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    • 专利摘要:
    The present invention provides a compound represented by the following general structural formula (I) having excellent anticancer activity and low toxicity, and a method for producing the same. (I) Wherein R 1 and R 2 are hydrogen atoms, C 1 -C 8 alkyl groups, C 1 -C 4 lower ester groups, C 1 -C 4 lower alkylhydroxy groups, ketone groups, substituted or unsubstituted carboxyl groups, Or R 1 and R 2 together form an unsaturated ring having 4 carbon atoms, and R 3 , R 4 , R 5 , R 6 and R 7 each represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, C 1 the lower ~C 4 lower alkyl group, C 1 ~C 4 lower ester group, a C 1 ~C 4 alkoxy group, a lower alkoxy group of C 1 ~C 4 and Y is an amine group, a substituted amine group, C 1 lower alkyl thio of ~C 4, Z is a hydrogen atom, a hydroxyl group, a lower alkoxy group or a C 1 ~C 4 lower alkyl group of C 1, C 1 ~C 4 lower alkyl amine group of, C 1 ~C 4 of ~ C 4 is a lower thioalkoxy group.
    公开号:KR20000061873A
    申请号:KR1019990011254
    申请日:1999-03-31
    公开日:2000-10-25
    发明作者:조의환；정순간；이순환；권호석；강동욱；이영희
    申请人:최승주；삼진제약 주식회사；
    IPC主号:
    专利说明:

    Piperazine derivatives and method for preparing the same
    The present invention relates to a novel piperazine derivative represented by the following general structural formula (I) and a preparation method thereof.

    (I)
    Wherein R 1 and R 2 are hydrogen atoms, C 1 -C 8 alkyl groups, C 1 -C 4 lower ester groups, C 1 -C 4 lower alkylhydroxy groups, ketone groups, substituted or unsubstituted carboxyl groups, Or R 1 and R 2 together form an unsaturated ring having 4 carbon atoms, and R 3 , R 4 , R 5 , R 6 and R 7 each represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, C 1 the lower ~C 4 lower alkyl group, C 1 ~C 4 lower ester group, a C 1 ~C 4 alkoxy group, a lower alkoxy group of C 1 ~C 4 and Y is an amine group, a substituted amine group, C 1 lower alkyl thio of ~C 4, Z is a hydrogen atom, a hydroxyl group, a lower alkoxy group or a C 1 ~C 4 lower alkyl group of C 1, C 1 ~C 4 lower alkyl amine group of, C 1 ~C 4 of ~ C 4 is a lower thioalkoxy group.
    C 1 ~C 4 lower alkyl group is methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, means a t- butyl.
    The lower ester group of C 1 to C 4 means a group in which the carboxyl group is esterified by a lower alkyl group.
    C 1 -C 4 lower alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and t-butoxy groups.
    The lower thioalkoxy group of C 1 to C 4 refers to methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, t-butylthio group.
    Group refers to a lower alkyl amine of the C 1 ~C 4 means group methylamine, ethylamine, propylamine, butylamine.
    The lower alkyl hydroxy group of C 1 to C 4 refers to methyl hydroxy, ethyl hydroxy, propyl hydroxy or butyl hydroxy group.
    Refers to a substituted amine group refers to a hydroxy amine, a lower alkyl amine of the C 1 ~C 4.
    The present inventors have long studied the compound which has anticancer activity. As a result, the present inventors have found the surprising fact that the compound of the general formula (I), its acid addition salts have an excellent anticancer effect, and extremely low toxicity, and completed the present invention.
    It is therefore an object of the present invention to provide compounds of general formula (I) and acid addition salts thereof having excellent anticancer effects and low toxicity.
    Another object of the present invention is to provide a method of preparing a compound of the general formula (I) and an acid addition salt thereof.
    The compounds of the present invention can be used for the prevention and treatment of various types of tumors by preparing pharmaceutical preparations according to the methods of preparing pharmaceutical preparations commonly used in combination with pharmaceutically acceptable excipients and the like.
    It is therefore another object of the present invention to provide a pharmaceutical formulation containing the compound of the general formula (I) as an active ingredient.
    Acids capable of reacting with compound (I) of the present invention to form acid addition salts are pharmaceutically acceptable inorganic or organic acids, and include inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; Organic acids such as formic acid, acetic acid, propionic acid, succinic acid, citric acid, maleic acid, malonic acid and the like; Amino acids such as serine, cysteine, cystine, asparagine, glutamine, lysine, arginine, leucine, proline and the like; Sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like can be used.
    Excipients that can be used as excipients in the preparation of pharmaceutical preparations containing the compound of general formula (I) as an active ingredient in the present invention include sweeteners, binders, solubilizers, dissolution aids, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants. , Antioxidants, preservatives, lubricants, fillers, fragrances and the like can be used, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, tragacanth Rubber, methyl cellulose, sodium carboxymethyl cellulose, agar, alginate, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, potassium chloride, orange essence, strawberry essence, vanilla flavor, and the like. .
    The normal dose of the compound of the general formula (I) of the present invention may vary depending on the age, sex, degree of disease, etc. of the patient, but may be administered once to several times daily from 1 mg to 5000 mg.
    Compounds of the general formula (I) of the present invention may be prepared by the following scheme (I).
    Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 , X, Y, Z are as described above and R 'is a lower alkyl group such as methyl, ethyl.
    A general structural formula (I ') is effectively prepared by reacting an alkylating agent under a base with a general formula (II) compound synthesized by a known method. And a general structural formula (I) is prepared by reacting a substituted or unsubstituted amino group under a base.
    When the compound of the general formula (II) is prepared by reacting an alkylating agent under a base to prepare the general formula (I '), the reaction is performed at 3 ° C. to the boiling point temperature of the solvent, preferably at 50 ° C. to 100 ° C. for 5 hours. Reaction for 24 hours. The amount of alkylating agent used is from 1 to 1.5 equivalents.
    This reaction is preferably using a conventional organic solvent such as tetrahydrofuran, dichloromethane, acetonitrile, chloroform, dimethylformamide and the like.
    As a normal base of this reaction, it is preferable to use sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like.
    As the alkylating agent for this reaction, C 1 to C 4 lower alkylhalogens, C 3 to C 8 substituted or unsubstituted cycloalkylating agents, and the like are used.
    C 1 refers to a lower alkyl, halogen is chloride, methane bromide, methane iodide, methane chloride, ethane ~C 4, ethane bromide, iodide, ethane, propane, chloride, bromide, propane, propane iodide, chloride, butane, butane bromide, iodide, butane and the like.
    A substituted or unsubstituted C 3 ~C 8 cycloalkyl, halogen is chloride, cyclopropane, cyclopropane bromide, iodide, cyclopropane, cyclobutane chloride, bromide, cyclobutane, iodide, cyclobutane, cyclopentane, chloride, bromide, cyclopentane, cyclopentane iodide, Cyclohexane chloride, cyclohexane bromide, cyclohexane iodide and the like.
    Compounds of the general formula (I ') effectively react the substituted or unsubstituted amino groups with a base to prepare general formula (I).
    This reaction is preferably using a conventional organic solvent such as tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, dimethyl sulfoxide and the like.
    Common bases for this reaction are preferably sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium hydrogen carbonate, triethylamine, pyridine, DBU and the like.
    In the reactions in which acidic substances are by-produced during the reaction, it is preferable to add a basic substance and then react to remove these substances from the reaction system. Such basic materials include alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, potassium carbonate, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium bicarbonate, potassium bicarbonate, and the like. It is preferred to react in the presence of hydroxides, oxides, carbonates or bicarbonates, and bases of the organic amine family.
    Compounds of the general formula (II) are known compounds, USP. 5,780,472 PCT / KR97 / 00128 or the like or may be prepared and used in a similar manner.
    Example
    The following compounds were prepared according to the method described above.
    (I)
    Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and X, Y, Z are as described above.
    ExampleR 1 R 2 R 3 R 4 R 5 R 6 R 7 XYZ OneCH 3 CH 3 OCH 3 HHHHNNHOHOCH 32CH 3 CH 3 HOCH 3 HOCH 3 HNNHOHOCH 33CH 3 CH 3 HCH 3 HCH 3 HNNHOHOCH 34CH 3 CH 3 HFHFHNNHOHOCH 35CH 3 EtHOCH 3 HOCH 3 HNNHOHOCH 36CH 3 EtHCH 3 HCH 3 HNNHOHOCH 37CH 3 EtHFHFHNNHOHOCH 38CH 3 CH 3 HOCH 3 HOCH 3 HCNHOHOCH 39CH 3 CH 3 HCH 3 HCH 3 HCNHOHOCH 310CH 3 CH 3 HFHFHCNHOHOCH 311CH 3 *OneHOCH 3 HOCH 3 HNNHOHOCH 312CH 3 *OneHCH 3 HCH 3 HNNHOHOCH 313CH 3 CH 2 OHHOCH 3 HOCH 3 HNNHOHOCH 314CH 3 CH 2 OHHCH 3 HCH 3 HNNHOHOCH 315CH 3 *2HCH 3 HCH 3 HNNHOHOCH 3
    ExampleR 1 R 2 R 3 R 4 R 5 R 6 R 7 XYZ 16CH 3 * 3HCH 3 HCH 3 HNNHOHOCH 317CH 2 = CH-CH-CH 2 HOCH 3 HOCH 3 HNNHOHOCH 318CH 2 = CH-CH-CH 2 HCH 3 HCH 3 HNNHOHOCH 319CH 2 = CH-CH-CH 2 HFHFHNNHOHOCH 320CH 3 CH 3 OCH 3 HHHHNSCH 3 OCH 321CH 3 CH 3 HOCH 3 HOCH 3 HNSCH 3 OCH 322CH 3 CH 3 HCH 3 HCH 3 HNSCH 3 OCH 323CH 3 CH 3 HFHFHNSCH 3 OCH 324CH 3 EtHOCH 3 HOCH 3 HNSCH 3 OCH 325CH 3 EtHCH 3 HCH 3 HNSCH 3 OCH 326CH 3 EtHFHFHNSCH 3 OCH 327CH 3 CH 3 HOCH 3 HOCH 3 HCSCH 3 OCH 328CH 3 CH 3 HCH 3 HCH 3 HCSCH 3 OCH 329CH 3 CH 3 HFHFHCSCH 3 OCH 330CH 3 *OneHOCH 3 HOCH 3 HNSCH 3 OCH 331CH 3 *OneHCH 3 HCH 3 HNSCH 3 OCH 332CH 3 CH 2 OHHOCH 3 HOCH 3 HNSCH 3 OCH 333CH 3 CH 2 OHHCH 3 HCH 3 HNSCH 3 OCH 334CH 3 *2HCH 3 HCH 3 HNSCH 3 OCH 335CH 3 * 3HCH 3 HCH 3 HNSCH 3 OCH 3
    ExampleR 1 R 2 R 3 R 4 R 5 R 6 R 7 XYZ 36CH 2 = CH-CH-CH 2 HOCH 3 HOCH 3 HNSCH 3 OCH 337CH 2 = CH-CH-CH 2 HCH 3 HCH 3 HNSCH 3 OCH 338CH 2 = CH-CH-CH 2 HFHFHNSCH 3 OCH 3
    *One : *2 : * 3:
    Example 1) N-hydroxy-N '-(5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (2-methoxyphenyl) piperazin-1-yl] carboxyimide Damide
    a) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (2-methoxyphenyl) piperazin-1-yl] iminothioate
    Dimethylformamide in 1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminothiocarbonyl] -4- (2-methoxyphenyl) piperazine (0.70 grams, 1.81 mmol) (20 milliliters) is added to dissolve, sodium hydride (60%, 94 milligrams, 2.35 mmol) and methyl iodide (0.33 grams, 2.35 mmol). The reaction is stirred for 2 hours, water (20 milliliters) is added to stop the reaction, and then extracted with ethyl ether. The organic layer was concentrated under reduced pressure to remove the solvent, and then separated and purified by tube chromatography to obtain the compound.
    Yield: 94.5%
    Melting Point: 77-79 ℃
    1 H NMR (CDCl 3 ): δ 2.10 (3H, s), 2.15 (3H, s), 2.35 (3H, s), 3.11 (4H, t), 3.71-3.89 (10H, m), 6.83-6.95 ( 5H, m)
    b) N-hydroxy-N ′-(5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (2-methoxyphenyl) piperazin-1-yl] carboxyimidamide
    Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (2-methoxyphenyl) piperazin-1-yl] iminothioate (0.68 grams, 1.70 mmol) Chloroform (20 milliliters) was added to dissolve it, and hydroxylamine hydrochloride (0.31 grams, 4.49 mmol) and triethylamine (0.52 grams, 5.10 mmol) were added. The reaction is stirred for 15 hours, water (30 milliliters) is added to stop the reaction, and then extracted with methylene chloride. The organic layer was concentrated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the compound.
    Yield: 64.5%
    Melting Point: 144 ~ 146 ℃
    1 H NMR (CDCl 3 ): δ 2.16 (3H, s), 2.33 (3H, s), 3.08 (4H, t), 3.25 (4H, t), 3.85 (3H, s), 3.98 (3H, s) , 6.87 (1H, d), 6.93 (2H, d), 7.02 (1H, m), 7.57 (1H, s)
    Example 2) N-hydroxy-N '-(5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl ] Carboxyimidamide
    Example 1 Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl] iminothioate Reaction was carried out in the same manner as to obtain the compound.
    Yield: 62.0%
    Melting Point: 188 ~ 190 ℃
    1 H NMR (CDCl 3 ): δ 2.14 (3H, s), 2.33 (3H, s), 3.17 (8H, d), 3.77 (6H, s), 3.98 (3H, s), 6.04 (1H, s) , 6.08 (2H, d), 7.54 (1H, s)
    Example 3) N-hydroxy-N '-(5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] carboxy Imidamide
    Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] iminothioate was prepared in the same manner as in Example 1. Reaction was carried out to obtain the above compound.
    Yield: 64.3%
    Melting Point: 120 ~ 122 ℃
    1 H NMR (CDCl 3 ): δ 2.14 (3H, s), 2.28 (6H, s), 2.33 (3H, s), 3.18 (8H, d), 3.98 (3H, s), 6.56 (3H, m) , 7.55 (1H, s)
    Example 4) N-hydroxy-N '-(5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (3,5-difluorophenyl) piperazin-1-yl ] Carboxyimidamide
    Example 1 Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (3,5-difluorophenyl) piperazin-1-yl] iminothioate Reaction was carried out in the same manner as to obtain the compound.
    Yield: 35.0%
    Melting Point: 175 ~ 177 ℃
    1 H NMR (CDCl 3 ): δ 2.15 (3H, s), 2.34 (3H, s), 3.18 (8H, d), 3.98 (3H, s), 6.28 (1H, t), 6.36 (2H, d) , 7.50 (1H, s)
    Example 5) N-hydroxy-N '-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazine-1- General] carboxyimidamide
    Example of methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl] iminothioate Reaction was carried out in the same manner as in 1 to obtain the compound.
    Yield: 65.4%
    Melting Point: 151 ~ 153 ℃
    1 H NMR (CDCl 3 ): δ 1.14 (3H, t), 2.36 (3H, s), 2.50 (2H, q), 3.18 (8H, d), 3.77 (6H, s), 3.98 (3H, s) , 6.04 (1H, s), 6.08 (2H, d), 7.56 (1H, s)
    Example 6) N-hydroxy-N '-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] Carboxylimidamid
    Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] iminothioate was prepared in accordance with Example 1 Reaction was carried out in the same manner to obtain the compound.
    Yield: 61.2%
    Melting Point: 163 ~ 165 ℃
    1 H NMR (CDCl 3 ): δ 3.14 (3H, t), 2.28 (6H, s), 2.36 (3H, s), 2.50 (2H, q), 3.17 (8H, d), 3.98 (3H, s) , 6.04 (1H, s), 6.08 (2H, d), 7.56 (1H, s)
    Example 7) N-hydroxy-N '-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-difluorophenyl) piperazine-1- General] carboxyimidamide
    Example of methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-difluorophenyl) piperazin-1-yl] iminothioate Reaction was carried out in the same manner as in 1 to obtain the compound.
    Yield: 41.5%
    Melting Point: 148 ~ 150 ℃
    1 H NMR (CDCl 3 ): δ 1.15 (3H, t), 2.37 (3H, s), 2.51 (2H, q), 3.18 (8H, s), 3.98 (3H, s), 6.28 (1H, t) , 6.36 (2H, d), 7.52 (1H, s)
    Example 8) N-hydroxy-N '-(4,5-dimethyl-2-methoxyphenyl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl] carboxyimida Maid
    Example 1 Methyl N- (4,5-dimethyl-2-methoxyphenyl-1-yl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl] iminothioate Reaction was carried out in the same manner as to obtain the compound.
    Yield: 62.7%
    Melting Point: 190 ~ 192 ℃
    1 H NMR (CDCl 3 ): δ 2.15 (3H, s), 2.20 (3H, s), 3.18 (8H, d), 3.77 (6H, s), 3.91 (3H, s), 6.03 (1H, s) , 6.08 (2H, d), 6.65 (1H, s), 7.36 (1H, s)
    Example 9) N-hydroxy-N '-(4,5-dimethyl-2-methoxyphenyl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] carboxyimidamide
    Methyl N- (4,5-dimethyl-2-methoxyphenyl-1-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] iminothioate was prepared in the same manner as in Example 1. Reaction was carried out to obtain the above compound.
    Yield: 67.4%
    Melting Point: 186 ~ 188 ℃
    1 H NMR (CDCl 3 ): δ 2.14 (3H, s), 2.20 (3H, s), 2.28 (6H, s), 3.17 (4H, t), 3.21 (4H, t), 3.85 (3H, s) , 6.54 (1H, s), 6.56 (2H, s), 6.65 (1H, s), 7.37 (1H, s)
    Example 10) N-hydroxy-N '-(4,5-dimethyl-2-methoxyphenyl)-[4- (3,5-difluorophenyl) piperazin-1-yl] carboxyimida Maid
    Example 1 Methyl N- (4,5-dimethyl-2-methoxyphenyl-1-yl)-[4- (3,5-difluorophenyl) piperazin-1-yl] iminothioate Reaction was carried out in the same manner as to obtain the compound.
    Yield: 50.5%
    Melting Point: 185 ~ 187 ℃
    1 H NMR (CDCl 3 ): δ 2.13 (3H, s), 2.21 (3H, s), 3.20 (8H, d), 3.87 (3H, s), 6.35 (1H, s), 6.38 (2H, d) , 6.67 (1H, s), 7.39 (1H, s)
    Example 11) N-hydroxy-N '-(5-methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazine -1-yl] carboxyimidamide
    Methyl N- (5-methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl] iminothioate Was reacted in the same manner as in Example 1 to obtain the compound.
    Yield: 60.7%
    Melting Point: 192 ~ 193 ℃
    1 H NMR (CDCl 3 ): δ 2.15 (3H, s), 3.22 (8H, s), 3.77 (6H, s), 3.81 (3H, s), 4.05 (3H, s), 6.04 (1H, s) , 6.07 (2H, d), 8.40 (1H, s)
    Example 12) N-hydroxy-N '-(5-methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazine-1 -Day] carboxyimidamide
    Methyl N- (5-methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] iminothioate The compound was reacted in the same manner as in Example 1.
    Yield: 58.5%
    Melting Point: 194 ~ 195 ℃
    1 H NMR (CDCl 3 ): δ 2.28 (6H, s), 2.70 (3H, s), 3.20 (8H, s), 3.80 (3H, s), 4.07 (3H, s), 6.57 (3H, m) , 8.41 (1H, s)
    Example 13) N-hydroxy-N '-(5-hydroxymethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazine- 1-yl] carboxyimidamide
    Methyl N- (5-hydroxymethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl] iminothioate The compound was obtained by reacting in the same manner as in Example 1.
    Yield: 45.8%
    Melting Point: 183 ~ 185 ℃
    1 H NMR (CDCl 3 ): δ 2.39 (3H, s), 3.17 (8H, d), 3.76 (6H, s), 4.00 (3H, s), 4.58 (2H, s), 6.05 (1H, s) , 6.07 (2H, d), 7.79 (1H, s)
    Example 14) N-hydroxy-N '-(5-hydroxymethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1- General] carboxyimidamide
    Example of methyl N- (5-hydroxymethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] iminothioate Reaction was carried out in the same manner as in 1 to obtain the compound.
    Yield: 47.3%
    Melting Point: 78 ~ 80 ℃
    1 H NMR (CDCl 3 ): δ 2.27 (6H, s), 2.40 (3H, s), 3.18 (8H, d), 4.01 (3H, s), 4.59 (2H, s), 6.54 (1H, s) , 6.56 (2H, d), 7.80 (1H, s)
    Example 15) N-hydroxy-N '-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] Carboxylimidamid
    Methyl N- (5-acetyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] iminothioate was prepared in accordance with Example 1 Reaction was carried out in the same manner to obtain the compound.
    Yield: 55.6%
    Melting Point: 174 ~ 176 ℃
    1 H NMR (CDCl 3 ): δ 2.27 (6H, s), 2.50 (3H, s), 2.65 (3H, s), 3.20 (8H, d), 4.08 (3H, s), 6.55 (2H, s) , 6.56 (1H, s), 8.20 (1H, s)
    Example 16) N-hydroxy-N '-[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) pipe Razin-1-yl] carboxyimidamide
    Methyl N- [5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] iminothio The compound was reacted in the same manner as in Example 1 to obtain the compound.
    Yield: 75.6%
    Melting Point: 89 ~ 91 ℃
    1 H NMR (CDCl 3 ): δ 1.43 (3H, d), 2.28 (6H, s), 2.40 (3H, s), 3.20 (8H, d), 4.00 (3H, s), 5.10 (1H, m) , 6.52 (1H, s), 6.54 (2H, d), 7.93 (1H, s)
    Example 17) N-hydroxy-N '-(2-methoxyquinolin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl] carboximidamide
    Methyl N- (2-methoxyquinolin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl] iminothioate was reacted in the same manner as in Example 1 to The compound was obtained.
    Yield: 55.3%
    Melting Point: 211∼212 ℃
    1 H NMR (CDCl 3 ): δ 3.25 (8H, brs), 3.76 (6H, s), 4.16 (3H, s), 6.01 (1H, s), 6.09 (2H, d), 7.32 (1H, t) , 7.43 (1H, t), 7.59 (1H, d), 7.72 (1H, d), 8.06 (1H, s)
    Example 18) N-hydroxy-N '-(2-methoxyquinolin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] carboxyimidamide
    The compound was reacted with methyl N- (2-methoxyquinolin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] iminothioate in the same manner as in Example 1. Got it.
    Yield: 61.5%
    Melting Point: 160 ~ 162 ℃
    1 H NMR (CDCl 3 ): δ 2.28 (6H, s), 3.26 (8H, d), 4.18 (3H, s), 6.57 (1H, s), 6.58 (2H, s), 7.34 (1H, t) , 7.48 (1H, t), 7.58 (1H, d), 7.79 (1H, d), 8.06 (1H, s)
    Example 19) N-hydroxy-N '-(2-methoxyquinolin-3-yl)-[4- (3,5-difluorophenyl) piperazin-1-yl] carboxyimidamide
    Methyl N- (2-methoxyquinolin-3-yl)-[4- (3,5-difluorophenyl) piperazin-1-yl] iminothioate was reacted in the same manner as in Example 1 to The compound was obtained.
    Yield: 40.9%
    Melting Point: 166 ~ 168 ℃
    1 H NMR (CDCl 3 ): δ 3.26 (8H, s), 4.19 (3H, s), 6.30 (1H, t), 6.38 (2H, d), 7.35 (1H, t), 7.49 (1H, t) , 7.59 (1H, d), 7.80 (1H, d), 8.02 (1H, s)
    Example 20) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (2-methoxyphenyl) piperazin-1-yl] iminothioate
    Dimethylformamide in 1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminothiocarbonyl] -4- (2-methoxyphenyl) piperazine (0.70 grams, 1.81 mmol) (20 milliliters) is added to dissolve, sodium hydride (60%, 94 milligrams, 2.35 mmol) and methyl iodide (0.33 grams, 2.35 mmol). The reaction is stirred for 2 hours, water (20 milliliters) is added to stop the reaction, and then extracted with ethyl ether. The organic layer was concentrated under reduced pressure to remove the solvent, and then separated and purified by tube chromatography to obtain the compound.
    Yield: 94.5%
    Melting Point: 77 ~ 79 ℃
    1 H NMR (CDCl 3 ): δ 2.10 (3H, s), 2.15 (3H, s), 2.35 (3H, s), 3.11 (4H, t), 3.71-3.89 (10H, m), 6.83-6.95 ( 5H, m)
    Example 21) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl] iminothioate
    Reaction of 1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine in the same manner as in Example 20 To obtain the compound.
    Yield: 95.2%
    Melting Point: 112 ~ 114 ℃
    1 H NMR (CDCl 3 ): δ 2.11 (3H, s), 2.16 (3H, s), 2.35 (3H, s), 3.14 (4H, t), 3.72 (4H, t), 3.75 (6H, s) , 3.87 (3H, s), 6.07 (1H, s), 6.09 (2H, s), 6.83 (1H, s)
    Example 22) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] iminothioate
    1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminothiocarbonyl] -4- (3,5-dimethylphenyl) piperazine was reacted in the same manner as in Example 20 to The compound was obtained.
    Yield: 92.8%
    Melting Point: 140 ~ 142 ℃
    1 H NMR (CDCl 3 ): δ 2.07 (3H, s), 2.27 (6H, s), 2.39 (3H, s), 2.43 (3H, s), 3.13 (4H, t), 3.72 (4H, t) , 3.89 (3H, s), 6.51 (1H, s), 6.53 (2H, s), 6.81 (1H, s)
    Example 23) Methyl N- (5,6-dimethyl-2-methoxypyridin-3-yl)-[4- (3,5-difluorophenyl) piperazin-1-yl] iminothioate
    Reaction of 1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminothiocarbonyl] -4- (3,5-difluorophenyl) piperazine in the same manner as in Example 20 To obtain the compound.
    Yield: 58.6%
    Melting Point: 120 ~ 122 ℃
    1 H NMR (CDCl 3 ): δ 2.10 (3H, s), 2.15 (3H, s), 2.36 (3H, s), 3.26 (4H, t), 3.70 (4H, t), 3.91 (3H, s) , 6.26 (3H, m), 6.83 (1H, s)
    Example 24) Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl] iminothio Rate
    1-[(5-ethyl-2-methoxy-6-methylpyridin-3-yl) aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine in the same manner as in Example 20 Reaction gave the above compound.
    Yield: 97.2%
    Melting Point: 78 ~ 79 ℃
    1 H NMR (CDCl 3 ): δ 1.16 (3H, t), 2.09 (3H, s), 2.39 (3H, s), 2.52 (2H, q), 3.24 (4H, t), 3.77 (4H, t) , 3.79 (6H, s), 3.92 (3H, s), 6.05 (1H, s), 6.12 (2H, d), 6.87 (1H, s)
    Example 25) Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] iminothioate
    1-[(5-ethyl-2-methoxy-6-methylpyridin-3-yl) aminothiocarbonyl] -4- (3,5-dimethylphenyl) piperazine was reacted in the same manner as in Example 20 The compound was obtained.
    Yield: 99.0%
    Melting Point: 93 ~ 95 ℃
    1 H NMR (CDCl 3 ): δ 1.66 (3H, t), 2.09 (3H, s), 2.29 (6H, s), 2.39 (3H, s), 2.52 (2H, q), 3.22 (4H, t) , 3.78 (4H, t), 3.93 (3H, s), 6.56 (1H, s), 6.59 (2H, s), 6.87 (1H, s)
    Example 26) Methyl N- (5-ethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-difluorophenyl) piperazin-1-yl] iminothio Rate
    1-[(5-ethyl-2-methoxy-6-methylpyridin-3-yl) aminothiocarbonyl] -4- (3,5-difluorophenyl) piperazine in the same manner as in Example 20 Reaction gave the above compound.
    Yield: 72.0%
    Melting Point: 116 ~ 118 ℃
    1 H NMR (CDCl 3 ): δ 1.16 (3H, t), 2.09 (3H, s), 2.43 (5H, m), 3.24 (4H, t), 3.71 (4H, t), 3.92 (3H, s) , 6.35 (3H, m), 6.86 (1H, s)
    Example 27) Methyl N- (4,5-dimethyl-2-methoxyphenyl-1-yl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl] iminothioate
    Reaction of 1-[(4,5-dimethyl-2-methoxyphenyl-1-yl) aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine in the same manner as in Example 20 To obtain the compound.
    Yield: 93.5%
    Melting Point: 84 ~ 86 ℃
    1 H NMR (CDCl 3 ): δ 2.12 (3H, s), 2.16 (3H, s), 2.22 (3H, s), 3.23 (4H, t), 3.74 (4H, t), 3.77 (3H, s) , 3.79 (6H, s), 6.05 (1H, s), 6.12 (2H, d), 6.59 (1H, s), 6.65 (1H, s)
    Example 28) Methyl N- (4,5-dimethyl-2-methoxyphenyl-1-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] iminothioate
    1-[(4,5-dimethyl-2-methoxyphenyl-1-yl) aminothiocarbonyl] -4- (3,5-dimethylphenyl) piperazine was reacted in the same manner as in Example 20 to The compound was obtained.
    Yield: 96.3%
    1 H NMR (CDCl 3 ): δ 2.12 (3H, s), 2.16 (3H, s), 2.22 (3H, s), 2.29 (6H, s), 3.22 (4H, t), 3.74 (4H, t) , 3.77 (3H, s), 6.56 (1H, s), 6.59 (3H, m), 6.65 (1H, s)
    Example 29) Methyl N- (4,5-dimethyl-2-methoxyphenyl-1-yl)-[4- (3,5-difluorophenyl) piperazin-1-yl] iminothioate
    Reaction of 1-[(4,5-dimethyl-2-methoxyphenyl-1-yl) aminothiocarbonyl] -4- (3,5-difluorophenyl) piperazine in the same manner as in Example 20 To obtain the compound.
    Yield: 57.8%
    Melting Point: 108 ~ 110 ℃
    1 H NMR (CDCl 3 ): δ 2.12 (3H, s), 2.17 (3H, s), 2.22 (3H, s), 3.25 (4H, t), 3.74 (4H, t), 3.77 (3H, s) , 6.28 (1H, t), 6.40 (2H, d), 6.59 (1H, s), 6.66 (1H, s)
    Example 30) Methyl N- (5-methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl] Iminothiorate
    Example 1-[(5-methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl) aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine Reaction was carried out in the same manner to obtain the compound.
    Yield: 61.7%
    Melting Point: 140 ~ 142 ℃
    1 H NMR (CDCl 3 ): δ 2.06 (3H, s), 2.25 (3H, s), 3.24 (4H, t), 3.72 (4H, t), 3.78 (6H, s), 3.82 (3H, s) , 4.04 (3H, s), 6.07 (1H, s), 6.09 (2H, s), 6.80 (1H, s)
    Example 31) Methyl N- (5-methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] imino Thiorate
    1-[(5-methoxycarbonyl-2-methoxy-6-methylpyridin-3-yl) aminothiocarbonyl] -4- (3,5-dimethylphenyl) piperazine in the same manner as in Example 20 Reaction to obtain the compound.
    Yield: 94.5%
    Melting Point: 123 ~ 125 ℃
    1 H NMR (CDCl 3 ): δ 2.07 (3H, s), 2.20 (3H, s), 2.29 (6H, s), 3.25 (4H, t), 3.70 (4H, t), 3.99 (3H, s) , 6.51 (1H, s), 6.53 (2H, d), 6.78 (1H, s)
    Example 32) Methyl N- (5-hydroxymethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl] already Nothiorate
    1-[(5-hydroxymethyl-2-methoxy-6-methylpyridin-3-yl) aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine was the same as in Example 20 Reaction was carried out to obtain the above compound.
    Yield: 92.0%
    Melting Point: 162 ~ 164 ℃
    1 H NMR (CDCl 3 ): δ 2.06 (3H, s), 2.21 (3H, s), 3.23 (4H, t), 3.71 (4H, t), 3.92 (3H, s), 4.56 (2H, s) , 6.06 (1H, s), 6.08 (2H, s), 6.81 (1H, s)
    Example 33) Methyl N- (5-hydroxymethyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] iminothio Rate
    1-[(5-hydroxymethyl-2-methoxy-6-methylpyridin-3-yl) aminothiocarbonyl] -4- (3,5-dimethylphenyl) piperazine in the same manner as in Example 20 Reaction gave the above compound.
    Yield: 91.7%
    Melting Point: 114 ~ 116 ℃
    1 H NMR (CDCl 3 ): δ 2.07 (3H, s), 2.20 (3H, s), 2.29 (6H, s), 3.20 (4H, t), 3.75 (4H, t), 3.90 (3H, s) , 4.60 (2H, s), 6.50 (1H, s), 6.52 (2H, s), 6.79 (1H, s)
    Example 34) Methyl N- (5-acetyl-2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] iminothioate
    1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) aminothiocarbonyl] -4- (3,5-dimethylphenyl) piperazine was reacted in the same manner as in Example 20 The compound was obtained.
    Yield: 89.5%
    Melting Point: 125 ~ 127 ℃
    1 H NMR (CDCl 3 ): δ 2.06 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 2.28 (6H, s), 3.21 (4H, t), 3.76 (4H, t) , 3.95 (3H, s), 6.53 (1H, s), 6.55 (2H, d), 6.82 (1H, s)
    Example 35) Methyl N- [5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl Iminothiorate
    Example 20 Example 1-{[5- (1-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl] aminothiocarbonyl} -4- (3,5-dimethylphenyl) piperazine Reaction was carried out in the same manner as to obtain the compound.
    Yield: 86.0%
    Melting Point: 161∼163 ℃
    1 H NMR (CDCl 3 ): δ 1.42 (3H, d), 2.27 (6H, s), 2.41 (3H, s), 3.22 (4H, t), 3.65 (4H, t), 3.97 (3H, s) , 5.15 (1H, m), 6.50 (1H, s), 6.51 (2H, d), 6.78 (1H, s)
    Example 36) Methyl N- (2-methoxyquinolin-3-yl)-[4- (3,5-dimethoxyphenyl) piperazin-1-yl] iminothioate
    1-[(2-methoxyquinolin-3-yl) aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine was reacted in the same manner as in Example 20 to obtain the compound.
    Yield: 90.1%
    Melting Point: 164 ~ 165 ℃
    1 H NMR (CDCl 3 ): δ 2.07 (3H, s), 3.27 (4H, t), 3.79 (6H, s), 3.86 (4H, t), 4.10 (3H, s), 6.07 (1H, s) , 6.12 (2H, d), 7.33 (1H, t), 7.36 (1H, s), 7.48 (1H, t), 7.62 (1H, d), 7.81 (1H, d)
    Example 37) Methyl N- (2-methoxyquinolin-3-yl)-[4- (3,5-dimethylphenyl) piperazin-1-yl] iminothioate
    1-[(2-methoxyquinolin-3-yl) aminothiocarbonyl] -4- (3,5-dimethylphenyl) piperazine was reacted in the same manner as in Example 20 to obtain the compound.
    Yield: 95.2%
    Melting Point: 113 ~ 115 ℃
    1 H NMR (CDCl 3 ): δ 2.07 (3H, s), 2.30 (6H, s), 3.25 (4H, t), 3.86 (4H, t), 4.11 (3H, s), 6.58 (1H, s) , 6.60 (2H, s), 7.32 (1H, t), 7.36 (1H, s), 7.48 (1H, t), 7.62 (1H, d), 7.81 (1H, d)
    Example 38) Methyl N- (2-methoxyquinolin-3-yl)-[4- (3,5-difluorophenyl) piperazin-1-yl] iminothioate
    The compound was obtained by reacting 1-[(2-methoxyquinolin-3-yl) aminothiocarbonyl] -4- (3,5-difluorophenyl) piperazine in the same manner as in Example 20.
    Yield: 93.4%
    Melting Point: 131 ~ 133 ℃
    1 H NMR (CDCl 3 ): δ 2.07 (3H, s), 3.24 (4H, t), 3.85 (4H, t), 4.10 (3H, s), 6.32 (1H, s), 6.34 (2H, d) , 7.33 (1H, t), 7.35 (1H, s), 7.47 (1H, t), 7.61 (1H, d), 7.82 (1H, d)
    The anticancer pharmacological activity of the compounds of the present invention prepared as described above was tested. The anticancer activity of the compounds of the present invention was tested using five human tumor cell lines and two leukemia tumor cell lines by in vitro methods. The results are shown in the following table. The in vitro test method is as follows.
    Experimental Example 1
    * In vitro anticancer effect on human tumor cell lines
    end. Tumor cell line: A549 (human non-small lung cell)
    SKOV-3 (human ovarian)
    HCT-15 (human colon)
    XF-498 (human CNS)
    SKMEL-2 (human melanoma)
    I. SRB Assay Method
    a. Human solid tumor cell lines A549 (non-small lung cell), SKMEL-2 (melanoma), HCT-15 (colon), SKOV-3 (ovarian), XF-498 (CNS), etc. RPMI 1640 medium was used to incubate in 37 o C, 5% CO 2 incubator and passage was performed 1-2 times a week. Cells were dissolved in 0.25% Trysin and 3 mM CDTA PBS (-) when detached from the adherent surface.
    b. 5 × 10 3 -2 × 10 4 cells were added to each well of a 96 well plate (Nunc) and incubated in 37 o C, 5% CO 2 incubator for 24 hours.
    c. Various drugs were dissolved in a small amount of DMSO and diluted with the experimental medium to the desired concentration for the test so that the final DMSO concentration was less than 0.5%.
    d. B. After aspiration to remove all the medium of each well cultured for 24 hours, and c. Drugs prepared in the section was added to each well 200μl and incubated for 48 hours. At the time of drug addition, Tz (Time Zero) plates were collected.
    e. Tz plates and each incubated plate were subjected to SRCA assay for cell fixing by TCA, staining with 0.4% SRB solution, washing with 1% acetic acid, and elution of dye with 10 mM Tris solution. .
    All. Calculate the result
    a. At the beginning of incubation with the addition of the drug, the SRB protein amount was obtained and time zero (Tz) was obtained.
    b. The OD value of the wells in which cells were not added was called control value (C).
    c. The OD value of drug-treated wells was called drug-treated test value (T).
    d. From Tz, C and T, the effects of drugs could be determined by growth stimulation, net growth inhibition and net killing.
    e. If T≥Tz, the cellular response function is 100 × (T-Tz) / (C-Tz), and if T <Tz, it was calculated as 100 × (T-Tz) / Tz. The results are shown in the following table.
    *references
    1) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd. ; Proc. Am. Assoc. Cancer Res., 30, 612 (1989).
    2) L. V. Rubinstein, R. H. Shoemaker, K. D. Paul, 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. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd. ; J. Natl. Cancer Inst., 82, 1107 (1990)
    la. result
    Anti-cancer effect of all compounds was higher than that of Cisplatin.
    ED 50 = µg / ml Example numberA 549SK-OV-3SK-MEL-2XF-498HCT 15 20.00030.00030.00030.00020.0001 30.0120.0080.0060.0100.003 Cisplatin0.911.320.870.773.17
    Experimental Example 2)
    * In vitro anticancer effect on animal leukemia cells
    end. Experimental material
    Tumor Cell Lines: P388 (mouse lymphoid neoplasma cell)
    I. Dye Exclusion Assay
    1) P388 cells incubated in RPMI 1640 medium containing 10% FBS were adjusted to a concentration of 1 × 10 6 cells / ml.
    2) Each drug of each concentration diluted with log dose was added and cultured in 37 ° C. and 5% CO 2 incubator to measure viable cell number at 48 hours. The viable cell number was measured by dye execlusion test using trypan blue.
    3) The concentration of each compound (IC 50 ) indicating 50% cell growth inhibition compared to the control was calculated from the measured cell number. The results are shown in the following table.
    *references
    1) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd. ; Proc. Am. Assoc. Cancer Res., 30, 612 (1989).
    2) L. V. Rubinstein, R. H. Shoemaker, K. D. Paul, 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. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd. ; J. Natl. Cancer Inst., 82, 1107 (1990)
    All. result
    Compounds of the present invention showed an anticancer effect of P388 mouse leukemia cells more than the control drug mitomycin C in all the compounds in the table.
    Example numberP388 20.002 30.04 Mitomycin C1.1
    Experimental Example 3)
    * Acute Toxicity Test (LD 50 )
    end. Test Method: Richfield-Wilcoxon Method
    Six-week-old ICR mice (30 ± 2.0 g males) were purchased and freely fed solid feed and water at room temperature 23 ± 1 ° C. and 60 ± 5% humidity. Drugs were administered intraperitoneally using 6 animals per group, and the appearance and live death were recorded for 14 days. The mortality was examined by necropsy. LD 50 value was calculated | required by the Richfield-Wilcoxon method.
    I. result
    Compounds of the present invention have been found to overcome the problems of prior art compounds in limiting dosage and toxicity in terms of higher safety than Cisplatin in acute toxicity.
    Example numberLD 50 (mg / kg) i.p.i.v. 2 〉 200 3 212 Cisplatin9.7
    The compound of the general formula (I) according to the present invention or a pharmaceutically acceptable salt thereof is expected to be useful as a new anticancer agent because of its excellent anticancer activity and extremely low toxicity.
    权利要求:
    Claims (2)
    [1" claim-type="Currently amended] A compound represented by the following general formula (I) or a pharmaceutically acceptable acid addition salt thereof.
    (I)
    Wherein R 1 and R 2 are hydrogen atoms, C 1 -C 8 alkyl groups, C 1 -C 4 lower ester groups, C 1 -C 4 lower alkylhydroxy groups, ketone groups, substituted or unsubstituted carboxyl groups, Or R 1 and R 2 together form an unsaturated ring having 4 carbon atoms, and R 3 , R 4 , R 5 , R 6 and R 7 each represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, C 1 the lower ~C 4 lower alkyl group, C 1 ~C 4 lower ester group, a C 1 ~C 4 alkoxy group, a lower alkoxy group of C 1 ~C 4 and Y is an amine group, a substituted amine group, C 1 lower alkyl thio of ~C 4, Z is a lower alkoxy group of a hydrogen atom, hydroxyl group, C 1 ~C 4 lower alkyl group, C 1 ~C 4 lower alkyl amine group of, C 1 ~C 4 a, C 1 ~ C 4 is a lower thioalkoxy group.
    [2" claim-type="Currently amended] A compound of the general formula (I) is prepared by reacting an alkylating agent in the presence of a base with the following compound of the general formula (II), and reacting a substituted or unsubstituted amino group under a base. Method for preparing acid addition salts.

    Wherein R 1 and R 2 are hydrogen atoms, C 1 -C 8 alkyl groups, C 1 -C 4 lower ester groups, C 1 -C 4 lower alkylhydroxy groups, ketone groups, substituted or unsubstituted carboxyl groups, Or R 1 and R 2 together form an unsaturated ring having 4 carbon atoms, and R 3 , R 4 , R 5 , R 6 and R 7 each represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, C 1 the lower ~C 4 lower alkyl group, C 1 ~C 4 lower ester group, a C 1 ~C 4 alkoxy group, a lower alkoxy group of C 1 ~C 4 and Y is an amine group, a substituted amine group, C 1 lower alkyl thio of ~C 4, Z is a lower alkoxy group of a hydrogen atom, hydroxyl group, C 1 ~C 4 lower alkyl group, C 1 ~C 4 lower alkyl amine group of, C 1 ~C 4 a, C 1 ~ C 4 is a lower thioalkoxy group. R 'is a lower alkyl group such as methyl, ethyl.
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    同族专利:
    公开号 | 公开日
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-03-31|Application filed by 최승주, 삼진제약 주식회사
    1999-03-31|Priority to KR1019990011254A
    2000-03-03|Priority claimed from CNB008002959A
    2000-10-25|Publication of KR20000061873A
    优先权:
    申请号 | 申请日 | 专利标题
    KR1019990011254A|KR20000061873A|1999-03-31|1999-03-31|Piperazine derivatives and process for the preparation thereof|
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