US 5,780,472 AGrant
Piperazine Derivatives and Methods for the Preparation Thereof and Compositions Containing the Same
Issue Date:1998-07-14
•6 Claims
Abstract
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. 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.
Metadata
Assignee
- Samjin Pharmaceuticazl Co., Ltd.
Inventors
- Eui-Hwan Cho
- Sun-Gan Chung
- Joong-Ypoung Kim
- Sun-Hwan Lee
- Ho-Seok Kwon
- Byung-Chul Kim
- Jae-Myeong Kong
- Jea-Eung Lee
- Dong-Wook Kang
Application Information
Application Number:US 6761747
Filing Date:1996-07-15
Priority Date:1995-01-11
Art Unit:161
Classifications
IPC:
A61K 31495C07D40112C07D40114
Field of Search:
544514360;364252
Patent Drawings
This patent does not have any drawings.
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.
Example 1
1-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-methoxypheny l)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-methoxypheny l)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-dimethoxyp henyl)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-dimethoxyp henyl)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-dimethoxyp henyl)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-trimetho xyphenyl)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-phenoxypheny l)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-fluoropheny l)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-difluorop henyl)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-dichloroph enyl)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-dichloroph enyl)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-dichloroph enyl)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-trichlor ophenyl)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-dibromophe nyl)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-dibromophe nyl)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)pipera zine
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-dimethylph enyl)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-dimethylphe nyl)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-dimethylph enyl)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-isopropylphe nyl)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-isopropylphe nyl)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-normalbutylp henyl)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)pip erazine
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)pip erazine
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-hydroxypheny l)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-hydroxypheny l)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-hydroxypheny l)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-acetoxypheny l)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-acetoxypheny l)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)pip erazine
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)pipe razine
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-me thylphenyl)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-me thylphenyl)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-me thylphenyl)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-met hioxyphenyl)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-met hoxyphenyl)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-met hoxyphenyl)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-me thoxyphenyl)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-me thoxyphenyl)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-p henyl)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-me thylphenyl)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-me thylphenyl)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-met hylphenyl)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-met hylphenyl)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-flu orophenyl)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-methoxypheny l)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-fluoro phenyl)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-chloro phenyl)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-fluoro phenyl)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-met hoxyphenyl)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-me thoxyphenyl)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-m ethoxyphenyl)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-m ethoxyphenyl)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-methoxy phenyl)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-meth oxyphenyl)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-chlor ophenyl)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-fluor ophenyl)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-methoxbenzy l)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-benzylpiperaz ine
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-methoxybenzy l)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-methoxypheny l)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-acetoxypheny l)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)pipe razine
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-dimethoxyp henyl)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-dichloroph enyl)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-me thoxyphenyl)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-hydroxypheny l)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-methoxyp henyl)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-dimeth oxyphenyl)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)piperazi ne
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)pipe razine
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-chlor ophenyl)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-methoxyp henyl)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-chloroph enyl)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-fluoroph enyl)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-dimeth oxyphenyl)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-dichlo rophenyl)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)p iperzine:
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-dimethoxyphe nyl)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-methoxyp henyl)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-chloroph enyl-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)pipe razine
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)pip erazine
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)pipera zine
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-hydroxypheny l)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)pi perazine
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-metho xyphenyl)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-dimethoxypheny l)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)piperazi ne
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)piperazi ne
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)piperazi ne
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-methyl phenyl)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-methox yphenyl)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)piperazi ne
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)piperazi ne
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-dimethoxyp henyl)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-methoxyphe nyl)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-chlorophen yl)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-fluorophen yl)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-methox yphenyl)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-chloro phenyl)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-fluoro phenyl)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-methoxyp henyl)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-chloroph enyl)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-fluoroph enyl)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-propargylam ino)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-propa rgylamino)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-propar gylamino)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-dibenz ylamino)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-et hylamino)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-methoxyphen yl)piperazine-2-yl!piperazine salt of hydrochloride:
After 1-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl!-4-(2-methoxyphen yl)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%
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.
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.
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 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 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.
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.
Capsules(Example 5-8)
Capsule(250 mg) was prepared with the ingredients of the following table by conventional capsule manufacturing method.
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.
Ointment(Examples 17-20)
Ointment(1 g) was prepared with the ingredients of the following table by the conventional ointment manufacturing method.
Suppository(Examples 21-24)
Suppository(1 g) was prepared with the ingredients of the following table by conventional suppository manufacturing method.
Oral solution(example 25o28)
Oral solution(100 ml) was prepared with the ingredients of the following tables by the conventional oral solution manufacturing method.
Troche(Examples 29-32)
Troche(500 mg) was prepared with the ingredients of the following table by conventional troche manufacturing method.
Claims
What is claimed is:
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 claim 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.
Patent Citations (1)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| JPX2-142770 | 1990-05-01 |
Non-Patent Literature (3)
- Courant et al, Eur. J. Med. Chem. 28 pp. 821-824, 1993.
- Kanoto, Chemical Abstracts, vol. 113, No. 172058 (1990) (Abstract of JP 02/42,770 May 31, 1990).
- Ried et al, Liebigs Ann. Chem. pp. 693-698 (1980).