KR19980076946A - Novel piperazine N-oxide derivatives and preparation method thereof - Google Patents

Abstract

The present invention relates to a novel piperazine N-oxide derivative represented by the following general structural formula (I) and a preparation method thereof.

Wherein _{R 1, R 2, R 3} , R 4, R 5, are each a hydrogen atom, a fair halo atom, a hydroxy group, a group by Nitto, lower esters of C ₁ -C ₄ group, a lower alkyl group of C ₁ -C ₄ , C ₁ -C ₄ lower thioalkyl group, C ₁ -C ₄ lower alkoxy, C ₁ -C ₄ lower thioalkoxy group, aryl group, arylalkoxy, unsaturated amine group, C ₃ -C ₈ substituted or unsubstituted Ring cyclic alkyl group, allyl group, and Y is

(Wherein, C _6, C ₇ are each hydrogen atom, C ₁ -C ₈ alkyl group, a substituted or unsubstituted cyclic C ₃ -C ₈ in the alkyl group, unsaturated alkyl group, a ketone group, a substituted alkyl, allyl, hydroxyl, Substituted carbamate group, urea group or thiourea group), W is a hydrogen atom C ₁ -C ₈ alkyl group, and C ₃ -C ₈ substituted or unsubstituted cyclic alkyl group, X is an oxygen atom, It is a sulfur atom and a substituted imine group. The compound of the general formula (I) according to the present invention exhibits excellent anticancer effect, and is extremely expected as a new anticancer agent due to its extremely low toxicity.

Description

Novel piperazine N-oxide derivatives and preparation method thereof

The present invention relates to a novel piperazine N-oxide derivative represented by the following general structural formula (I) and a preparation method thereof.

Wherein _{R 1, R 2, R 3} , R 4, R 5, are each a hydrogen atom, a fair halo atom, a hydroxy group, a group by Nitto, lower esters of C ₁ -C ₄ group, a lower alkyl group of C ₁ -C ₄ , C ₁ -C ₄ lower thioalkyl group, C ₁ -C ₄ lower alkoxy, C ₁ -C ₄ lower thioalkoxy group, aryl group, arylalkoxy, unsaturated amine group, C ₃ -C ₈ substituted or unsubstituted Ring cyclic alkyl group, allyl group, and Y is

(Wherein, C _6, C ₇ are each hydrogen atom, C ₁ -C ₈ alkyl group, a substituted or unsubstituted cyclic C ₃ -C ₈ in the alkyl group, unsaturated alkyl group, a ketone group, a substituted alkyl, allyl, hydroxyl, Substituted carbamate group, urea group or thiourea group), W is hydrogen atom C ₁ -C ₈ alkyl group, C ₃ -C ₈ substituted or unsubstituted cyclic alkyl group, X is oxygen atom, sulfur It is an atom, a substituted imine group.

An alkyl group of C ₁ -C ₈ means a straight or branched alkyl group such as methyl, ethyl, propyl, butyl, isobutyl, t-butyl, isopentyl, nuclear, haptyl, octyl, 2-methyl-pentyl and the like.

Lower alkyl group of C ₁ -C ₄ means methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl.

The lower thioalkyl group of C ₁ -C ₄ refers to a methylthiooxy group, ethylthiooxy group, propylthiooxy group, isopropylthiooxy group, butylthiooxy group, isobutylthiooxy group, t-butylthiooxy group.

The lower ester group of C ₁ -C ₄ means a group in which a carboxyl group is esterified by a lower alkyl group.

Lower alkoxy of C ₁ -C ₄ refers to a methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, t-butylthiooxy group.

The lower thioalkyl group of C ₁ -C ₄ refers to methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, t-butylthio group.

Substituted or unsubstituted cyclic alkyl group of C ₃ -C ₈ means cyclic propyl, cyclic butyl, cyclic pentyl, methyl cyclic propyl, methyl cyclic butyl, methyl cyclic pentyl, substituted cyclic allyl group Phenyl, benzyl, toluyl, benzoyl, paramethoxybenzyl, paranitrobenzyl.

Substituted carbamate groups refer to methyl, ethyl, propyl, butyl carbamate.

Substituted alkylhydroxy group means methyl hydroxy, ethyl hydroxy, propyl hydroxy group, aryl hydroxy group refers to phenyl hydroxy, tolyl hydroxy group, paranitro hydroxy.

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 compound of the general formula (I) and a process for preparing acid addition salts thereof.

The compounds of the present invention can be used in 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, inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; Amino acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, citric acid, maleic acid, malonic acid, and the like, organic acids serine, cysteine, cystine, aspartic acid, glutamic acid, lysine, arginine, pyrosine, 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 the general formula (I) as an active ingredient in the present invention include sweeteners, binders, solubilizers, solubilizers, humectants, emulsifiers, isotonic agents, adsorbents, bores Releases, antioxidants, preservatives, glidants, fillers, fragrances and the like can be used, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, tratra Gancan rubber, methyl cellulose, sodium carboxymethyl cellulose, agar, alginate, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, potassium chloride, orange essence, strawberry essence, vanilla scent Can be.

The usual 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 500 mg.

Compounds of the general formula (I) of the present invention may be prepared by the following scheme (I).

Scheme 1

When the starting material of the general formula (II) is reacted with an oxidizing agent in a conventionally used solvent, the general substance of the general formula (I) is effectively prepared.

The oxidizing agent for the preparation of the starting material (I) in II is generally metachloroperbenzoic acid (MCPBA), hydrogen peroxide, benzoyl peracid, aceticperacid, tertiary butylper Ter-Butylperaicd, superoxide (KO ₂ ), potassium perchlorate, sodium perchlorate, manganese dioxide, chromic acid, potassium dichromate, sodium bichromate, pyridine nitrochlorochromate (PCC), pyridine nifedichlorochromate (PDC), oxalic chloride, Dicyclohexyl carbodiimide (DCC), etc. These oxidizing agents are preferably used in an amount of 1 equivalent to 4 equivalents, and the reaction temperature ranges from 70 ° C. at room temperature, and the reaction time is from 0.5 hours to 24 hours. The final solvent (I) was prepared by dichloromethane, chloroform, acetonitrile, tetrahydrofuran, methanol, ethanol and propanol. And the like are generally used.

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 substances include hydroxides of alkali 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. Oxides, carbonates or bicarbonates; And in the presence of a base of an organic amine family.

Starting materials can be prepared and used in the manner described in the literature or in a similar manner.

EXAMPLE

The following compounds were prepared according to the method described above.

Example 1-25 When the substituent Y in the compound of formula (I) is

Example 26-29: When Y in the compound of formula (I) is

Examples 30 and 31 when Y is the following in the compound of formula (I).

Example 1) 1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine N-oxide

1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine (100 mg, 0.27 mmol) methylene chloride (10 Milliliters), and then 30 chloroperbenzoic acid (80 mg, 0.32 mmol) was slowly added thereto, followed by stirring at room temperature for 2 hours. The reaction product was washed with saturated sodium carbonate, the organic layer was dried, filtered and concentrated under reduced pressure, and then purified by column chromatography (methanol: methylene chloride = 1: 15) to obtain 100 mg of the compound.

Yield: 97%

Melting Point: 143-145 ℃

¹ H NMR (500 MHz, CDCl ₃ ): δ 2.21 (3H, s), 2.35 (3H, s), 2,39 (6H, s), 3.40 (2H, m), 3.86 (2H, m), 3.96 (3H, s), 4.07 (2H, m), 4.21 (2H, t), 6.95 (1H, s), 7.07 (1H, s), 7.57 (2H, s), 8.11 (1H, s).

Example 2) 1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine N-oxide

1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine (120 mg, 0.30 mmol) and 3-chloroper The desired compound was prepared in the same manner as in Example 1) using benzoic acid (88.8 mg, 0.36 mmol). (106 mg)

Yield: 85%

Melting Point: 135-137 ℃

¹ H NMR (500 MHz, CDCl ₃ ): δ 2.21 (3H, s), 2.35 (3H, s), 3.61 (2H, m), 3.80 (2H, m), 3.85 (6H, s), 3.98 (3H s), 4.09 (2H, m), 4.19 (2H, t), 6.52 (1H, s), 6.93 (1H, s), 7.12 (2H, s), 8.09 (1H, s).

Example 3) 1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (2-methyl-5-methoxyphenyl) piperazine N-oxide

1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (2-methyl-5methoxyphenyl) piperazine (157 mg, 0.41 mmol) and 3- Using chloroperbenzoic acid (121 mg, 0.49 mmol) in the same manner as in Example 1), the target compound was obtained. (142 mg)

Yield: 87%

Melting Point: 158-160 ℃

¹ H NMR (500 MHz, CDCl ₃ ): δ 2.19 (3H, s), 2.35 (3H, s), 2.63 (3H, s), 3.86 (3H, s), 3.98 (3H, s), 3.85-4.17 (8H, m), 6.92 (1H, d), 7.06 (1H, s), 7.12 (1H, d), 7.61 (1H, s), 8.04 (1H, s).

Example 4) 1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (3-chlorophenyl) piperazine N-oxide

1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (3-chlorophenyl) piperazine (165 mg, 0.44 mmol) and 3-chloroperbenzoic acid ( 130 mg, 0.53 mmol) was reacted in the same manner as in Example 1) to obtain the target compound. (138 mg)

Yield: 80%

Melting Point: 144-146 ℃

¹ H NMR (500 MHz, CDCl ₃ ): δ 2.20 (3H, s), 2.35 (3H, s), 3.60 (2H, m), 3.88 (2H, m), 3.97 (3H, s), 4.15 (4H m), 7.00 (1 H, s), 7.47 (1 H, s), 7.48 (1 H, s), 7.85 (1 H, m), 8.04 (1 H, s), 8.06 (1 H, s).

Example 5) 1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (2-methyl-5-methoxyphenyl) piperazine N-oxide

1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (2-methoxyphenyl) piperazine (166 mg, 0.45 mmol) with 3-chloroperbenzoic acid (133 mg, 0.54 mmol) was used in the same manner as in Example 1) to obtain the target compound. (144 mg)

Yield: 83%

Melting Point:

¹ H NMR (500 MHz, CDCl ₃ ): δ 2.21 (3H, s), 2.36 (3H, s), 3.49 (2H, m), 3.97 (3H, s), 3.99 (3H, s), 4.08 (2H , m), 4.19 (2H, m), 6.89 (1H, s), 6.98 (1H, d), 7.20 (1H, t), 7.48 (1H, t), 8.14 (1H, s) 8.63 (1H, d) ).

Example 6) 1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (3,5-di-prorophenyl) piperazine N-oxide

1-[(5,6-dimethyl-2-methoxypyridin-3-yl) aminocarbonyl] -4- (3,5-difluorophenyl) piperazine (130 mg, 0.35 mmol) and 3- Using chloroperbenzoic acid (102 mg, 0.41 mmol) in the same manner as in Example 1), the target compound was obtained. (94 mg)

Yield: 69.4%

Melting Point: 144-154 ℃

¹ H NMR (500 MHz, CDCl ₃ ): δ 2.20 (3H, s), 2.35 (3H, s), 3.50 (2H, m), 3.97 (3H, s), 4.09 (4H, m), 4.20 (2H m), 6.99 (1 H, t), 7.49 (1 H, s), 7.79 (2 H, d), 7.99 (1 H, s).

Example 7) 1-[(5,6-dimethyl-2-methoxypyridin-3-yl) -N-methylaminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine N- Oxide

1-[(5,6-dimethyl-2-methoxypyridin-3-yl) methylaminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (170 mg, 0.41 mmol) and 3 Using the chloroperbenzoic acid (121 mg, 0.49 mmol) in the same manner as in Example 1) to obtain the target compound. (137 mg)

Yield: 78%

Melting Point: 57-58 ℃

¹ H NMR (500 MHz, CDCl ₃ ): δ 2.19 (3H, s), 2.38 (3H, s), 3.05 (3H, s), 3.52-3.97 (3H, s), 3.78 (8H, m), 3.78 (6H, s), 3.97 (3H, s), 6.53 (1H, s), 6.89 (2H, s), 7.15 (1H, s).

Example 8) 1-[(5,6-dimethyl-2-methoxypyridin-3-yl) -N-isopropyl aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine N Oxide

1-[(5,6-dimethyl-2-methoxypyridin-3-yl) isopropyl aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (160 mg, 0.36 mmol) Using the 3-chloroperbenzoic acid (107 mg, 0.43 mmol) in the same manner as in Example 1) to obtain the target compound. (135 mg)

Yield: 82%

Melting Point: 158-160 ℃

¹ H NMR (500 MHz, CDCl ₃ ): 1.14 (3H, d, J = 6.7 HZ), 2.22 (3H, s), 2.42 (3H, s), 3.41 (2H, m), 3.65 (2H, t), 3.74-3.95 (4H, m), 3.84 (6H, s), 3.92 (3H, s), 4.30 (1H, m), 6.52 (1H, s), 6.90 (2H, s), 7.09 (1H, s) .

Example 9) 1-[(6-methyl-2-methoxy-5-ethylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine N-oxide

1-[(6-ethyl-2-methoxy-5-ethylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine (203 mg, 0.53 mmol) and 3-chloro The compound was reacted in the same manner as in Example 1) using loperbenzoic acid (157 mg, 0.64 mmol) to obtain the target compound. (196 mg)

Yield: 93%

Melting Point: 139-141 ℃

¹ H NMR (500 MHz, CDCl ₃ ): δ 1.88 (3H, t), 2.38 (3H, s), 2.39 (3H, s), 2.56 (2H, q), 3.55 (2H, m), 3.87 (2H, m), 3.98 (3H, s), 4.15 (4H, m), 7.03 (1H, s), 7.09 (1H, s), 7.54 (2H, s), 8.13 (1H, s).

Example 10) 1-[(6-methyl-2-methoxy-5-ethylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine N-oxide

1-[(6-ethyl-2-methoxy-5-ethylpyridin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (186 mg, 0.45 mmol) and 3 Using the chloroperbenzoic acid (133 mg, 0.54 mmol) in the same manner as in Example 1) to obtain the target compound. (155 mg)

Yield: 80%

Melting Point: 143-145 ℃

¹ H NMR (500 MHz, CDCl ₃ ): δ 1.86 (3H, t), 2.39 (3H, s), 2.57 (3H, q), 3.65-3.91 (4H, m), 3.85 (6H, s), 3.98 ( 3H, s), 4.14 (4H, m), 6.54 (1H, s), 6.98 (1H, s), 7.07 (2H, s), 8.11 (1H, s).

Example 11) 1-[(6-methyl-2-methoxy-5-ethylpyridin-3-yl) aminocarbonyl] -4- (5-chloro-2-methoxyphenyl) piperazine N-oxide

1-[(6-ethyl-2-methoxy-5-ethylpyridin-3-yl) aminocarbonyl] -4- (5-chloro-2-methoxyphenyl) piperazine (250 mg, 0.60 mmol) Using the 3-chloroperbenzoic acid (177 mg, 0.74 mmol) in the same manner as in Example 1) to obtain the target compound. (222 mg)

Yield: 85%

Melting Point: 157-159 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 1.19 (3H, t), 2.39 (3H, s), 2.58 (3H, q), 3.55 (2H, m), 3.97 (2H, s), 3.99 (3H, s), 4.10 (2H, s), 4.18 (2H, m), 4.62 (2H, m), 6.97 (1H, s), 6.99 (1H, d), 7.45 (1H, dd), 8.18 (1H, s ), 8.66 (1 H, s).

Example 12) 1-[(6-methyl-2-methoxy-5-ethylpyridin-3-yl) aminocarbonyl] -4- (2-chloro-5-methoxyphenyl) piperazine N-oxide

1-[(6-ethyl-2-methoxy-5-ethylpyridin-3-yl) aminocarbonyl] -4- (2-chloro-5-methoxyphenyl) piperazine (130 mg, 0.31 mmol) Using the 3-chloroperbenzoic acid (90 mg, 0.37 mmol) in the same manner as in Example 1) to obtain the target compound. (123 mg)

Yield: 91%

Melting Point: 142-143 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 1.19 (3H, t), 2.39 (3H, s), 2.56 (3H, q), 3.68 (2H, m), 3.93 (3H, s), 3.99 (3H, s), 4.15 (4H, m), 4.87 (2H, m), 6.97 (1H, s), 7.00 (1H, dd), 7.38 (1H, d), 8.14 (1H, s), 8.39 (1H, s ).

Example 13) 1-[(6-Methyl-2-methoxy-5-ethylpyridin-3-yl) aminocarbonyl] -4- (3.5-difluorophenyl) piperazine N-oxide

1-[(6-ethyl-2-methoxy-5-ethylpyridin-3-yl) aminocarbonyl] -4- (3.5-difluorophenyl) piperazine (130 mg, 0.39 mmol) and 3-chloro Using a loperbenzoic acid (115 mg, 0.47 mmol) in the same manner as in Example 1) to obtain the target compound. (124 mg)

Yield: 91.2%

Melting Point: 160-161 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 1.18 (3H, t), 2.58 (3H, s), 2.57 (2H, q), 3.45 (2H, m), 3.90 (3H, s), 3.97-4.20 ( 2H, m), 7.22 (1H, s), 7.44 (1H, s), 7.77 (2H, d), 8.06 (1H, s).

Example 14) 1-[(6-methyl-2-methoxy-5-ethylpyridin-3-yl) -N-methylaminocarbonyl] -4- (3,5-dimethylphenyl) piperazine N-oxide

1-[(6-ethyl-2-methoxy-5-ethylpyridin-3-yl) -N-methylaminocarbonyl] -4- (3.5-damethylphenyl) piperazine (197 mg, 0.05 mmol) and 3 Using the chloroperbenzoic acid (147 mg, 0.60 mmol) in the same manner as in Example 1) to obtain the target compound. (192 mg)

Yield: 93%

Melting Point: 100-102 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 1.19 (3H, t), 2.38 (3H, s), 2.44 (3H, s), 2.57 (2H, q), 3.10 (3H, s), 3.64-3.98 ( 8H, m), 3.97 (3H, s), 7.09 (1H, s), 7.14 (1H, s), 7.39 (2H, s).

Example 15) 1-[(6-Methyl-2-methoxy-5-ethylpyridin-3-yl) -N-methylaminocarbonyl] -4- (3.5-dimethoxyphenyl) piperazine N-oxide

1-[(6-ethyl-2-methoxy-5-ethylpyridin-3-yl) -N-methylaminocarbonyl] -4- (3.5-damethoxyphenyl) piperazine (157 mg, 0.37 mmol) Using the 3-chloroperbenzoic acid (108 mg, 0.44 mmol) in the same manner as in Example 1) to obtain the target compound. (152 mg)

Yield: 93%

Melting Point: 58-60 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 1.18 (3H, t), 2.43 (3H, s), 2.57 (3H, q), 3.09 (3H, s), 3.32-3.87 (8H, m), 3.84 ( 6H, s), 3.97 (3H, s), 6.52 (1H, s), 6.94 (2H, s), 7.12 (1H, s).

Example 16) 1-[(5-methyl-2-methoxy-6-ethylpyridin-3-yl) -aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine N-oxide

1-[(5-methyl-2-methoxy-6-ethylpyridin-3-yl) aminocarbonyl] -4- (3,5-damethylphenyl) piperazine (130 mg, 0.34 mmol) and 3-chloro Using a loperbenzoic acid (100 mg, 0.41 mmol) in the same manner as in Example 1), the target compound was obtained. (77 mg)

Yield: 57%

Melting Point: 153-155 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 1.23 (3H, t), 2.22 (3H, s), 2.39 (6H, s), 2.65 (2H, q), 3.65 (2H, m), 3.87 (2H, m), 3.98 (3H, s), 4.16 (4H, m), 7.00 (1H, s), 7.10 (1H, s), 7.52 (2H, s), 8.06 (1H, s).

Example 17) 1-[(5-methyl-2-methoxy-6-ethylpyridin-3-yl) -aminocarbonyl] -4- (3-hydroxyphenyl) piperazine N-oxide

1-[(5-methyl-2-methoxy-6-ethylpyridin-3-yl) aminocarbonyl] -4- (3-hydroxyphenyl) piperazine (156 mg, 0.42 mmol) and 3-chloroper Using the benzoic acid (125 mg, 0.51 mmol) in the same manner as in Example 1) to obtain the target compound. (102 mg)

Yield: 63%

Melting Point: 177-178 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 1.23 (3H, t), 2.19 (3H, s), 2.63 (2H, q), 3.67 (2H, m), 3.88-4.22 (6H, m), 3.98 ( 3H, s), 6.87-7.14 (3H, m), 7.52 (1H, m), 7.94 (1H, s), 8.10 (1H, s).

Example 18) 1-[(5-methyl-2-methoxy-6-propylpyridin-3-yl) -aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine N-oxide

1-[(5-methyl-2-methoxy-6-ethylpyridin-3-yl) -aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (130 mg, 0.30 mmol) Using the 3-chloroperbenzoic acid (89 mg, 0.36 mmol) in the same manner as in Example 1) to obtain the target compound. (100 mg)

Yield: 78%

Melting Point: 140-142 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 0.97 (3H, t), 1.70 (2H, m), 2.22 (3H, s), 2.60 (2H, t), 3.80-3088 (4H, m), 3.85 ( 6H, s), 3.97 (3H, s), 4.15 (2H, m), 6.53 (1H, s), 6.99 (1H, s), 7.08 (2H, s), 8.05 (1H, s).

Example 19) 1-[(5-methyl-2-methoxy-6-propylpyridin-3-yl) -aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine N-oxide

1-[(5-methyl-2-methoxy-6-propylpyridin-3-yl) -aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine (105 mg, 0.27 mmol) and 3- Using chloroperbenzoic acid (80 mg, 0.32 mmol) in the same manner as in Example 1) to obtain the target compound. (99 mg).

Yield: 89%

Melting Point: 160-161

¹ H NMR (500MHz, CDCl ₃ ): δ 0.97 (3H, t), 1.71 (2H, m), 2.22 (3H, s), 2.39 (6H, s), 2.61 (2H, t), 3.73 (2H, m), 3.87 (2H, m), 3.97 (3H, s), 4.14 (2H, m), 7.00 (1H, s), 7.11 (1H, s), 7.52 (2H, s), 8.06 (1H, s ).

Example 20) 1-[(5-methyl-2-methoxy-6-propylpyridin-3-yl) -N-methylaminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine N Oxide

1-[(5-methyl-2-methoxy-6-propylpyridin-3-yl) -N-methylaminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine N-oxide (130 Mg, 0.29 mmol) and 3-chloroperbenzoic acid (90 mg, 0.35 mmol) were reacted in the same manner as in Example 1) to obtain a target compound. (97 mg).

Yield: 73%

Melting Point: 118-120 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 0.99 (3H, t), 1.76 (2H, m), 2.23 (3H, s), 2.64 (2H, t), 3.10 (3H, s), 3.58-3.87 ( 8H, m), 3.83 (6H, s), 3.97 (3H, s), 6.49 (1H, s), 6.99 (2H, s), 7.11 (1H, s).

Example 21) 1-[(5- (2-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl) -aminocarbonyl] -4- (3,5-dimethoxyphenyl) Piperazine N-oxide

1-[(5- (2-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl) -aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (116 Mg, 0.27 mmol) and 3-chloroperbenzoic acid (80 mg, 0.32 mmol) were reacted in the same manner as in Example 1) to obtain a target compound. (80 mg).

Yield: 78.7%

Melting Point: 163-165 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 1.40 (3H, d), 2.41 (3H, s), 3.65 (2H, q), 3.75 (2H, m), 3.84 (6H, s), 3.97 (3H, s), 4.12 (2H, m), 4.22 (2H, m), 4.98 (1H, q), 6.53 (1H, s), 7.16 (2H, s), 7.44 (1H, s), 8.26 (1H, s ).

Example 22) 1-[(5- (2-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl) -aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine N-oxide

1-[(5- (2-hydroxyethyl) -2-methoxy-6-methylpyridin-3-yl) -aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine (130 mg, 0.33 mmol) and 3-chloroperbenzoic acid (97 mg, 0.39 mmol) were used in the same manner as in Example 1) to obtain a target compound. (121 mg).

Yield: 89%

Melting Point: 149-150 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 1.43 (3H, d), 2.38 (6H, s), 2.40 (3H, s), 3.65 (2H, m), 3.91 (2H, m), 3.95 (3H, s), 4.05 (2H, m), 4.13 (2H, m), 5.02 (1H, q), 7.09 (1H, s), 7.13 (1H, s), 7.51 (2H, s), 8.34 (1H, s ).

Example 23) 1-[(5- (2-methoxyethyl) -2-methoxy-6-methylpyridin-3-yl) -N-methylaminocarbonyl] -4- (3,5-dimeth Methoxyphenyl) piperazine N-oxide

1-[(5- (2-methoxyethyl) -2-methoxy-6-methylpyridin-3-yl) -N-methylaminocarbonyl] -4- (3,5-dimethoxyphenyl) pipe Reaction (112 mg, 0.24 mmol) and 3-chloroperbenzoic acid (71 mg, 0.39 mmol) were used in the same manner as in Example 1) to obtain a target compound. (101 mg).

Yield: 89%

Melting Point: 83-85 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 1.37 (3H, d), 2.43 (3H, s), 3.10 (3H, s), 3.45-3.98 (8H, m), 3.82 (6H, s), 3.92 ( 3H, s), 3.98 (3H, s), 4.46 (1H, m), 6.45 (1H, s), 6.93 (2H, s), 7.45 (2H, s), 8.15 (1H, s).

Example 24) 1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) -N-methylaminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine N Oxide

1-[(5-acetyl-2-methoxy-6-methylpyridin-3-yl) -N-methylaminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (207 mg, 0.47 Mmol) and 3-chloroperbenzoic acid (138 mg, 0.56 mmol) were reacted in the same manner as in Example 1) to obtain a target compound. (151 mg).

Yield: 70%

Melting Point: 140-141 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 2.37 (3H, s), 2.57 (3H, s), 3.10 (3H, s), 3.34-4.82 (8H, m), 3.78 (8H, m), 3.85 ( 3H, s), 6.51 (1H, s), 6.75 (1H, s), 7.32 (1H, s).

Example 25) 1-[(2-methoxy-6-methyl-5-vinylpyridin-3-yl) -aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine N-oxide

1-[(2-methoxy-6-methyl-5-vinylpyridin-3-yl) -aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine (110 mg, 0.29 mmol) and 3- Using the chloroperbenzoic acid (75 mg, 0.30 mmol) in the same manner as in Example 1) to obtain the target compound. (92 mg).

Yield: 80%

Melting Point: 153-155 ℃

¹ H NMR (500 MHz, CDCl ₃ ): δ 2.40 (6H, s), 2.44 (3H, s), 3.66 (2H, m), 3.87 (2H, m), 4.01 (3H, s), 4.11 (2H, m), 4.20 (2H, m), 5.25 (1H, d), 5.62 (1H, d), 6.57 (1H, s), 6.83 (1H, dd), 7.00 (1H, s), 7.09 (1H, s) ), 7.54 (2Hm, s), 8.48 (1H, s).

Example 26) 1-[(4,5-dimethyl-2-methoxyphenyl) -aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine N-oxide

1-[(4,5-dimethyl-2-methoxyphenyl) -aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine (150 mg, 0.41 mmol) and 3-chloroperbenzoic acid (120 Mg, 0.49 mmol) was reacted in the same manner as in Example 1) to obtain the target compound. (111 mg).

Yield: 96%

Melting Point: 134-136 ℃

¹ H NMR (500 MHz, CDCl ₃ ): δ 2.21 (3H, s), 2.23 (3H, s), 2.39 (6H, s), 3.44 (2H, m), 3.86 (3H, s), 3.88 (2H, m), 4.11 (4H, m), 6.67 (1H, s), 7.07 (1H, s), 7.10 (1H, s), 7.55 (2H, s), 7.85 (1H, s).

Example 27) 1-[(4,5-dimethyl-2-methoxyphenyl) -aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine N-oxide

1-[(4,5-dimethyl-2-methoxyphenyl) -aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (190 mg, 0.48 mmol) and 3-chloroperbenzoic acid (141 mg, 0.33 mmol) was used in the same manner as in Example 1) to obtain the target compound. (161 mg).

Yield: 81%

Melting Point: 130-131 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 2.21 (3H, s), 2.22 (3H, s), 3.79 (2H, m), 3.86 (9H, s), 3.97-4.19 (6H, m), 6.53 ( 1 H, s), 6.67 (1 H, s), 7.06 (2 H, s), 7.80 (1 H, s).

Example 28) 1-[(4,5-dimethyl-2-methoxyphenyl) -N-methylaminocarbonyl] -4- (3,5-dimethylphenyl) piperazine N-oxide

1-[(4,5-dimethyl-2-methoxyphenyl) -N-methylaminocarbonyl] -4- (3,5-dimethylphenyl) piperazine (105 mg, 0.28 mmol) and 3-chloroper Using benzoic acid (81.4 mg, 0.33 mmol) in the same manner as in Example 1), the target compound was obtained. (104 mg).

Melting Point: 137-139 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 2.21 (3H, s), 2.26 (3H, s), 2.37 (6H, s), 3.09 (3H, s), 3.29 (3H, s), 3.55 (2H, m), 3.77 (4H, m), 3.84 (3H, s), 6.75 (1H, s), 6.86 (1H, s), 7.04 (1H, s), 7.43 (2H, s).

Example 29) 1-[(4,5-dimethyl-2-methoxyphenyl) -N-methylaminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine N-oxide

1-[(4,5-dimethyl-2-methoxyphenyl) -N-methylaminocarbonyl] -4- (3,5-dimethylphenyl) piperazine (125 mg, 0.30 mmol) and 3-chloroper Using benzoic acid (89.4 mg, 0.36 mmol) in the same manner as in Example 1), the target compound was obtained. (106 mg).

Yield: 83%

Melting Point: 143-144 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 2.21 (3H, s), 2.26 (3H, s), 3.09 (3H, s), 3.48-3.80 (8H, m), 3.83 (6H, s), 3.84 ( 3H, s), 6.49 (1H.s), 6.75 (1H, s), 6.85 (1H, s), 6.98 (2H, s).

Example 30) 1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine N-oxide

1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (127 mg, 0.30 mmol) and 3-chloroperbenzoic acid (89 mg, 0.36 mmol) was reacted in the same manner as in Example 1) to obtain a target compound. (96 mg).

Yield: 73%

Melting Point: 133-134 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 3.47 (2H, m), 3.78 (2H, m), 3.84 (6H, s), 3.98 (3H, s), 4.12 (4H, m), 6.92 (1H, s), 7.05 (1H, t), 7.19 (1H, s), 7.35 (1H, t), 7.41 (2H, s), 7.52 (1H, d), 8.34 (1H, s).

Example 31) 1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine N-oxide

1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine (130 mg, 0.33 mmol) and 3-chloroperbenzoic acid (89 mg, 0.36 mmol ) Was reacted in the same manner as in Example 1) to obtain the target compound. (124 mg).

Yield: 91.9%

Melting Point: 183-185 ℃

¹ H NMR (500MHz, CDCl ₃ ): δ 2.39 (6H, s), 3.45 (2H, m), 3.72 (2H, m), 4.18 (3H, s), 4.14-4.26 (4H, m), 7.08 ( 1H, s), 7.38 (1H, s), 7.44 (1H, s), 7.52 (1H, t), 7.57 (2H, s), 7.71 (1H, d), 7.79 (1H, d), 8.76 (1H , s)

Experimental Example

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, and the results are shown in the following table. In vitro test method is as follows.

Experimental Example 1

* In vitro anticancer effect on human tumor cell line

A, 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)

B, 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), etc. RPMI 1640 medium was used to incubate in 37 ℃, 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. 5x10 ³ -2x10 ⁴ cells were added to each well of a 96 well plate (Nunc) and incubated in a 37 ° C., 5% CO ₂ incubator for 24 hours.

c. Various drugs were dissolved in a small amount of DMSO and diluted as a demonstration 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 the 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 cell fixing by TCA, staining with 0.4% SRB solution, washing with 1% acetic acid and elution of dye with 10 mM Tris solution in the SRB assay method. Measured.

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 such as growth stimulation, net growth inhibition and net killing could be determined.

e. If T≥Tz, the cellular response function is 100x (T-Tz) / (C-Tz), and for TTz, it is calculated as 100x (T-Tz) / Tz. The results are shown in Table 1 below.

* 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.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. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd. ; J. Natl. Cancer Inst., 82, 1107 (1990)

la. result

In 12 examples, anticancer effects of human cancers were comparable to those of the control drugs Cispaltin and Adriamycin.

TABLE 1

Experimental Example 2

* In vitro anticancer effect on animal leukemia cells

end. Experimental material

Tumor Cell Lines: L1210 (mouse leukemia cell)

I. Dye Exclusion Assay

1) L 1210 cells incubated in RPMI 1640 medium containing 10% FBS were adjusted to a concentration of 1x10 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) From the measured cell number, the concentration of each compound (lC ₅₀ ) showing 50% cell trowth inhibition compared to the control was calculated. The results are shown in Table 2 below.

* 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.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. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd. ; J. Natl. Cancer Inst., 82, 1107 (1990)

All. result

In six examples, the anticancer effect of hematologic cancer was higher than that of the control drug Mitomycin C.

TABLE 2

Claims (2)

The compound represented by the following general formula (I) and its pharmaceutically acceptable acid addition salt. Wherein _{R 1, R 2, R 3} , R 4, R 5, are each a hydrogen atom, a fair halo atom, a hydroxy group, a group by Nitto, lower esters of C ₁ -C ₄ group, a lower alkyl group of C ₁ -C ₄ , C ₁ -C ₄ lower thioalkyl group, C ₁ -C ₄ lower alkoxy, C ₁ -C ₄ lower thioalkoxy group, aryl group, arylalkoxy, unsaturated amine group, C ₃ -C ₈ substituted or unsubstituted Ring cyclic alkyl group, allyl group, and Y is (Wherein, C _6, C ₇ are each hydrogen atom, C ₁ -C ₈ alkyl group, a substituted or unsubstituted cyclic C ₃ -C ₈ in the alkyl group, unsaturated alkyl group, a ketone group, a substituted alkyl, allyl, hydroxyl, Substituted carbamate group, urea group or thiourea group), W is hydrogen atom C ₁ -C ₈ alkyl group, C ₃ -C ₈ substituted or unsubstituted cyclic alkyl group, X is oxygen atom, sulfur It is an atom, a substituted imine group. A method for preparing a compound of general formula (I) or an acid addition salt thereof by reacting a starting material with an oxidizing agent by the following general formula (II). Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , are hydrogen atom, halogen atom, hydroxy group, nitoro group, C ₁ -C ₄ lower ester group, C ₁ -C ₄ lower alkyl group, C ₁ -C ₄ lower thioalkyl group, C ₁ -C ₄ lower alkoxy, C ₁ -C ₄ lower thioalkoxy group, aryl group, arylalkoxy, unsaturated amine group, C ₃ -C ₈ substituted or unsubstituted Cyclic alkyl group, allyl group, Y is (Wherein, C _6, C ₇ are each hydrogen atom, C ₁ -C ₈ alkyl group, a substituted or unsubstituted cyclic C ₃ -C ₈ in the alkyl group, unsaturated alkyl group, a ketone group, a substituted alkyl, allyl, hydroxyl, Substituted carbamate group, urea group or thiourea group), W is hydrogen atom C ₁ -C ₈ alkyl group, C ₃ -C ₈ substituted or unsubstituted cyclic alkyl group, X is oxygen atom, sulfur It is an atom, a substituted imine group.