Piperazine derivatives and methods for the preparation thereof and compositions containing the same

Abstract

The present invention relates to novel compound of the general formula(I) and acid addition salt thereof. ##STR1## wherein R.sub.1 and R.sub.2 are independently hydrogen, C.sub.1 -C.sub.8 alkyl or optionally substituted C.sub.3 -C.sub.6 membered cycloalkyl containing C.sub.3 -C.sub.8 ; R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are independently hydrogen, halogen, hydroxy, nitro, C.sub.1 -C.sub.4 lower ester, C.sub.1 -C.sub.4 lower alkyl, C.sub.1 -C.sub.4 lower alkoxy, aryl, arylalkoxy or unsaturated amine; l is an integer of 0-7; m and n are independently an integer of 0-1; W is carbon or nitrogen; X is oxygen, sulfur, optionally substituted imine; Y is nitrogen or oxygen; and Z is hydrogen, C.sub.1 -C.sub.8 alkoxy, aryloxy, C.sub.1 -C.sub.4 alkylamine, cycloamine containing N.sub.1 -N.sub.5 or oxo group.The present compounds of the above formula (I) has no only strong antimumor activities but lower toxicities, and accordingly are expected as novel antitumor agents.

Description

THE PRESENT INVENTION RELATES TO NEW PIPERAZINE DERIVATIVES OF THE GENERAL FORMULA(I) ##STR2## wherein R.sub.1 and R.sub.2 are independently hydrogen, C.sub.1 -C.sub.8 alkyl or optionally substituted C.sub.3 -C.sub.6 membered cycloalkyl containing C.sub.3 -C.sub.8 ; R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are independently hydrogen, halogen, hydroxy, nitro, C.sub.1 -C.sub.4 lower ester, C.sub.1 -C.sub.4 lower alkyl, C.sub.1 -C.sub.4 lower alkoxy, aryl, arylalkoxy or unsaturated amine; l is an integer of 0-7; m and n are independently an integer of 0-1; W is carbon or nitrogen; X is oxygen, sulfur, optionally substituted imine; Y is nitrogen or oxygen; and Z is hydrogen, C.sub.1 -C.sub.8 alkoxy, aryloxy, C.sub.1 -C.sub.4 alkylamine, cycloamine containing N.sub.1 -N.sub.5 or oxo group.

C.sub.1 -C.sub.8 alkyl means straight or branch alkyl group such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, iso-pentyl, hexyl, heptyl, octyl, 2-methyl-pentyl or the like.

C.sub.1 -C.sub.4 lower alkyl means methyl, propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl or the like.

Optionally substituted 3-6 membered cycloalkyl containing C.sub.3 -C.sub.8 means substituted or unsubstituted cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted cyclopropyl, substituted cyclopentyl, substituted cyclohexyl or the like.

C.sub.1 -C.sub.4 lower ester means a carboxyl group esterified by lower alkyl group.

C.sub.1 -C.sub.4 lower alkoxy means methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy group or the like.

Aryioxy means phenoxy, substituted phenoxy, naphthyloxy or substituted naphthyloxy or the like.

Cycloamine group containing N.sub.1 -N.sub.5 means pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, piperazinyl or the like.

The general formula(I) compound wherein Z is oxo has the structural formula(I') by tautomerism. ##STR3##

The present inventors had studied to find compounds having intensive antitumor activity for a long time. As the results, we finally found out the facts that the foresaid compounds of the general formula(I) and acid addition salts thereof have not only prominant antitumor activity but very low toxicity. Accordingly, the one object of the present invention is to provide the novel compounds of the general formula(I) and acid addition salts thereof having not only prominent antitumor activity but very low toxicity.

The other object of the present invention is to provide a process for the preparation of the compounds of general formula(I) and acid addition salts thereof.

The compounds of the present invention can be mixed with pharmaceutically acceptable vehicles by a known method to give pharmaceutical compositions and the pharmaceutical compositions can be used to prevent or treat various kinds of tumors of human beings or mammals.

Therefore, another object of the present invention is to provide pharmaceutical compositions containing the compounds of the general formula(I) and acid addition salts thereof as active ingredients.

Acids which can be reacted with the compounds of the general formula(I) to form acid addition salts are pharmaceutically acceptable inorganic or organic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, succinic acid, citric acid, maleic acid, malonic acid, glycolic acid, lactic acid, glycine, alanine, valine, luecine, isoleucine, serine, cysteine, cystine, asparaginic acid, glutamic acid, lysine, arginine, tyrosine, proline, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid or the like.

Vehicles which can be used in the preparation of pharmaceutical compositions containing the compounds of the general formula(I) as active ingredient are sweetening agent, binding agent, dissolving agent, aids for dissolution, wetting agent, emulsifying agent, isotonic agent, adsorbent, degrading agent, antioxident, antiseptics, lubricating agent, filler and perfume or the like such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, sodium carboxy methyl cellulose, agar, talc, stearic acid, magnesium stearate, calcium stearate, magnesium aluminum silicate, starch, gelatine, tragacanth gum, methyl cellulose, glycine, silica, alginic acid, sodium alginate, water, ethanol, polyethylenglycol, polyvinyl pyrrolidone, sodium chloride, potassium chloride, orange essence, vanila aroma or the like.

Daily dosage of the compound of the general formula(I) may be varied depending on age, sex of patient and the degree of desease. Daily dosage is 1.0 mg to 5,000 mg and may be administered one to several times.

The compounds of the general formula(I) may be prepared by the following scheme I. ##STR4## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, W, X, Y, Z, I and n are the same above and Lie.sub.1 is a leaving group like hydrogen.

The compounds of the general formula(I) may be prepared by reacting a compound of the general formula(a) in the presense of --CX-- group-providing agent with a compound of the general formula(b). --CX--group-providing agent comprises 1,1-carbonyldiimidazole, 1,1-carbonylthiodiimidazole, phosgene, thiophosgene, carbonyldiphenoxide, chlorophenoxyformate or the like. The reaction may be carried out in conventional organic solvent such as tetrahydrofuran, dichloromethane, acetonitrile or the like. And also the reaction is preferably carried out in the presence of scavenger such as conventional inorganic or organic base.

The reaction may be carried out between 3.degree. C. and boiling point of the solvent used, preferably at 50.degree. C.-100.degree. C. for 5 -48 hours, preferably for 10-24 hours. Quantity of --CX--group-providing agent may be 1-1.5 equivalent, preferably 1-1.1 equivalent to the starting compound.

The compounds of the general formula(I) may be prepared by Scheme II. ##STR5## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, W, X, Y. Z, l, n, and Lie.sub.1 are the same above and Lie.sub.2 is halogen.

The compound of the general formula(c) may be prepared by reacting a compound of the general formula(a) in the presence of --CX--providing agent with piperazine in a solvent such as tetrahydrofuran, acetonitrile or the like under the same reaction condition of Scheme I. And then the compound of the general formula(I) may be prepared by reacting the compound of the general formula(c) in a solvent such as tetrahydrofuran or the like with a compound of the general formula (d) at 25.degree.80.degree. C. for 30 min-20 hours.

The compounds of the general formula(I) may be prepared by Scheme III. ##STR6## wherein, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, l, m, n, W, X, Y, Z and Lie.sub.1 are the same above and Hal is halogen.

The compound of the general formula(f) may be prepared by reacting a compound of the general formula(a) with a compound of the general formula(e) and halogenating agent. And then the compound of the general formula(I) may be prepared by reacting the compound of the general fomula(f) with a compound of the general formula(b).

The compound of the general formula(I') may be prepared by Scheme IV. ##STR7## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, l, m, n, W, X, Y, Z, and Lie.sub.1 are the same above.

The compound of the general formula(I') may be prepared by reacting a compound of the general formula(a') in the presence of --CX--providing agent in a solvent like tetrahydrofuran or the like with a compound of the general formula (b) at ambient temperature for 30 min-5 hours.

The compounds of the general formula(I) may be prepared by Scheme V. ##STR8## wherein, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, l, m, n, W, X, Y, Z are the same above and R.sub.8 is C.sub.1 -C.sub.5 alkyl or aryl group, Lie.sub.3 is a leaving group like hydrogen. The compound of general formula(g) and the compound of general formula(h) may be prepared by condensing agent.

In the above reactions, if any acid material is formed, any basic material is preferably added as scavenger in order to eleminating the acid material from the reaction phase. Such basic material may be alkali metal hydroxide, alkali earth metal hydroxide, alkali metal oxide, alkali earth metal oxide, alkali metal carbonate, alkali earth metal carbonate, alkali metal hydrogen carbonate, alkali earth metal hydrogen carbonate such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, calcium oxide, magnesium oxide, potassium carbonate, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium bicarbonate, calcium bicarbonate or the like and organic amines.

The compound of the general formula(a) is described in prior art (J. Med. Chem., 1992, 35, 3784, 3792) or may be prepared in a similar method to the art.

EXAMPLES:

The compounds of the general formula(I) and (I') are prepared by, the following examples. ##STR9## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, l, m, n, W, X, Y, Z are the same above.

__________________________________________________________________________ex. l m nno R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.7 X Y Z W (l, m, n = integer)__________________________________________________________________________ 1 Me Et OMe H H H H O NH OMe C 0 0 0 2 Me Et H H H H H O NH OMe C 0 0 0 3 Me Et H H OMe H H O NH OMe C 0 0 0 4 Me Et H OMe OMe H H O NH OMe C 0 0 0 5 Me Et OMe H OMe H H O NH OMe C 0 0 0 6 Me Et H OMe H OMe H O NH OMe C 0 0 0 7 Me Et H OMe OMe OMe H O NH OMe C 0 0 0 8 Me Et OEt H H H H O NH OMe C 0 0 0 9 Me Et OPh H H H H O NH OMe C 0 0 010 Me Et H OPh H H H O NH OMe C 0 0 011 Me Et F H H H H O NH OMe C 0 0 012 Me Et H H F H H O NH OMe C 0 0 013 Me Et H F H F H O NH OMe C 0 0 014 Me Et H CF.sub.3 H H H O NH OMe C 0 0 015 Me Et Cl H H H H O NH OMe C 0 0 016 Me Et H Cl H H H O NH OMe C 0 0 017 Me Et Cl H H H Cl O NH OMe C 0 0 018 Me Et H Cl H Cl H O NH OMe C 0 0 019 Me Et Cl H Cl H H O NH OMe C 0 0 020 Me Et Cl H Cl H Cl O NH OMe C 0 0 021 Me Et Br H H H H O NH OMe C 0 0 022 Me Et H Br H H H O NH OMe C 0 0 023 Me Et H H Br H H O NH OMe C 0 0 024 Me Et Br H Br H H O NH OMe C 0 0 025 Me Et Br H H Br H O NH OMe C 0 0 026 Me Et Me H H H H O NH OMe C 0 0 027 Me Et H H Me H H O NH OMe C 0 0 028 Me Et Me Me H H H O NH OMe C 0 0 029 Me Et H Me H Me H O NH OMe C 0 0 030 Me Et Me H H H Me O NH OMe C 0 0 031 Me Et H H i-Pr H H O NH OMe C 0 0 032 Me Et i-Pr H H H H O NH OMe C 0 0 033 Me Et H H n-Bu H H O NH OMe C 0 0 034 Me Et H H Ac H H O NH OMe C 0 0 035 Me Et Ph H H H H O NH OMe C 0 0 036 Me Et H H Ph H H O NH OMe C 0 0 037 Me Et OH H H H H O NH OMe C 0 0 038 Me Et H OH H H H O NH OMe C 0 0 039 Me Et H H OH H H O NH OMe C 0 0 040 Me Et H H OAc H H O NH OMe C 0 0 041 Me Et H OAc H H H O NH OMe C 0 0 042 Me Et H H NO.sub.2 H H O NH OMe C 0 0 043 Me Et NHCH.sub.3 H H H H O NH OMe C 0 0 044 Me Et H H Hbenzo- O NH OMe C 0 0 045 Me Et H H Hnaphtho- O NH OMe C 0 0 046 Me Et OMe H H H Me O NH OMe C 0 0 047 Me Et OMe H H Me H O NH OMe C 0 0 048 Me Et Me H H OMe H O NH OMe C 0 0 049 Me Et OMe H H Cl H O NH OMe C 0 0 050 Me Et Cl H H OMe H O NH OMe C 0 0 051 Me Et H Cl OMe H H O NH OMe C 0 0 052 Me Et H OH OMe H H O NH OMe C 0 0 053 Me Et H OAc OMe H H O NH OMe C 0 0 054 Me Et OMe H H Ph H O NH OMe C 0 0 055 Me Et Me OH H H H O NH OMe C 0 0 056 Me Et OH H H H Me O NH OMe C 0 0 057 Me Et OH H Me H H O NH OMe C 0 0 058 Me Et Me H H Cl H O NH OMe C 0 0 059 Me Et H Cl F H H O NH OMe C 0 0 060 Me Et OMe H H H H O NH OMe C 1 0 061 Me Et F H H H H O NH OMe C 1 0 062 Me Et H H F H H O NH OMe C 1 0 063 Me Et H Cl H H H O NH OMe C 1 0 064 Me Et H H F H H O NH OMe C 2 0 065 Me Et OMe H H H H O NH OMe C 2 0 066 Me Et OMe H H H H O NH OMe C 3 0 067 Me Et OMe H H H H O NH OMe C 5 0 068 Me Et OMe H H H H O NH OMe C 7 0 069 Me Et OMe H H H H O NH OMe C 0 1 070 Me Et H Cl H H H O NH OMe C 0 1 071 Me Et F H H H H O NH OMe C 0 1 072 Me Et H H H H H O NH OMe C 0 0 173 Me Et H H OMe H H O NH OMe C 0 0 174 Me Et OMe H H H H O NH OMe C 0 0 175 Me Et H H F H H O NH OMe C 0 0 176 Me Et OMe H H H H O NH OEt C 0 0 077 Me Et F H H H H O HH OEt C 0 0 078 Me Et H Cl H H H O NH OEt C 0 0 079 Me Et OEt H H H H O NH OEt C 0 0 080 Me Et OMe H H H H O NH OPh C 0 0 081 Me Et H Cl H H H O HH OPh C 0 0 082 Me Et H OAc H H H O NH OPh C 0 0 083 Me Et F H H H H O NH OPh C 0 0 084 Me Et H Me H Me H O NH OPh C 0 0 085 Me Et H OMe H OMe H O NH OPh C 0 0 086 Me Et H Cl H Cl H O NH OPh C 0 0 087 Me Et H OH OMe H H O NH OPh C 0 0 088 Me Et H OH H H H O NH OPh C 0 0 089 Me Et OMe H H H H O NH NHCH.sub.3 C 0 0 090 Me Et H OMe H OMe H O NH NHCH.sub.3 C 0 0 091 Me Et H Cl H H H O NH NHCH.sub.3 C 0 0 092 Me Et OMe H H H H O NH H C 0 0 093 Me Et H OMe H OMe H O NH H C 0 0 094 Me Et H Cl H H H O NH piperazine C 0 0 095 Me Et H Cl H H H O NH piperazine C 0 0 0Boc96 Me Et OMe H H H H O NH piperazine C 0 0 0Boc97 Me Et OMe H H H H S NH OMe C 0 0 098 Me Et H Cl H H H S NH OMe C 0 0 099 Me Et F H H H H S NH OMe C 0 0 0100 Me Et H OMe H OMe H S NH OMe C 0 0 0101 Me Et H Cl H Cl H S NH OMe C 0 0 0102 Me Et OMe H H H H O O OMe C 0 0 0103 Me Et H Cl H H H O O OMe C 0 0 0104 Me Et H OMe H OMe H O O OMe C 0 0 0105 Me Et OMe H H H H O O OMe C 1 0 0106 Me Et H Cl H H H O O OMe C 1 0 0107 Me Me H H H H H O NH OMe C 0 0 0108 Me Me OMe H H H H O NH OMe C 0 0 0109 Me Me H Cl H H H O NH OMe C 0 0 0110 Me Me F H H H H O NH OMe C 0 0 0111 Me Me H F H F H O NH OMe C 0 0 0112 Me Me OH H H H H O NH OMe C 0 0 0113 Me Me H OH H H H O NH OMe C 0 0 0114 Me Me H H OH H H O NH OMe C 0 0 0115 Me Me H OAc H H H O NH OMe C 0 0 0116 Me Me H H OAc H H O NH OMe C 0 0 0117 Me Me H OAc OMe H H O NH OMe C 0 0 0118 Me Me H OMe H OMe H O NH OMe C 0 0 0119 Me Me Me Me H H H O NH OMe C 0 0 0120 Me Me H Me H Me H O NH OMe C 0 0 0121 Me Me Me H H OMe H O NH OMe C 0 0 0122 Me Me OH H Me H H O NH OMe C 0 0 0123 Me Me H OH OMe H H O NH OMe C 0 0 0124 Me Me H H Hbenzo- O NH OMe C 0 0 0125 Me Me H H Hnaphtho- O NH OMe C 0 0 0126 Me Me H Cl H H H S NH OMe C 0 0 0127 Me Me H Cl H Cl H S NH OMe C 0 0 0128 Me Me OMe H H H H S NH OMe C 0 0 0129 Me Me H OMe H OMe H S NH OMe C 0 0 0130 --(CH.sub.2).sub.3 -- OMe H H H H O NH OMe C 0 0 0131 --(CH.sub.2).sub.3 -- H Cl H H H O NH OMe C 0 0 0132 --(CH.sub.2).sub.3 -- F H H H H O NH OMe C 0 0 0133 --(CH.sub.2).sub.4 -- OMe H H H H O NH OMe C 0 0 0134 --(CH.sub.2).sub.4 -- H Cl H H H O NH OMe C 0 0 0135 --(CH.sub.2).sub.4 -- F H H H H O NH OMe C 0 0 0136 Me i-Pr OMe H H H H O NH OMe C 0 0 0137 Me i-Pr H Cl H H H O NH OMe C 0 0 0138 Me i-Pr F H H H H O NH OMe C 0 0 0139 H H H H H H H O NH OMe C 0 0 0140 H H OMe H H H H O NH OMe C 0 0 0141 H H H H OMe H H O NH OMe C 0 0 0142 H H H Cl H H H O NH OMe C 0 0 0143 Me Et NHCH.sub.2 CCH H H H H O NH OMe N 0 0 0144 Me Et NHCH.sub.2 CCH H H H H O NH OMe N 1 0 0145 Me Et NHCH.sub.2 CCH H H H H O NH .dbd.O N 1 0 0146 Me Et N(CH.sub.2 Ph).sub.2 H H H H O NH .dbd.O N 1 0 0147 Me i-Pr NHEt H H H H O NH .dbd.O N 1 0 0148 Me Et OMe H H H H O NH OMe C 0 0 0 HCl salt149 Me Et H Cl H H H O NH OMe C 0 0 0 HCl salt__________________________________________________________________________

Example 1

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-methoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate(0.29 g, 1.0 mmol) and 1-(2-methoxyphenyl)piperazine(0.19 g, 1.0 mmol) were dissolved in tetrahydrofuran(10 ml) and DBU(0.15 g, 1.0 mol) was added thereto and the mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was concentrated and chromatographed to obtain 0.33 g of the titled compound.

yield: 89%; .sup.1 H-NMR(500 MHZ, CDCl.sub.3): .delta. 1.17(3H,t,J=7.5 Hz), 2.37(3H,s), 2.55(2H,q,J=7.5 Hz), 3.11(4H,t,J=4.6 Hz), 3.69(4H,t,J=5.0 Hz), 3.88(1H,s), 3.98(3H,s), 6.89(1H,s), 6.94(3H,m), 7.05(1H,m), 8.21(1H,s).

Elemental Analysis: C.sub.21 H.sub.28 N.sub.4 O.sub.3 : Calc., C,65.60, H,7.34, N,14.57. Found, C,66.10, H,7.25, N,14.57.

Example 2

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-phenylpiperazin

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-phenylpiperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 86%

Example 3

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(4-methoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 78%

Example 4

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3,4-dimethoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,4-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 69%

Example 5

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2,4-dimethoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,4-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 77%

Example 6

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3,5-dimethoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 82%

Example 7

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3,4,5-trimethoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 52%

Example 8

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-ethoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-ethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 78%

Example 9

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbony!-4-(2-phenoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-phenoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 69%

Example 10

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3-phenoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-phenoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 72%

Example 11

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)-aminocarbonyl!-4-(2-fluorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 67%

Example 12

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(4-fluorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin 3-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 81%

Example 13

1-�(5-ethyl-2-methoxy-6-methylpyridine-3-yl)aminocarbonyl!-4-(3,5-difluorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 69%

Example 14

1�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(.alpha., .alpha., .alpha.-trifluoro-m-tolyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(.alpha., .alpha., .alpha.-trifluoro-m-tolyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 67%

Example 15

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-chlorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 82%

Example 16

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3-chlorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 84%

Example 17

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2,6-dichlorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,6-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 80%

Example 18

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3,5-dichlorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 69%

Example 19

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2,4-dichlorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,4-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 72%

Example 20

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2,4,6-trichlorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,4,6-trichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 54%

Example 21

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-bromophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-bromophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 58%

Example 22

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3-bromophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-bromophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 65%

Example 23

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(4-bromophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-bromophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 64%

Example 24

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2,4-dibromophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,4-dibromoplhenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 68%

Example 25

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2,5-dibromophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,5-dibromophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 66%

Example 26

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-tolyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-tolyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 89%

Example 27

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(4-methylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 87%

Example 28

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2,3-dimethylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 82%

Example 29

1-�(5-ethyl-2-methoxy-6-methylpyrdin-3-yl)aminocarbonyl!-4-(3,5-dimethylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 68%

Example 30

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2,6-dimethylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound

yield: 80%

Example 31

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(4-isopropylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-isopropylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 68%

Example 32

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-isopropylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-isopropylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 65%

Example 33

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(4-normalbutylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-normalbutylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 57%

Example 34

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(4-acetylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 67%

Example 35

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-biphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-biphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 82%

Example 36

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(4-biphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-biphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 81%

Example 37

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-hydroxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 59%

Example 38

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3-hydroxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 63%

Example 39

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(4-hydroxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 58%

Example 40

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(4-acetoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 89%

Example 41

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3-acetoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-acetoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 87%

Example 42

1-�(5-ethyl-2-metoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(4-nitrophenyl) piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 70%

Example 43

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-�(2-methylamino)phenyl!piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-�2-(methylamino)phenyl!piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 59%

Example 44

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(1-naphthyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(1-naphthyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 63%

Example 45

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(1-anthryl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(1-anthryl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 57%

Example 46

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-methoxy-6-methylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-methoxy-6-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 67%

Example 47

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-methoxy-5-methylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-methoxy-5-phenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 62%

Example 48

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(5-methoxy-2-methylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(5-methoxy-2-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 66%

Example 49

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(5-chloro-2-methioxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(5-chloro-2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 69%

Example 50

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-chloro-5-methoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin3-yl)carbamate and 1-(2-chloro-5-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 70%

Example 51

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3-chloro-4-methoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-chloro-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 62%

Example 52

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3-hydroxy-4-methoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-hydroxy-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield: 59% Example 53

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3-acetoxy-4-methoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-acetoxy-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound. 25 yield: 62% Example 54

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-�(2-methoxy-5-phenyl)phenyl!piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-�(2-methoxy-5-phenyl)phenyl!piperazine were reacted by the same way with the example 1 to obtain the titled compound. yield: 67%

Example 55

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3-hydroxy-2-methylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-hydroxy-2-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 54%

Example 56

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-hydroxy-6-methylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-hydroxy-6-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 57%

Example 57

1�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-hydroxy-4-methylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-hydroxy-4-methylphenyl)piperazine were reacted by the same way with example 1 to obtain the titled compound.

yield: 52%

Example 58

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(5-chloro-2-methylphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(5-chloro-2-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 63%

Example 59

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3-chloro-4-fluorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 65%

Example 60

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-methoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 69%

Example 61

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-chlorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 72%

Example 62

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)methylaminocarbonyl!-4-(4-fluorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 63%

Example 63

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)methylaminocarbonyl!-4-(3-chlorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 68%

Example 64

1-{�(5-ethyl-2-methoxy-6-methylpyridin-3-yl!ethylaminocarbonyl}-4-(4-fluorophenyl)piperazine

Phenyl-N-�2-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)ethyl!carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 65%

Example 65

1-{�2-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)ethyl!aminocarbonyl}-4-(2-methoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 63%

Example 66

1-{�3-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)propyl!aminocarbonyl}-4-(2-methoxyphenyl)piperazine

Phenyl-N-�3-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)propyl!carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 67%

Example 67

1-{�(5-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)pentyl!aminocarbonyl}-4-(2-methoxyphenyl)piperazine

Phenyl-N-�5-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)pentyl!carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 52%

Example 68

1-{�6-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)heptyl!aminocarbonyl-}-4-(2-methoxyphenyl)piperazine

Phenyl-N-�6-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)heptyl!carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 49%

Example 69

1-�(5-ethyl-2-methoxy-6-methylpyridin3-yl)aminocarbonyl!methyl-4-(2-methoxyphenyl)piperazine a) N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)chloroacetamide:

After chloroacetic acid (1.35 g, 14.3 mmol) were dissolved into 20 ml of tetrahydrofuran, added 1,1-carbonyldiimidazole(2.32 g, 14.3 mmol), stirred at room temperature for 1 hour, 3-amino-5-ethyl-2-methoxy-6-methylpyridine (2.0 g, 13.0 mmol) were added. After the reaction mixture were stirred for 2 hours, the mixture of reaction were concentrated, purified by column chromatography to obtain 2.20 g of the titled compound.

yield: 73.3%; .sup.1 H-NMR(500 MHz, CDCl.sub.3); .delta.1.17(3H,t), 2.39(5H,m), 3.99(3H,s), 4.17(2H,s), 8.62(1H,s)

b) 1-�(5-ethyl-2-methoxy-6-methylpyridine-3-yl)aminocarbonyl!methyl-4-(2-methoxyphenyl)piperazine

After N-(5-ethyl-2-methoxy-6-metylpyridine-3-yl)chloroacetamide(0.10 g, 0.43 mmol) and 1-(2-methoxyphenyl)piperazine(0.0091 g, 0.47 mmol) were dissolved into tetrahydrofuran(5 ml) and was added DBU(0.060 g, 0.43 mmol), the reaction mixtures were stirred at room temperature for 2 hours. After the product of reaction were concentrated, separated by column chromatography to obtain 0.12 g of the titled compound.

yield: 70%

Example 70

1-�(5-ethyl-2-methoxy-6-methylpyridine-3-yl)aminocarbonyl!methyl-4-(3-chlorophenyl)piperazine

N-(5-ethyl-2-methoxy-6-methylpyridine -3-yl)chloroacetamide and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 69 to obtain the titled compound.

yield: 68%

Example 71

1-�(5-ethyl-2-methoxy-6-methylpyridine-3-yl)aminocarbonyl!methyl-4-(2-fluorophenyl)piperazine

N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)chloroacetamide and 1-(3-fluorophenyl)piperazine were reacted by the same way with the example 69 to obtain the titled compound.

yield: 68%

Example 72

1�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-benzylpiperazine a) 1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarhonyl!-4-(4-methoxbenzyl)piperazine.

After 3-amino-5-ethyl-2-methoxy-6-methylpyridine(1.06 g, 6.35 mmol) was dissolved in 20 ml of tetrahydrofuran, 1,1-carbonyldiimidazole(1.08 g, 6.67 mmol) was added thereto. The mixture of reaction was stirred at room temperature for half hour and then benzylpiperazine(1.12 g, 6.35 mmol) was added. After the reaction mixture was stirred for 2 hours, the reaction mixture was concentrated and chromatographed to obtain 1.78 g of the oil phase of the titled compound.

yield: 76%; .sup.1 H-NMR(500 MHz,CDCl.sub.3): .delta.1.16(3H,t), 2.36(3H,s), 2.48(4H,t), 3.42(4H,s), 3.54(2H,t), 3.95(H,s), 7.31(5H,s), 8.19(1H,s)

b) 1-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl piperazine

After 1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-benzyl piperazine (1.71 g, 4.61 mmol) was added the solution of 30 ml of ethanol and 10 ml of glacial acetic acid in the presence of 5% Pd/C, the reaction mixture were stirred under hydrogen gas(40 psi) for 4 hours and extracted with dichloromethane. The mixture was dried with anhydrous magnesium sulfate, filtrated, concentrated and chromatographed to obtain 1.2 g of white solid of the titled compound.

yield: 93%; .sup.1 H-NMR(500 MHz, CDCl.sub.3): .delta.1.16(3H,s), 2.35(3H,s), 2.48(2H,q), 2.94(4H,t), 3.52(4H,t), 8.02(1H,s)

c) 1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarboniyl!-4-benzylpiperazine

After 1-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl piperazine (0.16 g, 0.57 mmol) and benzylchloride(0.076 g, 0.60 mmol) were added in DMF 5 ml in the presence of NaHCO.sub.3 (0.114 g, 1.36 mmol), the reaction mixtures were stirred in 90.degree. C. for 4 hours. The reaction solution was cooled at room temperature and the reaction mixture was extracted with dichloromethane and chromatographed to obtain 0.082 gm of the titled compound.

yield: 39%; .sup.1 H-NMR(500 MHz, CDCl.sub.3) .delta.1.16(3H,t), 2.36(3H,s), 2.48(4H,t), 3.42(4H,t) 3.54(2H,s), 3.95(5H,s), 7.31(5H,s), 8.19(1H,s)

Example 73

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(4-methoxybenzyl)piperazine

1-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonylpiperazine and 4-methoxybenzylchloride were reacted by the same way with the example 72 to obtain the titled compound.

yield: 42%

Example 74

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!4-(2-methoxybenzyl)piperazine 1-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonylpipeazine and 2-methoxybenzylchloride were reacted by the same way with the example 72 to obtain the titled compound.

yield: 47%

Example 75

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(4-fluorobenzyl)piperazine

1-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonylpipeazine and 4-fluorobenzylchloride were reacted by the same way with the example 72 to obtain the titled compound.

yield: 52%

Example 76

1-�(2-ethoxy-5-ethyl-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-methoxyphenyl)piperazine

Phenyl-N-(2-ethoxy-5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 82%

Example 77

1-�(2-ethoxy-5-ethyl-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-fluorophenyl)piperazine

Phenyl-N-(2-ethoxy-5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 87%

Example 78

1-�(2-ethoxy-5-ethyl-6-methylpyridin-3-yl)aminocarbonyl!-4-(3-chlorophenyl) piperazine

Phenyl-N-(2-ethoxy-5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 83%

Example 79

1-�(2-ethoxy-5-ethyl-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-ethoxyphenyl) piperazin:

Phenyl-N-(2-ethoxy-5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(2-ethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 79%

Example 80

1-�(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)aminocarbonyl!-4-(2-methoxyphenyl)piperazine

Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 88%

Example 81

1-�(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)aminocarbonyl!-4-(3-chiorophenyl)piperazine

Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 85%

Example 82

1-�(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)aminocarbonyl!-4-(3-acetoxyphenyl)piperazine

Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3-acetoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 83%

Example 83

1-�(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)aminocarbonyl!-4-(2-fluorophenyl)piperazine

Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 72%

Example 84

1-�(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)aminocarbonyl!-4-(3,5-xylyl)piperazine

Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3,5-xylyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 78%

Example 85

1-�(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)aminocarbonyl!-4-(3,5-dimethoxyphenyl)piperazine

Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 75%

Example 86

1-�(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)aminocarbonyl!-4-(3,5-dichlorophenyl)piperazine

Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 82%

Example 87

1-�(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)aminocarbonyl!-4-(3-hydroxy-4-methoxyphenyl)piperazine

Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3-hydroxy-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 69%

Example 88

1-�(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)aminocarbonyl!-4-(3-hydroxyphenyl)piperazine

Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 72%

Example 89

1-�(5-ethyl-6-methyl-2-methylaminopyridin-3-yl)aminocarbonyl!-4-(2-methoxyphenyl)piperazine

Phenyl-N-(5-ethyl-6-methyl-2-methylaminopyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 73%

Example 90

1-�(5-ethyl-6-methyl-2-methylaminopyridin-3-yl)aminocarbonyl!-4-(3,5-dimethoxyphenyl)piperazine

Phenyl-N-(5-ethyl-6-methyl-2-methylaminopyridin-3-yl)carbamate and 1-(3,5-dimetoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 82%

Example 91

1-�(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)aminocarbonyl!-4-(3-chlorophenyl)piperazine

Phenyl-N-(5-ethyl-6-methyl-2-methylaminopyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 79%

Example 92

1-�(5-ethyl-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-methoxyphenyl)piperazine

Phenyl-N-(5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 80%

Example 93

1-�(5-ethyl-6-methylpyridin-3-yl)aminocarbonyl!-4-(3,5-dimethoxyphenyl)piperazine

Phenyl-N-(5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 85%

Example 94

1-{�5-ethyl-6-methyl-2-(-piperazinyl)pyridin-3-yl!aminocarbonyl}-4-(3-chlorophenyl)piperazine

Phenyl-N-{�5-ethyl-6-methyl-2-(1-piperazinyl)pyridin-3-yl!carbamate and 4-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 87%

Example 95

1-{�5-ethyl-6-methyl-2-(4-boc-piperazinyl)pyridin-3-yl!aminocarbonyl}-4-(3-chlorophenyl)piperazine

Phenyl-N-{�5-ethyl-6-methyl-2-(4-bocpiperazinyl)pyridin-3-yl!carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 92%

Example 96

1-{�5-ethyl-6-methyl-2-(4-boc-piperazinyl)pyridin-3-yl!-aminocarbonyl}-4-(2-methoxyphenyl)piperazine

Phenyl-N-{�5-ethyl-6-methyl-2-(4-boc-piperazinyl)pyridin-3-yl!carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 94%

Example 97

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl!-4-(2-methoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 93%

Example 98

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl!-4-(3-chlorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 88%

Example 99

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl!-4-(2-fluorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 82%

Example 100

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl!-4-(3,5-dimethoxyphenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridine-3-yl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 85%

Example 101

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminothiocarbonyl!-4-(3,5-dichlorophenyl)piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 84%

Example 102

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)oxycarbonyl!-4-(2-methoxyphenyl)piperazine

Phenyl-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbonate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 72%

Example 103

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)oxycarbonyl!-4-(3-chlorophenyl)piperzine:

Phenyl-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbonate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 74%

Example 104

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)oxycarbonyl!-4-(3,5-dimethoxyphenyl)piperazine

Phenyl-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbonate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 77%

Example 105

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)methyloxycarbonyl!-4-(2-methoxyphenyl)piperazine

Phenyl-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)methylcarbonate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 82%

Example 106

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)methyloxycarbonyl!-4-(3-chlorophenyl-l)piperazine

Phenyl-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)methylcarbonate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 79%

Example 107

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-phenylpiperazine

Phenyl-N-(5,6-dimethyl-1-methoxypyridin-3-yl)carbamate and 1-phenylpiperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 84%

Example 108

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarboniyl!-4-methoxyphenyl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 8%

Example 109

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(3-chlorophenyl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 92%

Example 110

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-fluorophenyl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 79%

Example 111

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(3,5-difluorophenyl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 87%

Example 112

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminothiocarbonyl!-4-(2-hydroxyphenyl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

Example 113

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)!-4-(3-hydroxyphenyl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield 78%

Example 114

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(4-hydroxyphenyl) piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(4-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 72%

Example 115

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(3-acetoxyphenyl)piperazine

Phenyl N (5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3-acetylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield 92%

Example 116

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl !-4-(4-acetoxyphenyl) piperazine

Phenyl-N-(5,6-dimethyl 2methoxypyridin 3-yl)carbamate and 1-(4-acetoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 89%

Example 117

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(3-acethoxy-4-methoxyphenyl)piperazine

Phenyl N (5,6-dimethyl-2-methoxypyridine 3-yl)carbamate and 1-(3-acetoxy-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 69%

Example 118

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(3,5-dimethoxyphenyl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 88%

Example 119

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(2,3-xylyl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2,3-xylyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 72%

Example 120

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(3,5-xylyl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3,5-xylyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 68%

Example 121

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(2,5-xylyl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2,5-xylyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 72%

Example 122

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(2-hydroxy-4-methylphenyl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2-hydroxy-4-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 77%

Example 123

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(3-hydroxy-4-methoxyphenyl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3-hydroxy-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 69%

Example 124

1�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(1-naphthyl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(1-naphthyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 74%

Example 125

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(1-anthryl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(1-anthryl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 62%

Example 126

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminothiocarbonyl!-4-(3-chlorophenyl) piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 69%

Example 127

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(3,5-dichlorophenyl) piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 82%

Example 128

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminocarbonyl!-4-(2-methoxyphenyl) piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 70%

Example 129

1-�(5,6-dimethyl-2-methoxypyridin-3-yl)aminothiocarbonyl!-4-(3,5-dimethoxyphenyl)piperazine

Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 69%

Example 130

1-�(2-methoxy-5,6,7-trihydro-1-pyrinden-3-yl)aminocarbonyl!-4-(2-methoxyphenyl)piperazine

Phenyl-N-(2-methoxy-5,6,7-trihydro-1-pyrinden-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 64%

Example 131

1-�(2-methoxy-5,6,7-trihydro-1-pyrinden-3-yl)aminocarbonyl!-4-(3-chlorophenyl)piperazine

Phenyl-N-(2-methoxy-5,6,7-trihydro 1-pyrinden-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 63%

Example 132

1-�(2-methoxy-5,6,7-trihydro-1-pyrinden-3-yl)aminocarbonyl!-4-(2-fluorophenyl)piperazine

Phenyl-N-(2-methoxy-5,6,7-trihydro-1-pyrinden-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 59%

Example 133

1-�(2-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)aminocarbonyl!-4-(2-methoxyphenyl)piperazine

Phenyl-N-(2-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 64%

Example 134

1-�(2-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)aminocarbonyl!-4-(3-chlorophenyl)piperazine

Phenyl-N-(2-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 69%

Example 135

1-�(2-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)aminocarbonyl!-4-(2-fluorophenyl)piperazine

Phenyl-N-(2-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 70%

Example 136

1-�(5-isopropyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-methoxyphenyl)piperazine

Phenyl-N-(5-isopropyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 64%

Example 137

1-�(5-isopropyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3-chlorophenyl)piperazine

Phenyl-N-(5-isopropyl-2-methoxy-6-methylpyridine-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 63%

Example 138

1-�(5-isopropyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-fluorophenyl)piperazine

Phenyl-N-(5-isopropyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 59%

Example 139

1-�(2-methoxypyridin-3-yl)aminocarbonyl!-4-phenylpiperazine

Phenyl-N-(2-methoxypyridin-3-yl)carbamate and 1-phenylpiperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 88%

Example 140

1-�(2-methoxypyridin-3-yl)aminocarbonyl!-4-(2-methoxyphenyl)piperazine

Phenyl-N-(2-methoxypyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 86%

Example 141

1-�(2-methoxypyridin-3-yl)aminocarbonyl!-4-(4-methoxyphenyl)piperazine

Phenyl-N-(2-methoxypyridin-3-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 85%

Example 142

1-�(2-methoxypyridin-3-yl)aminocarbonyl!-4-(3-chlorophenyl)piperazine

Phenyl-N-(2-methoxypyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 72%

Example 143

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-�(3-propargylamino)pyridin-2-yl!piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-�(3-propargylamino)pyridine-2-yl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 61%

Example 144

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)methylaminocarbonyl!-4-�(3-propargylamino)pyridin-2-yl!piperazine

Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)methylcarbamate and 1-�(3-propargylamino)pyridin-2-yl!piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 74%

Example 145

1-{�5-ethyl-6-methyl-2(1H)-pyridinon-3-yl!methylaminocarbonyl}-4-�(3-propargylamino)pyridin-2-yl!piperazine

Phenyl-N-�5-ethyl-6-methyl-2(1H)-pyridinon-3-yl!methylcarbamate and 1-�(3-propargylamino)pyridin-2-yl!piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 77%

Example 146

1-{�5-ethyl-6-methyl-2(1H)-pyridinon-3-yl!methylaminocarbonyl}-4-�(3-dibenzylamino)pyridin-2-yl!piperazine

Phenyl-N-�5-ethyl-6-methyl-2(1H)-pyridinon-3-yl!methylcarbamate and 1-�(3-dibenzylamino)pyridine-2-yl!piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 65%

Example 147

1-{�5-isopropyl-6-methyl-2(1H)-pyridinon-3-yl!methylaminocarbonyl}-4-�(3-ethylamino)pyridin-2-yl!piperazine

Phenyl-N-�5-ethyl-6-methyl-2(1H)-pyridinon-3-yl!methylcarbamate and 1-�(3-ethylamino)pyridin-2-yl!piperazine were reacted by the same way with the example 1 to obtain the titled compound.

yield: 62%

Example 148

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-�(2-methoxyphenyl)piperazine-2-yl!piperazine salt of hydrochloride:

After 1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-methoxyphenyl)piperazine(5.0 g, 13 mmol) was dissolved in 400 ml of diethylether, the mixture was saturated by hydrogen chloride gas at 0.degree. C. and stirred for 30 minutes and purified to obtain the titled compound.

yield: 98%

Example 149

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3-chlorophenyl)piperazine salt of hydrochloride:

1-�(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(3-chlorophenyl)piperazine was reacted by the same way with the example 148 to obtain the titled compound.

yield: 98%

__________________________________________________________________________examplenumber elementary analysis .sup.1 H NMR (500 MHz, CDCl.sub.3) .delta. melting point__________________________________________________________________________1 C.sub.21 H.sub.28 N.sub.4 O.sub.3 : theoretical, 1.17 (3H,t, J = 7.5 Hz), 2.37 (3H, s), 115-118.degree. C. C, 65.60, H, 7.34, N, 14.57 (2H, q, J = 7.5 Hz), 3.11 (4H, t, J = 4.6 Hz). experimental, 3.69 (4H, t, J = 5.0 Hz), 3.88 (1H, s), 3.98 C, 66.10, H, 7.25, N, 14.57 (3H, s), 6.89 (1H, s), 6, 94 (3H, m), 7.05 (1H, m), 8.21 (1H, s).2 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 102-103.degree. C. (2H, q, J = 7.5 Hz), 3.26 (4H, t, J = 4.5 Hz). 3.68 (4H, t), 3.98 (3H, s), 6.91 (1H, s), 6.95 (4H, m), 7.28 (1H, m), 8.35 (1H, s).3 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s.), 84-85.degree. C. (2H, q, J = 8.0 Hz), 3.12 (4H, t), 3.63 (4H, t), 3.78 (3H, s), 3.97 (3H, s), 6.85 (1H, s), 6.87 (2H, m), 6.97 (2H, m), 8.19 (1H, s).4 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 116-119.degree. C. (2H, q, J = 7.5H z), 3.04 (4H, t), 3.68 (4H, t), 3.79 (3H, s), 3.86 (3H, s), 3.97 (3H, s), 6.43 (1H,d), 6.50 (1H, s), 6.87 (1H, d), 6.92 (1H, s), 8.21 (1H, s).5 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 103-104.degree. C. (2H, q, J = 7.5 Hz), 3.14 (4H, t), 3.68 (4H, t), 3.85 (3H, s), 3.88 (3H, s), 3.97 (3H, s), 6.49 (1H, d), 6.60 (1H, s), 6.82 (1H, d), 6.92 (1H, s), 8.21 (1H, s).6 C.sub.22 H.sub.30 N.sub.4 O.sub.4 : theoretical, 1.17 (2H, q, J = 7.5 Hz), 2.37 (3H, s), 126-127.degree. C. C, 63.75, H, 7.30, N, 13.52 (2H, q, J = 7.5 Hz), 3.27 (4H, t), 3.74 experimental (4H, t), 3.79 (6H, s), 3.98 (3H, s), 6.09 C, 63.81, H, 7.31, N, 13.32 (1H, s), 6.16 (2H, s), 6.90 (1H, s), 8.19 (1H, s)7 1.16 (3H, t, J = 7.5 Hz), 2.37 (3H, s), oil phase (2H, q, J = 7.5 Hz), 3.20 (4H, t, J = 4.7 Hz). 3.69 (4H, t), 3.80 (3H, s), 3.86 (6H, s). 3.98 (3H, s), 6.20 (2H, s), 8.19 (1H, s).8 C.sub.22 H.sub.30 N.sub.4 O.sub.3 : theoretical, 1.17 (3H, q, J = 7.5 Hz), 1.48 (3H, t, J 96-97.degree. C. C, 66.31, H, 7.59, N, 14.06 Hz), 2.37 (3H,s), 2,56 (2H, q, J = 7.5 Hz), experimental 3.14 (4H, t, J = 4.7 Hz), 3.69(4H, t, J = 4.6 C, 66.13, H, 7.72, N, 13.78 Hz), 3.98 (3H, s), 4.10 (2H, q), 6.87 (1H, s), 6.92 (3H, m), 7.01 (1H, m), 8.21 (1H, s)9 1.16 (3H, t, J = 7.5 Hz), 2.36 (3H, s), 167-168.degree. C. (2H, q, J = 7.5 Hz), 3.14 (4H, t), 3.45 (4H. t), 3.95 (3H, s), 6.83 (1H, s), 6.92 (2H, m), 7.03 (5H, m), 7.15 (1H, m), 7.31 (2H m), 8.16 (1H,s).10 1.17 (3H, t, J = 7.5 Hz), 2.38 (3H, s), oil phase (2H, q, J = 7.5 Hz), 3.27 (4H, t, J = 5.0 Hz). 3.70 (4H, t), 3.99 (3H, s), 6.55 (1H, d). 6.67 (1H, m), 6.91 (1H, m), 7.02 (2H, d), 7.11 (1H, m), 7.24 (2H, m), 7.34 (2H, m), 8.19 (1H, s).11 1.19 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 120-121.degree. C. (2H, q, J = 7.5 Hz), 3.14 (4H, t), 3.68 (4H, t), 3.97 (3H, s), 6.92 (1H, s), 6.94 (2H, m), 7.06 (2H, m), 8.20 (1H, s).12 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), oil phase (2H, q, J = 7.5 Hz), 3.16 (4H, t, J = 5.0 Hz), 3.66 (4H, t, J = 5.1 Hz), 3.98 (3H, s), 6.89 (1H, s), 6.91 (2H, m), 6.99 (2H, m), 8.19 (1H, s).13 C.sub.20 H.sub.24 N.sub.2 O.sub.2 F.sub.2 : theoretical 1.17 (3H, t, J = 7.5 Hz), 2.38 (3H, s), 115-116.degree. C. C, 61.53, H, 6.20, N, 14.35 (2H, q), 3.29 (4H, t, J = 5.5 Hz), 3.68 (4H, experimental, t, J = 5.5 Hz), 3.99 (3H, s), 6.28 (1H, m), C, 61.31, H, 6.27, N, 14.04 6.32 (2H, d), 6.89 (1H, s), 8.18 (1H, s).14 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 113-115.degree. C. (2H, q, J = 7.5 Hz), 3.31 (4H, t, J = 5.0 Hz). 3.69 (4H, t, J = 5.0 Hz), 3.98 (3H, s). 6.91 (1H, d), 7.09 (1H, d), 7.12 (2H, m), 7.39 (1H, m), 8.19 (1H, s).15 1.19 (3H, t, J = 7.5 Hz), 2.38 (3H, s), 97-99.degree. C. (2H, q, J = 7.0 Hz), 3.10 (4H, t, J = 5.0 Hz), 3.69 (4H, t, J = 5.0 Hz), 3.99 (3H, s), 6.82 (1H, d), 6.91 (1H, s), 7.04 (2H, m), 7.40 (1H, m), 8.22 (1H, s).16 C.sub.20 H.sub.25 N.sub.4 O.sub.2 Cl.sub.1 : theoretical, 1.17 (3H, t, J = 7.5 Hz), 2.38 (3H, s), 104-105.degree. C. C, 61.77, H, 6.48, N, 14.41 (2H, q, J = 7.5 Hz), 3.26 (4H, t, J = 5.0 Hz), experimental, 3.66 (4H, t, J = 5.0 Hz), 3.98 (3H, s). 6.79 C, 61.79, H, 6.54, N, 14.26 (1H, d), 6.86 (1H, d), 6.89 (2H, d), 7.19 (1H, m), 8.18 (1H, m).17 1.17 (3H, t, J = 7.5 Hz), 2.38 (3H, s), 74-75.degree. C. (2H, q, J = 5.0 Hz), 3.48 (4H, t, J = 5.0 Hz), 3.75 (4H, t, J = 5.0 Hz), 3.98 (3H, s). 6.84 (3H, m), 8.35 (1H, s).18 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 85-86.degree. C. (2H, q, J = 7.5 Hz), 3.26 (4H, t, J = 5.0 Hz), 3.77 (4H, t, J = 5.0 Hz), 3.98 (3H, s), 6.85 (1H, s), 6.97 (2H, m), 7.31 (1H, m), 8.19 (1H, s).19 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), oil phase (2H, q, J = 7.5 Hz), 3.26 (4H, t), 3.69 (4H, t), 3.98 (3H, s), 6.84 (1H, m), 6.91 (1H, s), 6.96 2h, m), 7.29 (1H, m), 8.19 (1H, s).20 1.18 (3H, t, J = 7.5 Hz), 2.39 (3H, s), 162-163.degree. C. (2H, q, J = 7.0 Hz), 3.28 (4H, t, J = 4.5 Hz), 3.65 (4H, t, J = 4.5 Hz), 3.99 (3H, s), 6.90 (1H, s), 7.26 (2H, m), 8.23 (1H, s).21 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 94-94.degree. C. (2H, q, J = 7.5 Hz), 3.27 (4H, t), 3.69 (4H, t), 3.98 (3H, s), 6.84 (1H, s), 6.98 (3H, m), 7.39 (1H, m), 8.35 (1H, s).22 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 99-101.degree. C. (2H, q, J = 7.5 Hz), 3.27 (4H, t), 3.74 (4H, t), 3.98 (3H, s), 6.91 (1H, s), 6.98 (3H, m), 7.46 (1H, m), 8.19 (1H, s).23 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 97-98.degree. C. (2H, q, J = 7.5 Hz), 3.25 (4H, t, J = 5.0 Hz), 3.67 (4H, t, J = 5.0 Hz), 3.98 (3H, s), 6.94 (2H, m), 7.29 (2H, m), 8.21 (1H, s).24 1.17 (3H, t, J = 7.5 Hz), 2.38 (3H, s), oil phase (2H, q, J = 7.5 Hz), 3.48 (4H, t, J = 5.0 Hz), 3.75 (4H, t, J = 5.0 Hz), 3.96 (3H, s), 6.84 (2H, m), 7.22 (1H, s), 8.18 (1H, s).25 1.17 (3H, t, J = 7.5 Hz), 2.38 (3H, s), oil phase (2H, q, J = 7.5 Hz), 3.48 (4H, t, J = 5.0 Hz), 3.75 (4H, t, J = 4.5 Hz), 3.96 (3H, s), 6.81 (1H, s), 6.84 (2H, m), 7.22 (1H, s), 8.18 (1H, s).26 1.18 (3H, t, J = 7.5 Hz), 2.34 (3H, s), 129-130.degree. C. (3H, s), 2.57 (2H, q, J = 7.5 Hz), 2.96 (4H, t, J = 5.0 Hz), 3.65 (4H, t, J = 4.5 Hz), 3.97 (3H, s), 6.92 (1H, s), 7.02 (2H, m), 7.17 (2H, m), 8.21 (1H, s).27 1.17 (3H, t, J = 7.5 Hz), 2.28 (3H, s), oil phase (3H, s), 2.55 (2H, q, J = 7.5 Hz), 3.18 (4H, t, J = 5.0 Hz), 3.66 (4H, t, J = 5.0 Hz), 3.97 (3H,s), 6.87(2H,w), 6.91(1H,s), 7.11 (2H, m), 8.19 (1H, s).28 C.sub.22 H.sub.30 N.sub.4 O.sub.2 : theoretical, 1.18 (3H, t, J = 7.5 Hz), 2.25 (3H, s), 99-100.degree. C. C, 69.08, H, 7.91, N, 14.65 (3H, s), 2.37 (3H, s), 2.56 (2H, q, J = 7.5 experimental Hz), 2.95 (4H, t), 3.65 (4H, t), 3.97 (3H C, 68.48, H, 8.04, N, 14.04 .s), 6.89 (2H, m), 7.07 (1H, m), 8.21 (1H, s).29 C.sub.22 H.sub.30 N.sub.4 O.sub.2 : theoretical 1.17 (3H, t, J = 7.5 Hz), 2.29 (6H, s), 83-84.degree. C. C, 69.08, H, 7.91, N, 14.65 (3H, s), 2.55(2H, q), 3.22 (4H, t, J = 4.5 experimental Hz), 3.73 (4H, t, J = 4.5 Hz), 3.98 (3H, s), C, 69.31, H, 7.82, N, 14.14 6.42 (3H, s), 6.90 (1H, s), 8.35 (1H, s).30 1.18 (3H, t, J = 8.0 Hz), 2.33 (6H, s), 122-123.degree. C. (3H, s), 2.53 (2H, q, J = 7.5 Hz), 3.15 (4H, t, J = 5.0 Hz), 3.60 (4H, t, J = 5.0 Hz), 4.00 (3H, s), 6.91 (1H, s), 6.99 (3H, m). 8.24 (1H, s).31 1.17 (3H, t, J = 7.5 Hz), 1.22 (3H, s), 99-100.degree. C. (3H, s), 2.37 (3H, s), 2.55 (2H, q, J = 7.5 Hz), 2.87 (1H, m), 3.21 (4H, t), 3.67 (4H, t), 3.97 (3H, s), 6.90 (3H, m), 7.17 (2H, d), 8.35 (1H, s).32 1.15 (3H, t, J = 7.5 Hz), 1.22 (3H, s), 137-139.degree. C. (3H, s), 2.38 (3H, s), 2.94 (4H, t), 3.07 (1H, m), 3.16 (4H, t), 4.00 (3H, s), 6.84 (1H, s), 7.16 (3H, m), 7.30 (1H, m), 8.22 (1H, s).33 0.91 (3H, t, J = 7.5 Hz), 1.17 (3H, t, J = 7.5 72-73.degree. C. 1.35 (2H, m), 1.59 (2H, m), 2.37 (3H, s), 2.55 (4H, q, J = 4.0 Hz), 3.20 (4H, t, J = 5.0 Hz), 3.66 (4H, t, J = 5.0 Hz), 3.97 (3H, s); 6.82 (2H, m), 6.88 (1H, s), 7.11 (2H, m), 8.19 (1H, s).34 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 149-150.degree. C. 3H, s), 2.57 (2H, q, J = 7.5 Hz), 3.55 (4H, t), 3.69 (4H, t), 3.98 (3H, s), 6.88 (3H, m), 7.91 (2H, m), 8.18 (1H, s).35 1.15 (3H, t, J = 7.5 Hz), 2.37 (3H, s), oil phase (2H, q, J = 7.5 Hz), 2.89 (4H, t, J = 4.8 Hz), 3.38 (4H, t, J = 4.8 Hz), 3.95 (3H, s), 6.78 (1H, s), 7.03 (1H, d), 7.12 (1H, m), 7.31 (3H, m), 7.41 (2H, m), 7.63 (2H, m), 8.17 (1H, s).36 1.18 (3H, t, J = 7.5 Hz), 2.38 (3H, s), 160-161.degree. C. (2H, q, J = 7.5 Hz), 3.32 (4H, t), 3.72 (4H, t), 3.99 (3H, s), 6.92 (1H, s), 7.04 (2H, m), 7.40 (2H, m), 7.57 (5H, m), 8.20 (1H, s).37 1.18 (3H, t, J = 7.5 Hz), 2.38 (3H, s), oil phase (4H, t), 3.70 (4H, t), 3.98 (1H, s), 6.92 (2H, m), 7.11 (2H, m), 8.19 (1H, s).38 C.sub.20 H.sub.26 N.sub.4 O.sub.3 : theoretical, 1.16 (3H, t, J = 7.5 Hz), 2.39 (3H, s), 148-149.degree. C. C, 64.85, H, 7.07, N, 15.12 (4H, t, J = 5.0 Hz), 3.67 (4H, t), 3.98 (3H, experimental, s), 6.39 (1H, d), 6.45 (1H, s), 6.51 (1H, C, 59.89, H, 7.17, N, 14.73 d), 6.90 (1H, s), 7.13 (1H, m), 8.17 (1H, s).39 1.18 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 103-104.degree. C. (2H, q, J = 7.5 Hz), 3.16 (4H, t), 3.73 (4H, t), 3.98 (3H, s), 6.80 (2H, m), 6.91 (2H, m), 8.17 (1H, s)40 1.17 (3H, t, J = 7.5 Hz), 2.29 (3H, s), 161-162.degree. C. (3H, s), 2.56 (2H, q, J = 7.5 Hz), 3.24 (4H, t), 3.72 (4H, t), 3.99 (3H, s), 6.90 (1H, s), 7.03 (4H, m), 8.21 (1H, s).41 C.sub.22 H.sub.28 N.sub.4 O.sub.4 : theoretical, 1.17 (3H, t, J = 7.5 Hz), 2.29 (3H, s), 90"91.degree. C. C, 64.06, H, 6.84, N, 13, 58 (3H, t), 2.56 (2H, q, J = 7.5 Hz), 3.28 (4H, t, experimental J = 5.0 Hz), 3.68 (4H, t), 3.99 (3H, s), 6.65 C, 64.31, H, 13.50, N, 7.00 (2H, m), 6.84 (1H, d), 6.89 (1H, s). 7.30 (1H, m), 8.19 (1H, s).42 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), oil phase (2H, q, J = 7.5 Hz), 3.18 (4H, t), 3.68 (4H, t), 3.99 (3H, s), 6.89 (2H, m), 6.99 (2H, m), 8.19 (1H, s).43 1.18 (3H, t, J = 7.5 Hz), 2. 37 (3H, s), 108-109.degree. C. (2H, q, J = 7.5 Hz), 2.89 (3H, s), 2.97 (4H, t), 3.65 (4H, t), 3.96 (3H, s), 6.77 (2H, m), 6.94 (1H, s), 7.03 (1H, d), 7.13 (1H, m).44 1.17 (3H, t, J = 7.5 Hz), 2.26 (3H, s), 159-160.degree. C. (2H, q), 3.17 (4H, t), 3.79 (1H, d), 4.00 (3H, s), 6.91 (1H, s), 7.09 (1H, d), 7.42 (1H, m), 7.50 (3H, m), 7.59 (1H, d), 7.84 (1H, d).45 1.17 (3H, t, J = 7.5 Hz), 2.47 (3H, s), oil phase (2H, q), 3.04 (4H, t), 4.05 (3H, s), 6.97 (1H, s), 7.49 (4H, m), 8.01 (2H, m), 8.27 (2H, m), 8.43 (1H, s).46 1.18 (3H, t, J = 7.5 Hz), 2.26 (3H, s), 151-152.degree. C. (3H, s), 2.56 (2H, q, J = 7.5 Hz), 2.82 (2H, m) 3.20 (2H, m), 3.46 (2H, m), 3.78 (3H, s), 3.99 (2H, m), 4.14 (3H, s), 6.71 (1H, d), 6.82 (1H, d), 6.91 (1H, s), 7.04 (1H, m), 8.25 (1H, s).47 C.sub.22 H.sub.30 N.sub.4 O.sub.3 : theoretical, 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 90-91.degree. C. C, 66.31, H, 7.59, N, 14.06 (3H, s), 2.55 (2H, q, J = 7.5 Hz), 3.11 (4H, t), experimental 3.77 (4H, t), 3.86 (3H, s), 3.96 (3H, s), C, 66.46, H, 7.75, N, 13.71 6.77 (3H, m), 8.37 (1H, s).48 C.sub.22 H.sub.30 N.sub.4 O.sub.3 : 1.17 (3H, t, J = 7.5 Hz), 2.23 (3H, s), 84-85.degree. C. C, 66.31, H, 7.59, N, 14.06 (3H, s), 2.38 (3H, s), 2.53 (2H, q, J = 7.5 Hz), experimental 2.95 (4H, t, J = 4.8 Hz), 3.65 (4H, t, J = 4.6 Hz), C, 65.24, H, 7.49, N, 13.91 3.96 (3H, s), 3.98 (3H, s), 6.57 (2H, m), 6.84 (1H, s), 7.03 (1H, s), 8.20 (1H, s).49 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 97-98.degree. C. (2H, q, J = 7.5 Hz), 3.12 (4H, t). 3.70 (4H, t), 3.89 (3H, s), 3.97 (3H, s), 6.80 (2H m), 6.94 (1H, s), 8.21 (1H, s).50 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s). oil phase (2H, q, J = 7.5 Hz), 3.27 (4H, t), 3.69 (4H, t), 3.80 (3H, s), 3.98 (3H,s), 6.50 (1H, m), 6.90 (1H, s), 7.54 (1H, m), 7.71 (1H, m), 8.19 (1H, s).51 1.19 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 94-95.degree. C. 2.55 (2H, q, J = 7.5 Hz), 3.13 (4H, t), 3.67 (4H, t), 3.78 (3H, s), 3.97 (3H, s), 6.87 (3H, m), 8.19 (1H, s).52 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 149-150.degree. C. (2H, q, J = 7.5 Hz), 3.15 (4H, t), 3.69 (4H, t), 3.83 (3H, s), 3.98 (3H, s), 6.46 (1H, d), 6.69 (1H, d), 6.90 (1H, s), 8.18 (1H, s).53 1.17 (3H, t, J = 7.5 Hz), 2.31 (3H, s), 128-135.degree. C. (3H, s), 2.55 (2H, q, J = 7.5 Hz), 3.14 (4H, t), 3.66 (4H, t), 3.79 (3H, s), 3.95 (3H, s), 6.77 (1H, s), 6.92 (2H, m), 8.18 (1H, m), 7.53 (2H, m), 8.21 (1H, s).54 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 134-135.degree. C. (2H, q, J = 7.5 Hz), 3.19 (4H, t), 3.73 (4H, t), 3.93 (3H, s), 3.98 (3H, s), 6.82 (1H, s), 6.84 (2H, m), 7.31 (2H, m), 7.42 (2H, m), 7.53 (2H, m), 8.21 (1H, s).55 C.sub.22 H.sub.27 N.sub.4 O.sub.3 Cl.sub.1 :theoretical 1.17 (3H, t, J = 7.5 Hz), 2.23 (3H, s), 188-189.degree. C. C, 60.20, H, 6.50, N, 13.37 (3H, s), 2.56 (2H, q, J = 7.5 Hz), 2.95 (4H, experimental, t, J = 5.0Hz), 3.66 (4H, t), 3.99 (3H, s), C, 59.33, H, 6.16, N, 12.80 6.85 (1H, d), 6.64 (1H, d), 6.91 (1H, s), 7.05 (1H, m), 8.21 (1H, s).56 C.sub.21 H.sub.28 N.sub.4 O.sub.3 : theoretical, 1.18 (3H, t, J = 8.0 Hz), 2.36 (3H, s), 208-211.degree. C. C, 65.60, H, 7.34, N, 14.57 (3H, s), 2.57 (2H, q, J = 7.5 Hz), 2.93 (2H, experimental m), 3.20 (2H, m), 3.43 (2H, m), 3.99 (3H, C, 65.65, H, 7.32, N, 14.40 s), 4.11 (2H, m), 6.60 (1H, d), 6.83 (2H, s).57 1.18 (3H, t, J = 7.5 Hz), 2.29 (3H, s), 192-193.degree. C. (3H, s), 2.56 (2H, q, J = 7.5 Hz), 2.97 (4H, t), 3.71 (4H, t), 3.98 (3H, s), 6.69 (1H, d), 6.82 (1H, s), 6.90 (1H, s), 7.05 (1H, d), 8.18 (1H, s).58 1.13 (3H, t, J = 7.5 Hz), 2.24 (3H, s), 74-75.degree. C. (2H, q, J = 7.5 Hz), 3.48 (4H, t, J = 5.0 Hz), 3.75 (4H, t, J = 5.0 Hz), 3.97 (3H, s), 6.89 (2H, m), 7.20 (1H, s), 8.35 (1H, s).59 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 85-86.degree. C. (2H, q, J = 7.5 Hz), 3.04 (4H, t, J = 5.0 85-86.degree. C. 3.68 (4H, t, J = 5.0 Hz), 3.98 (3H, s). 6.94 (2H, m), 6.98 (1H, m), 8.19 (1H, s).60 C.sub.22 H.sub.30 N.sub.4 O.sub.3 : theoretical, 1.11 (3H, t, J = 7.5 Hz), 2.38 (3H, s), oil phase C, 66.31, H, 7.59, N, 14.06 (2H, q, J = 7.5 Hz), 3.05 (4H, t, J = 5.0 Hz), experimental, 3.53 (4H, t, J = 4.5 Hz), 3.86 (3H, s), 3.95 C, 65.38, H, 7.65, N, 13.74 (3H, s), 4.33 (2H, d), 6.86 (1H, d), 6.93 (2H, m), 7.01 (1H, m), 7.25 (1H, s).61 C.sub.21 H.sub.27 N.sub.4 O.sub.2 F.sub.1 : theoretical 1.14 (3H, t, J = 7.5 Hz), 2.40 (3H, s), oil phase C, 65.27, H, 7.04, N, 14.50 (2H, q, J = 7.5 Hz), 3.04 (4H, t, J = 7.5 Hz) experimental 5.0 Hz), 3.52 (4H, t, J = 5.0 Hz), C, 65.87, H, 7.35, N, 14.48 4.33 (2H, d), 6.92 (2H, m), 7.06 (2H, m), 7.32 (1H, s).62 1.16 (3H, t, J = 7.5 Hz), 2.40 (3H, s), oil phase (2H, q, J = 7.5 Hz), 3.07 (4H, t, J = 5.0 Hz), 3.50 (4H, t, J = 5.0 Hz), 3.95 (3H, s), 4.34 (2H, d), 6.85 (2H, m), 6.97 (2H, m), 7.32 (1H, s).63 1.15 (3H, t, J = 8.0 Hz), 2.38 (3H, s), oil phase (2H, q, J = 7.5 Hz), 3:16 (4H, t, J = 5.0 Hz), 3.49 (4H, t, J = 5.0 Hz), 3.96 (3H, s), 4.33 (2H, d), 6.75 (1H, m), 6.85 (2H, m), 7.15 (1H, m), 7.46 (2H, s).64 1.15 (3H, t, J = 7.5 Hz), 2.40 (3H, s), oil phase (2H, q, J = 7.5 Hz), 2.76 (2H, t, J = 6.5Hz), 3.05 (4H, t, J = 4.8 Hz), 3.47 (6H, m), 3.93 (3H, s), 6.87 (2H, m), 6.97 (2H, m), 7.26 (1H, s).65 1.14 (3H, t, J = 7.5 Hz), 2.43 (3H, s), oil phase (2H, q, J = 7.5 Hz), 2.76 (2H, m), 3.00 (4H, t, J = 5.0 Hz), 3.44 (2H, m), 3.50 (4H, t), 3.87 (3H, s), 3.93 (3H, s), 6.72 (1H, m), 6.92 (2H, m), 7.01 (1H, m), 7.16 (1H, s).66 1.16 (3H, t, J = 7.5 Hz), 1.80 (2H, q), oil phase (3H, s), 2.53 (2H, q), 2.58 (2H, t), 3.26 (2H, q), 3.89 (3H, s), 3.93 (3H, s), 6.92 (4H, m), 7.16 (1H, s).67 1.15 (3H, t, J = 7.5 Hz); 1.38 (2H, m), 128-129.degree. C. (4H, m), 2.39 (3H, s), 2.52 (4H, m), 3.06 (4H, t), 3.25 (2H, m), 3.55 (4H, t), 3.87 (3H, s), 3.91 (3H, s), 6.88 (2H, m), 6.94 (2H, m), 7.46 (1H, s).68 1.15 (3H, t, J = 7.5 Hz), 1.33 (6H, m), 118-120.degree. C. (2H, m), 2.39 (3H, s), 2.52 (4H, m), 3.05 (4H, t), 3.25 (2H, m), 3.54 (4H, t), 3.87 (3H, s), 3.90 (3H, s), 6.87 (2H, m), 6.93 (2H, m), 7.10 (1H, s).69 1.20 (3H, t), 2.39 (3H, s), 2.58 (2H, 164.165.degree. C. 2.83 (4H, t), 3.20 (6H, brs), 3.90 (3H, s), 3.98 (3H, s), 7.00 (4H, m), 8.40 (1H,s).70 1.18 (3H, t), 2.39 (3H, s), 2.56 (2H, 120-123.degree. C. 2.77 (4H, t), 3.21 (2H, m), 3.28 (4H,t), 6.82 (2H, m), 6.90 (1H, s), 7.19 (1H, m), 8.37 (1H, s).71 1.18 (3H, t), 2.39 (3H, s), 2.56 (2H, 139-140.degree. C. 2.81 (4H, t), 3.20 (6H, brs), 3.97 (3H, s), 7.04 (4H, m), 8.38 (1H, s).72 1.16 (3H, t, J = 7.5 Hz), 2.36 (3H, s), 96-97.degree. C. (6H, m), 3.96 (3H, s), 6.85 (1H, s), 7.33 (5H, s).73 1.16 (3H, t, J = 7.5 Hz), 2.36 (3H, s), 96-98.degree. C. (6H, m), 3.53 (6H, m), 3.81 (3H, s), 3.95 (3H, s), 6.84 (1H, s), 6.88 (2H, m), 7.27 (2H, m), 8.16 (1H, s).74 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 83-84.degree. C. (2H, q), 2.65 (4H, t), 3.61(6H, m), 3.83 (3H, s), 3.95 (3H, s), 6.83 (1H, s), 6.90 (2H, m), 6.97 (2H, m), 8.15 (1H, s).75 1.16 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 74-75.degree. C. (6H, m), 3.53 (6H, m), 3.97 (3H, s), 6.85 (1H, s), 7.02 (2H, m), 7.32 (2H, m), 8.17 (1H, s).76 1.17 (3H, t, J = 7.5 Hz), 1.39 (3H, t, J 114-115.degree. C. 7.0 Hz), 2.35 (3H, s), 2.55 (2H, q, J = 5.0 Hz), 3.13 (4H, t, J = 4.6 Hz), 3.68 (4H. t, J = 4.6 Hz), 3.89 (3H, s), 4.42 (2H, q, J = 9.3 Hz), 6.90 (1H, d), 6.96 (2H, m), 7.04 (1H, m), 8.21 (1H, s).77 1.17 (3H, t, J = 7.5 Hz), 1.40 (3H, t, J 126-127.degree. C. 7.0 Hz), 2.38 (3H, s), 2.55 (2H, q, J = 7.5 Hz), 3.14 (4H, t, J = 4.5 Hz), 3.68 (4H, t, J = 4.5 Hz), 4.43 (2H, q, J = 7.0 Hz), 6.96 (2H, m), 7.08 (2H, m), 8.19 (1H, s).78 1.17 (3H, t, J = 7.5 Hz), 1.40 (3H, t, J 101-102.degree. C. 7.5 Hz), 2.35 (3H, s), 2.55 (2H, q, J = 7.5 Hz), 3.27 (4H, t, J = 5.0 Hz), 3.66 (4H, t, J = 5.0 Hz), 4.43 (2H, q, J = 7.0 Hz), 6.79 (1H, d), 6.81 (1H, d), 6.86 (1H, s), 6.94 (1H, s), 7.19 (1H, m), 8.18 (1H, s).79 1.17 (3H, t, J = 7.5 Hz), 1.40 (3H, t, J oil phase 7.0 Hz), 1.49 (3H, t, J = 6.9 Hz), 2.35 (3H, s), 2.55 (2H, q), 3.14 (4H, t), 3.68 (4H, t), 4.10 (2H, q), 4.44 (2H, q), 6.87 (1H, d), 6.92 (2H, m), 6.96 (1H, s), 7.00 (1H, m), 8.20 (1H, s).80 1.22 (3H, t, J = 7.5 Hz), 2.31 (3H, s), 104-105.degree. C. (2H, q, J = 7.5 Hz), 3.08 (4H, t), 3.66 (4H, t), 3.88 (3H, s), 6.96 (3H, m), 7.13 (2H, m), 7.23 (2H, m), 7.36 (2H, m), 8.36 (1H, s).81 1.22 (3H, t, J = 7.5 Hz), 2.31 (3H, s), 120-121.degree. C. (2H, q, J - 7.5 Hz), 3.22 (4H, t), 3. 66 (4H, t), 3.88 (3H, s), 6.93 (1H, s), 6.96 (3H, m), 7.13 (2H, m), 7.23 (2H, m), 7.36 (2H, m), 8.36 (1H, s).82 1.22 (3H, t, J = 7.5 Hz), 2.29 (3H, s), 52-53.degree. C. (3H, s), 2.60 (2H, q, J = 7.5 Hz), 3.24 (4H, t, J = 5.0 Hz), 3.63 (4H, t, J = 4.5 Hz), 6.62 (2H, m), 6.80 (1H, d), 6.93 (1H, s), 7.10 (2H, m), 7.17 (1H, m), 7.27 (1H, m), 7.46 (2H, m), 8.34 (1H, s).83 1.22 (3H, t, J = 7.5 Hz), 2.31 (3H, s), 166-167- C. (2H, q), 3.11 (4H, t, J = 4.8 Hz), 3.65 (4H, t, J = 4.8 Hz), 6.99 (3H, m), 7.09 (4H, m), 7.36 (2H, m)m 8.35 (1H, s).84 1.23 (3H, t, J = 7.5 Hz), 2.28 (3H, s), oil phase (3H, s), 2.60 (2H, q, J = 7.5 Hz), 3.19 (4H, t, J = 5.0 Hz), 3.95 (4H, t), 6.55 (3H, m), 6.94 (1H, s), 7.09 (2H, m), 7.20 (1H, m), 7.38 (2H, m), 8.35 (1H, s).85 1.25 (3H, t, J = 7.2 Hz), 2.30 (3H, s), 94-95.degree. C. (2H, q, J = 7.5 Hz), 3.21 (4H, t, J = 5.2 Hz). 3.62 (4H, t), 3.77 (6H, s). 6.08 (3H, m), 7.13 (2H, m), 6.93 (1H, s), 7.16 (1H, m), 7.36 (2H, m), 8.34 (1H, s).86 1.19 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 156-157.degree. C. (2H, q, J = 7.5 Hz), 3.26 (4H, t, J = 5.0 Hz), 3.78 (4H, t, J = 6.0 Hz), 3.98 (3H, s), 6.91 (1H, s), 6.97 (2H, m), 7.31 (1H, m). 8.91 (1H, s).87 1.22 (3H, t, J = 8.0 Hz), 2.31 (3H, s), 117-118.degree. C. (2H, q, J = 7.5 Hz), 3.10 (4H, t), 3.66 (4H, t), 3.99 (3H, s), 6.79 (1H, m), 6.91 (1H, s), 6.93 (2H, m), 7.10 (2H, m), 7.16 (1H, m), 7.38 (2H, m), 8.34 (1H, s).88 1.23 (3H, t, J = 7.5 Hz), 2.18 (3H, s), 92-93.degree. C. (2H, q, J = 7.5 Hz), 3.22 (4H, t, J = 4.5 Hz). 3.95 (4H, t), 6.40 (1H, m), 6.52 (2H, m), 7.13 (2H, m), 7.37 (2H, m), 8.32 (1H, s).89 1.24 (3H, t, J = 7.5 Hz), 2.52 (3H, s), 185-186.degree. C. (2H, q, J = 8.0 Hz), 3.21 (4H, t), 3.45 (3H, s), 3.82 (4H, t), 4.12 (3H, s), 7.02 (4H, m), 7.43 (1H, s).90 1.25 (3H, t, J = 7.5 Hz), 2.52 (3H, s), 1-2-103.degree. C. (2H, q), 3.45 (3H, s), 3.89 (6H, s), 6.95 (3H, m), 7.43 (1H, s).91 1.22 (3H, t, J = 7.5 Hz), 2.53 (3H, s), oil phase (2H, q, J = 7.5 Hz), 3.35 (4H, t), 3.47 (3H, s), 3.81 (4H, t), 4.23 (1H, q, J = 5.7 Hz), 6.88 (2H, m), 6.94 (1H, s), 7.22 (2H, m), 7.71 (1H, s).92 1.22 (3H, t, J = 7.5 Hz), 2.49 (3H, s), 161-162.degree. C. (2H, q, J = 8.0 Hz), 3.11 (4H, t, J = 5.0 Hz) 3.70 (4H, t, J = 5.0 Hz), 3.72 (6H, s), 6.68 (1 H, m), 6.88 (2H, m), 7.05 (1H, m), 7.88 (1 H, s), 8.23 (1H, s).93 1.21 (3H, t, J = 7.5 HZ), 2.42 (3H, s), 179-180.degree. C. (2H, q, J = 7.5 Hz), 3.24 (4H, t, J = 5.0 Hz), 3.67 (4H, t, J = 5.0 Hz), 3.78 (6H, s), 6.05 (1H, s), 6.09 (2H, s), 7.89 (1H, s). 8.26 (1H, s).94 1.20 (3H, t, J = 7.5 Hz), 2.40 (3H, s), oil phase (2H, q, J = 7.5 Hz), 3.02 (4H, t), 3.09 (4H, t), 3.28 (4H, t), 3.68 (4H, t), 6.80 (2H, d), 6.82 (1H, d), 6.90 (1H, s), 7.22 (1H, m), 8.22 (1H, s).95 1.20 (3H, t, J = 7.5 Hz), 1.48 (9H, s), 188-189.degree. C. (3H, s), 2.58 (2H, q), 2.95 (4H, t), 3.28 (4H, t), 3.57 (4H, t), 3.67 (4H, t), 6.79 (1H, dd), 6.87 (1H, dd), 7.21 (1H, m), 7.26 (1H, s), 8.24 (1H, s).96 1.20 (3H, t, J = 7.5 Hz), 1.48 (9H, s), 152-153.degree. C. (3H, s), 2.58 (2H, q), 2.95 (4H, t), 3.12 (4H, t), 3.57 (4H, t), 3.70 (4H, t), 3.91 (3H, s), 6.94 (3H, m), 7.06 (1H, m), 7.58 (1H, s), 8.25 (1H, s).97 C.sub.21 H.sub.28 N.sub.4 O.sub.2 S.sub.1 : theoretical, 1.19 (3H, t, J = 7.5 Hz), 2.39 (3H, s), 133-134.degree. C. C, 62.97, H, 7.05, N, 13.99, (2H, q, J = 7.5 Hz), 3.16 (4H, t, J = 5.0 Hz). S, 8.00, experimental, 3.89 (3H, s), 3.96 (3H, s), 4.10 (4H, t, J = C, 62.61, H, 6.96, N, 14.08, 4.5 Hz), 6.89 (1H, m), 6.93 (2H, m), 7.04 S, 7.77, (1H, m), 8.11 (1H, s).98 1.17 (3H, t), 2.47 (3H, s), 2.55 (2H, q, J 90-91.degree. C. 7.5 Hz), 3.39 (4H, t, J = 5.1 Hz), 3.98 (3H, s), 4.18 (4H, t), 6.79 (1H, m), 6.90 (2H, m), 7.19 (1H, m), 8.11 (1H, s).99 1.19 (3H, t, J = 7.5 Hz), 2.39 (3H, s), 132-133.degree. C. (2H, q, J = 7.5 Hz), 3.19 (4H, t, J = 5.0 Hz), 3.96 (3H, s), 4.09 (4H, t, J = 5.0 Hz), 6.95 (2H, m), 7.00 (2H, m), 8.11 (1H, s).100 C.sub.22 H.sub.30 N.sub.4 O.sub.3 S.sub.1 : theoretical, 1.19 (3H, t, J = 7.5 Hz), 2.40 (3H, s), 166-167.degree. C. C, 61.37, H, 7.02, N, 13.01, (2H, q, J = 7.5 Hz), 3.36 (4H, t, J = 4.5 Hz), S, 7.45, experimental 3.75 (6H, s), 3.96 (3H, s), 4.13 (4H, t), C, 61.47, H, 7.25, N, 13.21, 6.09 (3H, m), 8.13 (1H, s).101 S, 7.47, 1.20 (3H, t, J = 7.5 Hz), 2.40 (3H, s), 166-167.degree. C. (2H, q, J = 8.0 Hz), 3.37 (4H, t), 3.96 (3H, s), 4.15 (4H, t), 6.98 (2H, m), 7.46 (1H, s), 8.13 (1H, s).102 1.18 (3H, t, J = 8.0 Hz), 2.40 (3H, s). 89-90.degree. C. (2H, q, J = 7.5 Hz), 3.11 (4H, t), 3.75 (2H, t), 3.87 (2H, t), 3.89 (3H, s), 3.97 (3H, s), 6.86 (1H, d), 6.94 (2H, m), 7.04 (1H, m), 7.26 (1H, s).103 1.26 (3H, t, J = 7.5 Hz), 2.40 (3H, s). 119-120.degree. C. (2H, q), 3.25 (4H, t), 3.72 (2H, t), 3.84 (2H, t), 3.93 (3H, s), 6.82 (1H, d), 6.86 (1H, d), 6.92 (1H, s), 7.04 (1H. s), 7.22 (1H, m), 7.46 (1H, s).104 1.17 (3H, t, J = 7.5 Hz), 2.39 (3H, s), oil phase (2H, q, J = 7.5 Hz), 3.23 (4H, t, J = 5.0 Hz), 3.64 (2H, t), 3.79 (6H, s), 3.79 (2H, t), 5.96 (1RH, s), 6.12 (2H, s), 7.30 (1H, s).105 1.17 (3H, t, J = 7.5 Hz), 2.42 (3H, s), oil phase (2H, q, J = 7.5 Hz), 3.01(4H, t), 3.78 (4H, t), 3.87 (3H, s), 3.93 (3H, s), 5.11 (2H, s), 6.91 (3H, s), 7.03 (1H, m), 7.33 (1H, s).106 1.15 (3H, t, J = 7.5 Hz), 2.42 (3H, s), oil phase (2H, q), 3.15 (4H, t), 3.64 (4H, t), 3.93 (3H, s), 3.96 (3H, s), 4.59 (2H, s), 6.85 (3H, m), 7.15 (1H, s), 7.33(1H, s).107 2.19 (3H, s), 2.34 (3H, s), 3.26( 4H, 140"141.degree. C. 3.69 (4H, t), 3.97 (3H, s), 6.82 (1H, s), 6.94 (3H, m), 7.30 (2H, m), 8.14 (1H, s).108 C.sub.20 H.sub.26 N.sub.4 O.sub.3 : theoretical, 1.55 (3H, s), 2.19 (3H, s), 2.33 (3H, 135-136.degree. C. C, 64.85, H, 7.07, N, 15.12 3.12 (4H, t), 3.69 (4H, t), 3.89(3H, s), experimental, 3.97 (3H, s), 6.89 (2H, m), 6.90 (1H, s), C, 65.13, H, 7.24, N, 15.10 7.04 (2H, m), 8.16 (1H, s).109 C.sub.19 H.sub.23 N.sub.4 O.sub.2 Cl.sub.1 : theoretical, 2.19 (3H, s), 2.34 (3H, s), 3.27 (4H, t, J 95-96.degree. C. C, 60.88, H, 6.18, N, 14.95 5.2 Hz), 3.66 (4H, t, J = 5.0 Hz), 3.98 experimental, (3H, s), 6.80 (1H, d), 6.86 (2H, m), 6.90 C, 60.87, H, 6.28, N, 14.86 (1H, s), 7.21 (1H, m), 8.14 (1H, s).110 2.19 (3H, s), 2.34 (3H, s), 3.14 (4H, t, J 164-167.degree. C. 4.9 Hz), 3.68 (4H, t, J = 4.8 Hz), 3.98 (3H, s), 6.88 (1H, s), 6.98(2H, m), 7.09 (2H, m), 8.15 (1H, s).111 2.20 (3H, s), 2.39 (3H, s), 3.29 (4H, t, J 133-134.degree. C. 5.0 Hz), 3.67 (4H, t, J = 5.0 Hz), 4.04 (3H. s), 6.30 (1H, m), 6.38(2H, d), 6.86 (1H, s), 8.18 (1H, s).112 2.19( 3H, s), 2.35 (3H, s), 2.99 (4H, 174-175.degree. C. 3.72 (4H, t), 3.98 (3H, s), 6.90 (2H, m), 7.15 (2H, m), 8.14 (1H, s).113 2.18 (3H, s), 2.33 (3H, s), 3.25 (4H, t, J 176-178.degree. C. 5.0 Hz), 3.67 (4H, t, J = 4.3 Hz), 3.97 (3H, s), 6.38 (1H, d), 6.46 (1H, s), 6.54 (1H, d), 6.87 (1H, s), 7.13 (1H, t), 8.13 (1H, s).114 2.18 (3H, s), 2.33 (3H, s), 3.12 (4H, 168-169.degree. C. 3.68 (4H, t), 3.97 (3H, s), 6.80 (2H, m), 6.91 (2H, m), 8.13 (1H, s)115 2.09 (3H, s), 2.29 (3H, s), 2.34 (3H, 108-109.degree. C. 3.27 (4H, t, J = 5.0 Hz), 3.67 (4H, t, J = 5.0 Hz), 3.98 (3H, s), 6.44 (2H, m), 6.81 (1H, m), 6.88 (1H, s), 8.14 (1H,s).116 2.19 (3H, s), 2.28 (3H, s), 2.34 (3H, 159-160.degree. C. 3.22 (4H, t), 3.68 (4H, t), 3.98 (3H, s), 6.87 (1H, s), 7.01 (4H, m), 8.14 (1H, s).117 2.04 (3H, s), 2.31 (3H, s), 2.34 (3H, 139-140.degree. C. 3.20 (4H, t), 3.76 (4H, t), 3.81 (3H, s), 3.98 (3H, s), 6.86 (1H, s), 7.01 (3H, m), 8.15 (1H, s).118 C.sub.21 H.sub.28 N.sub.4 O.sub.4 : theoretical, 2.18 (3H, s), 2.33 (3H, s), 3.25 (4H, t, J 150-151.degree. C. C, 62.98, H, 7.05, N, 13.99 5.0 Hz), 3.67 (4H, t), 3.80 (6H, s), 3.97 experimental, (3H, s), 6.07 (3H, m), 6.86 (1H, s), 8.14 C, 63.21, H, 7.19, N, 13.96 (1H, s).119 C.sub.21 H.sub.30 N.sub.4 O.sub.2 : 2.19 (3H, s), 2.26 (3H, s), 2.28 (3H, 134-135.degree. C. C, 68.45, H, 7.66, N, 15.20 2.34 (3H, s), 2.94 (4H, t), 3.66 (4H, t), experimental 3.97 (3H, s), 6.89 (3H, m), 8.33 (1H, s). C, 68.26, H, 7.97, N, 14.99120 2.16 (3H, s), 2.29 (6H, s), 2.33 (3H, 125-126.degree. C. 3.23 (4H, t), 3..66 (4H, t), 3.97 (3H, s), 6.53 (3H, m), 6.87 (1H, s), 8.14 (1H, s).121 2.19 (3H, s), 2.26 (3H, s), 2.34 (3H, 127-130.degree. C. 2.95 (4H, t, J = 4.8 Hz), 3.64 (4H, t, J = 4.8 Hz), 3.78 (3H, s), 3.97 (3H, s), 6.57 (1H, d), 6.58 (1H, s), 7.11 (1H, d), 8.32 (1H, s).122 2.19 (3H, s), 2.30 (3H, s), 2.42 (3H, 184-185.degree. C. 2.94 (4H, t), 3.69 (4H, t), 3.97 (3H, s), 6.69 (1H, d), 6.82 (1H, s), 6.88 (1H, s), 7.04 (1H, d), 8.14 (1H, s).123 2.04 (3H, s), 2.33 (3H, s), 3.15 (4H, 172-176.degree. C. 3.67 (4H, t), 3.89 (3H, s), 3.97 (3H, s), 6.65 (1H, d), 6.81 (1H, d), 8.14 (1H, s).124 2.20 (3H, s), 2.48 (3H, s), 3.17 (4H, 202-204.degree. C. 3.76 (4H, t), 4.00 (3H, s), 6.94 (1H, s), 7.11 (1H, d), 7.40 (1H, m), 7.50 (1H, m), 7.61 (1H, d), 8.19 (1H, s).125 2.21 (3H, s), 2.44 (3H, s), 3.04 (4H, 103-104.degree. C. 3.77 (4H, t), 4.05 (3H, s), 6.97 (1H, m), 7.49 (4H, m), 8.01 (2H, m), 8.27 (1H, m), 8.43 (1H, s).126 2.22 (3H, s), 2.43 (3H, s), 3.39 (4H, t, J 168-169.degree. C. 5.0 Hz), 4.02 (3H, s), 4.17 (4H, t), 6.87 (lH,d), 6.91(1H,d), 6.96(lH,s), 7.24 (2H, m), 8.12 (1H, s).127 2.21 (3H, s), 2.42 (3H, s), 3.38 (4H, oil phase J = 5.0 Hz), 4.02 (3H, s), 4.17 (4H, t), 6.87 (1H, s), 6.91 (2H, d), 6.96 (1H, s), 8.12 (1H, s).128 C.sub.20 H.sub.26 N.sub.4 O.sub.2 S.sub.1 : theoretical, 2.17 (3H, s), 2.36 (3H, s), 3.30 (4H, 160-161.degree. C. C, 62.15, H, 6.78, N, 14.50, 3.19 (3H, s), 3.96 (3H, s), 4.21 (4H, t), S, 8.49, experimental, 6.05 (4H, m), 8.03 (1H, s). N, 14.70, S, 8.48129 2.21 (3H, s), 2.36 (3H, s), 3.37 (4H, 166-167.degree. C. 3.79 (6H, s), 3.96 (3H, s), 4.10 (4H, t), 6.10 (2H, m), 7.46 (1H, s), 8.10 (1H, s).130 2.11 (2H, m), 2.87 (4H, m), 3.12 (4H, t, J 130-131.degree. C. 4.95 Hz), 3.70 (4H, t, J = 4.8 Hz), 3.89 (3H, s), 4.00 (3H, s), 6.89 (2H, m), 7.05 (2H, m), 8.26 (1H, s).131 2.12 (2H, m), 2.87 (4H, m), 3.27 (4H, t, J 142-146.degree. C. 5.0 Hz), 3.67 (4H, t, J = 5.0 Hz), 4.00 (3H, s), 6.80 (1H, m), 6.90 (2H, m), 7.21 (1H, m), 8.23 (1H, s).132 2.12 (2H, m), 2.87 (4H, m), 3.27 (4H, t, J 152-153.degree. C. 5.0 Hz), 3.68 (4H, t, J = 5.0 Hz), 4.00 (3H, s), 6.97 (3H, m), 7.07 (1H, m), 8.24 (1H, s).133 1.76 (2H, m), 1.83 (2H, m), 2.68 (2H, t, J oil phase 5.7 Hz), 2.72 (2H, t, J = 5.9 Hz), 3.13 (4H, t), 3.71 (4H, t), 3.89 (3H, s), 3.97 (3H, s), 6.95 (4H, m), 8.09 (1H, s).134 1.75 (2H, m), 1.83 (2H, m), 2.68 (2H, t, J oil phase 6.1 Hz), 2.75 (2H, t, J = 6.0 Hz), 3.27 (4H, t, J = 5.15 Hz), 3.67 (4H, t, J = 4.9 Hz), 4.00 (3H, s), 6.81 (1H, d), 6.90 (2H, m), 7.20 (1H, m), 8.08 (1H, s).135 1.76 (2H, m), 1.84 (2H, m), 2.68 (2H, 134-135.degree. C. 2.72 (2H, t), 3.14 (4H, t, J = 5.0 Hz), 3.68 (4H, t, J = 5.0 Hz), 3.97 (1H, s), 6.99 (1H, s), 7.00 (2H, m), 7.09 (2H, m), 8.08 (1H, s).136 0.90 (3H, s), 0.91 (3H, s), 2.07 (2H, oil phase 2.48 (3H, d), 3.22 (4H, t), 3.80 (4H, t), 3.88 (3H, s), 3.99 (3H, s), 6.67 (1H, s), 6.94 (1H, s), 6.98 (3H, m), 8.24 (1H, s).137 0.90 (3H, s), 0.91 (3H, s), 2.07 (1H, oil phase 2.49 (3H, d), 3.29 (3H, t, J = 5.0 Hz), 3.74 (4H, t, J = 4.8 Hz), 4.00 (3H, s), 6.69 (1H, m), 6.89 (2H, m), 7.21 (1H, m), 8.24 (1H, m).138 0.91 (3H, s), 0.92 (3H, s), 2.08 (1H, oil phase 2.54 (3H, d), 3.32 (4H, t), 3.95 (4H, t), 4.20 (3H, s), 6.70 (1H, d), 6.93 (1H, s), 7.14 (3H, m), 8.26 (1H, s).139 3.03 (4H, t), 3.69 (4H, t), 3.78 (3H, 168-169.degree. C. 4.02 (3H, s), 6.89 (4H, m), 7.04 (1H, s), 7.77 (1H, dd), 8.40(1H, dd).140 3.13 (4H, t), 3.71 (4H, t), 3.89 (3H, 173-174.degree. C. 4.02 (3H, s), 6.84 (4H, m), 6.91 (1H, m), 7.05 (1H, m), 7.78 (1H, m), 8.42 (1H, m),141 3.27 (3H, t, J = 5.0 Hz), 3.69 (4H, t), 133-135.degree. C. (3H, s), 6.89 (1H, m), 7.04 (1H, s), 7.32 (2H, m), 7.78 (1H, dd), 8.40 (1H, dd).142 3.28 (4H, t, J = 5.2 Hz), 3.69 (4H, t, J 95-96.degree. C. 5.0 Hz), 4.03 (3H, s), 6.83 (1H, m), 6.90 (3H, m), 7.20 (1H, m), 7.79 (1H, m), 8.40 (1H, m).143 1.17 (3H, t, J = 7.5 Hz), 2.37 (3H, s), 225-227.degree. C. (2H, q), 3.17 (4H, t, J = 3.2 Hz), 3.66 (4H, t), 3.98 (3H, s), 4.56 (1H, s), 6.93 (1H, s), 7.00 (2H, m), 8.19 (1H, s).144 1.16 (3H, t, J = 7.5 Hz), 2.40 (3H, s), 143-145.degree. C. (2H, q, J = 7.5 Hz), 3.07 (4H, t), 3.49 (4H, t), 3.95 (3H, s), 4.34 (2H, d), 4.53 (1H, s), 6.97 (2H, m), 7.32 (1H, s), 7.79 (1H, s).145 1.11 (3H, t, J = 7.5 Hz), 2.30 (3H, s), oil phase (2H, q), 3.04 (4H, t), 3.48 (4H, t), 4.06 (2H, d), 4.28 (2H, d), 4.36 (1H, s), 6.97 (2H, m), 7.34 (1H, s), 7.84 (1H, s).146 1.22 (3H, t), 2.29 (3H, s), 2.37 (2H, q), 3.13 (4H, t), 3.41 (4H, t), 3.56 (2H, d), 4.27 (4H, s), 6.90 (3H, m), 7.04 (5H, s), 7.25 (5H, s).147 0.91 (3H, s), 1.02 (3H, s), 1.28 (3H, oil phase 2.48 (3H, s), 3.04 (4H, t), 3.54 (4H, t), 4.36 (2H, q), 5.98 (2H, d), 6.90 (3H, m), 7.68 (1H, s).148 1.14 (3H, t, J = 7.5 Hz), 2.35 (3H, s), 158-159.degree. C. (2H, q, J = 7.5 Hz), 3.51 (4H, t, J = 4.6 Hz), 3.90 (4H, t, J = 4.6 Hz), 3.92 (3H, s), 6.19 (1H, d), 7.21 (2H, dd), 7.65 (1H, m), 7.78 (1H, s).149 1.09 (3H, t, J = 7.5 Hz), 2.38 (3H, s), 198-199.degree. C. (2H, q, J = 7.5 Hz), 3.31 (4H, t, J = 5.0 Hz), 3.63 (4H, t, J = 5.0 Hz), 3.92 (3H, s), 6.84 (1H, d), 6.96 (2H, dd), 7.21 (1H, d), 7.69 (1H, s).__________________________________________________________________________

Antitumor activities of the compounds of present invention were tested. Antitumor activities of compounds of the present invention were tested in vitro against 5 kinds of human tumor cell lines and 2 kinds of leukemia tumor cell lines. The method of in vitro test is as follows.

Example 1)

In Vitro Antitumor Effect Against Human Tumor Cell Lines

A. Tumor cell line:

A549 (human non-small lung cell)

SKOV-3 (human ovarian)

HCT-15 (human colon)

XT 498 (human CNS)

SKMEL 2 (human melanoma)

B. Method of test(SRB Assay Method)

a. Human solid tumor cell lines, A594(non-small lung cell), SKMEL-2(melanoma), HCT-15(colon), SKOV-3(ovarian), XF-498(CNS) were cultured at 37.degree. C., in 5% CO.sub.2 incubater using the RPMI 1640 media containing 10% FBS, while they were transfer-cultured successively once or twice per week. Cell cultures were dissolved into the solution of 0.25% trypsin and 3 mM CDTA PBS(-) and then cells were separated from media which the cells were sticked on.

b. 5.times.10.sup.3 -2.times.10.sup.4 cells were added into each well of 96-well plate and cultured in 5% CO.sub.2 incubater, at 37.degree. C., for 24 hours.

c. Each sample drugs was dissolved in a small quantity of DMSO, and diluted to concentrations prescribed in experiment with media, and then the final concentration of DMSO was controlled below 0.5%.

d. A medium of each well cultured for 24 hours as above b., was removed by aspiration. 200 .mu.l of drug samples prepared in c. was added into each well and the wells were cultured for 48 hours. Tz(time zero) plates were collected at the point of time drugs were added.

e. After Tz plates and plates were treated with cell fixing by TCA of SRB assay method, staining of 0.4% SRB solution, washing with 1% acetic acid, OD values were measured at 520 nm, following elution of dye with 10 mM Tris solution.

C. Calculation of Result

a. Time zero(Tz) value was determined by obtainment of SRB protein value at the point of time drugs were added.

b. Control value(C) was determined with OD value of well that was not added with drug.

c. Drug-treated test value(T) was determined with OD value of well treated with dug.

d. Drug effects of growth stimulation, net growth inhibition, net killing etc. were determined with Tz, C and T.

e. If T.gtoreq.Tz, cellular response function was calculated with 100.times.(T-Tz)/(C-Tz), and if T<Tz, with 100.times.(T-Tz)/Tz. The results are shown in the next table.

Reference

1) P. Skehan, R. Strong, D Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesh, S. Kenny and M. R. Boyd : Proc. Am. Assoc. Cancer Res., 30, 612(1989)

2) L. V. Rubinstein, R. H. Shoemarker, K. D. Paull, R. M. simon, S. Tosini, P. Skehan, D. Scudiero, A. Monks and M. R. boyd.; J. Natl. Cancer Inst., 82, 1113(1990)

3) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Memahan, D. t. Vistica, J. Warren, H. Bokesh, S. Kenny and M. R. Boyd.; J, Natl. Cancer ins., 82, 1107(1990)

D. Results.

It was found that the compounds of present invention have the superior antitumor activities to those of the control, cisplatin against 5 kinds of human solid cancer cell lines. Especially, compounds of example 1), 6), 13), 16), 28), 29), 38), 41), 47), 48), 49), 50), 55), 61), 91), 97), 98), 100), 108), 109), 111), 113), 115), 118), 119), 120), 121), 126), 128), 129), 144), 148), 149) have superior antitumor activities to those of cisplatin.

______________________________________EX-AMPLE NET GROWTH AS % OF CONTROL (Conc. .mu.g/mL)NUMBER A594 SK-OV-3 SK-MEL-2 XF-498 HCT-15______________________________________ 1 0.1372 0.0269 0.0172 0.1149 0.0479 6 0.0091 0.0072 0.0092 0.0156 0.0108 8 1.1428 0.3930 0.8302 1.2938 1.049913 0.2483 0.0697 0.1771 0.2769 0.082916 0.4491 0.0263 0.0182 0.1662 0.116018 1.0813 0.7207 0.8138 0.8275 0.685021 1.9952 1.0423 1.7609 2.8475 0.668422 2.2086 1.2588 1.8210 2.3352 0.676423 1.9836 0.5929 0.8665 2.2896 1.005328 0.5958 0.3192 0.6495 0.7663 0.375629 0.0002453 0.0001310 0.0007708 0.0001901 0.000770738 0.4266 0.0709 0.0833 0.2836 0.065241 0.4464 0.0836 0.0981 0.3818 0.087847 0.3693 0.2094 0.4384 0.4998 0.297548 0.0913 0.0583 0.0954 0.1430 0.049849 0.0917 0.0223 0.0723 0.0955 0.094650 0.0984 0.0732 0.0954 0.0736 0.082855 0.5074 0.1088 0.2812 0.4094 0.157760 2.8176 1.7486 0.6468 2.1795 0.341061 0.8539 0.1710 0.1594 0.4343 0.091062 3.5875 0.2431 0.2894 1.1457 0.295091 0.5284 0.3156 0.5562 0.9176 0.597997 0.3518 0.0536 0.01778 0.2965 0.148998 0.3489 0.0645 0.1822 0.2229 0.1801100 0.0016111 0.0015197 0.0032233 0.0020713 0.0065666108 0.1158 0.0797 0.1277 0.1352 0.0741109 0.1088 0.0832 0.1079 0.1494 0.0581111 0.1611 0.0661 0.1258 0.0949 0.0749113 0.4371 0.1680 0.3368 0.5967 0.0973115 0.6168 0.2201 0.3672 1.4025 0.2081118 0.0038 0.0011 0.0046 0.0042 0.0024119 0.3824 0.1129 0.2414 0.5133 0.2026120 0.0001299 0.0000226 0.0002677 0.0001193 0.0001265121 0.0116039 0.0020599 0.0177227 0.0087927 0.0070088126 0.006171 0.0005225 0.0110493 0.0048476 0.0058752127 1.5462 0.4162 0.4776 1.3486 0.5366128 0.0059411 0.0013953 0.0127665 0.0039702 0.0065951129 0.0000119 0.0000033 0.0000389 0.0000117 0.0000384144 1.0350 0.6289 0.6060 4.4550 0.4738148 0.6767 0.3129 0.1582 0.7615 0.3203149 0.3883 0.1819 0.1731 0.4255 0.0471Cisplatin 0.8184 0.7134 0.7147 0.7771 3.0381______________________________________

Example 2)

* In Vitro Antituimor Effects Against Animal Leukemia Cells.

A. Material of Experiment

Tumor cell lines:

L1210(mouse leukemia cell) P388 (mouse lymphoid neoplasma cell) B. Method of Experiment(Dye Exclusion Assay)

1) L-1210 and P388 cells that were cultured in RPMI 1640 media containing 10% FBS were regulated as the cell concentration of 1.times.10.sup.6 cells/ml.

2) Sample drugs diluted with log dose were added into the cells, and it were cultured at 37.degree. C., for 48 hours, in 50% CO.sub.2 incubater, and then viable cell number was measured, Viable cell number was measured with dye exclusion test using trypan blue.

3) The concentration of sample compounds of 50% cell growth inhibition compared with standard group was determined as IC.sub.50. The results are shown at the next table.

* Reference

1) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesh, s. Kenney and M. R. Boyd.: Proc. Am. Assoc. Cancer Res., 30, 612(198).

2) I. V. Rubinstein, R. H. Shoemaker, K. D. Paull, R. M. Simon, s. Tosini, P. Skehan, D. Scudiero, A. Monks, J. Natl. Cancer Inst., 82, 1113(1990)

3) P. Skellan, R. Strong, D. Scudiero, J. B. Mcmanhan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd.: J. Natl. Cancer Inst., 82, 1107(1990)

C. Result

As the results of measurement of antitumor activities of compounds of the present invention against L1210 and P388 mouse cancer cells, it was found that compouds of example 1), 6), 13), 16), 29), 38), 41), 47), 48), 49), 108), 118), 120), 128), 148), 149) had same or more excellent antitumor activities than those of the control drug, mytomicin C.

______________________________________EXAMPLE ED.sub.50 (.mu.g/mL)NUMBER L1210 P388______________________________________ 1 1.6 0.6 6 0.6 0.313 1.7 1.616 1.8 1.629 0.4 0.538 1.4 1.041 1.4 2.047 0.3 0.348 1.9 1.849 1.3 0.650 2.0 1.597 2.0 1.698 2.0 2.1108 0.8 0.9118 0.06 0.06119 2.2 2.0120 0.3 0.1128 0.5 0.2148 1.5 1.3149 0.9 1.6mitomycin C 1.6 1.1______________________________________

In vivo antitumor activity test was carried out in mice with samples having significance in in vitro test.

Example 3

* In Vivo Antitumor Effects Against Mouse Leukemia P388 Cells.

A. Material of Experiment

BDFI mice were used.

B. Method of Experiment

1) Leukemia P388 cells being transfer-cultured succesively in DBA/2 mouse, were grafted i.p. into each mouse of a group comprising 8 mice of 6 week old BDFI mouse as the dose of 1.times.10.sup.6 cells/0.1 ml.

2) Sample drugs were dissolved in PBS or suspended in 0.5% Tween 80, and then injected into abdominal cavity of mouse at each prescribed concentration on days 1, 5, 9, respectively.

3) With observation every day, survival times of tested mice were measured. Antitumor activities was determined in such a manner that the increasing ratio(T/C %) of average survival days of drug-treated groups compared with the control group was calculated using the mean survival times of each tested groups.

The results are shown at the next table.

* Reference

A. Goldin, J. M. Venditti, J. S. Macdonald, F. M. Muggia, J. E. Henney and V. T. DeVita.: Euro. J. S. Macdonald, F. M. Muggia, J. E. Henney and V. T. DeVita: Euro. J. Cancer, 17, 129 (1981).

* Experimental Conditions for Mouse P388 Animal: BDFI mouse (8 mice/group) Tumor: mouse P388 Inoculum size: 10.sup.6 cells/mouse Inoculum site: i. p. Treatment site: i. p. Treatment time: days 1, 5, 9 Parameter: median survival time Criteria: T/C % C. Result

Through in vivo experiment using P388 mouse cancer cells, significant antitumor effect of the compounds of example 1), 6), 16), 29) were observed.

______________________________________Example No. Dose (mg/kg) T/C (%) etc.______________________________________ 1 100 134.6 50 109.1 6 100 183.3 50 133.316 100 131.8 50 113.629 100 190.9 50 136.4______________________________________

Example 4)

* In Vivo Antitumor Activities Against Mouse Solid Tumor, 1316 Melanoma.

A. Material of Experiment.

BDF1 mouse was used in experiment while being successively transfer cultured in C57BL/6 mice by s.c.

B. Methods

1) After 1 g of tumor was added into cold balanced salt solution up to be 10 ml, it was homogenized (10:1,brei).

2) 0.5 ml Brei of the above 1) were grafted into each BDFI mouse by i.p.

3) Median survival time was measured, and the activity was determined in such a manner that if T/C was over 125%, it presented moderate activity, while if it is over 150%, it had significant activity.

The results are shown at the next table.

*Reference

A. Goldin, J. M. Venditti, J. S. Macdonald, F. M. Muggia, J. E. Henney and V. T. DeVita, Euro. J. Cancer, 17, 129(1981).

* Experimental Conditions for Mouse B16 Melanoma. Animal: BDFI mouse (8 mice/group) Inoculum size: 10.sup.5 cells/mouse Inoculum site: i. p. Treatment site: i. p. Treatment time: days 1, 5, 9 Parameter: median survival time Criteria: T/C % C. Results

With in vivo experiment using B16 mouse melanoma solid tumor, it was observed that the compounds of examples 6), 16) etc. have the significant antitumor activities.

______________________________________Example No. Dose T/C (%) Etc.______________________________________ 6 200 139.4 100 124.2 50 127.316 200 118.2 100 127.3 50 115.2______________________________________

Example 5)

* Acute Toxicity Test (LD.sub.50)

Litchfield-Wilcoxon Method.

6 week old ICR mice(male 30.+-.2.0 g) was fed freely with solid feed and water at room temperature, 23.+-.1.degree. C. and at humidity 60.+-.5%. Sample drugs were injected into the abdominal cavities of mice, while each goup comprises 6 mice.

Observed during 14 days, external appearances and life or dead were recorded, and then, visible pathogenies were observed from dead animals by dissection. LD.sub.50 value was calculated by Litchfiled-wilcoxon method.

The results are shown at the next table.

______________________________________ LD.sub.50 (mg/ml)Example No. i.p. p.o.______________________________________ 6 248.5 >622 28 >1,800 >2,000 61 >1,687 97 1,100 98 >1,800 >2,000108 >2,000 >3,110109 2,000 >2,073118 182.8 571.8148 425.3149 410.5cisplatin 21.4______________________________________ As described above, it was found that the compouds of the present invention are more safer and have superior antitumor activities to cisplatin, and accordingly have solved the problems of drugs by the prior art such as restriction of dosage, toxicity, etc.

Examples of Pharmaceutical Preparations

Tablets: (Examples 1-4)

Tablet(250 mg) was prepared with the ingredients of the following table by conventional tablet manufacturing method.

______________________________________Examples ingredients (mg)______________________________________1 compound of example 1 20 lactose 120 microcrystalline cellulose 30 corn starch 40 povidone 30 sodium starch glycolate 8 magnesium stereate 22 compound of example 148 20 lactose 110 microcrystalline cellulose 40 corn starch 45 povidone 25 sodium starch glycolate 8 magnesium stearate 23 compound of example 16 20 lactose 120 microcrystalline cellulose 35 corn starch 35 povidone 30 sodium starch glycolate 8 magnesium stearate 24 compound of example 149 20 lactose 100 microcrystalline cellulose 45 corn starch 50 povidone 25 sodium starch glycolate 8 magnesium stearate 2______________________________________ Capsules(Example 5-8)

Capsule(250 mg) was prepared with the ingredients of the following table by conventional capsule manufacturing method.

______________________________________Examples ingredients (mg)______________________________________5 compound of example 1 10 lactose 100 corn starch 100 povidone 30 sodium starch glycolate 7 magnesium stearate 36 compound of example 148 10 lactose 105 corn starch 100 povidone 25 sodium starch glycolate 7 magnesium stearate 37 compound of example 16 10 lactose 90 corn starch 110 povidone 30 sodium starch glycolate 7 magnesium stearate 38 compound of example 149 10 lactose 95 corn starch 110 povidone 25 sodium starch glycolate 7 magnesium stearate 3______________________________________ Injectable Preparations (Examples 9-16)

Injectable preparations(5 ml of ampoule and vial) were prepared with the ingredients of the following tables by the conventional injection manufacturing method.

______________________________________Examples (ampoule) ingredients______________________________________ 9 compound of example 1 30 mg polyoxy 35 castor oil 4000 mg absolute ethanol 1.17 ml distilled water for inj. q.s.10 compound of example 148 30 mg polyoxy 35 castor oil 3200 mg absolute ethanol 1.97 ml distilled water for inj. q.s.11 compound of example 16 30 mg polyoxy 35 castor oil 3500 mg absolute ethanol 1.68 ml distilled water for inj. q.s.12 compound of example 149 30 mg polyoxy 35 castor oil 3000 mg absolute ethanol 2.16 ml distilled water for inj. q.s.Example 13 (vial) compound of example 1 30 mg polyoxy 35 castor oil 4000 mg absolute ethanol 1.17 ml distilled water for inj. q.s.14 compound of example 148 30 mg polyoxy 35 castor oil 3200 mg absolute ethanol 1.97 ml distilled water for inj. q.s.15 compound of example 16 30 mg polyoxy 35 castor oil 3500 mg absolute ethanol 168 ml distilled water for inj. q.s.16 compound of example 149 30 mg polyoxy 35 castor oil 3000 mg absolute ethanol 2.16 ml distilled water for inj. q.s.______________________________________ Ointment(Examples 17-20)

Ointment(1 g) was prepared with the ingredients of the following table by the conventional ointment manufacturing method.

______________________________________Examples ingredients (mg)______________________________________17 compound of example 1 6 polyoxy 40 hydrogenated castor oil 350 absolute ethanol 100 sodium p-oxybenzoate 1.5 NaH.sub.2 PO.sub.4 1.06 citric acid 1.48 propyleneglycol 200 glycerine 150 cetostearyl alcohol 50 cetiol H. E. 130 purified water q.s.18 compound of example 148 6 polyoxy 40 hydrogenated castor oil 300 absolute ethanol 100 sodium p-oxybenzoate 1.5 NaH.sub.2 PO.sub.4 1.06 citric acid 1.48 propyleneglycol 200 glycerine 150 cetostearyl alcohol 50 cetiol H. E. 145 purified water q.s.19 compound of example 16 6 polyoxy 40 hydrogenated castor oil 350 absolute ethanol 150 sodium p-oxybenzoate 1.5 NaH.sub.2 PO.sub.4 1.06 citric acid 1.48 propyleneglycol 150 glycerine 150 cetostearyl alcohol 100 cetiol H. E. 135 purified water q.s.20 compound of example 149 6 polyoxy 40 hydrogenated castor oil 300 absolute ethanol 100 sodium p-oxybenzoate 1.5 NaH.sub.2 PO.sub.4 1.06 citric acid 1.48 propyleneglycol 200 glycerine 100 cetostearyl alcohol 100 cetiol H. E. 147 purified water q.s.______________________________________ Suppository(Examples 21-24)

Suppository(1 g) was prepared with the ingredients of the following table by conventional suppository manufacturing method.

______________________________________Example ingredients (mg)______________________________________21 compound of example 1 6 polyoxy 35 castor oil 250 glycerine 80 propyleneglycol 50 stearyl alcohol 50 stearic acid 50 Witepsol .RTM. 364 glycerylmonostearate 15022 compound of example 148 6 polyoxy 35 castor oil 230 glycerine 80 propyleneglycol 70 stearyl alcohol 50 stearic acid 50 Witepsol .RTM. 414 glycerylmonostearate 10023 compound of example 16 6 polyoxy 35 castor oil 245 glycerine 80 propyleneglycol 65 stearyl alcohol 70 stearic acid 60 Witepsol .RTM. 394 glycerylmonostearate 8024 compound of example 149 6 polyoxy 35 castor oil 225 glycerine 70 propyleneglycol 60 stearyl alcohol 55 stearic acid 50 Witepsol .RTM. 459 glycerylmonostearate 75______________________________________ Oral solution(example 25o28)

Oral solution(100 ml) was prepared with the ingredients of the following tables by the conventional oral solution manufacturing method.

______________________________________Example ingredients______________________________________25 compound of example 1 30 mg polyoxy 40 hydrogenated castor oil 30 g absolute ethanol 2 ml propyleneglycol 15 g polyethyleneglycol 400 10 g Tween 80 5 g methy p-oxybenzoate 0.1 g punfied sugar 12 g herb perfume 0.1 mg purified water q.s.26 compound of example 148 30 mg polyoxy 35 castor oil 30 g absolute ethanol 2 ml propyleneglycol 12 g polyethyleneglycol 15 g Tween 80 10 g methyl p-oxybenzoate 0.1 g purified sugar 12 g herb perfume 0.1 ml purified water q.s.27 compound of example 16 30 mg polyoxy 35 castor oil 25 g absolute ethanol 2 ml propyleneglycol 20 g polyethyleneglycol 400 15 g Tween 80 7 g methyl p-oxybenzoate 0.1 g purified sugar 15 g herb perfume 0.15 ml purified water q.s.28 compound of example 149 30 mg polyoxy 35 castor oil 30 g absolute ethanol 2 ml propyleneglycol 17 g polyethyleneglycol 400 12 g Tween 80 10 g methyl p-oxybenzoate 0.1 g purified sugar 13 g herb perfume 0.15 ml purified water q.s.______________________________________ Troche(Examples 29-32)

Troche(500 mg) was prepared with the ingredients of the following table by conventional troche manufacturing method.

______________________________________Example ingredients (mg)______________________________________29 compound of example 1 20 mannitol 300 sugar 100 corn starch 40 povidone 30 sodium starch glycoate 8 magnesium stearate 230 compound of example 148 20 mannitol 280 sugar 120 corn starch 45 povidone 25 sodium starch glycolate 8 magnesium stearate 231 compound of example 16 20 mannitol 320 sugar 100 corn starch 20 povidone 30 sodium starch glycolate 8 magnesium stearate 232 compound of example 149 20 mannitol 300 sugar 110 corn starch 50 povidone 10 sodium starch glycolate 8 magnesium stearate 2______________________________________

Claims

1. A compound of the general formula (I) ##STR10## wherein R.sub.1 and R.sub.2 are independently selected from the group consisting of hydrogen, and C.sub.1 -C.sub.8 alkyl;

R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, --OCOC.sub.1 -C.sub.4 lower alkyl, C.sub.1 -C.sub.4 lower alkyl, C.sub.1 -C.sub.4 lower alkoxy, phenyl, and --NR.sup.x R.sup.y, wherein R.sup.x and R.sup.y are independently selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 lower alkyl, C.sub.2 -C.sub.4 unsaturated lower alkyl, phenyl and benzyl;

l is an integer of 0, 1, 2, 3, 4, 5, 6 or 7;

m and n are independently an integer of 0 or 1;

W is carbon or nitrogen;

X is selected from the group consisting of oxygen and sulfur;

Y is NH or oxygen; and

Z is selected from the group consisting of C.sub.1 -C.sub.8 alkoxy, phenoxy , C.sub.1 -C.sub.4 alkylamine and oxo group, provided that when Z is an oxo group the compound is of the general formula (I') ##STR11## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, l, m, n, W, X and Y are as defined above; or

a pharmaceutically acceptable acid addition salt thereof.

2. The compound according to claim 1, which is a compound of the formula (I'): ##STR12## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, l, m, n, W, X and Y are as defined above.

3. The compound according to claim 1, wherein W is carbon.

4. The compound according to claim 1, wherein W is nitrogen.

5. A pharmaceutical composition, comprising:

an pharmaceutically effective amount of the compound as set forth in claims 1 or 2; and

one or more conventional adjuvents.

6. The pharmaceutical composition according to claim 5, wherein said conventional adjuvent is selected from the group consisting of conventional vehicles, binding agent, degrading agent, lubricating agent, dissolving agent, aids for dissolution, stabilizing agent, base of ointment, pH-adjusting agent and perfume.