KR100634399B1 - Composition of anticancer agent comprising pyrazole oxime derivative as active ingredient - Google Patents

Abstract

The present invention relates to an anticancer agent composition comprising a pyrazole oxime derivative of the general formula (1) as an active ingredient.

The pyrazole oxime derivatives of the general formula (1) used in the composition of the present invention not only have a very simple synthesis method but also exhibit excellent anticancer activity against various cancers such as lung cancer, ovarian cancer, melanoma, central nervous system tumor or colon cancer. Can be used for prevention and treatment:

Where

R is a nitrogen-containing hetero ring, substituted or unsubstituted phenoxy, phenylthio, hydroxy, amino, alkylamino or halogen.

Description

Anticancer composition comprising a pyrazole oxime derivative as an active ingredient {COMPOSITION OF ANTICANCER AGENT COMPRISING PYRAZOLE OXIME DERIVATIVE AS ACTIVE INGREDIENT}

The present invention relates to an anticancer agent composition comprising a pyrazole oxime derivative as an active ingredient.

The pyrazole oxime derivative used in the composition of the present invention is a substance prepared from pyrazole derivatives and used in many compounds such as antibiotics, insecticides and the like. For example, Korean Patent Publication No. 2004-93857 discloses a method for preparing various pyrazole derivatives under mild conditions and the novel pyrazole derivatives produced are COX-2 inhibitors, p38 MAP kinase inhibitors, CDK2 / Cyclin A It is disclosed that it is a useful intermediate of the synthesis of compounds with various biological effects such as inhibitors, antibiotics, pesticides.

In addition, Korean Patent Publication No. 2004-46000 discloses a method for preparing various pyrazole oxime derivatives by reacting the pyrazole derivatives with benzoic acid t-butyl ester derivatives. In particular, phenpyrimate represented by the following formula is a pesticide or tick control agent that is widely used in rice farming in Japan, China, Southeast Asia, including Korea.

The present inventors have completed the present invention while studying the efficacy of the pyrazole oxime derivatives and found that they are excellent in various types of human cancer cell lines.

Accordingly, it is an object of the present invention to provide an anticancer composition comprising a pyrazole oxime derivative as an active ingredient.

In order to achieve the above object, the present invention provides an anticancer composition comprising a pyrazole oxime derivative of the general formula (1) as an active ingredient:

Formula 1

Where

R is a nitrogen containing hetero ring, substituted or unsubstituted phenoxy, phenylthio, hydroxy, amino, alkylamino or halogen.

Examples of the nitrogen-containing hetero ring include pyrrolyl, pyrrolidinyl, imidazolyl, 2-imidazolinyl, pyrazolyl, 3-pyrazolinyl, pyrazolidinyl, 1H-1, 2, 3-triazolyl, Piperidinyl, piperazinyl, morpholinyl, indolinyl, isoindoleyl, 1H-indazolyl, benzimidazolyl, carbazolyl and the like.

The compounds have an excellent effect on lung cancer, ovarian cancer, melanoma, central nervous system tumor or colon cancer.

Hereinafter, the present invention will be described in more detail.

The pyrazole oxime derivatives of the general formula (1) used in the present invention may be prepared according to the methods described in Korean Patent Publication Nos. 2004-46000 and 2004-93857 as compounds known as insecticides.

Synthesis method of the pyrazole oxime derivative of the present invention can be represented by, for example, Scheme 1.

Scheme 1

In Scheme 1, the starting compound may be prepared by a known method (Chemical Abstract Vol. 73, 1970, 3844w), and the compound of Formula 2 is prepared in the presence of a conventional base as in step a. When nucleophilic substitution reaction with RX under the present, it is possible to prepare a pyrazole derivative such as the formula (3) (Korean Patent Publication No. 2004-93857). In the formula R-X, R is as defined in the formula (1), X is a hydrogen atom or an alkali metal such as Na, K, Li, Cs.

In step b, the pyrazole oxime derivative of formula (4) can be obtained by dehydrating the compound of formula (3) with hydroxyamine in the presence of a base in a conventional manner.

In addition, in step c, the benzoic acid t-butylester derivative of the compound of formula 5 may be easily obtained by adding benzoic acid to isobutene, which is obtained by dehydrating t-butanol in the presence of an acid such as sulfuric acid. Pub. 2004-46000). In this case, Y in Formula 5 is a halogen element such as Cl, Br, I. A pyrazole oxime derivative represented by Formula 1 of the present invention may be prepared by reacting the compound of Formula 4 obtained in step b with the compound of Formula 5.

Representative compounds belonging to the general formula (1) of the present invention are represented as follows:

[Formula 1a] [Formula 1b]

[Formula 1c] [Formula 1d]

       [Formula 1e] [Formula 1f]

      [Formula 1g] [Formula 1h]

      Formula 1i]

Compound names of the compounds are as follows.

Formula (1a): 4- (1,3-dimethyl-5-dimethylamine- 1H -pyrazol-4-ylmethyleneaminooxymethyl) -benzoic acid thi-butyl ester

Formula (1b): 4- (1,3-dimethyl-5-pyrrolidine- 1H -pyrazol-4-ylmethyleneaminooxymethyl) -benzoic acid thi-butyl ester

Formula (1c): 4- (1,3-dimethyl-5-morpholin-1 H -pyrazol-4-ylmethyleneaminooxymethyl) -benzoic acid thi-butyl ester

4- (1,3-dimethyl-5-pyrrole- 1H -pyrazol-4-ylmethyleneaminooxymethyl)-benzoic acid thi-butyl ester

Formula (1e): 4- (1,3-Dimethyl-5-pyrazole-1 H -pyrazol-4-ylmethyleneaminooxymethyl) -benzoic acid thi-butyl ester

4- (1,3-dimethyl-5-imidazol- 1H -pyrazol-4-ylmethyleneaminooxymethyl) -benzoic acid thi-butyl ester

[Formula 1g]: 4- (1,3-dimethyl-5-indole- 1H -pyrazol-4-ylmethyleneaminooxymethyl) -benzoic acid thi-butyl ester

[Formula 1h]: phenpyrioxymate

4- (1,3-dimethyl-5-thiophenoxy- 1H -pyrazol-4-ylmethyleneaminooxymethyl) -benzoic acid thi-butyl ester

The compositions of the present invention can be prepared in pharmaceutical formulations according to conventional methods. In the preparation of the formulation, it is preferred that the active ingredient is mixed or diluted with the carrier or enclosed in a carrier in the form of a container. When the carrier is used as a diluent, it may be a solid, semisolid or liquid substance which acts as a vehicle, excipient or medium for the active ingredient. Thus, the formulations may be in the form of tablets, pills, powders, assays, elixirs, suspensions, emulsions, solutions, syrups, aerosols, soft or hard gelatin capsules, sterile injectables, sterile powders and the like.

Examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate And propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. The formulation may further comprise fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like.

Compositions of the present invention may be formulated using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.

The pharmaceutical compositions of the invention can be administered via several routes including oral, transdermal, subcutaneous, intravenous or intramuscular. In humans, a typical daily dosage of the active compound may range from 1 to 1,000 mg / kg body weight, preferably 10 to 100 mg / kg body weight, and may be administered once or in several doses. However, it should be understood that the actual dosage of the active ingredient should be determined in light of several relevant factors such as the disease to be treated, the route of administration, the age, sex and weight of the patient, and the severity of the disease, and therefore the dosage may be determined in any way. Also, the scope of the present invention is not limited.

Hereinafter, the present invention will be described in more detail with reference to Examples, which are only intended to assist in understanding the configuration and operation of the present invention, and the scope of the present invention is not limited to these Examples.

Test Example 1: Test of cell proliferation inhibitory effect on cancer cell lines of human origin

In order to confirm the cancer cell proliferation inhibitory effect of compounds 1 to 9, the prepared compounds 1 to 9 were assayed by the following test method, and the 50% proliferation inhibitory concentration (IC ₅₀ ) for each cancer cell line is shown in Table 1 below. As a comparative example, IC ₅₀ was measured in the same manner as in Example 1 using cisplatin, which is most widely used in clinical practice.

Test Methods

A549 (human lung cancer cell line), SK-OV-3 (human ovarian cancer cell line), SK-MEL-2 (human melanoma cell line), XF498 (human central nervous system cancer cell line), and HCT-15 (human colon cancer cell line) Five human-derived cancer cell lines were distributed from the US National Cancer Research Center (NCI) and used for subculture, and the cancer cell proliferation inhibitory effect was most widely used as a measure of the primary anticancer effect of drugs in the US NCI and various other testing institutions. According to the sulforhodamine B (SRB) assay (Skehan P. et al., J. Natl. Cancer. Inst. , 1990, 82; 1107).

1) Cancer cells in passage were treated with trypsin-CDTA solution and separated from the container attachment surface, and the cell numbers were 5 × 10 ³ (A549, HCT-15), 1 × 10 ⁴ (SKMEL-2, XF498) and 2 × 10, respectively. Dilutions were made to ⁴ cells / mL (SKOV-3) and aliquoted into each well of a 96-well flat bottom microplate (Falcon). These were incubated for 24 hours in a CO ₂ incubator to allow the cells to adhere to the bottom of the well, the medium was removed by an inhaler, and the sample dissolved in the medium was added to each well by concentration, and the culture was continued for 48 hours.

2) After 48 hours of incubation, the medium in each well is aspirated, and 10 µl of 10% trichloroacetic acid (TCA) solution is added to each well, and the cells are left at room temperature for 1 hour to fix the cells, followed by 5 to 6 water. Washing was done to remove excess TCA solution completely and dried.

3) 100 μl of SRB staining solution (0.4% sulforhodamine in 1% acetic acid) was added to each well, followed by dyeing for 30 minutes, and the excess dye solution was repeatedly washed 5 to 6 times with 1% acetic acid and dried at room temperature. .

4) 100 μl of 10 mM Trisma base (unbuffered) solution was added to each well, followed by shaking for 10 minutes with a titer plate shaker to elute the stained cells. Absorbance at 520 nm was measured using a microplate reader.

5) The cancer cell proliferation rate (% cell growth, inverse of anticancer activity) of the sample group into which the sample solution was added was calculated according to the following Equations 1 and 2 below. That is, the cell number (C) of the control group in which the same amount of medium was added instead of the sample solution, the number of cells (Tz) and the number of cells (T) of the sample group were converted from the absorbance of each group, respectively. The cancer cell growth rate (% cell growth) of the sample group was calculated by Equation 1 when Tz> T and by Equation 2 when Tz <T.

[(T-Tz) / (C-Tz)] × 100

 [(T-Tz) / Tz] × 100

6) Concentration IC ₅₀ (µg / ml) that the sample inhibits the proliferation of the cancer cells by 50% using the data regression of the Lotus program based on the cancer cell proliferation rate of the sample group measured at each concentration. ) Was calculated.

Formula 1

As can be seen in Table 1, the compounds 1 to 9 shows an excellent cell proliferation inhibitory effect against various cancer cell lines.

Since the pyrazole oxime derivative-containing composition according to the present invention shows excellent anticancer activity against cancer cells, it can be usefully used as an inhibitor against growth of cancer cells.

Claims (3)

An anticancer composition comprising as an active ingredient a pyrazole oxime derivative of the formula Formula 1

Where R is a nitrogen-containing hetero ring, phenoxy, phenylthio, hydroxy, amino, alkylamino or halogen. The method of claim 1, R in formula 1 is pyrrolyl, pyrrolidinyl, imidazolyl, 2-imidazolinyl, pyrazolyl, 3-pyrazolinyl, pyrazolidinyl, 1H-1, 2, 3-triazolyl, piperidinyl , An anticancer agent characterized in that the group selected from the group consisting of piperazinyl, morpholinyl, indolinyl, isoindoleyl, 1H-indazolyl, benzimidazolyl, carbazolyl, phenoxy, phenylthio, and dimethylamino Composition. The method of claim 1, An anticancer agent composition, characterized in that it is used for the prophylactic light treatment of lung cancer, ovarian cancer, melanoma, central nervous system tumor or colon cancer.