at room temperature for 2 hours. The excess reagent is distilled away under reduced pressure. The residue is washed with ether and dried under reduced pressure to give 1.067 g (Yield: 99.2%) of the objective compound (V-3) as a light yellowish powder.

IR (CHCl.sub.3): 1600, 1510, 1460, 1410.

NMR (CDCl.sub.3): 2.046 (quint, J=7 Hz, 2H); 2.334 (s, 3H); 2.54, 2.64 (m, 2H); 2.629 (t, J=7 Hz, 2H); 2.723 (t, J=5 Hz, 2H); 3.173 (q, J=2 Hz, 2H); 3.630 (t, J=7 Hz, 2H); 6.023 (quint, J=2 Hz, 1H); 7.123, 7.287 (ABq, J=8 Hz, 4H).

(3) A mixture of 466 mg of the compound (V-3) and 0.78 ml of pyrrolidine is stirred at 50.degree. C. for 3 hours and treated in the same manner as Example 19(3) to give the maleate of the objective compound (Ia-21). It is recrystallized from methanol-iPrOH to prepare 225 mg (Yield: 42.5%) of the compound (Ia-21) as needles. mp. 180.0.degree.-181.0.degree. C. (dec.)

Anal Calcd. (%) for C.sub.19 H.sub.28 N.sub.2.2C.sub.4 H.sub.4 O.sub.4 : C, 62.84; H, 6.99; N, 5.48. Found: C, 62.78; H, 7.02; N, 5.42.

EXAMPLE 22-29

The compound (V-1), (V-2) and (V-3), each of which were obtained in Step 1 of Example 19-21, are reacted with amine (VII) in the same manner as Step 3 in Example 19-21 to prepare the compound (Ia). The reaction conditions and physical constants are shown in table 5 and 6.

TABLE 5__________________________________________________________________________ ##STR26## ##STR27##Ex. starting reaction purification productNo. material RH condition condition mg (%)__________________________________________________________________________22 (V-1) HN(i-Bu).sub.2 33 hours CH.sub.2 Cl.sub.2 /MeOH = Ia-22*.sup.1 0.628 g 3.76 ml reflux 49/1-19/1 685 mg (51.1%)23 (V-2) HN(i-Bu).sub.2 32 hours CH.sub.2 Cl.sub.2 /MeOH = Ia-23*.sup.1 0.602 g 1.50 g reflux 49/1-19/1 338 mg (27.1%)24 (V-3) HN(i-Bu).sub.2 20 hours CH.sub.2 Cl.sub.2 /MeOH = Ia-24*.sup.1 0.517 g 1.36 g reflux 49/1 457 mg (38.4%)25 (V-3) 0.924 g ##STR28## 150.degree. C. 8.15 hours toluene/acetone = 19/1-9/1 Ia-25*.sup.1 930 mg (54.4%)26 (V-3) 0.624 g ##STR29## 150.degree. C. 4.1 hours CH.sub.2 Cl.sub.2 /MeOH = 19/1 Ia-26*.sup.1 963 mg 66.6%)27 (V-2) 1.02 g ##STR30## 100.degree. C. 25 hours (in DMF) toluene/acetone = 3/11/1 Ia-27*.sup.1 266 mg (15.3%)28 (V-2) H.sub.2 N-i-Bu 15.6 hours CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH Ia-28 0.645 g 1.1 ml reflux 64/8/1 461 mg (63.8%)29 (V-1) 0.828 g ##STR31## 150.degree. C. 3 hours CH.sub.2 Cl.sub.2 /MeOH = 29/1-19/1 Ia-29*.sup.1 773__________________________________________________________________________ mg (70.2%) *.sup.1 separated as maleate *.sup.2 prepared by the reaction with 492 mg of isoindoline and 162 mg of 60% NaH in 5 ml of DMF at 100.degree. C. for 1 hour. TABLE 6__________________________________________________________________________Compd. mp. (.degree.C.) Anal Cald. (%)No. Rec. sol.*.sup.1 Found (%) IR (cm.sup.-1) NMR (.delta.) (200MHz)__________________________________________________________________________Ia-22 (maleate) C.sub.26 H.sub.44 N.sub.2 O.sub.2.C.sub.4 H.sub.4 O.sub.4 (Nujol) (CD.sub.3 OD) 176.5.about.178.0 C, 63.46 (63.68) 2620, 2510, 1690 1.083(d, J=7Hz, 12H); 1.314(s, 9H); 2.158(7tet, J=7Hz, (MeOH--Et.sub.2 O) H, 8.02 (8.18) 1657, 1618, 1579 2H); 2.20-2.37(m, 2H); 2.913(brs, 2H); 3.042(d, J=7Hz, needleshaped N, 6.83 (6.75) 1533, 1488, 1460 4H); 3.25-3.37(m, 4H); 3.588(t, J=6Hz, 2H); 3.974(s, 2H); crystals F, 7.98 (8.54) 1409, 1378 6.131(s, 1H); 6.272(s, 4H); 7.419(s, 4H)Ia-23 (maleate) C.sub.23 H.sub.35 N.sub.2 F.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4 (Nujol) (CD.sub.3 OD) 135.0.about.136.5 C, 59.12 (59.23) 2420, 1707, 1616 1.071(d, J=7Hz, 12H); 2.05-2.35(m, 4H); 2.90-3.30(m, (MeOH--Et.sub.2 O) H, 6.76 (6.89) 1572, 1485, 1456 4H); 3.20-3.30(m, 4H); 3.559(brs, 2H); 3.972(brs, 2H); needleshaped N, 4.35 (4.46) 1377 J=7Hz, 2H) 2.54-2.61(m, 2H); 2.747(t, J=5Hz, 2H); crystals F, 9.05 (9.07) 6.260(s, 5H); 7.674(s, 4H)Ia-24 (maleate) C.sub.23 H.sub.38 N.sub.2.C.sub.4 H.sub.4 O.sub.4 (Nujol) (CDCl.sub.3) 140.5.about.142.5 C, 64.67 (64.79) 2710, 2500, 1706 0.872(d, J=7Hz, 12H); 1.685(quint, J=7Hz, 4H); 2.059(d, (MeOH--Et.sub.2 O) H, 7.99 (8.07) 1572, 1480, 1455 J=7Hz, 4H); 2.329(s, 3H); 2.33-2.60(m, 6H); 2.712(t, needleshaped N, 4.69 (4.87) 1375 J=5Hz, 2H); 3.161(q, J=3Hz, 2H); 6.021(quint, J=2Hz, crystals 1H); 7.116, 7.283(ABq, J=9Hz, 4H)Ia-25 (maleate) C.sub.24 H.sub.30 N.sub.2 O.sub.2.C.sub.4 H.sub.4 O.sub.4 (Nujol) (CD.sub.3 OD) 148.0.about.150.0 C, 72.65 (72.70) 2720, 2575(sh), 1.80-2.01(m, 4H); 2.331(s, 3H); 2.48-2.63(m, 4H); 2.712(t, (iPrOH--Et.sub.2 O) H, 7.36 (7.41) 2490(sh), 2330, J=7Hz, 2H); 2.747(t, J=7Hz, 2H); 3.162(q, J=3Hz, 2H); N, 6.11 (6.06) 1708, 1652, 1600 3.283(t, J=6Hz, 2H); 3.329(t, J=7Hz, 2H); 6.026(quint, 1571, 1502, 1459 J=2Hz, 1H); 6.50-6.64(m, 2H); 6.91-7.32(m, 6H)Ia-26 (maleate) C.sub.24 H.sub.30 N.sub.2 O.sub.2.C.sub.4 H.sub.4 O.sub. (Nujol) (CDCl.sub.3) 191.0.about.192.0 C, 66.48 (66.42) 3030, 2720, 2278 1.322(s, 9H); 1.76-1.94(m, 8H); 2.262(t-d, J.sub.1 =14Hz, (MeOH--H.sub.2 O) H, 6.61 (6.62) 1711, 1623, 1572 J.sub.2 =4Hz, 2H); 2.50-2.65(m, 4H); 2.951(d, J=11Hz, 2H); needleshaped N, 4.92 (4.84) 1532, 1513(sh), 3.30-3.39(m, 4H); 5.738(brs, 1H); 7.378, 7.418(ABq, crystals 1485, 1463, 1435 J=8Hz, 4H)Ia-27 (maleate) C.sub.23 H.sub.23 F.sub.3 N.sub.2 O.C.sub.4 H.sub.4 (CHCl.sub.3) (CD.sub.3 OD) 152.5.about.154.0 C, 62.64 (62.79) 2700-1750 (br): 2.236(quint, J=7Hz, 2H); 2.934(brs, 2H); 3.334(t, J=7Hz, (MeOH--Et.sub.2 O) H, 5.29 (5.27) 1695, 1663, 1619 2H); 2.369(t, J=5Hz, 2H); 3.808(t, J=7Hz, 2H); 4.010(s, needleshaped N, 5.48 (5.42) 1532, 1463, 1412 2H); 4.606(s, 2H); 6.230(brs, 2H); 6.298(brs, 1H); crystals F, 11.00 (11.03) 1378, 1358 7.51-7.81(m, 9H)Ia-28 (maleate) C.sub.19 H.sub.27 N.sub.2 F.sub.3.C.sub.4 H.sub.4 O.sub.4 (Nujol) (CDCl.sub.3) 182.5.about.184.0 -- 3483, 2723, 2679 0.952(d, J=7Hz, 6H); 2.093(quint, J=7Hz, 3H); 2.636(brs, (MeOH--Et.sub.2 O) 2587, 2415, 1703 2H); 2.727(d, J=7Hz, 2H); 2.771(t, J=6Hz, 2H); 2.898(t, needleshaped 1618, 1579, 1478 J=6Hz, 2H); 3.149(t, J=6Hz, 2H); 3.29-3.33(m, 2H); crystals 1460, 1412, 1382 6.184(quint, J=2Hz, 1H); 7.474, 7.587(ABq, J=8Hz, 4H)Ia-29 (maleate) C.sub.27 H.sub.36 N.sub.2.2C.sub.4 H.sub.4 O.sub.4.1/10H.sub .2 O (Nujol) (CD.sub.3 OD) 183.5.about.185.0 C, 67.29 (67.59) 2340, 1708, 1619 1.330(s, 9H); 2.424(brs, 2H); 2.867(brs, 2H); 3.204(brs, (CHCl.sub.3 --MeOH) H, 7.08 (7.16) 1568, 1528(sh), 2H); 3.370(brs, 4H); 3.544(brs, 4H); 3.948(s, 2H); 4.403(s, needleshaped N, 4.56 (4.50) 1485, 1461 2H); 6.060(s, 1H); 6.252(s, 4H); 7.15-7.44(m, 8H) crystals__________________________________________________________________________ *.sup.1 a solvent for recrystallization

EXAMPLE 30

1-[(3-methylamino)propyl]-4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridine (Ia-30) ##STR32##

(1) A solution of 3.60 g of the compound (II-6) and 2.80 g of 1-ethoxycarbonylamino-3-chloropropane in 30 ml of DMF is reacted in the presence of 4.26 g of K.sub.2 CO.sub.3 and 3.46 g of NaI at 105.degree.-110.degree. C. for 6 hours. The reaction mixture is poured into ice water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over MgSO.sub.4 and evaporated under reduced pressure. The residue is subjected to column chromatography with silica gel, eluting with methylene chlorde/methanol (10/1-5/1 v/v) to give 4.60 g (Yield: 82.0%) of the compound (IV-6) as crystals. Recrystallization from methylene chloride-ether gives colorless needles. mp. 111.5.degree.-113.0.degree. C.

Anal Calcd. (%) for C.sub.21 H.sub.34 N.sub.2 O.sub.3.1/5H.sub.2 O: C, 68.92; H, 9.37; N, 7.78 Found: C, 68.89; H, 9.47; N, 7.65

IR (Nujol): 3320, 1715, 1700, 1535

NMR (CDCl.sub.3) .delta.:1.242 (t, J=7 Hz, 3H); 1.320 (s, 9H); 1.66-1.84 (m, 4H); 2.210 (td, J.sub.1 =13 Hz, J.sub.2 =4 Hz, 2H) 2.45-2.60 (m, 4H); 2.877 (d, J=12 Hz, 2H); 3.286 (q, J=6 Hz, 2H); 4.103 (q, J=7 Hz, 2H); 5.929 (brs, 1H); 7.376,7.443 (ABq, J=8 Hz, 4H)

(2) A solution of 4.30 g of the compound (IV-6) obtained above in 35 ml of trifluoroacetic acid is refluxed for 5 hours and treated in the same manner as Example 7(2) to prepare 4.05 g (Yield: 99.0%) of the compound (V-4) as an oil.

(3) To a suspension of 146 mg of lithium aluminium hydride in 15 ml of dry ether is added dropwise a solution of 530 mg of the compound (V-4) in 15 ml of THF under stirring. After reflux for 8 hours, the excess reagents are decomposed by careful addition of aq. NaOH and filtered off. The resulting organic layer is dried and evaporated under reduced pressure to prepare 420 mg (Yield: 95.2%) of the compound (Ia-30) as an oil.

IR (CHCl.sub.3):3290, 1602, 1510, 1470, 1445.

NMR (CDCl.sub.3):1.321 (s, 9H); 1.780 (quint, J=7 Hz, 2H); 2.444 (s, 3H); 2.48-2.62 (m, 2H); 2.532 (t, J=7 Hz, 2H); 2.672 (t, J=7 Hz, 2H); 3.152 (q, J=3 Hz, 2H); 6.039 (quint, J=2 Hz, 1H); 7.333 (s, 4H)

EXAMPLE 31

1-[N-methyl-N-[3-{4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propylcarbamoyl]]-2-oxopyrrolidine (Ia-31) ##STR33##

A mixture of 400 mg of the compound (Ia-30) obtained in Example 30 and 280 mg of 1-phenoxycarbonyl-2-oxopyrrolidine is heated at 115.degree. C. for 2 hours. The reaction mixture is subjected to column chromatography with silica gel, eluting with toluene/ethyl acetate (1/1)-methylene chloride/methanol (20/1) to prepare 370 mg (Yield: 68.5%) of the compound (Ia-31) as an oil. The tosylate is recrystallized from ethyl acetate/methanol to prepare needles.

mp. 128.0.degree.-134.0.degree. C.

Anal Calcd. (%) for C.sub.24 H.sub.35 N.sub.3 O.sub.2.C.sub.7 H.sub.8 O.sub.3 S.H.sub.2 O: C, 63.51; H, 7.56; N, 7.16; S, 5.37 Found:C, 63.35; H, 7.72; N, 7.15; S, 5.45

IR (Nujol) cm.sup.- :3570, 3500, 2740, 2630, 1720, 1690, 1675(sh), 1663, 1475, 1120, 1033.

NMR (CDCl.sub.3) .delta.:1.314 (s, 9H); 1.895 (quint, J=7 Hz, 2H); 2.071 (quint, J=7 Hz, 2H); 2.454 (t, J=8 Hz, 2H); 2.50-2.60 (m, 4H); 2.720 (t, J=5 Hz, 2H); 2.995 (s, 3H); 3.174 (q, J=3 Hz, 2H); 3.461 (t, J=7 Hz, 2H); 3.735 (t, J=7 Hz, 2H); 6.024 (quint, J=2 Hz, 1H); 7.244, 7.348 (ABq, J=8 Hz, 4H)

EXAMPLE 32

1-[(3-methylamino)propyl]-4-(4-phenylphenyl-1,2,5,6-tetrahydropyridine (Ia-32) ##STR34##

(1) A solution of 3.20 g of the compound (II-5) and 2.30 g of 1-ethoxycarbonylamino-3-chloropropane in 30 ml of DMF is reacted in the presence of 3.48 g of K.sub.2 CO.sub.3 and 2.83 g of NaI at 105.degree. C. for 41 hours. The reaction mixture is poured into ice water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over MgSO.sub.4 and evaporated under reduced pressure. The residue is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol (10/1-5/1v/v). The resulting purified substance is recrystallized from methylene chloride to prepare 2.46 g (Yield: 51.0%) of the compound (IV-7).

mp. 138.0.degree.-139.0.degree. C.

Anal Calcd. (%) for C.sub.23 H.sub.30 N.sub.2 O.sub.3 : C, 72.22; H, 7.84; N, 7.30 Found: C, 72.22; H, 7.91; N, 7.32

IR (CHCl.sub.3) cm.sup.-1 :3600, 3450, 1705, 1602, 1512, 1490.

NMR (CDCl.sub.3) .delta.: 1.240 (t, J=7 Hz, 3H); 1.60-1.80 (m, 4H); 1.830 (s, 1H); 2.195 (t-d, J.sub.1 =13 Hz, J.sub.2 =4 Hz, 2H); 2.480 (d-d, J.sub.1 =14 Hz, J.sub.2 =2 Hz, 2H); 2.524 (t, J=7 Hz, 2H); 2.850 (d, J=14 Hz, 2H); 3.280(q, J=6 Hz, 2H); 4.101 (q, J=7 Hz, 2H); 6.962 (brs, 1H); 7.25-7.70 (m, 9H) 9H).

(2) A solution of 2.29 g of the compound (IV-7) in 25 ml of trifluoroacetic acid is refluxed for 9.5 hours and treated in the same manner as Example 7 (2) to prepare 2.08 g (Yield: 95.3%) of the compound (V-5). mp. 135.0.degree.-138.0.degree. C.

(3) To a solution of 1.80 g of the compound (V-5) in 26 ml of THF is added dropwise 375 mg of lithium alminium hydride. After reflux for 8 hours, the reaction mixture is treated in the same manner as Example 29 (3) to prepare (Ia-32) as an oil.

EXAMPLE 33

1-[3-{4-(4-phenylphenl)-1,2,5,6-tetrahydropyridin-1-yl}propylmethylcarbamoyl]-2-oxopyrrolidine (Ia-33) ##STR35##

To the compound (Ia-32) obtained Example 32 is added dropwise 810 mg of 1-phenoxycarbonyl-2-oxopyrrolidine, and the mixture is heated at 115.degree.-120.degree. C. for 5 hours. The reaction mixture is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol (20/1 v/v) to prepare 650 mg (Yield: 31.5%) of the compound (Ia-33). The oxalate is recrystallized from i-PrOH to give needles. mp. 186.0.degree.-187.0.degree. C. (dec.).

Anal Calcd. (%) for C.sub.26 H.sub.31 N.sub.3 O.sub.2.C.sub.2 H.sub.2 O.sub.4.1/2H.sub.2 O: C, 64.71; H, 6.52; N,7.97. Found: C, 65.10; H, 6.63; N,8.13.

IR (Nujol): 3500(br), 2720, 2600, 1720, 1665, 1485, 1455, 1405, 1405, 1375.

NMR (CDCl.sub.3) .delta.:1.900 (quint, J=7 Hz, 2H); 2.107 (quint, J=7 Hz, 2H); 2.455 (t, J=8 Hz, 2H); 2.55-2.64 (m, 4H); 2.741 (t, J=5 Hz, 2H); 3.002 (s, 3H); 3.198 (q, J=3 Hz, 2H); 3.469 (t, J=7 Hz, 2H); 3.737 (t, J=7 Hz, 2H); 6.124 (quint, J=2 Hz, 1H) 7.3-7.6 (m, 9H).

EXAMPLE 34

1-[3-(N-methyl-N-isobutyl)aminopropyl]-4-(4-trifluoromethylphenyl)-1,2,5,6-tetrahydropyridine (Ia-34) ##STR36##

A mixture of 342 mg of the compound (Ia-23), 1 ml of formaldehyde, and 1 ml of formic acid is stirred at 70.degree. C. for 3 hours and 40 minutes. The reaction mixture is concentrated, and the residue is poured into aq.NaHCO.sub.3. The solution is extracted with methylene chloride-methanol, and the organic layer is dried over MgSO.sub.4 and evaporated under reduced pressure. The resulting oily substance is subjected to column chromatography with silica gel, eluting with methylene chloride/methanol (19/1-5/1 v/v) to prepare 252 mg of the objective compound (Ia-34). The maleate is recrystallized from ethnol-ether to prepare 325 mg (Yield: 55.2%) of colorless needles. mp. 182.0.degree.-183.5.degree. C.

Anal Calcd. (%) for C.sub.20 H.sub.29 N.sub.2 F.sub.3.2C.sub.4 H.sub.4 O.sub.4 : C, 57.16; H, 6.32; N, 4.82; F, 9.46. Found: C, 57.33; H, 6.36; N, 4.78; F, 9.72.

IR (Nujol): 2360, 1708, 1621, 1570, 1533, 1481, 1460, 1447(sh), 1377, 1359.

NMR (CDCl.sub.3): 0.938 (d, J=7 Hz, 6H); 1.826 (quint, J=7 Hz, 3H); 2.212 (d, J=7 Hz, 2H); 2.309 (s, 3H); 2.513 (t, J=7 Hz, 2H); 2.548 (t, J=7 Hz, 2H); 2.58, 2.63 (m, 2H); 2.747 (t, J=5 Hz, 2H); 3.208 (q, J=3 Hz, 2H); 6.161 (quint, J=2 Hz, 1H); 7.474, 7.567 (ABq, J=8 Hz, 4H).

EXAMPLE 35

4-[3-{4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propyl]morpholine (Ia-35) ##STR37##

(1) A mixture of 1.09 g of the compound (IV-2) obtained in Example 18 and 1.4 g of morpholine is refluxed for 4 hours. After removal of the excess reagent under reduced pressure, the residue is poured into aq.Na.sub.2 SO.sub.4 and evaporated. The residue is purified by column chromatography with silic gel, eluting with mthylene chloride/methanol (20/1 v/v). The hydrochloride of the compound (III-19) is crystallized from methylene chloride-ether to prepare 850 mg (Yield: 66.3%) of needles. mp. 242.degree. C. (dec.)

NMR (CDCl.sub.3.CD.sub.3 OD=10/1): 1.307 (s, 9H); 2.10-2.22 (m, 2H); 2.48-2.55 (m, 4H); 2.760 (td, J.sub.1 =15 Hz, J.sub.2 =4 Hz, 2H); 3.06-3.15 (m, 4H); 3.25-3.50 (m, 4H); 3.731 (t, J=5 Hz, 4H); 7.387, 7.454 (ABq, J=9 Hz, 4H).

(2) A solution of 880 mg of the compound (III-19) in 10 ml of trifluoroacetic acid is refluxed for 8 hours and evaporated under reduced pressure. The residue is poured into aq. sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer is washed with saline, dried over Na.sub.2 SO.sub.4 and evaporated. The residue is purified by column chromatography followed by crystallization as the maleate. Recrystallization from methanol gives 760 mg (Yield: 97.5%) of reddish needles.

mp. 213.0.degree.-214.5.degree. C. (dec.).

Anal Calcd. (%) for C.sub.22 H.sub.34 N.sub.2 O.2C.sub.4 H.sub.4 O.sub.4 : C, 62.63; H, 7.35; N, 4.93. Found: C, 62.70; H, 7.37; N, 4.87.

IR (Nujol): 2300 (br); 1717, 1622, 1675, 1535, 1500, 1465, 1458, 1450(sh).

NMR (CDCl.sub.3): 1.314 (s, 9H); 1.783 (quint, J=7 Hz, 2H); 2.36, 2.63 (m, 8H); 2.709 (t, J=5 Hz, 2H); 3.164 (q, J=3 Hz, 2H); 3.725 (t, J=5 Hz, 2H); 6.031 (quint, J=1 Hz, 1H); 7.330 (s, 4H).

EXAMPLE 36-71

The reaction is performed in the same manner as Example 1 to prepare the compound (Ia). The reaction conditions are shown in Table 7 and 8. Further the physical constants of the compound (Ia) obtained in Example 36-71 are shown in Table 9.

TABLE 7 starting reaction g (%) Exam. material DMF K.sub.2 CO.sub.3 NaI condition (1) purification Compd. No. X = R(CH.sub.2).sub.n Y (VI) (ml) (g) (g) (.degree.C., hr.) condition No. m.p. (.degree.C.) IR (cm.sup.-1) ##STR38## (Step 1) 36 Me(p)2.50 g(II-8) ##STR39## 35 4.53 2.95 105-110 7 hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 3.46(76.4)(III-20) 116.0.about.117.0 (CHCl.sub.3)3600, 3320, 1713,1688(sh), 1680,1545, 1490 37 Me(p)2.34 g(II-8) ##STR40## 25 4.21 2.74 105 6 hr. toluene/ethyl acetate = 20/1-10/1 3.07(70.0)(III-21) 143.5.about.144.5 (CHCl.sub.3)3600, 3320, 1715,1618, 1550-1520 38 Me(m) (VI-1) 2.35 g 30 3.18 2.59 105-110 8 hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 1.70 -- (CHCl.sub.3) 1.85 g (49.0) 3600, 3320, 1715, (II-9) (III-22) 1680, 1608, 1545, 1490, 1470 39 Me(o) (VI-1) 2.68 g 35 4.53 2.95 105-110 7 hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 3.18 -- (CHCl.sub.3) 2.50 g (67.5) 3600, 3320, 1712, (II-10) (III-23) 1680, 1600, 1545, 1489, 1470, 1460 40 3,4-di-Me (VI-1) 2.09 g 35 2.82 2.29 105 7 hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 2.56 -- -- 2.10 g (67.2) (II-11) (III-24) 41 3,5-di-Me (VI-1) 2.81 g 35 3.79 3.08 105.degree. C. 6 hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 3.81 -- (CHCl.sub.3) 2.82 g (74.4) 3595, 3310, 1715, (II-12) (III-25) 1680, 1590, 1565, 1545, 1489, 1470 1460. 42 Cl(m) (VI-1) 2.49 g 30 4.18 2.72 105-110.degree. C. 7 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1-10/1 3.78 90.5.about.91.5 (CHCl.sub.3) 2.70 g (81.8) 3600, 3220, 1713, (II-13) (III-26) 1658, 1595, 1545, 1490, 1470, 1460 43 Cl(m) (VI-7) 2.31 g 30 4.18 2.72 105-110.degree. C. 7 hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 3.30 94.0-98.0 (Nujol) 2.70 g (74.3) 3280, 2720-2520, (II-13) (III-27) 1713, 1685, 1600, (sh), 1588, 1560 44 Cl(o) (VI-1) 2.42 g 30 4.08 2.65 105-110 6 hr. ethyl acetate/toluene = 1/1 2.10 -- (CHCl.sub.3) 2.50 g CH.sub.2 Cl.sub.2 /MeOH = 15/1 (46.7) 3580, 3320, 1715, (II-14) (III-28) 1680, 1547 45 Cl(o) (VI-7) 1.28 g 20 2.32 1.51 105-110 6 hr. CH.sub.2 Cl.sub.2 /MeOH = 15/1 0.840 -- (CHCl.sub.3) 1.45 g (34.1) 3580, 3220, 1715, (II-14) (III-29) 1680, 1545(sh), 1540(sh), 1525 46 3,5-diCl (VI-1) 3.0 g 35 4.04 3.28 105.degree. C. 7.0 hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 5.25 138.0-140.0 (CHCl.sub.3) 3.86 g (86.8) 3595, 3310, 1715, (II-15) (III-30) 1680, 1590, 1565, 1545 47 Br(p) (VI-1) 1.96 g 25 2.64 2.15 105.degree. C. 8 hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 3.16 -- (CHCl.sub.3) 2.57 g (77.9) 3590, 3310, 1713, (II-16) (III-31) 1680, 1545, 1489, 1460 48 F(p) (VI-1) 4.20 g 50 7.08 4.61 105-110.degree. C. 6.0 hr. CH.sub.2 Cl.sub.2 /MeOH = 15/1-8/1 4.96 102.5-104.0 (CHCl.sub.3) 4.00 g (66.5) 3600, 3320, 1713, (II-17) (III-32) 1680, 1545, 1510, 1489 49 F(p) (VI-7) 2.25 g 25 4.08 2.65 105.degree. C. 6 hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 2.78 118.0-119.0 (CHCl.sub.3) 2.30 g (67.4) 3600, 3320, 1713, (II-17) (III-33) 1680, 1605, 1545, 1510, 1489 50 CF.sub.3 (m) (VI-1) 2.56 g 50 3.46 2.81 105-110.degree. C. 9 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1-10/1 5.20 238.5-240.5 (Nujol) Cl(p) (92.9) 3350, 2650, 2525, 3.50 g (III-34) 2450, 1720, 1677 (II-18) 1557 51 CF.sub.3 (m) (VI-7) 2.38 g 50 3.46 2.81 105-110 15 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1-10/1 4.75 255.0-257.0 (Nujol) Cl(p) (87.6) 3400, 3260, 2640, 3.50 g (III-35) 2500, 2430, 1713, (II-18) 1672, 1547 ##STR41## 52 2.80 g (VI-1) 2.64 g 36 4.46 2.90 105-110 8 days CH.sub.2 Cl.sub.2 /MeOH = 10/1 3.55 122.0.about.123.0 (CHCl.sub.3) (II-19)*.sup.1 (71.3) 3590, 3320, 1713, (III-36) 1680, 1544, 1490, 1470, 1460(sh), 1450 53 2.10 g (VI-1) 1.70 g 30 1.73 2.50 105 7 days CH.sub.2 Cl.sub.2 /MeOH = 10/1 3.00 -- (CHCl.sub.3) (II-20)*.sup.2 (85.7) 3600, 3320, 1712, (III-37) 1680, 1543 54 Cl(p) (VI-5) 1.03 g 10 1.63 1.06 90 12 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1-10/1 1.37 111.5-112.0 (CDCl.sub.3) 1.00 g (74.0) 3600, 3280, 1702, (II-21) (III-38) 1698, 1530, 1645, 1495, 1480, 1463 55 C l(p)2.0 g(II-21) ##STR42## 25 3.26 2.12 90-95 10 hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 1.75(48.7)(III-39) 128.0-129.0 (CDCl.sub.3)3600, 3280, 1525,1492, 1480, 1460 56 t-Bu(p)1.00 g(II-6) ##STR43## 10 K.sub.2 CO.sub.31.184 NaI0.96 100.degree. C. 3 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH = 64/8/1 1.13(71.0)(III-40) -- (CHCl.sub.3)3590, 2498, 1510,1470, 1455, 1399 57 Me(p) (VI-9) 1.10 g 10 K.sub.2 CO.sub.3 NaI 100.degree. C. 2.5 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH = 64/8/1 1.445 -- (CHCl.sub.3) 1.00 g 1.45 1.18 (83.6) 3580, 2498, 1510, (II-8) (III-41) 1463, 1450, 1375 58 tBu(p)0.81 g(II-6) ##STR44## 12 K.sub.2 CO.sub.30.96 NaI0.78 100.degree. C. 2.7 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH = 64/8/1 1.053(84.6)(III-42) -- (CHCl.sub.3)3580, 2498, 1510,1463, 1450, 1375 59 tBu(p)0.727 g(II-6) ##STR45## 11 K.sub.2 CO.sub.30.86 NaI0.70 100.degree. C. 2.5 hr. -- 0.736(62.4)(III-43) -- (CHCl.sub.3)3630, 3590, 3390,2499, 1506, 1467,1440, 1421, 1399 60 Me(p) HO(CH.sub.2).sub.3 Cl (VI-12) -- Et.sub.3 N 140.degree. C. 4.0 hr. CH.sub.2 Cl.sub.2 /MeOH = 9/1 8.51 g 183.0-185.0 (CHCl.sub.3) 10.2 g 5.81 ml 11.16 ml (64.0) 3597, 3220, 1513, (II-8) (III-44) 1470, 1452, 1437, 1423, 1397 61 Me(p) (VI-3) 964 mg 15 K.sub.2 CO.sub.3 NaI 105.degree. C. 5.75 hr. CH.sub.2 Cl.sub.2 /MeOH = 9/1 0.74 g 170.0.about.172.5 (CHCl.sub.3) 0.964 g 1.40 g 1.14 g CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH = 64/8/1 (41.7) 3675, 3599, 3465, (II-8) (III-45) 3285, 2465, 1631, 1521, 1488, 1478, 1462, 1457(sh), 1439(sh), 1402 62 Ph(p) (VI-3) 0.70 g 11 K.sub.2 CO.sub.3 NaI 105.degree. C. 5.75 hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 616 mg 225.0.about.228.0 (Nujol) 0.93 g 1.02 g 0.83 g CH.sub.2 Cl.sub.2 /MeOH/ (41.0) (dec.) 3300, 3055, 3030, (II-5) NH.sub.4 OH = 128/16/1 = 32/6/1 (III-46) 2810, 2770, 2670, 1606, 1528, 1487, 1471, 1456, 1448 63 CF.sub.3 (p)1.50 g(II-2) ##STR46## 20 K.sub.2 CO.sub.31.69 g NaI1.38 mg 105.degree. C. 8.0 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1-10/1 0.56 g(19.1)(III-47) 142.5-144.0 (CHCl.sub.3)3690, 3600, 1637(sh)1632, 1587, 1552,1510(sh), 1495, 1440 64 Me(p)1.44 g (II-8) ##STR47## CH.sub.2 Cl.sub.220 Et.sub.2 N1.16 ml room temperature92 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH = 128/10/1.about.64/8/1 2.11 g(88.4)(III-48) -- -- Exam. No. (II) R(CH.sub.2).sub.n Y (VI) DMF ml K.sub.2 CO.sub.3 g NaI g reaction condition purification condition (1) g (%) (III) m.p. (.degree.C.) 65 (II-6) 3.67 g (VI-7) 3.00 g 45 4.35 3.54 105.degree. C., 8 hr. CH.sub.2 Cl.sub.2 /MeOH = 29/1.about.9/1 4.90 (73.5) (III-49) 219.0.about.222.0 66 (II-1) 3.60 g (VI-7) 3.07 g 45 4.04 3.28 105.degree. C., 9 hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 5.57 (95.0) (III-50) 232.0.about.239.0 67 (II-2) 4.70 g (VI-7) 3.34 g 45 4.83 3.93 105.degree. C., 9 hr. CH.sub.2 Cl.sub.2 /MeOH = 15/1.about.10/1 6.11 (87.4) (III-51) 266.0.about.268.0 68 (II-16) 3.36 g (VI-7) 2.50 g 35 3.62 2.95 105.degree. C., 12 hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 4.50 (83.7) (III-52) 230.0.about.232.0 69 (II-5) 3.99 g (VI-7) 3.00 g 45 4.35 3.54 105.degree. C., 8 hr. CH.sub.2 Cl.sub.2 /MeOH = 39/1.about.19/1 5.61 (80.3) (III-53) 233.0.about.238.0 70 (II-3) 3.45 g (VI-1) 3.00 g 45 4.35 3.54 105.degree. C., 6.5 hr CH.sub.2 Cl.sub.2 /MeOH = 39/1.about.9/1 5.34 (82.7) (III-54) 203.0.about.207.5 71 (II-22)* 2.60 g (VI-1) 2.23 g 30 3.01 2.44 105.degree. C., 8.5 hr CH.sub.2 Cl.sub.2 /MeOH = 10/1.about.5/1 1.35 (30.5) (III-55) 95.0.about.96.5 ##STR48## ##STR49## ##STR50## TABLE 8__________________________________________________________________________(Step 2)(III) purification Product(g) acid solvent (ml) reflux time condition (2) g (%)__________________________________________________________________________(III-20) TsOH.H.sub.2 O toluene (60) 13 hr. ethyl acetate Ia-362.53 g (2.68 g) CH.sub.2 Cl.sub.2 (20) CH.sub.2 Cl.sub.2 /MeOH = 10/1 2.17 g (90.3)(III-21) TsOH.H.sub.2 O toluene (300) 30 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1 Ia-372.66 g (2.93 g) CH.sub.2 Cl.sub.2 (50) 2.27 g (90.0)(III-22) TsOH.H.sub.2 O toluene (300) 48 hr. ethyl acetate Ia-383.30 g (3.49 g) CH.sub.2 Cl.sub.2 /MeOH = 20/1 2.50 g (80.0)(III-23) TsOH.H.sub.2 O toluene (250) 69 hr. toluene/ethyl Ia-393.18 g (4.21 g) CH.sub.2 Cl.sub.2 (60) acetate = 1/1 2.96 g CH.sub.2 Cl.sub.2 /MeOH = 20/1 (quantitative)(III-24) CF.sub.3 COOH -- 8 hr. toluene/ethyl Ia-402.56 g (27 ml) acetate = 30/1 2.40 g (98.0)(III-25) CF.sub.3 COOH -- 8.5 hr. CH.sub.2 Cl.sub.2 /MeOH = 30/1 Ia-413.80 g (26 ml) 3.50 g (96.8)(III-26) TsOH.H.sub.2 O toluene (250) 27 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1 Ia-423.16 g (3.16 g) CH.sub.2 Cl.sub.2 (70) 2.20 g (73.1)(III-27) TsOH.H.sub.2 O toluene (200) 48 hr. toluene/ethyl Ia-432.45 g (2.55 g) CH.sub.2 Cl.sub.2 (50) acetate = 1/1 1.87 g CH.sub.2 Cl.sub.2 /MeOH = 20/1 (80.2)(III-28) TsOH.H.sub.2 O toluene (100) 29 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1 Ia-442.10 g (1.60 g) ethyl acetate 1.480 g (73.8)(III-29) TsOH.H.sub.2 O toluene (60) 31 hr. CH.sub.2 Cl.sub.2 /MeOH = 15/1 Ia-450.84 g (0.52 g) 0.80 g (quantitative)(III-30) CF.sub.3 COOH -- 39 hr. CH.sub.2 Cl.sub.2 /MeOH = 30/1 Ia-462.10 g (10 ml) 1.34 g (70.2)(III-31) CF.sub.3 COOH -- 8 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1 Ia-473.51 g (36 ml) 2.80 g (92.9)(III-32) TsOH.H.sub.2 O toluene (250) 26.5 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1 Ia-484.14 g (3.25 g) 3.16 g (80.3)(III-33) TsOH.H.sub.2 O toluene (160) 16 hr. CH.sub.2 Cl.sub.2 /MeOH = 15/1 Ia-491.93 g (2.10 g) CH.sub.2 Cl.sub.2 (60) 1.50 g (81.9)(III-34) CF.sub.3 COOH -- 25 hr. CH.sub.2 Cl.sub.2 /MeOH = Ia-503.10 g (35 ml) 30/1-20/1 2.80 g (94.1)(III-35) CF.sub.3 COOH -- 19.5 hr. CH.sub.2 Cl.sub.2 /MeOH = Ia-512.70 g (35 ml) 50/1-20/1 2.40 g (92.7)(III-36) TsOH.H.sub.2 O toluene (280) 26 hr. toluene = Ia-524.09 g (4.03 g) CH.sub.2 Cl.sub.2 (70) ethyl acetate = 3/1 3.76 g CH.sub.2 Cl.sub.2 /MeOH = 20/1 (96.4)(III-37) CF.sub.3 COOH -- 8 hr. CH.sub.2 Cl.sub.2 /MeOH = 25/1 Ia-533.00 g (30 ml) 2.57 g (89.5)(III-38) TsOH.H.sub.2 O benzene (150) 23 hr. CH.sub.2 Cl.sub.2 /MeOH = Ia-542.86 g (2.76 g) CH.sub.2 Cl.sub.2 (50) 10/1-20/1 1.48 g (48.7)(III-39) TsOH.H.sub.2 O benzene (150) 25 hr. toluene/ethyl Ia-551.00 g (1.00 g) toluene (100) acetate = 1/1 0.93 g CH.sub.2 Cl.sub.2 /MeOH = 20/1 (97.7)(III-40) CF.sub.3 COOH 1.0 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH Ia-561.134 g (10 ml) 64/8/1 1.416 g (79.3)(III-41) CF.sub.3 COOH 1.5 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH Ia-57*1.445 g (10 ml) 64/8/1 1.787 g (75.1)(III-42) CF.sub.3 COOH 50 min. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH Ia-58*1.002 g (10 ml) 64/8/1 1.117 g (69.8)(III-43) CF.sub.3 COOH 1 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH Ia-59*0.722 g (6 ml) 128/12/1-64/8/1 0.881 g (64.6)(III-44) CF.sub.3 COOH 3.17 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH Ia-6012.82 g (38.3 ml) 128/16/1-32/6/1 7.719 g (64.9)(III-45) CF.sub.3 COOH 1.5 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH Ia-61*721 mg (10 ml) 128/16/1 644 mg (73.1)(III-46) CF.sub.3 COOH 1 hr. CH.sub.2 Cl.sub.2 /MeOH = Ia-62*766 mg (10 ml) 19/1.about.9/1 572 mg (60.5)(III-47) CF.sub.3 COOH 48 hr. CH.sub.2 Cl.sub.2 /MeOH = Ia-63540 mg (8 ml) 30/1.about.10/1 529 mg (69.2)(III-48) CF.sub.3 COOH 1.25 hr. CH.sub.2 Cl.sub.2 /MeOH = 19/1 Ia-642.105 g (5 ml) room temperature 1.693 g (85.3)(III-49) CF.sub.3 COOH 50 min. CH.sub.2 Cl.sub.2 /MeOH = 49/1 Ia-652.87 g (35 ml) 2.61 g (86.7)(III-50) CF.sub.3 COOH 8 hr. CH.sub.2 Cl.sub.2 /MeOH = Ia-662.85 g (30 ml) 20/1-10/1 2.70 g (98.6)(III-51) CF.sub.3 COOH 3 days. CH.sub.2 Cl.sub.2 /MeOH = Ia-673.85 g (50 ml) 15/1-10/1 3.53 g (96.0)(III-52) CF.sub.3 COOH 7 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1 Ia-681.75 g (25 ml) 1.54 g (92.0)(III-53) CF.sub.3 COOH 50 min. CH.sub.2 Cl.sub.2 /MeOH = 49/1 Ia-692.98 g (34 ml) 2.71 g (87.1)(III-54) CF.sub.3 COOH 50 min. toluene/acetone = Ia-702.62 g (33 ml) 9/1-3/1 2.41 g (87.5)(III-55) CF.sub.3 COOH 2.5 hr. CH.sub.2 Cl.sub.2 /MeOH = Ia-711.58 g (20 ml) 15/1-7/1 1.28 g (49.5)__________________________________________________________________________ *maleate TABLE 9__________________________________________________________________________Compd. m.p. (.degree.C.) Anal. Calcd. (%)No. (solvent*) Found (%) IR (cm.sup.-1) NMR (.delta.)__________________________________________________________________________Ia-36 130.5-132.0 C.sub.19 H.sub.25 N.sub.3 O.sub.2 : (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- C, 69.42 (69.70) 3310, 1713, 1680 2.020(quint, J=8Hz, 2H); 2.329(s, 3H, J=7Hz, 2H); 2.56-2.59(m, Et.sub.2 O) H, 7.65 (7.70) 1545, 1489, 1460 4H); 2.671(t, J=7Hz, 2H); 2.766(t, J=6Hz, 2H); 3.217(q, N, 12.76 (12.83) J=3Hz, 2H); 3.510(q, J=7Hz, 2H); 3.859(t, J=7Hz, 2H); 6.016 (quint, J=3Hz, 1H); 7.116(d, J=8Hz, 2H); 7.284(d, J=8Hz, 2H); 8.596(br, 1H)Ia-38 161.5-163.0 C.sub.22 H.sub.29 N.sub.3 O.sub.6 : (Nujol) (CDCl.sub.3) (iPrOH) C, 60.86 (61.24) 3330, 2600, 2500 1.782(quint, J-7Hz, 2H); 1.969(quint, J=8Hz, 2H); 2.302(s, 3H); (oxalate) H, 6.79 (6.77) 1717, 1645, 1605 2.44-2.59(m, 6H); 2.658(t, J=6Hz, 2H); 3.111(q, J=3Hz, 2H); N, 9.51 (9.74) 1533, 1485, 1460 3.347(q, J= 7Hz, 2H); 3.813(t, J=7Hz, 2H); 5.999(quint, J=3Hz, 1H); 6.00-7.02(m, 1H); 7.14-7.16(m, 3H); 8.456(brs, 1H)Ia-39 146.0-147.0 C.sub.22 H.sub.29 N.sub.3 O.sub.6 : (Nujol) (CDCl.sub.3) (iPrOH) C, 61.08 (61.24) 3300, 2600(br), 1.873(quint, J=7Hz, 2H); 2.030(quint, J=8Hz, 2H); 2.297(s, 3H); (oxalate) H, 6.70 (6.77) 1708, 1683, 1548 2.38-2.48(m, 2H); 2.593(t, J=7Hz, 2H); 2.606(t, J=8Hz, 2H); N, 9.71 (9.74) 1490(sh), 1460 2.746(t, J=6Hz, 2H); 3.184(q, J=3Hz, 2H); 3.402(quint, J=7Hz, 2H); 5.531(quint, J=2Hz, 1H); 7.11-7.17(m, 4H); 8.519(brs, 1H)Ia-40 146.5-147.5 C.sub.25 H.sub.33 N.sub.3 O.sub.6 (Nujol) (CDCl.sub.3) (iPrOH) C, 63.40 (63.68) 3330, 2420-2300, 1.825(quint, J=8Hz, 2H); 2.020(quint, J=7Hz, 2H); 2.240(s, 3H); (maleate) H, 6.99 (7.05) 1700, 1620, 1575 2.254(s, 3H); 2.48-2.56(m, 4H); 2.594(t, J=8Hz, 2H); 2.697(t, N, 3.87 (8.91) 1530, 1460, 1450 J=5Hz, 2H); 3.147(q, J=3Hz, 2H); 3.390(q, J=7Hz, 2H); 3.859 (sh) (t, J=7Hz, 2H); 6.002(quint, J=2Hz, 1H); 7.04-7.16(m, 3H); 8.489(brs, 1H)Ia-41 159.0-160.0 C.sub.25 H.sub.33 N.sub.3 O.sub.6 (Nujol) (CDCl.sub.3) (iPrOH) C, 63.71 (63.38) 3290, 2400-2300, 1.821(quint, J=7Hz, 2H); 2.013(quint, J=8Hz, 2H); 2.300(s, 6H); (maleate) H, 7.05 (7.05) 1720(sh), 1710, 2.48-2.55(m, 4H); 2.592(t, J=7Hz, 2H); 2.690(t, J=6Hz, 2H); N, 8.86 (8.91) 1685, 1620, 1600 3.142(q, J=3Hz, 2H); 3.385(q, J=7Hz, 2H); 3.855(d-d, J.sub.1 =8Hz, (sh), 1577, 1550 J.sub.2 =7Hz, 2H); 6.014(quint, J=2Hz, 1H); 6.878(s, 1H); 6.998(s, 1513 2H)Ia-42 155.5-157.0 C.sub.23 H.sub.28 N.sub.3 O.sub.6 Cl (Nujol) (CDCl.sub.3) (iPrOH) C, 57.74 (57.80) 3310, 2350, 2260 1.825(quint, J=7Hz, 2H); 2.022(quint, J=8Hz, 2H); 2.49-2.56(m, (maleate) H, 5.84 (5.90) 1715, 1682, 1585 4H); 2.538(t, J=7Hz, 2H); 2.709(t, J=6Hz); 3.159(q, J=3Hz, N, 8.78 (8.79) 1520, 1485(sh), 2H); 3.389(q, J=7Hz, 2H); 3.861(t, J=7Hz, 2H); 6.084(quint, Cl, 7.14 (7.42) 1455 J=2Hz, 1H); 7.18-7.30(m, 3H); 7.346(s, 1H); 8.499(brs, 1H)Ia-43 102.0-103.5 C.sub.18 H.sub.22 N.sub.3 O.sub.2 Cl (CHCl.sub.3) (CDCl.sub.3) (ethyl C, 61.99 (62.15) 3310, 1715, 1680 2.024(quint, J=7Hz, 2H); 2.55-2.64(m, 4H); 2.673(t, J=7Hz, acetate/ H, 6.31 (6.37) 1595, 1545, 1489 2H); 2.766(t, J=6Hz, 2H); 3.218(q, J=3Hz, 2H); 3.504(q, Et.sub.2 O) N, 12.07 (12.08) 1460 J=6Hz, 2H); 3.860(t, J=7Hz, 2H); 6.082(quint, J=2Hz, 1H); Cl, 9.96 (10.19) 7.19-7.27(m, 3H); 7.361(s, 1H); 8.615(brs, 1H)Ia-44 140.5-142.0 C.sub.23 H.sub.28 N.sub.3 O.sub.5 Cl. (Nujol) (CDCl.sub.3) (iPrOH) 1/5H.sub.2 O 3280, 2580, 2360 1.846(quint, J=7Hz, 2H); 2.048(quint, J=8Hz, 2H); 2.47-2.51(m, (maleate) C, 57.35 (57.37) 1715, 1690, 1620 2H); 2.566(t, J=8Hz, 2H); 2.606(t, J=8Hz, 2H); 2.728(t, J=6Hz, H, 5.87 (5.94) 1580, 1545, 1490 2H); 3.172(q, J=3Hz, 2H); 3.397(q, J=7Hz, 2H); 3.865(t, N, 8.67 (8.37) (sh), 1460 J=7Hz, 2H); 5.656(quint, J=2Hz); 7.15-7.37(m, 4H); 8.510 Cl, 7.72 (7.36) (brs, 1H)Ia-45 142.0-143.5 C.sub.22 H.sub.26 N.sub.3 O.sub.6 Cl (Nujol) (CDCl.sub.3) (maleate) C, 56.54 (56.96) 3300, 2580-2400, 2.007(t, quint, J=7Hz, 2H); 2.35-2.57(m, 2H); 2.610(t, J=8Hz); H, 5.89 (5.65) 1710, 1682, 1617 2.746(t, J=7Hz, 2H); 2.830(t, J=6Hz, 2H); 3.723(q, J=3Hz, N, 8.79 (9.06) 1565, 1528 2H); 3.544(q, J=6Hz, 2H); 3.869(t, J=7Hz, 2H); 5.656(q, Cl, 7.98 (7.64) J=2Hz, 1H); 7.15-7.37(m, 4H); 8.626(brs, 1H)Ia-46 216.0-217.5 C.sub.21 H.sub.25 N.sub.3 O.sub.6 Cl.sub.2. (Nujol) (CDCl.sub.3) (MeOH) 1/5H.sub.2 O 3340, 1710, 1645 1.807(quint, J=7Hz, 2H); 2.027(quint, J=8Hz, 2H); 2.48-2.56(m, (oxalate) C, 51.31 (51.48) 1588, 1562, 1538 4H); 2.599(t, J=8Hz, 2H); 2.689(t, J=6Hz, 2H); 3.155(q, H, 5.15 (5.23) 1488, 1460, 1420 J=3Hz, 2H); 3.383(q, J=7Hz, 2H); 3.859(t, J=7Hz, 2H); 6.111 N, 8.53 (8.58) (quint, J=2Hz, 1H); 7.20-7.25(m, 3H); 8.510(brs, 1H) Cl, 14.65(14.47)Ia-47 99.0-100.0 C.sub.19 H.sub.24 N.sub.3 O.sub.2 Br: (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- C, 56.32 (56.16) 3320, 1712, 1680 1.819(quint, J=7Hz, 2H); 2.023(quint, J=7Hz, 2H); 2.49-2.56(m, Et.sub.2 O) H, 6.04 (5.95) 1545, 1489, 1465 4H); 2.598(t, J=7Hz, 2H); 2.699(t, J=6Hz, 2H); 3.145(q, N, 10.35 (10.34) (sh), 1460, 1440 J=3Hz, 2H); 3.386(q, J=6Hz, 2H); 3.861(t, J=7Hz, 2H); 6.064 Br, 19.59 (19.67) (quint, J=2Hz, 1H); 7.247(d, J=8Hz, 2H); 7.462(d, J=8Hz, 2H); 8.495(brs, 1H)Ia-48 97.5-98.5 C.sub.19 H.sub.24 N.sub.3 O.sub.2 F: (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- C, 65.89 (66.07) 3320, 1713, 1682 1.825(quint, J=7Hz, 2H); 2.021(quint, J-8Hz, 2H); 2.49-2.56(m, Et.sub.2 O) H, 7.03 (7.00) 1605, 1545, 1510 4H); 2.597(t, J=8Hz, 2H); 2.705(t, J=6Hz); 3.152(q, J=3Hz, N, 12.07 (12.16) 1490, 1460 2H); 3.389(q, J=7Hz, 2H); 3.862(t, J=7Hz, 2H); 5.998(quint, F, 5.57 (5.50) J=2Hz, 1H); 6.992(t, J=8Hz, 2H); 7.343(d-d, J.sub.1 =8Hz, J.sub.2 =5Hz, 2H); 8.495(brs, 1H)Ia-49 136.0-136.5 C.sub.22 H.sub.26 N.sub.3 O.sub.6 F: (Nujol) (CDCl.sub.3) (iPrOH) C, 59.13 (59.05) 3300, 2600(br) 2.028(quint, J=8Hz, 2H); 2.50-2.60(m, 4H); 2.674(t, J=7Hz, (maleate) H, 5.85 (5.86) 1720, 1675, 1610 2H); 2.741(t, J=5Hz, 2H); 3.216(q, J=3Hz, 2H); 3.551(q, N, 9.31 (9.39) 1602, 1570, 1535 J=6Hz, 2H); 3.866(t, J=7Hz, 2H); 5.993(quint, J=2Hz, 1H); F, 4.48 (4.25) 1515 6.997(t, J=9Hz, 2H); 7.350(d-d, J.sub.1 =9Hz, J.sub.2 =5Hz, 2H); 8.615 (brs, 1H)Ia-50 185.0-188.0 C.sub.20 H.sub.23 N.sub.3 O.sub.2 ClF.sub.3. (Nujol) (CDCl.sub.3) (iPrOH--MeOH-- HCl.1/5H.sub.2 O 3320, 2670, 2550 1.822(quint, J=7Hz, 2H); 2.030(quint, J=8Hz, 2H); 2.544(t, Et.sub.2 O) C, 50.92 (51.11) 2420, 1710 J=8Hz, 2H); 2.55-2.60(m, 2H); 2.602(t, J=8Hz, 2H); 2.718(t, (hydro- H, 5.15 (5.23) J=5Hz, 2H); 3.177(q, J=2Hz, 2H); 3.393(q, J=7Hz, 2H); 3.865 chloride) N, 8.71 (8.94) (t, J=7Hz, 2H); 6.10-6.18(m, 1H); 7.40-7.50(m, 2H); 7.679 Cl, 14.95 (15.08) (brs, 1H); 8.511(brs, 1H) F, 11.83 (12.12)Ia-51 213.0-215.0 C.sub.19 H.sub.21 N.sub.3 O.sub.2 ClF.sub.3.HCl (Nujol) (CDCl.sub.3) (iPrOH--MeOH) C, 50.38 (50.45) 3500, 2520, 1704 2.030(quint, J=7Hz, 2H); 2.50-2.60(m, 2H); 2.597(t, J=8Hz, (hydro- H, 4.90 (4.90) 1683, 1548, 1493 2H); 2.678(t, J=6Hz, 2H); 2.777(t, J=6Hz, 2H); 3.236(q, chloride) N, 9.22 (9.29) 1462 J=3Hz, 2H); 3.504(q, J=6Hz, 2H); 3.864(t, J=7Hz, 2H); 6.10- Cl, 15.65 (15.68) 6.16(m, 1H); 7.40-7.50(m, 2H); 7.685(brs, 1H); 8.625(brs, 1H) F, 12.61 (12.60)Ia-52 83.0-84.0 C.sub.17 H.sub.22 N.sub.3 O.sub.2 SCl (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- C, 55.38 (55.50) 3320, 1712, 1680 1.801(quint, J=7Hz, 2H); 2.024(quint, J=7Hz, 2H); 2.50(brs, Et.sub.2 O) H, 5.96 (6.03) 1545 2H) 2.520(t, J=7Hz, 2H); 2.596(t, J=8Hz, 2H); 2.670(t, J=6Hz, N, 11.51 (11.42) 2H); 3.119(q, J=3Hz, 2H); 3.376(q, J=7Hz, 2H); 3.857(t, S, 8.69 (8.71) J=7Hz, 2H); 5.953(quint, J=2Hz, 1H); 6.688(d, J=4Hz, 1H); Cl, 9.69 (9.64) 6.756(d, J=4Hz, 2H); 8.485(brs, 1H)Ia-53 156.5-157.5 C.sub.21 H.sub.25 N.sub.3 O.sub.6 SCl.sub.2 : (Nujol) (CDCl.sub.3) (iPrOH) C, 48.58 (48.65) 3300, 1708, 1680 1.808(quint, J=7Hz, 2H); 2.030(quint, J=7Hz, 2H); 2.48-2.56(m, (maleate) H, 4.89 (4.86) 1585, 1535 4H); 2.604(t, J=8Hz, 2H); 2.659(t, J=6Hz, 2H); 3.136(q, N, 8.02 (8.11) J=3Hz, 2H); 3.383(q, J=7Hz, 2H); 3.862(t, J=7Hz, 2H); 5.995 S, 5.92 (6.18) (quint, J=2Hz, 1H); 6.712(s, 1H); 8.497(brs, 1H)Ia-54 144.0-145.0 C.sub.24 H.sub.30 N.sub.3 O.sub.6 Cl (Nujol) (CDCl.sub.3) (iPrOH) C, 58.44 (58.59) 3280, 2400-2280, 1.78-1.91(m, 6H); 2.45-2.60(m, 6H); 2.703(t, J=6Hz, 2H); 3.161 (maleate) H, 6.05 (6.15) 1692, 1650, 1622 (q, J=3Hz, 2H); 3.383(q, J=7Hz, 2H); 3.76-3.83(m, 2H); 6.056 N, 8.52 (8.54) 1575, 1522, 1495 (quint, J=2Hz, 1H); 7.264, 7.322(ABq, J=9Hz, 4H); 9.449 Cl, 7.33 (7.21) (brs, 1H)Ia-55 134.0-135.5 C.sub.19 H.sub.24 N.sub.3 O.sub.2 Cl (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- C, 62.84 (63.06) 3280, 1795, 1645 1.78-1.85(m, 4H); 2.45-2.60(m, 4H); 2.680(t, J=7Hz, 2H); 2.770 Et.sub.2 O) H, 6.67 (6.68) 1527, 1495, 1480 (t, J=6Hz, 2H); 3.238(q, J=2Hz, 2H); 3.513(q, J=7Hz, 2H); N, 11.41 (11.61) 1463, 1450 3.80-3.83(m, 2H); 6.051(quint, J=2Hz, 1H); 7.24-7.35(m, 4H); Cl, 10.05 (9.80) 9.521(brs, 1H)Ia-56 192.5-193.5 C.sub.24 H.sub.38 N.sub.2.2C.sub.4 H.sub.4 O.sub.4 (Nujol) (CDCl.sub.3)(free) (CH.sub.2 Cl.sub.2 -- C, 65.32 (65.51) 2340, 1916, 1707 0.966(d, J=5Hz, 3H); 1.314(s, 9H); 1.43-1.57(m, 3H); 1.67-1.78 MeOH--iPrOH) H, 7.84 (7.90) 1619, 1563, 1542 (m, 2H); 1.930(quint, J=7Hz, 2H); 2.239(t, J=12Hz, 2H); 2.49- (di-maleate) N, 4.77 (4.77) 1481, 1460, 1446 2.58(m, 2H); 2.528(t, J=7Hz, 2H); 2.63-2.74(m, 4H); 3.14-3.21 1378 (m, 4H); 6.027(quint, J=1Hz, 1H); 7.330(ABq, J=8Hz, 4H)Ia-57 191.5-193.0 C.sub.21 H.sub.32 N.sub.2.2C.sub.4 H.sub.4 O.sub.4 (Nujol) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- C, 63.75 (63.95) 2340, 1995, 1709 0.980(d, J=5Hz, 3H); 1.48-1.66(m, 3H); 1.70-1.82(m, 2H); 1.953 MeOH--iPrOH) H, 7.31 (7.40) 1621, 1525(sh), (quint, J=7Hz, 2H); 2.333(s, 3H); 2.357(t, J=12Hz, 2H); 2.544 (di-maleate) N, 5.16 (5.14) 1510(sh), 1483, (t, J=7Hz, 4H); 2.715(t, J=8Hz, 2H); 2.78-2.84(m, 2H); 3.160(q, 1462, 1449(sh), J=3Hz, 2H); 3.298(d, J=12Hz); 6.013(quint, J=1Hz, 1H); 1379 7.123, 7.284(ABq, J=8Hz, 4H)Ia-58 190.0-192.0 C.sub.23 H.sub.36 N.sub.2.2C.sub.4 H.sub.4 O.sub.4 (Nujol) (CDCl.sub.3) (MeOH--iPrOH) C, 64.92 (65.02) 2360, 1997, 1708 1.324(s, 9H); 1.50-2.00(m, 8H); 2.50-2.80(m, 12H); 3.200(q, (di-maleate) H, 7.68 (7.74) 1619, 1570, 1535 J=3Hz, 2H); 6.056(s, 1H); 7.347(ABq, J=8Hz, 4H) N, 4.91 (4.89) 1480, 1457, 1448 (sh), 1379Ia-59 193.0-195.0 C.sub.23 H.sub.37 N.sub.3.3C.sub.4 H.sub.4 O.sub.4 (Nujol) (CDCl.sub.3) (CHCl.sub.3 -- C, 59.39 (59.58) 2335, 1995, 1706 1.313(s, 9H); 1.786(quint, J=7Hz, 2H); 2.296(s, 3H); 2.37-2.60 MeOH) H, 6.95 (7.03) 1621, 1568, 1542 (m, 17H); 2.703(t, J=5Hz, 2H); 3.158(q, J=3Hz, 2H); 6.028 (tri-maleate) N, 6.01 (5.96) (sh), 1478, 1460 (quint, J=1Hz, 1H); 7.382(ABq, J=8Hz, 4H) 1439, 1380(sh)Ia-60 75.0-77.0 C.sub.16 H.sub.21 NO (Nujol) (CDCl.sub.3) (Et.sub.2 O- C, 77.94 (77.88) 3110, 3023, 2773 1.791(quint, J=7Hz, 2H); 2.332(s, 3H); 2.50-2.60(m, 2H); 2.735 n-hexane) H, 9.16 (9.15) 1518, 1467, 1412 (t, J=6Hz, 2H); 2.775(t, J=6Hz, 2H); 3.221(q, J=3Hz, 2H); N, 6.22 (6.05) 1397, 1379 3.834(t, J=5Hz, 2H); 6.001(quint, J=2Hz, 1H); 7.123, 7.272 (ABq, J=8Hz, 4H)Ia-61 115.0-116.0 C.sub.20 H.sub.39 N.sub.3 O.C.sub.4 H.sub.4 O.sub.4 (Nujol) (CD.sub.3 OD) (iPrOH--Et.sub.2 O) C, 64.88 (64.99) 3405, 2720, 2570 1.87-12.05(m, 6H); 2.333(s, 3H); 2.886(brs, 2H); 3.21-3.36(m, (maleate) H, 7.54 (7.50) 2295, 1642, 1580 1H); 3.522(brs, 2H); 3.913(s, 2H); 6.099(s, 1H); 6.245(s, 2H); N, 9.42 (9.47) 1538, 1499, 1457 7.188, 7.369(ABq, J=9Hz, 4H) 1411, 1380Ia-62 164.0-166.0 C.sub.25 H.sub.31 N.sub.3 O.C.sub.4 H.sub.4 O.sub.4 (Nujol) (CD.sub.3 OD) (MeOH--Et.sub.2 O) C, 68.89 (68.89) 3403, 3037, 2330 1.88-2.06(m, 4H); 2.951(brs, 2H); 3.20-3.40(m, 6H); 3.557(brs, (maleate) H, 6.97 (6.98) 1700, 1640, 1578 2H); 3.959(brs, 2H); 6.220(s, 1H); 6.248(s, 2H); 7.30-7.70(m, N, 8.30 (8.31) 1537, 1498, 1457 9H) (sh), 1449, 1409Ia-63 150.0-151.5 C.sub.24 H.sub.28 N.sub.5 OF.sub.3 (CHCl.sub.3) (CDCl.sub. 3) (CH.sub.2 Cl.sub.2 -- C, 62.55 (62.73) 1632, 1617(sh), 1.940(quint, J=7Hz, 2H); 2.450(t, J=8Hz, 2H); 2.547(t, Et.sub.2 O) H, 6.08 (6.14) 1588, 1552, 1495 J=7Hz, 2H); 5.565(brs, 2H); 2.727(t, J=6Hz, 2H); 6.142(s, N, 15.13 (15.24) 1437 1H); 6.515(t, J=5Hz, 1H); 7.448, 7.540(ABq, J=8Hz, 4H); 8.301 F, 12.36 (12.40) (d, J=5Hz, 2H)Ia-64 108.0-109.0 C.sub.19 H.sub.26 N.sub.2 O (CHCl.sub.3) (CDCl.sub.3) (CH.sub.2 Cl.sub.2 -- C, 76.26 (76.47) 1625, 1512, 1466 1.78-2.04(m, 4H); 2.332(s, 3H); 2.574(t, J=8Hz, 4H); 2.765(t, Et.sub.2 O- H, 8.70 (8.78) 1448, 1378 J=6Hz, 2H); 2.881(t, J=8Hz, 2H); 3.211(q, J=3Hz, 2H); 3.448 n-hexane) N, 9.32 (9.39) (t, J=6Hz, 2H); 3.477(t, J=6Hz, 2H); 6.02(quint, J=2Hz, 1H); 7.122, 7.285(ABq, J=8Hz, 4H)Ia-65 183.0-190.0 C.sub.22 H.sub.31 N.sub.3 O.sub.2.HCl (Nujol) (CDCl.sub.3) (MeOH--Et.sub.2 O) C, 65.06 (65.09) 3310, 2725, 2670 1.313(s, 9H); 2.018(quint, J=8Hz, 2H); 2.52-2.64(m, 6H); 2.678 (hydro- H, 8.04 (7.95) 2405, 1709, 1688 (t, J=7Hz, 2H); 2.774(t, J=6Hz, 2H); 3.212, 3.242(ABq, chloride) N, 10.38 (10.35) 1549, 1519, 1488 J=3Hz, 2H) 3.545, 3.484(ABq, J=7Hz, 2H); 3.859(t, J=7Hz, Cl, 8.46 (8.73) 1459, 1430, 1412 2H); 6.029(quint, J=2Hz, 1H); 7.332(s, 4H); 8.604(brs, 1H) 1392Ia-66 216.0-219.0 C.sub.18 H.sub.21 N.sub.3 O.sub.2 Cl.sub.2.HCl (Nujol) (CDCl.sub.3) (MeOH--Et.sub.2 O) C, 51.66 (51.63) 3290, 2510, 1712 2.024(quint, J=7Hz, 2H); 2.45-2.55(m, 2H); 2.594(t, J=8Hz, (hydro- H, 5.34 (5.30) 1672, 1521 2H); 2.665(t, J=7Hz, 2H); 2.754(t, J=6Hz, 2H); 3.214(q, chloride) N, 10.01 (10.03) J=3Hz, 2H); 3.497(q, J=6Hz, 2H); 3.860(t, J=7Hz, 2H); 6.0- Cl, 25.12 (25.40) 6.14(m, 1H); 7.208(dd, J.sub.1 =8Hz, J.sub.2 =2Hz, 1H); 7.365(d, J=8Hz, 1H); 7.450(d, J=2Hz, 1H); 8.615(brs, 1H)Ia-67 238.0-248.0 C.sub.19 H.sub.22 N.sub.3 O.sub.2 F.sub.3.HCl (Nujol) (CDCl.sub.3) (MeOH--Et.sub.2 O) C, 54.43 (54.61) 3310, 2930, 2860 2.032(quint, J=8Hz, 2H); 2.50-2.66(m, 4H); 2.69(t, J=6Hz, 2H); (hydro- H, 5.59 (5.55) 2460, 1711, 1687 2.722(t, J=6Hz, 2H); 3.256(q, J=3Hz, 2H); 3.518(q, J=6Hz, chloride) N, 9.89 (10.06) 1617, 1541 2H); 3.868(t, J=7Hz, 2H); 6.14-6.17(m, 1H); 7.478, 7.567(ABq, Cl, 8.45 (8.48) J=9Hz, 4H); 8.625(brs, 1H) F, 13.68 (13.64)Ia-68 228.0-232.0 C.sub.18 H.sub.22 N.sub.3 O.sub.2 Br.HCl (Nujol) (CD.sub.3 OD) (MeOH--Et.sub.2 O) C, 50.89 (50.42) 3320, 2920, 2860 2.029(quint, J=8Hz, 2H); 2.50-2.60(m, 2H); 2.598(t, J=8Hz, (hydro- H, 5.58 (5.41) 2460, 1710, 1685 2H); 2.675(t, J=7Hz, 2H); 2.769(t, J=6Hz, 2H); 3.216(q, chloride) N, 9.90 (9.80) 1537 J=3Hz, 2H); 3.509(q, J=6Hz, 2H); 3.865(t, J=7Hz, 2H); 6.04- Cl, 8.22 (8.27) 6.08(m, 1H); 7.429, 7.247(ABq, J=9Hz, 4H); 8.611(brs, 1H)Ia-69 205.0-210.0 C.sub.24 H.sub.27 N.sub.3 O.sub.2.HCl (Nujol) (CDCl.sub.3) (MeOH--Et.sub.2 O) C, 67.72 (67.67) 3305, 3045, 2415 2.205(quint, J=8Hz, 2H); 2.54-2.66(m, 4H); 2.695(t, J=7Hz, (hydro- H, 6.64 (6.63) 2405, 1702, 1679 2H); 2.803(t, J=6Hz, 2H); 3.261(q, J=3Hz, 2H); 3.558, 3.497 chloride) N, 9.80 (9.87) 1578, 1540, 1488 (ABq, J=7Hz, 2H); 3.865(t, J=7Hz, 2H); 6.128(quint, J=2Hz, Cl, 8.10 (8.32) 1457, 1444, 1420 1H); 7.28-7.67(m, 9H); 8.624(brs, 1H) 1392__________________________________________________________________________ *a solvent for recrystallization

EXAMPLE 72

1-{3-(1-Methyl-2-oxo-imidazolidin-1-yl)propyl}-4-(4-tolyl)-1,2,5,6-tetrahydropyridine (Ia-72) ##STR51##

(1) A mixture of 870 mg of the compound (Ia-60) and 8.0 ml of thionylchloride is stirred at room temperature for 2 hours. After removal of the excess reagent under reduced pressure, the residue was washed with Et.sub.2 O and dried under reduced pressure to prepare 1.067 g (Yield: 99.2%) of the compound (V-3) as pale yellow powder.

IR (CHCl.sub.3) cm.sup.-1 : 1600, 1510, 1460, 1410.

NMR (CDCl.sub.3): 2.046 (quint, J=7 Hz, 2H); 2.334 (s, 3H); 2.54-2.64 (m, 2H); 2.629 (t, J=7H, 2H); 2.273 (t, J=5 Hz, 2H); 3.173 (q, J=2 Hz, 2H); 3.630 (t, J=7 Hz, 2H); 6.023 (quint, J=2 Hz, 1H); 7.123, 7.287 (ABq, J=8 Hz, 4H).

(2) To a solution of 266 mg of 1-methyl-2-oxoimidazolidine in 5 ml of DMF was added 115 mg of 60% NaH under ice-cooling. After stirring at room temperature for 20 minutes, a solution of 553 mg of the compound (V-3) in 4 ml of DMF was added to the reaction mixture and stirred at room temperature for 90.5 hours. The reaction mixture was concentrated under reduced pressure and poured into d-HCl. The aqueous layer is made alkaline with NaHCO.sub.3, extracted with CHCl.sub.3 -MeOH (19/1), dried over MgSO.sub.4, and evaporated. The residue is subjected to column chromatography with silica gel, eluting with CHCl.sub.3 -MeOH (19/1) to prepare 491 mg of the compound (Ia-72). The maleate is recrystallized from iPrOH-Et.sub.2 O to prepare 439 mg (Yield: 45.8%) of colorless needles. mp. 126.5.degree.-128.0.degree. C.

Anal Calcd. (%) for C.sub.19 H.sub.27 N.sub.3 O.C.sub.4 H.sub.4 O.sub.4. 1/5H.sub.2 O: C, 63.73; H, 7.20; N, 9.61. Found: C, 63.78; H, 7.31; N, 9.70.

IR (CHCl.sub.3): 2450, 2340, 1910, 1689, 1622, 1502, 1451, 1409, 1382.

NMR (CDCl.sub.3): 1.797 (quint, J=8 Hz, 2H); 2.329 (s, 3H); 2.46-2.62 (m, 4H); 2.712 (t, J=5 Hz, 2H); 2.790 (s, 3H); 3.166 (q, J=3 Hz, 2H); 3.255 (t, J=7 Hz, 2H); 3.295 (s, 4H); 6.014 (quint, J=2 Hz, 1H); 7.117, 7.283 (ABq, J=8 Hz, 4H).

EXAMPLE 73-91

The compounds (V) obtained in Example 19-21 are reacted in the same manner as Example 72 to prepare the compound (Ia). The reaction conditions are shown in Table 10.

TABLE 10__________________________________________________________________________ ##STR52##Ex. reaction purification productNo. (V) (VIII) solvent condition condition mg (Yield) m.p. (.degree.C.) IR__________________________________________________________________________73 (V-3) 742 mg ##STR53## DMF 5 ml 100.degree. C. 47 min. CH.sub.2 Cl.sub.2 /MeOH= 19/1 Ia-73*.sup.1 602 119.0- 121.0 (iPrOH) (CHCl.sub.3) 2455, 2310, 1677 1622, 1512, 1497 1464, 1380, 135174 (V-2) 1.02 g ##STR54## DMF 10 ml 100.degree. C. 25 hr. toluene/ acetone=3/1-1/1 Ia-74*.sup.1 266 152.0- 154.0 (MeOH Et.sub.2 O) (Nujol) 2700-1750(b r), 1695, 1663, 1619 1532, 1463, 1412 1378, 135875 (V-3) 500 mg ##STR55## DMF 8 ml 70.degree. C. 10 hr. CH.sub.2 Cl.sub.2 /MeOH= 39/1 Ia-75 409 mg (62.4%) 98.0-100.0 (CDCl.sub.3 MeOH) (CHCl.sub.3) 3690, 1771, 1602 1511, 1488, 1454 1429, 1416, 138476 (V-3) H.sub.2 NPh 0.192 ml DMF 8 ml 80.degree. C. toluene/ Ia-76*.sup.1 154.0- (Nujol) 500 mg (K.sub.2 CO.sub.3 576 mg 15 hr. acetone = 4/1 130 mg 155.5 3050, 2660, 2615 NaI 468 mg (72.1%) (MeOH 2570, 2480, 2410 Pyridine 178 ml) Et.sub.2 O) 1606, 1590, 1578 1517, 1498, 1479 1447, 1423, 1398 137677 (V-3) 650 mg ##STR56## DMF 6 ml 100.degree. C. 5 hr. toluene/ acetone = 9/1 Ia-77*.sup.1 1.08 174.0- 176.0 (dec.) (MeOH Et.sub.2 O) (CHCl.sub.3) 3685, 3495, 3350 2700-1800(br), 1778, 1707, 1621 1511, 1496, 1446 139578 (V-2) CH.sub.3 NHPh 0.20 ml DMF 8 ml 110.degree. C. toluene/ Ia-78*.sup.1 149.0- (CHCl.sub.3) 440 mg (Pyridine 0.157 ml 6 hr. 20 min. acetone = 9/1 135 mg 151.0 3575, 3338 NaI 412 mg) (17.6%) (MeOH Et.sub.2 O)79 (V-3) NaOPh 207 mg DMF 8 ml 70.degree. C. toluene/ Ia-79*.sup.1 148.0- (Nujol) 0.828 g 3 hr. 10 min. acetone = 9/1 562 mg 150.0 2720, 2370, 1701 (66.3%) (MeOH 1620, 1598, 1584 Et.sub.2 O 1499, 1467, iPrOH 1458(sh), 138780 (V-3) 942 mg ##STR57## -- 150.degree. C. 8 hr. 15 min. toluene/ acetone = 19/1-9/1 Ia-80*.sup.1 930 148.0-150.0 (iPrOH Et.sub.2 O) (Nujol) 2720, 2575(sh), 2490(sh), 2330, 1708, 1652, 1600 1571, 1502, 145981 (V-3) 624 mg ##STR58## -- 150.degree. C. 4 hr. 10 min. CH.sub.2 Cl.sub.2 /MeOH= 19/1 Ia-81*.sup.1 963 191.0- 192.0 (dec.) (MeOH Et.sub.2 O) (Nujol) 3030, 2720, 2278 1711, 1623, 1572 1532, 1513(sh), 1485, 1463, 143582 (V-3) HN(iBu).sub.2 1.358 g -- 20 hr. CH.sub.2 Cl.sub.2 /MeOH= Ia-82*.sup.1 140.5- (Nujol) 517 mg reflux 49/1 457 mg 142.5 2710, 2500, 1706 (38.4%) (CH.sub.2 Cl.sub.2 1572, 1480, 1455 Et.sub.2 O) 137583 (V-3) H.sub.2 N(iBu) 1.02 ml -- 10.5 hr. CH.sub.2 Cl.sub.2 /MeOH/ Ia-83*.sup.1 179.5- (Nujol) 511 mg reflux NH.sub.4 OH= 471 mg 182.5 3340, 2780, 2545 128/12/1 (44.4%) (CH.sub.2 Cl.sub.2 2460, 1699, 1618 Et.sub.2 O) 1577, 1474, 1458 1441, 138184 (V-3) 466 mg ##STR59## -- 50.degree. C. 3 hr. CH.sub.2 Cl.sub.2 /MeOH/ NH.sub.4 OH= 128/16/1- 32/4/0.5 Ia-84*.sup.1 225 180.0- 181.0 (Nujol) 2340, 1709, 1550 1458, 1377, 15685 (V-3) H.sub.2 N(CH.sub.2).sub.2 N(iPr).sub.2 -- 105.degree. C. CH.sub.2 Cl.sub.2 /MeOH/ Ia-85*.sup.1 125.0- (Nujol) 511 mg 1.054 g 7 hr. NH.sub.4 OH= 436 mg 127.0 2668, 2500, 2400 128/16/1- (32.0%) (sh), 1702, 1619 64/8/1 1570, 1462, 137886 (V-2) HN(iBu).sub.2 1.50 g -- 32 hr. CH.sub.2 Cl.sub.2 /MeOH= Ia-86*.sup.1 135.0- (Nujol) 654 mg reflux 49/1-19/1 338 mg 136.5 2420, 1707, 1616 (27.1%) 1572, 1485, 1456 137787 (V-2) HN(iBu).sub.2 1.1 ml -- 32 hr. CH.sub.2 Cl.sub.2 /MeOH= Ia-87*.sup.1 135.0- (Nujol) 645 mg reflux 49/1-19/1 338 mg 136.0 2420, 1707, 1616 (27.1%) (MeOH 1572, 1485, 1456 Et.sub.2 O) 137788 (V-2) 1.05 g ##STR60## -- room temperature 32.5 hr. CH.sub.2 Cl.sub.2 /MeOH/ NH.sub.4 OH= 128/16/1- 32/4/0.5 Ia-88*.sup.1 1.034 176.0- 178.0 (MeOH) (Nujol) 3483, 2723, 2679 2587, 2415, 1703 1608, 1579, 1478 1460, 1412, 138289 (V-2) 621 mg ##STR61## -- room temperature 5 days CH.sub.2 Cl.sub.2 /MeOH/ NH.sub.4 OH= 128/16/1 Ia-89*.sup.1 800 190- 191.0 (dec.) (Nujol) 2355, 1711, 1620 1577, 1543, 1479 (sh), 1461, 137890 (V-1) 828 mg ##STR62## -- 150.degree. C. 3 hr. CH.sub.2 Cl.sub.2 /MeOH= 29/1-19/1 Ia-90*.sup.1 1.025 183.5- 185.0 (CHCl.sub. 3 MeOH) (Nujol) 2340, 1708, 1619 1568, 1528(sh), 1485, 146191 (V-1) HN(iBu).sub.2 3.76 ml -- 33 hr. CH.sub.2 Cl.sub.2 /MeOH= Ia-91*.sup.1 176.5- (Nujol) 628 mg reflux 49/1-19/1 685 mg 178.0 2620, 2510, 1690 (51.6%) (dec.) 1657, 1618, 1579 (MeOH 1533, 1488, 1460 Et.sub.2 O) 1409,__________________________________________________________________________ 1378 *.sup.1 maleate

EXAMPLE 92

4-(4-tert-Butylphenyl)-1-[3-{4-(pyrimidin-2-yl)piperazin-1-yl}propyl]-1,2,5,6-tetrahydropyridine (Ia-92) ##STR63##

(1) A mixture of 1.1 g of 3-{4-(pyrimidin-2-yl)piperazin-1-yl)propylchloride, 1.07 g of the compound (II-6), 1.26 g of K.sub.2 CO.sub.3, and 1.03 g of NaI in 12 ml of DMF is stirred at 100.degree. C. for 4 hours. The reaction mixture is poured into ice-water and extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated. The residue is purified by silica gel chromatography (CH.sub.2 Cl.sub.2 /MeOH=10/1) followed by recrystallization from CH.sub.2 Cl.sub.2 -Et.sub.2 O to prepare 1.70 g (Yield: 85%) of the compound (III-56). mp. 215.0.degree.-225.0.degree. C. (dec.)

(2) A solution of 1.58 g of the compound (III-56) in 15 ml of CF.sub.3 COOH is refluxed for 3.5 hours. After removal of the excess reagent, the residue is poured into ice-cooled aq.NaHCO.sub.3 and extracted. The organic layer is dried over Na.sub.2 SO.sub.4 and evaporated under reduced pressure. The oily residue is purified by column chromatography with silica gel, eluting with CH.sub.2 Cl.sub.2 /MeOH (10/1-5/1) to prepare 1.44 g (Yield: 95%) of the compound (Ia-92) as crystals (mp. 79.0.degree.-81.0.degree. C.). The maleate is recrystallized from methanol to prepare colorless needles. mp. 209.0.degree.-211.0.degree. C. (dec.).

EXAMPLE 93-94

The reactions are performed in the same manner as Example 92 to prepare the compound (III) and (Ia). The reaction conditions and physical constants are shown in Tables 11 and 12.

TABLE 11__________________________________________________________________________(Step 1) ##STR64##Ex. DMF K.sub.2 CO.sub.3 NaI reaction purification g (Yield)No. (II) R(CH.sub.2)nY (VI) (ml) (g) (g) condition (1) condition (1) Compd. No. m.p.__________________________________________________________________________ (.degree.C.)93 (II-6) 980 mg ##STR65## 20 1.16 0.94 105 6.5 hr. CH.sub. 2 Cl.sub.2 /MeOH 1.69 (92.6) (III-57) 129.0-130.5 (CH.sub.2 Cl.sub.2Et .sub.2 O) (maleate)94 (II-6) 2.67 g ##STR66## 20 3.18 2.60 95-100 CH.sub.2 Cl.sub.2 /MeOH 4.04 (93.3) (III-58) 137.0-138.5 (CH.sub.2 Cl.sub.2Et .sub.2 O) (maleate)__________________________________________________________________________ TABLE 12__________________________________________________________________________(Step 2)(III) purification (I .sup.a)(g) CF.sub.3 COOH reflux time condition g (Yield) m.p. (.degree.C.) IR__________________________________________________________________________(III-57) 20 ml 4 hr. CH.sub.2 Cl.sub.2 /MeOH = Ia-93 105-106 (Nujol)1.50 g 20/1- 10/1 1.40 g (MeOH) 1710, 1622, 1598, 1575, (97.4) 1495 (sh), 1480, 1462, 1450, 1385, 1360(III-58) 10 ml 8 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1 Ia-94 213.0- (Nujol)0.88 g maleate 214.5 2300, 1717, 1622, 1575, 0.74 g (MeOH) 1535, 1500, 1465, 1458, (97.5) 1450__________________________________________________________________________

EXAMPLE 95

4-(4-Hydroxyphenyl)-1-{3-(4-morpholinyl)propyl}-1,2,5,6-tetrahydropyridine (Ia-95) ##STR67##

(1) A mixture of 2.829 g of 4-(4-methoxyphenyl)-4-hydroxypiperidine, 2.02 ml of 3-bromopropylchloride, and 3.773 g of K.sub.2 CO.sub.3 in 30 ml of DMF is stirred at room temperature for 3 hours. The reaction mixture is poured into ice-water and extracted with ethyl acetate. The organic layer is dried and evaporated under reduced pressure to prepare 4.525 g of pale yellow solid. Purification is conducted by column chromatography with silica gel, eluting with CH.sub.2 Cl.sub.2 /MeOH (29/1-5/1) to prepare 3.316 g (Yield: 85.6%) of the compound (IV-8) as solid which is recrystallized from n-hexane-Et.sub.2 O to prepare colorless needles. mp. 103.5.degree.-105.0.degree. C.

Anal Calcd. (%) for C.sub.15 H.sub.22 ClNO.sub.2 : C, 63.48; H, 7.81; N, 4.94; Cl, 12.49. Found: C, 63.47; H, 7.78; N, 5.01; Cl,12.45.

IR (CHCl.sub.3): 3595, 1610, 1582, 1510, 1468, 1462, 1454, 1441, 1375.

NMR (CDCl.sub.3) .delta.:1.761 (d-d, J.sub.1 =14 Hz, J.sub.2 =3 Hz, 2H); 1.998 (quint, J=7 Hz, 2H); 2.121 (t-d, J.sub.1 =13 Hz, J.sub.2 =4 Hz, 2H); 2.475 (t-d, J.sub.1 =12 Hz, J.sub.2 =3 Hz, 2H); 2.560 (t, J=7 Hz, 2H); 2.782 (d-d, J.sub.1 =14 Hz, J.sub.2 =3 Hz, 2H); 3.618 (t, J=7 Hz, 2H); 3.805 (s, 3H); 6.886, 7427 (ABq, J=9 Hz, 4H).

(2) To a solution of 3.176 g of the compound (IV-8) is added 3.17 ml of BBr.sub.3 with stirring under ice-cooling. After refluxing for 1.5 hours, the reaction mixture is poured into ice-water and the aqueous layer is made alkaline with c.NH.sub.4 OH and extracted with CH.sub.2 Cl.sub.2 /MeOH (4/1). The organic layer is dried and evaporated to dryness. The crude product is dissolved in 20 ml of CF.sub.3 COOH and refluxed for 1 hour. The reaction mixture is concentrated under reduced pressure and poured into ice-water. The aqueous layer is made alkaline with c.NH.sub.4 OH and extracted with CH.sub.2 Cl.sub.2 /MeOH (4/1). The organic layer is dried and evaporated to prepare 1.701 g (Yield: 57.2%) of the compound (V-6) as solid, which is recrystallized from MeOH-n-hexane to prepare the compound (V-6) as pale orange plates. mp. 208.0.degree.-209.0.degree. C.

Anal Calcd. (%) for C.sub.14 H.sub.18 ClNO: C, 66.79; H, 7.21; N, 5.56; Cl, 14.08. Found: C, 66.79; H, 7.26; N, 5.52; Cl, 14.25.

IR(Nujol): 3025, 2773, 2650, 2560, 1607, 1578, 1515, 1453, 1429, 1382.

NMR (CDCl.sub.3 -CD.sub.3 OD) .delta.:2.66 (quint, J=8 Hz, 2H); 2.47-2.76 (m, 4H); 2.774 (t, J=6 Hz, 2H); 3.200 (q, J=2 Hz, 2H); 3.637 (t, J=6 Hz, 2H); 5.972 (s, 1H); 6.803, 7.275 (ABq, J=9 Hz, 4H).

(3) A stirred mixture of 1.482 g of the compound (V-6) and 2.57 ml of morpholine is refluxed for 2 hr. 15 min. After removal of the reagent, the residue is purified by column chromatography with silica gel, eluting with CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH (128/16/1-64/8/1) to give 1.047 g (Yield: 58.8%) of the compound (Ia-95) as a solid. The maleate is recrystallized from MeOH-Et.sub.2 O to prepare pale yellow plates. mp. 166.0.degree.-167.5.degree. C. (d.)

Anal Calcd. (%) for C.sub.18 H.sub.26 N.sub.2 O.sub.2. 2C.sub.4 H.sub.4 O.sub.4 : C, 58.22; H, 6.48; N, 5.35. Found: C, 58.42; H, 6.41; N, 5.24.

IR (Nujol): 3230, 3063, 2725, 2355, 1715, 1625, 1579, 1519, 1464, 1387.

NMR (CD.sub.3 OD) .delta.:2.13-2.35 (m, 2H); 2.866 (brs, 2H); 3.03-3.25 (m, 6H); 3.25-3.40 (m, 2H); 3.564 (t, J=6 Hz, 3H); 3.883 (t, J=5 Hz, 4H); 3.953 (brs, 2H); 5.999 (brs, 1H); 6.264 (s, 4H); 6.778, 7.320 (ABq, J=9 Hz, 4H).

EXAMPLE 96

4-(4-Hydroxyphenyl)-1-(3-(1-pyrrolidinyl)propyl}-1,2,5,6-tetrahydropyridine (Ia-96) ##STR68##

A mixture of 1.50 g of the compound (V-6) and 4.97 ml of pyrrolidine is stirred at room temperature for 18.5 hours and treated in the same manner as Example 95 (3) to prepare 2.041 g (Yield: 66.1%) of the maleate of the compound (Ia-96) as needles. mp. 145.0.degree.-147.0.degree. C. (dec.).

Anal Calcd. (%) for C.sub.18 H.sub.26 N.sub.2 O.2C.sub.4 H.sub.4 O.sub.44 : C, 60.03; H, 6.42; N, 5.50. Found: C, 60.22; H, 6.61; N, 5.40.

IR (Nujol): 3230, 3041, 2710(sh), 2590, 2360, 1709, 1622, 1578, 1518, 1461, 1377.

NMR (CD.sub.3 OD) .delta.:2.00-2.175 (m, 4H); 2.175-2.375 (m, 2H); 2.859 (brs, 2H); 3.23-3.48 (m, 8H); 3.542 (t, J=6 Hz, 3H); 3.992 (brs, 2H); 5.995 (brs, 1H); 6.257 (s, 4H); 6.778, 7.320 (ABq, J=8 Hz, 4H).

EXAMPLE 97

1-{3-(N-methylamino)propyl}-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine (Ia-97) ##STR69##

A mixture of 3.00 g of the compound (V-6) and 11.84 ml of BuNH.sub.2 is refluxed for 5 hours, and treated in the same manner as Example 96 to prepare 2.188 g (Yield: 63.7%) of the compound (Ia-97) as needles. mp. 233.0.degree.-236.0.degree. C. (dec.).

IR(Nujol): 3425, 3055, 2778, 2670, 2582, 1665, 1613, 1590, 1515, 1471, 1453, 1439, 1428.

NMR (CDCl.sub.3): 0.920 (d, J=7 Hz, 6H); 1.92-2.18 (m, 3H); 2.554 (brs, 2H); 2.692 (d, J=7 Hz, 2H); 2.751 (t, J=6 Hz, 2H); 2.854 (t, 2H); 2.854 (t, J=6 Hz, 2H); 3.134 (t, J=6 Hz, 2H); 3.247 (brs, 2H); 5.922 (brs, 1H); 6.818, 7.194 (ABq, J=9 Hz, 4H).

EXAMPLE 98

1-{3-(N-isobutyl-N-methylamino)propyl}-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine (Ia-98) ##STR70##

Treatment of 2.138 g of the compound (Ia-97) in the same manner as Example 34 prepares 1.528 g (Yield: 70.1%) of the compound (Ia-98) as solid, which is crystallized as maleate and recrystallized from MeOH-Et.sub.2 O to prepare pale yellow plates. mp. 150.0.degree.-153.0.degree. C. (dec.).

Anal Calcd. (%) for C.sub.19 H.sub.30 N.sub.2 O.2C.sub.4 H.sub.4 O.sub.4 : C, 60.38; H, 7.16; N, 5.38. Found: C, 60.66; H, 7.16; N, 5.24.

IR (Nujol): 3235, 2700(sh), 2400, 1618, 1576, 1517, 1459, 1380 (sh), 1372(sh), 1359.

NMR (CD.sub.3 OD) .delta.:1.051 (d, J=7 Hz, 6H); 2.025-2.400 (m, 3H); 2.852 (brs, 2H); 2.916 (s, 3H); 3.026 (d, J=7 Hz, 2H); 3.15-3.38 (m, 4H); 3.533 (t, J=6 Hz, 2H); 3.917 (brs, 2H); 5.995 (brs, 1H); 6.257 (s, 4H); 6.777,7.318 (ABq, J=9 Hz, 4H).

EXAMPLE 99

4-(4-Methoxyphenyl)-1-{3-(4-morpholinyl)propyl}-1,2,5,6-tetrahydropyridine (Ia-99) ##STR71##

A stirred mixture of 1.147 g of the compound (IV-8) and 1.76 ml of morpholine is refluxed for 1 hour. After removal of the reagent, the residue is purified by silica gel column chromatography (CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH=64/8/1-32/6/1) to prepare 1.34 g of the compound (III-59) as oily substance. The oily product is dissolved in 10 ml of CF.sub.3 COOH and refluxed for 1 hour. After removal of the reagent, the residue is poured into aq. NH.sub.4 OH and extracted with methylene chloride. The organic layer is dried and evaporated under reduced pressure to prepare 1.012 g of the oily product. The oily product is subjected to column chromatography with silica gel, eluting with CH.sub.2 Cl.sub.2 /MeOH(19/1). The eluate is recrystallized from Et.sub.2 O-n-hexane to prepare of 637 mg (Yield: 50.2%) of the compound (Ia-99) as colorless needles.

mp. 69.0.degree.-70.5.degree. C.

Anal Calcd. (%) for C.sub.19 H.sub.28 N.sub.2 O.sub.2 : C, 72.12; H, 8.92; N, 8.85. Found: C, 72.01; H, 8.88; N, 9.05.

IR (CHCl.sub.3): 2490, 1610, 1572, 1512, 1466, 1446, 1417, 1402, 1378.

NMR (CHCl.sub.3) .delta.:1.779 (quint, J=7 Hz, 2H); 2.33-2.63 (m, 10H); 2.706 (t, J=5 Hz, 2H); 3.151 (q, J=4 Hz, 2H); 3.725 (t, J=5 Hz, 4H); 3.802 (s, 3H); 5.969 (quint, J=2 Hz, 1H); 6.851, 7.322 (ABq, J=9 Hz, 4H).

EXAMPLE 100

4-(4-tert-Butylphenyl)-1-{3-(2,6-dimethylmorpholino)propyl}-1,2,5,6-tetrahydropyridine (Ia-100) ##STR72##

(1) A mixture of 1.150 g of the compound (IV-2) and 2.29 ml of cis 2,6-dimethylmorpholine is stirred at 103.degree.-135.degree. C. for 4 hours. After removal of the reagent, the residue is poured into aq.NaOH and extracted with methylene chloride. The organic layer is dried and evaporated under reduced pressure. The residue is purified by column chromatography with silica gel, eluting with CH.sub.2 Cl.sub.2 --MeOH (15/1-5/1) to prepare 1.37 g (Yield: 95.0%) of the compound (III-60) as crystals. mp. 137.5.degree.-138.0.degree. C. (dec.)

IR (CHCl.sub.3): 3610, 3010, 2970, 2870, 2820, 1780, 1605, 1512 cm.sup.-1.

NMR (CDCl.sub.3) .delta.:1.161 (d, J=6 Hz, 6H); 1.319 (s, 9H); 1.63-1.88 (m, 7H); 2.215 (td, J.sub.1 =13 Hz, J.sub.2 =4 Hz, 2H); 2.30-2.60 (m, 6H); 2.753 (dd, J.sub.1 =12 Hz, J.sub.2 =2 Hz, 2H); 2.875 (dd, J.sub.1 =11 Hz, J.sub.2 =2 Hz, 2H); 3.60-3.75 (m, 2H); 7.377,7.451 (ABq, J=9 Hz, 4H).

(2) A solution of 1.35 g of the compound (III-60) in 10 ml of CF.sub.3 COOH is refluxed for 4 hour. After removal of the reagent, the residue is poured into aq.NaHCO.sub.3 and extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated under reduced pressure. The oily residue is purified by column chromatography with silica gel, eluting with CH.sub.2 Cl.sub.2 /MeOH (25/1-15/1) to prepare 1.29 g (Yield: 86.8%) of the compound (Ia-100) as an oil. The maleate is recrystallized from MeOH-iPrOH to prepare colorless needles. mp. 192.0.degree.-193.0.degree. C.

Anal Calcd. (%) for C.sub.24 H.sub.38 N.sub.2 O.2C.sub.4 H.sub.4 O.sub.4 : C, 63.58; H, 7.79; N, 4.64. Found: C, 63.77; H, 7.69; N, 4.65.

IR (Nujol): 1707, 1618 cm.sup.-1.

NMR (CDCl.sub.3): 1.260 (d, J=7 Hz, 6H); 1.330 (s, 9H); 2.20-2.40 (m, 2H); 2.491 (t, J=12 Hz, 2H); 2.80-2.95 (m, 2H); 3.111 (t, J=8 Hz, 2H); 3.28-3.40 (m, 4H); 3.542 (t, J=6 Hz, 2H); 3.80-4.00 (m, 4H); 3.542 (t, J=6 Hz, 2H); 3.80-4.00 (m, 4H); 6.02-6.08 (m, 1H); 6.283 (s, 2H); 7.355,7.422 (ABq, J=9 Hz, 4H).

EXAMPLE 101-104

The reaction is performed in the same manner as Example 100 to prepare the compound (Ia). The reaction condition are shown in Tables 13 and 14.

TABLE 13__________________________________________________________________________ ##STR73## ##STR74##Ex. reaction purification product m.p.No. (IV) (XI) solvent condition condition g (Yield) (.degree.C.) IR__________________________________________________________________________101 X = Me Z = O, R = -- 2 hr. CH.sub.2 Cl.sub.2 /MeOH = III-61 103.0- (CHCl.sub.3) 3.55 g 5.77 g reflux 15/1-5/1 4.23 g 104.5 3600, 3020, 2950, 2920, 2820, (96.0%) 1513, 1472102 X = Cl Z = O, R = H -- 130-135.degree. C. -- III-62 236.0- (Nujol) 5.1 g 7.71 g 2.5 hr. 5.97 g 237.0 3440, 2930, 2807, 2640, 2550, (99.5%) 2460103 X = t-Bu Z = NH, R = Me DMF 95-100.degree. C. CH.sub.2 Cl/MeOH/ III-63 -- (CHCl.sub.3) 2.35 g 1.73 g 20 ml 2 hr. NH.sub.4 OH = 1.92 g 3000, 3330, 2960, 2820, 2470, 30/6/1 (65.3%) 1665, 1635, 1605, 1590, 1510104 X = Cl Z = NH, R = Me DMF 80-85.degree. C. CH.sub.2 Cl/MeOH/ III-64 -- (CHCl.sub.3) 2.05 g 1.62 g 15 ml 3.5 hr. NH.sub.4 OH = 2.10 g 3590, 3160, 2930, 2810, 2490, 32/6/1 (80.9%) 1677, 1596,__________________________________________________________________________ 1492 TABLE 14__________________________________________________________________________Ex. reaction purification productNo. (III) CF.sub.3 COOH condition condition g (Yield) m.p. (.degree.C.) IR__________________________________________________________________________101 (III-61) 45 ml 2.5 hr. CH.sub.2 Cl.sub.2 /MeOH = Ia-101 186.5- (Nujol) 4.45 g reflux 15/1-5/1 3.99 g 188.5*.sup.1 1709, 1621 (92.0%)102 (III-62) 45 ml 7 hr. CH.sub.2 Cl.sub.2 /MeOH = Ia-102 185.5- (Nujol) 3.78 g reflux 15/1-5/11 3.00 g 186.5*.sup.1 2300 (br), 1709, 1622 (84.2%)103 (III-63) 20 ml room CH.sub.2 Cl.sub.2 /MeOH/ Ia-103 235.0- (Nujol) 1.92 g temperature NH.sub.4 OH = 1.60 g 250.0*.sup.2 3440, 3410, 2670, 2580, 2470 2.5 hr. reflux 128/16/1 (87.4%) 2420, 1658, 1555, 1507104 (III-64) 25 ml room CH.sub.2 Cl.sub.2 /MeOH/ Ia-104 179.0- (Nujol) 2.10 g temperature NH.sub.4 OH = 1.79 g 181.0*.sup.2 3600, 2680, 2530, 2440, 1642 15 hr. reflux 128/16/1 (89.6%) 1597, 1496__________________________________________________________________________ *.sup.1 maleate *.sup.2 hydrochloride

EXAMPLE 105

1-[3-{4-(3,4-Dimethoxyphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propylcarbamoyl]-2-oxopyrrolidine (Ia-105) ##STR75##

To a solution of 3.76 g of 4-(3,4-dimethoxyphenyl)-1,2,5,6-tetrahydropyridine (V-7), which was prepared by the reaction of 4-hydroxy-4-(3,4-dimethoxyphenyl)piperidine and p-toluenesulfonic acid, and 2.94 g of 1-(3-chloropropylcarbamoyl)-2-oxopyrrolidine in 35 ml of DMF is added 3.98 g of K.sub.2 CO.sub.3 and 3.22 g of NaI. The reaction mixture is stirred at 100.degree.-105.degree. C. for 6 days under nitrogen gas. After cooling to room temperature, the mixture is diluted with ethyl acetate, washed with brine and dried over MgSO.sub.4. After removal of the solvent, the residue is subjected to column chromatography with silica gel, eluting with CH.sub.2 Cl.sub.2 /MeOH (20/1) to prepare 1.78 g (Yield: 33.4%) of the compound (Ia-105) as solid. The oxalate is recrystallized from iPrOH-MeOH to prepare needles. mp. 178.0.degree.-182.0.degree. C.

Anal Calcd. (%) for C.sub.23 H.sub.31 N.sub.3 O.sub.8.1/5H.sub.2 O: C, 57.35; H, 6.33; N, 8.67. Found: C, 57.42; H, 6.58; N, 8.73.

IR (Nujol): 3310, 1725(sh), 1708, 1682, 1675, 1600, 1580, 1545, 1545, 1520.

NMR (CDCl.sub.3): 1.764 (quint, J=7 Hz, 2H); 1.954 (quint, J=8 Hz, 2H); 2.44-2.51 (m, 4H); 2.530 (t, J=8 Hz, 2H); 2.646 (t, J=5 Hz, 2H); 3.094 (q, J=3 Hz, 2H); 3.328 (q, J=7 Hz, 2H); 3.795 (t, J=7 Hz, 2H); 3.809, 3.827 (sx2, 6H); 5.915 (quint, J=3 Hz, 1H); 6.755 (d, J=9 Hz, 2H); 6.84-6.89 (m, 2H); 8.434 (brs, 1H).

EXAMPLE 106

1-[3-{4-(4-Methoxyphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propylcarbamoyl]-2-oxopyrrolidine (Ia-106) ##STR76##

The compound (V-8) is reacted in the same manner as Example 105 to prepare the compound (Ia-106). mp. 199.5.degree.-200.0.degree. C. (dec.).

Anal Calcd. (%) for C.sub.22 H.sub.29 N.sub.3 O.sub.7 : C, 58.81; H, 6.31; N, 9.32. Found: C, 59.02; H, 6.53; N, 9.39.

IR (Nujol): 3300, 2730, 2620, 1700, 1685, 1612, 1548, 1529, 1465.

NMR (CDCl.sub.3): 1.90-2.10 (m, 4H); 2.590 (t, J=7 Hz, 2H); 2.80-2.86 (m, 2H); 3.23-3.30 (m, 2H); 3.33-3.52 (m, 4H); 3.778 (s, 3H); 3.898 (m, 2H); 5.995 (s, 1H); 6.893, 7.379 (ABq, J=8 Hz, 4H).

EXAMPLE 107

1-[4-(4-Tolyl)-1,2,5,6-tetrahydropyridin-1-ylbutylcarbamoyl]-2-oxopyrrolidine (Ia-107) ##STR77##

(1) To a solution of 4.00 g of the compound (II-8) and 4.675 g of N-Boc-.beta.-alanine in 90 ml of THF are added 5.178 g of 1,3-dicyclohexylcarbodiimide and 848 mg of 1-hydroxybenzotriazole hydrate. The reaction mixture is stirred at room temperature for 2 hours and 10 minutes. After removal of precipitates, the reaction mixture is concentrated under reduced pressure. The residue is poured into d.HCl and extracted with CH.sub.2 Cl.sub.2. The organic layer is washed with aq.NaHCO.sub.3 and water in order, dried over MgSO.sub.4 and evaporated under reduced pressure. The residue is subjected to column chromatography with silica gel, eluting with toluene/acetone (3/1-2/1) to prepare 6.862 g of crystalline residue. It is recrystallized from methylene chloride-ether-n-hexane to prepare 6.674 g (Yield: 84.8%) of the compound (IV-9) as colorless needles. mp. 161.5.degree.-163.0.degree. C.

Anal calcd. (%) for C.sub.21 H.sub.32 N.sub.2 O.sub.4 : C, 67.18; H, 8.46; N, 7.50. Found: C, 66.99; H, 8.57; N, 7.44.

IR (CHCl.sub.3): 3597, 3457, 1709, 1628, 1508, 1474, 1448, 1393, 1369.

NMR (CDCl.sub.3) .delta.:1.432 (s, 9H); 1.75,2.05 (m, 8H); 2.344 (s, 3H); 2.147 (t, J=7 Hz. 2H); 3.04,3.20 (m, 3H); 3.560 (td, J.sub.1 =12 Hz, J.sub.2 =4 Hz, 1H); 3.737 (d, J=14 Hz, 1H); 4.548 (d, J=13 Hz, 1H); 4.833 (brs, 1H); 7.177,7.353 (ABq, J=8 Hz, 4H).

(2) A solution of 6.654 g of the compound (IV-9) in 13 ml of CF.sub.3 COOH is stirred at room temperature for 2.5 hours. After removal of the excess reagent, 6.36 g of the crystalline residue is obtained. The residue is recrystallized from MeOH-Et.sub.2 O to prepare 5.798 g of colorless plates. Then to a solution of 4.818 g of the plates in 30 ml of methanol is added 5 ml of triethylamine. After removal of the solvent to dryness, the resulting solid is dropwise added to a stirred suspension of 737 mg of LiAlH.sub.4 in 80 ml of THF at room temperature and stirred at the same temperature for 2.5 hours. After decomposition of the excess reagent by careful addition of water, the resulting precipitate is filtered off. The organic layer is evaporated to dryness to prepare 3.612 g of the yellow oily residue. The residue is subjected to column chromatography with silica gel, eluting with CHCl.sub.3 /MeOH/c.NH.sub.4 OH (32/4/0.5-32/6/1) to prepare 1.341 g (Yield: 42.4%) of the compound (V-9).

(3) A mixture of 1.341 g of the compound (V-9) and 1.126 g of 1-phenoxycarbonyl-2-oxopyrrolidine is heated at 115.degree. C. for 1 hour 43 minutes. The reaction mixture is purified by column chromatography with silica gel, eluting with toluene/acetone (2/1-1/1) followed by recrystallization from Et.sub.2 O-n-hexane to prepare 540 mg (Yield: 24.7%) of the compound (Ia-107) as prisms.

mp. 104.0.degree.-104.5.degree. C.

Anal Calcd. (%) for C.sub.21 H.sub.29 N.sub.3 O.sub.2 : C, 71.05; H, 8.22; N, 11.84. Found: C, 70.95; H, 8.22; N, 11.82.

IR (CHCl.sub.3): 3325, 1714, 1682, 1602, 1548, 1516, 1490, 1461, 1442, 1387.

NMR (CDCl.sub.3) .delta.:1.62,1.66 (m, 4H); 2.025 (quint, J=7 Hz, 2H); 2.330 (s, 3H); 2.30-2.73 (m, 8H); 3.145 (q, J=3 Hz, 2H); 3.338 (q, J=6 Hz, 2H); 3.858 (t, J=7 Hz, 2H); 6.016 (quint, J=2 Hz, 1H); 7.117, 7.283 (ABq, J=8 Hz, 4H); 8.430 (brs, 1H).

EXAMPLE 108

1-[{5-(4-Tolyl)-1,2,5,6-tetrahydropyridin-1-yl}pentylcarbamoyl]-2-oxopyrroridine (Ia-108) ##STR78##

A mixture of 4.675 g of BocNH(CH.sub.2).sub.4 COOH and 4.00 g of the compound (II-8) is treated in the same manner as Example 107 (1)-(3) to prepare 392 mg (Yield: 15.0%) of the compound (Ia-108). mp.58.5.degree.-59.5.degree. C.

Anal Calcd. (%) for C.sub.22 H.sub.31 N.sub.3 O.sub.2 : C, 71.23; H, 8.42; N, 11.46. Found: C, 71.51; H, 8.46; N, 11.37.

IR (CHCl.sub.3): 3321, 1714, 1681, 1548, 1516, 1489, 1461, 1387.

NMR (CDCl.sub.3 -CD.sub.3 OD) .delta.:1.32-1.45 (m, 2H); 1.52-1.70 (m, 4H); 2.039 (quint, J=7 Hz, 2H); 2.333 (s, 3H); 2.429-2.507 (m, 2H); 2.615 (t, J=8 Hz, 4H); 2.723 (t, J=6 Hz, 2H); 3.161 (q, J=3 Hz, 2H); 3.303 (q, J=6 Hz, 2H); 3.854 (t, J=7 Hz, 2H); 6.032 (s, 1H); 7.126, 7.292 (ABq, J=8 Hz, 4H); 8.460 (brs, 1H).

EXAMPLE 109

1-{3-(3,4-Dichlorophenoxy)propyl}-4-(4-hydroxyphenyl)1,2,5,6-tetrahydropyridine (Ia-109) ##STR79##

(1) A mixture of 3.6 g of 3-(3,4-dichlorophenoxy)propylchloride, which was prepared by the reaction of 3,4-dichlorophenol with 3-bromopropylchloride, and 3.12 g of 4-hydroxy-4-(4-methoxyphenyl)piperidine, 4.15 g of K.sub.2 CO.sub.3, and 3.37 g of NaI in 35 ml of DMF is stirred at 105.degree. C. for 10 hour. The reaction mixture is poured into ice-water, and the resulting precipitates are extracted with methylene chloride. The organic layer is dried and evaporated under reduced pressure. The residue is purified by column chromatography with silica gel, eluting with CH.sub.2 Cl.sub.2 /MeOH (20/1-10/1) followed by recrystallization from methylene chloride to prepare 5.86 g (Yield: 95.2%) of the compound (III-65) as colorless needles. mp. 131.0.degree.-132.0.degree. C.

Anal Calcd. (%) for C.sub.21 H.sub.25 N.sub.2 O.sub.3 Cl.sub.2 : C, 61.39; H, 6.20; N, 3.55; Cl, 17.28. Found: C, 61.47; H, 6.14; N, 3.41; Cl, 17.30.

IR (CHCl.sub.3): 3600, 1612, 1595, 1568, 1513, 1480(sh), 1468.

NMR (CDCl.sub.3) .delta.:1.563 (s, 1H); 1.772 (dd, J.sub.1 =14 Hz, J.sub.2 =3 Hz, 2H); 1.999 (quint, J=6 Hz, 2H); 2.137 (td, J.sub.1 =13 Hz, J.sub.2 =4 Hz, 2H); 2.478 (td, J.sub.1 =12 Hz, J.sub.2 =2 Hz, 2H); 2.575 (t, J=7 Hz, 2H); 2.811 (J.sub.1 =11 Hz, J.sub.2 =3 Hz, 2H); 3.803 (s, 3H); 4.004 (t, J=6 Hz, 2H); 6.760 (dd, J.sub.1 =9 Hz, J.sub.2 =3 Hz, 1H); 6.887 (d, J=9 Hz, 2H); 7.013 (d, J=3 Hz, 1H); 7.308 (d, J=9 Hz, 1H); 7.438 (d, J=9 Hz, 2H).

(2) To a stirred solution of 2.08 g of the compound (III-65) in 50 ml of methylene chloride is added 1.44 ml of BBr.sub.3 under ice-cooling. After removal of the reagent, the residue is poured into aq.NaHCO.sub.3 and extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated under reduced pressure. The resulting oily residue 1.91 g is dissolved in 20 ml of CF.sub.3 COOH and refluxed for 2 hour. After removal of the reagent, the residue is poured into aq.NaHCO.sub.3 and extracted with ethylacetate. The organic layer is washed, dried and evaporated. The residue is purified by column chromatography with silica gel(toluene/ethyl acetate(1/1)-CH.sub.2 Cl.sub.2 /MeOH (20/1)) to prepare 270 mg (Yield: 33%) of the compound (Ia-109) as a solid. The maleate is recrystallized from MeOH-iPrOH to prepare needles. mp. 167.0.degree.-168.0.degree. C. (dec.).

Anal Calcd. (%) for C.sub.20 H.sub.21 NO.sub.2 Cl.sub.2 : C,58.08; H,5.05; N,2.93; Cl,14.55. Found: C,58.31; H,5.10; N,2.83; Cl,14.34.

EXAMPLE 110

1-{3-(3,4-Dichlorophenoxy)propyl}-4-(3,4-dichlorophenyl)1,2,5,6-tetrahydropyridine (Ia-110) ##STR80##

(1) 3-(3,4-dichlorophenoxy)propylchloride 1.38 g and 4-hydroxy-4-(3,4-dichlorophenyl)piperidine 1.35 g are reacted in the same manner as Example 109 (1) to prepare 2.40 g (Yield: 97.5%) of 1-{3-(3,4-dichlorophenoxy)propyl}-4-hydroxy-4-(3,4-dichlorophenyl) piperidine (III-66). mp.118.0.degree.-118.5.degree. C.

(2) A solution of 1.61 g of the compound (III-66) in 20 ml of trifluoroacetic acid is refluxed for 3.5 hours. After removal of the reagent, the residue is poured into aq.NaHCO.sub.3 and extracted with methylene chloride. The organic layer is washed, dried and evaporated. The residue is purified by column chromatography with silica gel, eluting with CH.sub.2 Cl.sub.2 /MeOH(25/1) to prepare 1.45 g (Yield: 94.0%) of the compound (Ia-110) as oxalate. The oxalate is recrystallized from MeOH-iPrOH to prepare the compound (Ia-110) as needles. mp. 163.5.degree.-165.0.degree. C. (dec.).

Anal Calcd. (%) for C.sub.20 H.sub.19 NO.sub.2 Cl.sub.4 : C, 50.43; H, 4.09; N, 2.72; Cl, 27.15. Found: C, 50.70; H, 4.06; N, 2.69; Cl, 27.21.

IR (Nujol): 2930, 1713, 1695(sh), 1615, 1597, 1563.

NMR (CDCl.sub.3): 2.045 (quint, J=7 Hz, 2H); 2.657 (t, J=8 Hz, 2H); 2.554 (m, 2H); 2.745 (t, J=5 Hz, 2H); 3.202 (q, J=3 Hz, 2H); 4.026 (t, J=6 Hz, 2H); 6.110 (m, 1H); 6.766 (dd, J.sub.1 =19 Hz, J.sub.2 =3 Hz, 1H); 7.015 (d, J=3 Hz, 1H); 7.19-7.47 (m, 4H).

EXAMPLE 111

1-{3-(3,4-Dichlorophenoxy)propyl}-4-(4-trifluoromethylphenyl)-1,2,5,6-tetrahydropyridine (Ia-111) ##STR81##

(1) 3-(3,4-dichlorophenoxy)propylchloride 2.00 g and 4-hydroxy-4-(4-trifluoromethylphenyl)piperidine 1.95 g are reacted in the same manner as Example 109 (1) to prepare 3.16 g (Yield: 88.7%) of the compound (III-67). mp. 196.0.degree.-196.5.degree. C.

(2) A solution of 2.65 g of the compound (III-67) in 30 ml of trifluoroacetic acid is refluxed for 41 hours. After removal of the reagent, the residue is poured into aq.NaHCO.sub.3 and extracted with ethyl acetate. The organic layer is dried and evaporated. The residue is purified by column chromatography with silica gel (toluene/ethyl acetate (3/1), CH.sub.2 Cl.sub.2 /MeOH(25/1)) to prepare 1.65 g (Yield: 65.9%) of the compound (Ia-111) as a solid, which is recrystallized from Et.sub.2 O to prepare colorless needles, mp.83.5.degree.-84.0.degree. C. The oxalate melts at mp. 195.5.degree.-196.0.degree. C.

Anal Calcd. (%) for C.sub.21 H.sub.20 NO.sub.2 Cl.sub.2 F.sub.3.C.sub.2 H.sub.2 O.sub.4 : C, 52.93; H, 4.33; N, 2.71; Cl, 13.42; F, 11.08. Found: C, 53.09; H, 4.26; N, 2.69; Cl, 13.65; F, 10.95.

IR (CHCl.sub.3): 2950, 2930, 2830, 2790, 1618, 1597, 1469.

NMR (CDCl.sub.3): 2.052 (quint, J=7 Hz, 2H); 2.52-2.65 (m, 2H); 2.661 (t, J=7 Hz, 2H); 2.759 (t,J=6 Hz, 2H); 3.222 (q, J=3 Hz, 2H); 6.171 (m, 1H); 6.765 (dd, J.sub.1 =9 Hz, J.sub.2 =3 Hz, 1H); 7.015 (d, J=3 Hz, 1H); 7.312 (d, J=9 Hz, 1H); 7.479, 7.574 (ABq, J=8 Hz, 4H).

REFERENCE EXAMPLE 1

4-Hydroxy-4-(3,4-dichlorophenyl)piperidine (II-1) ##STR82##

A mixture of 64.2 g of 1-ethoxycarbonyl-4-hydroxy-4-(3,4-dichlorophenyl)piperidine (X-1) and a solution of 72.4 g of KOH in 700 ml of nBuOH is refluxed for 2 hours and evaporated. The reaction mixture is concentrated under reduced pressure and extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated. The resulting crystalline residue is recrystallized from ethyl acetate to prepare 44.7 g (Yield: 90.0%) of the compound (II-1). mp. 144.5.degree.-146.0.degree. C.

Anal Calcd. (%) for C.sub.14 H.sub.17 NO.sub.3 Cl.sub.2 : C, 53.62; H, 5.26; N, 5.68; Cl, 28.98. Found: C, 53.68; H, 5.32; N, 5.69; Cl, 28.81.

IR (Nujol): 3320, 3100, 1438.

NMR (CD.sub.3 OD) .delta.:1.651 (dd, J.sub.1 =12 Hz, J.sub.2 =2 Hz, 2H); 1.936 (td, J.sub.1 =12 Hz, J.sub.2 =5 Hz, 2H); 1.651 (dd, J.sub.1 =12 Hz, J.sub.2 =2 Hz, 2H); 3.074 (td, J.sub.1 =12 Hz, J.sub.2 =3 Hz, 2H); 7.402 (dd, J.sub.1 =8 Hz, J.sub.2 =2 Hz, 1H); 7.480 (d, J=8 Hz, 1H); 7.662 (d, J=2 Hz, 1H).

REFERENCE EXAMPLE 2-19

The reaction is performed in the same manner as Reference Example 1 to prepare the compound (II). The reaction conditions and physical constants are shown in Tables 15 and 16.

TABLE 15__________________________________________________________________________ ##STR83## (X) (II) g (Yield)Ref. Ex. No. X = Base solvent reflux time m.p. (.degree.C.) IR__________________________________________________________________________2 CF.sub.3 (p) KOH EtOH 5 hours (II-2) 27.3 g (28.07 g) (450 ml) 13.24 g (63.0%) (X-2)3 n-Pr (p) KOH n-BuOH 5.5 hours (II-3) 44.0 g (49.3 g) (640 ml) 30.47 g (92.0%) (X-3)4 Et (p) KOH n-BuOH 2 days (II-4) 22.42 g (26.37 g) (500 ml) 13.88 g (83.7%) (X-4)5 Ph (p) KOH n-BuOH 15 hours (II-5) 18.65 g (18.70 g) (500 ml) 13.44 g (92.6%) (X-5)6 t-Bu (p) KOH n-BuOH 5.5 hours (II-6) 46.67 g (50.9 g) (700 ml) 33.64 g (92.0%) (X-6)7 CH.sub.3 (p) KOH BuOH 3.5 hours (II-8) (Nujol) 49.86 g (61.8 g) (700 ml) 33.20 g (92.0%) 3310, 1598, 1502, 1490 (X-7) 135.5-137.5 14458 CH.sub.3 (m) KOH EtOH 6 days (II-9) (Nujol) 21.2 g (26.3 g) (450 ml) 10.25 g (66.6%) 3440, 3280, 3220, 3179 (X-8) 154.5-155.5 1606, 1590, 1490, 14759 CH.sub.3 (o) KOH EtOH 5 days (II-10) (Nujol) 14.7 g (18.21 g) (350 ml) 7.90 g (74.0%) 3440, 3280, 3220, 3170 (X-9) 141.0-142.0 1608, 1590, 149010 3,4-diMe KOH EtOH 10 days (II-11) (Nujol) 20.2 g (23.76 g) (500 ml) 13.97 g (93.5%) 3590, 3380, 1600, 1502 (X-10) -- 1467, 144811 3,5-diMe KOH EtOH 12 days (II-12) (Nujol) 22.7 g (26.7 g) (650 ml) 14.85 g (88.4%) 3280, 3120(br), 1605 (X-11) 182.0-183.0 141512 Cl (m) KOH EtOH 2 days (II-13) (Nujol) 22.2 g (25.5 g) (350 ml) 13.68 g (82.6%) 3220, 3080, 1595, 1570 (X-12) 100.0-101.0 1432, 140813 Cl (o) NaOH THF/H.sub.2 O 5 days (II-14) (KBr) 9.2 g (3.89 g) (10 ml/20 ml) 4.95 g (72.0%) 3440, 3280, 3060, 1475 (X-13) 166.5-167.5 1442, 143014 3,5-diCl KOH EtOH 11 days (II-15) (Nujol) 25.11 g (25.74 g) (550 ml) 15.5 g (79.8%) 3310, 3100, 3080, 1591 (X-14) 213.0-214.0 1568, 1450, 1425, 141015 Br (p) KOH EtOH 10 days (II-16) (Nujol) 21.0 g (20.87 g) (500 ml) 9.23 g (56.3%) 3280, 3050, 1588, 1492 (X-15) 159.5.about.161.5 1478, 142016 F (p) KOH Dioxane/H.sub.2 O 6 days (II-17) (Nujol) 23.2 g (17.36 g) (170/70 ml) 9.82 g (58.8%) 3280, 3130, 1602, 1512 (X-16) -- 145517 CF.sub.3 (m) (II-18) (CHCl.sub.3) Cl (p) KOH nBuOH 2 hours 22.30 g (67.0%) 3595, 2950, 2850, 1607 41.8 g (42.7 g) (580 ml) 135.0-136.5 1576, 1483 (X-17)18 *.sup.1 KOH EtOH 2 days (II-19) (Nujol) (X-18) (18.30 g) (350 ml) 11.88 g 3290, 1540, 1417 27.1 g 149.5- 150.019 *.sup.2 KOH nBuOH 2 days (II-20) (Nujol) (X-19) (19.82 g) (500 ml) 9.51 g (62.1%) 3280, 1640, 1540 19.7 g 151.0-152.5__________________________________________________________________________ ##STR84## ##STR85## TABLE 16__________________________________________________________________________Compd. m.p. (.degree.C.) Anal Calcd. (%)No. (solvent*) Found (%) IR (cm.sup.-1) NMR (.delta.)__________________________________________________________________________II-2 136.0-137.0 C.sub.12 H.sub.14 NOF.sub.3 : (Nujol) (CD.sub.3 OD) (ethyl C, 58.83(58.77) 3290, 1619, 1443 1.680(d-d, J.sub.1 =14Hz, J.sub.2 =2Hz, 2H):2.004(t-d, J.sub.1 =14Hz, J.sub.2 =5Hz, 2H): acetate) H, 5.74(5.75) 1439, 1422, 1410 2.866(d-d, J.sub.1 =13Hz, J.sub.2 =2Hz, 2H):3.107(t-d, J.sub.1 =13Hz, J.sub.2 =2Hz, N, 5.73(5.71) 2H):7.625(d, J=9Hz, 2H):7.698(d, J=9Hz, 2H) F, 23.13(23.24)II-3 178.5-179.5 C.sub.14 H.sub.21 NO.C.sub.2 H.sub.2 O.sub.4 (CHCl.sub.3) (CDCl.sub.3) (oxalate) C, 61.77(62.12) 3600, 3350(br), 0.933(t, J=7Hz, 3H):1.620(sextet, J=8Hz, 2H):1.876(d, J=14Hz, (i-PrOH) H, 7.42(7.49) 1593, 1510, 1468 2H):2.330(t-d, J.sub.1 =14Hz, J.sub.2 =4Hz, 2H):2.564(t, J=7Hz, 2H):3.244 N, 4.50(4.53) 1422 (d, J=12Hz, 2H):3.367(t, J=12Hz, 2H):7.164(d, J=8Hz, 2H):7.40 (d, J=8Hz, 2H)II-4 119.0-120.0 C.sub.13 H.sub.14 NO (CHCl.sub.3) (CD.sub.3 OD) (Et.sub.2 O- C, 75.97(76.05) 3600, 1510, 1469 1.204(t, J=7Hz, 3H):1.676(d-d, J.sub.1 =14Hz, J.sub.2 =2Hz, 2H):1.933 ethyl H, 9.33(9.33) 1440, 1420, 1410 (t-d, J.sub.1 =14Hz, J.sub.2 =5Hz, 2H):2.616(q, J=8Hz, 2H):2.852(d-d, J.sub.1 =12 acetate) N, 6.78(6.82) (sh) Hz, J.sub.2 =3Hz, 2H):3.084(t-d, J.sub.1 =12Hz, J.sub.2 =3Hz, 2H):7.156(d, J=8 Hz, 2H):7.397(d, J=8Hz, 2H)II-5 182.5-184.0 C.sub.17 H.sub.19 NO.1/6H.sub.2 O (Nujol) (CDCl.sub.3 --CD.sub.3 OD = 4/1) (MeOH-- C, 79.84(79.65) 3320, 1595, 1581 1.804(d, J=12Hz, 2H):2.052(t-d, J.sub.1 =14Hz, J.sub.2 =5Hz, 2H):2.096(d- CH.sub.2 Cl.sub.2) H, 7.48(7.60) 1563, 1490, 1450 d, J.sub.1 =13Hz, J.sub.2 =2Hz, 2H):3.172(t-d, J.sub.1 =12Hz, J.sub.2 =3Hz, 2H):7.29- N, 5.44(5.46) 7.63(m, 9H)II-6 185.0-186.0 C.sub.15 H.sub.23 NO.H.sub.2 O (Nujol) (CD.sub.3 OD) (CHCl.sub.3 -- C, 71.18(71.67) 3480(sh), 3390, 1.301(s, 9H):1.684(d-d, J.sub.1 =14Hz, J.sub.2 =2Hz, 2H):1.839(t-d, J.sub.1 =14 MeOH) H, 9.86(10.02) 3320, 3290, 3090 Hz, J.sub.2 =4Hz, 2H):2.857(d-m, J.sub.1 =12Hz, 2H):3.086(t-d, J.sub.1 =13Hz, J.sub.2 = N, 5.67(5.57) 1668, 1508, 1470 3Hz, 2H):7.360(d, J=9Hz, 2H):7.404(d,__________________________________________________________________________ J=9Hz) *a solvent for recrystallization

EVALUATION OF BIOLOGICAL ACTIVITY

Experiment

After the decapitation of rats, the objective tissues were rapidly removed and each was weighed. Each tissue was homogenized with twenty-fold amount of ice-cold 50 mM Tris-HCl buffer (pH7.8), homogenized, and centrifuged at 40,000.times.g for 10 minutes. The supernatant was removed and pellets were then resuspended in the buffer and recentrifuged. The procedure is repeated 3 times. Then these obtained samples were freeze-dried in liquid nitrogen and preserved at -80.degree. C. On the test day, the sample was thawed at room temperature and centrifuged at 40,000.times.g for 10 minutes, the pellets were then suspended in an incubation buffer and used as the receptor preparation. The preparation was added to the mixture containing the labelled ligand and the test drug, and filtered through Whatman GF/C filters and washed to terminate the on reaction. Radioactivity on the filters was determined by a liquid scintillation counter and Ki value was calculated.

1. .sigma. receptor

Sigma receptor binding was initiated by the addition of the receptor preparation (cortex tissue, 0.7 mg protein/ml) to a mixture containing 5 nM of [.sup.3 H]3PPP [3-hydroxyphenyl-N-(1-propyl)piperidine] and the test compound dissolved in 50 mM Tris-HCl buffer (pH 7.8). Incubation was carried out at 25.degree. C. for 90 minutes. Specific sigma receptor binding was defined as the difference in amount of [.sup.3 H]3PPP bound to the tissue in the presence or the absence of 10 .mu.M haloperidol.

2. DA2 receptor

DA2 receptor binding was initiated by the addition of the receptor preparation (striatal tissue, 0.3 mg protein/ml) to a mixture containing 0.2 nM of [.sup.3 H]spiroperidol and the test compound dissolved in 50 mM Tris-HCl buffer containing 100 mM-NaCl and 5 mM-KCl (pH 7.4). Incubation was carried out at 37.degree. C. for 10 minutes. Specific DA2 receptor binding was defined as the difference in amount of [.sup.3 H]spiroperidol bound to the tissue in the presence or the absence of 10 .mu.M haloperidol.

3. 5HT2 receptor

5HT2 receptor binding was initiated by the addition of the receptor preparation (cortex tissue, 0.5 mg protein/ml) to a mixture containing 1 nM of [.sup.3 H]spiroperidol and the test compound dissolved in 50 mM Tris-HCl buffer (pH 7.4). Incubation was carried out at 37.degree. C. for 15 minutes. Specific 5HT2 receptor binding was defined as the difference in amount of [.sup.3 H]spiroperidol bound to the tissue in the presence or the absence of 1 mM serotonin.

4. PCP receptor

PCP receptor binding was initiated by the addition of the receptor preparation (cortex tissue, 0.2 mg protein/ml) to a mixture containing 5 nM of [.sup.3 H]TCP and the test compound dissolved in 5 mM Tris-HCl buffer (pH 7.8). Incubation was carried out at 25.degree. C. for 30 minutes. Specific PCP receptor binding was defined as the difference in amount of [.sup.3 H]TCP bound to the tissue in the presence or the absence of 10 .mu.M PCP.

The test results are shown in Table 17.

TABLE 17______________________________________Test Ki (.mu.M)compound PCP .sigma. DA2 5-HT2______________________________________Ia-2 31 0.0041 4.7 0.55Ia-3 16 0.0095 4.0 1.70Ia-6 49 0.0027 2.2 2.50Ia-8 >62 0.0013 1.20 2.90Ia-9 33 0.0061 1.60 1.20Ia-11 23 0.0026 4.50 4.40Ia-13 26 0.0022 0.32 0.77Ia-24 32 0.0058 1.10 0.38Ia-30 >63 0.0013 2.00 3.70Ia-35 18 0.0018 4.60 3.20Ia-56 44 0.0065 4.50 8.90Ia-57 44 0.0063 2.40 0.14Ia-94 27 0.0013 1.40 1.90Ia-101 >63 0.00031 1.80 7.70Ia-102 >71 0.00071 3.20 5.70Ia-111 >63 0.0029 0.63 0.39Ia-112 >63 0.0025 >21 2.60______________________________________

From the above, the compound of the present invention has low affinity to DA2 receptor and high affinity to .sigma. receptor, and has useful activity as psychotropic agents.

Claims

1. A compound of the formula: ##STR86## wherein Ar is phenyl which has identically or differently one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, trifluoromethyl, hydroxy and phenyl, which latter phenyl may be substituted by hydroxy, lower alkyl, lower alkoxy or halogen, or Ar is phenyl which is substituted by two halogen atoms;

n is an integer of from 2 to 6;

R.sup.1 is hydrogen or lower alkyl;

the group ##STR87## may have identically or differently 1 to 3 substituents selected from the group consisting of lower alkyl, halogen, oxo and phenyl, which phenyl may be substituted by hydroxy, lower alkyl, lower alkoxy or halogen; and

p and q each is an integer of 0 to 1, excluding the case where p is 0 when q is 1;

or a pharmaceutically acceptable acid addition salt thereof.

2. A compound of the formula: ##STR88## wherein n is an integer of from 2 to 6; p and q each is an integer of 0 or 1, excluding the case where p is 0 when q is 1; or a pharmaceutically acceptable acid addition salt thereof.

3. A compound of the formula: ##STR89## wherein n is an integer of from 2 to 6; p and q each is an integer of 0 or 1, excluding the case where p is 0 when q is 1; or a pharmaceutically acceptable acid addition salt thereof.

4. A compound of the formula: ##STR90## wherein R.sup.1 is hydrogen or lower alkyl; n is an integer of from 2 to 6; p and q each is an integer of 0 or 1, excluding the case where p is 0 when q is 1; or a pharmaceutically acceptable acid addition salt thereof.