JPH03101620A - Carcinostatic agent - Google Patents

Abstract

PURPOSE:To obtain a carcinostatic agent having synergistically increased carcinostatic activity by using a benzoylurea compound as an active component and using the compound in combination with other carcinostatic compound. CONSTITUTION:The objective agent contains a benzoylurea compound of formula I (X is halogen or nitro; Y is H, halogen, etc.; Z1 is halogen or trifluoromethyl; Z2 is H or halogen; A is CH or N) as an active component. The compound of formula I is e.g. the compound of formula II or formula III. The carcinostatic compound to be used in combination with the compound of formula I is e.g. an alkylation agent (e.g. cyclophosphamide: commercial name, Endoxane: Shionogi & Co., Ltd.).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an anticancer agent that synergistically enhances the anticancer action of the anticancer compound when used in combination with another anticancer compound. General formula (wherein, X is a halogen atom or a nitro group, Y is a hydrogen atom, a halogen atom, a nitro group, or a trifluoromethyl group, zI is a halogen atom or a trifluoromethyl group, and Z8 is a hydrogen atom or a halogen atom) , A is CH
The penzoyl urea compound (I) represented by (or a nitrogen atom) is a substantially known compound and is known to have an excellent anticancer effect (Japanese Patent Application Laid-open No. 57-1993).
-109721, JP-A-61-1670, JP-A-6193163, etc.). The object of the present invention is to provide new uses for penzoyl urea compounds (1). [Means for Solving the Problems] As a result of further studies on the pharmacological action of the penzoyl urea compound (1), the present inventors found that in the presence of the penzoyl urea compound (1), other types of anti-inflammatory agents The present invention has been completed based on the discovery that the anticancer effect of the anticancer compound is significantly enhanced by administering the cancerous compound. That is, the present invention relates to an anticancer agent which uses the penzoyl urea compound (1) as an effective ingredient and is used in combination with other types of anticancer compounds. Regarding the 17G formula (1), examples of the halogen atom include michlorine, bromine, and iodine. Penzoyl urea compound (1) which is the active ingredient of the present invention
) is exemplified by a compound represented by the following formula. The benzoylurea compound (1) is a generally known compound, and is produced, for example, by the method described in JP-A-57-109721 or a method analogous thereto. By the way, the penzoyl urea compound (1) is generally poorly soluble in water and has poor absorption into the blood.
Various formulation innovations have been proposed (Japanese Unexamined Patent Publication No. 1986-1
-27965, JP 61-191623, JP 61-205257, JP 6 2-
Publication No. 185013, EP Publication No. 264904 Specification 1g
), it is preferable to follow the method.

The anti-beneficial compound is a compound other than the penzoyl urea compound (1), and is not particularly limited as long as it has an anticancer effect and can be used clinically. Specifically, alkylating agents [e.g., cyclophosphamide (trade name Endoxan, Shionogi & Co., Ltd.), nitrogen mustard N-oxide (trade name Nitromine, Yoshitomi Pharmaceutical), nimustine (trade name Nidoran, Sankyo Pharmaceutical Co., Ltd.), ), antimetabolites [e.g., fluorouracil (trade name 5-FU, Kyowa Hakko, others), methotrexate (trade name Methotrexate, Nippon Redari Ichiichi Takeda Pharmaceutical), cytarabine (trade name Kilocide, Nippon Shinyaku, others), Mel Kabutopurine (trade name: Ikerin, Takeda Pharmaceutical, others), antibiotic *MC, doxorubicin (trade name: Adriacin, Kyowa Hakko), mitomycin C
(trade name mitomycin, Kyowa Uhko), pleomycin (trade name Breo, Nippon Shinyaku), neocarzinostatin (
Product name Neocarcinostatin, Kayaku Pharmaceutical Ichiyamanouchi Pharmaceutical)
, plant alkaloids [e.g., pincristin (trade name: Oncovin, Shiono I Pharmaceutical Co., Ltd.), vindesine (trade name: Fildecine, Shionogi Pharmaceutical Co., Ltd.), etoboside (trade name: Bevucide, Pristol-Myers, others), etc.], immunotherapeutic agents [e.g., bisibanil] (Product name Hishibanil, Chugai Pharmaceutical), Krestin (Product name Krestin, Kureha Kagaku Ichisankyo), Schizophyllan (Product name Sonifilan (Kaken Pharmaceutical), Lentinan (Product name Krestin, Kureha Kagaku Ichisankyo),
commercial name lentinan (Yamanouchi Pharmaceutical, etc.)], other anticancer drugs [e.g., cisplatin (trade name: bribratin, others)]
etc.] etc. All anticancer compounds are available in commercially available formulations. Penzoyl urea compound (1) which is an anticancer agent of the present invention
are chewing mammals including humans (cows, horses, dogs, rats,
It has the effect of significantly and synergistically enhancing the anticancer effects of other anticancer compounds in mice, etc.). The penzoyl urea compound (1) is administered together with other anticancer compounds or separately from other anticancer compounds, but when the other anticancer compounds act, the penzoyl urea compound (1) It must be present in the body. Therefore, it may be formulated together with the penzoyl urea compound (1) or separately. Penzoylurea compound (1) is usually administered orally, but administration via other routes such as intravenous administration and rectal administration is also possible. The penzoyl urea compound (1) is
It is formulated by a known formulation method, and known additives such as excipients and carriers may be used. The dosage of penzoyl urea compound (1) may vary depending on symptoms, gender, body weight, dosage form, etc., but when administered orally, penzoyl urea compound (I)
It is usually administered to adults at a dose of about 1 to 100 mg/kg body weight per day, about 1 to 3 times a week. The dosage form of the above-mentioned other types of anticancer compounds may be the conventional dosage form of each anticancer drug, and the dosage thereof can also be the same as the conventional dosage of each anticancer drug. Moreover, since the anticancer effect is enhanced by the combined use with the penzoyl urea compound (1) according to the present invention, its dosage can be reduced as appropriate. Regarding the administration route, the compound may be administered orally, intravenously, etc. in accordance with the conventional administration method of each compound. [Effect] Penzoyl urea compound (1
) is a compound with a completely different mechanism of action from conventionally known anticancer active compounds, and its anticancer effect is significantly and synergistically enhanced when used in combination with other types of anticancer compounds. Therefore, the present invention is considered to be extremely useful from the viewpoint of multidrug therapy in cancer chemotherapy. [Examples] Examples are given to explain the present invention in more detail, but the present invention is not limited by these in any way. Example! Compound 3 (20 g) was suspended in 5 w/v% polyoxyethylene hydrogenated castor oil (HCO-60) aqueous solution, and 50 g of glass beads (φ between 0.25 and 0.5) were mixed using Dynomill. Wet grinding (3000 rpm
, 45 minutes). $53 After the crushing was completed, the glass beads were removed using a sieve to obtain a wet-pulverized preparation of Compound 3. This liquid preparation 50Id was added to SigI1 fatty acid ester (PI
670, manufactured by Mitsubishi Kasoko Co., Ltd.), and dry ice.
After freezing with methanol, it was vacuum dried for 24 hours to remove water to produce a lyophilized preparation. The formulation was filled into capsules to make a capsule formulation. Example 2 Compound 3 (15 g) was suspended in 50% w/v% polyoxyethylene polyoxypropylene glycol (Bruronic F68) aqueous solution, and glass beads (0.2
Wet pulverization (3000 rpm, 45 minutes) was carried out using a dyno tool. After the pulverization was completed, the glass beads were removed using a sieve to obtain a wet-pulverized preparation of Compound 3. See Il in this liquid preparation 50 times! 30 g of fatty acid ester (P1670, manufactured by Mitsubishi Kasho Co., Ltd.) was added, frozen with dry ice and methanol, and vacuum dried for 24 hours to remove water to produce a lyophilized preparation. The formulation was filled into capsules to make a capsule formulation. Example 3 A dry preparation was obtained in the same manner as in Example 2, except that decaglycerin monolaurate (Decagrin IL, manufactured by Nikko Chemical Co., Ltd.) was used instead of polyoxyethylene polyoxypropylene glycol. Example 4 Compound 3 (1.8+ag) was added to polyethylene glycol 1
90% of 000, 4% of polyethylene glycol 4000
%, polyethylene glycol 400 was heated and dispersed in a suppository base containing 6% polyethylene glycol 400, and a suppository was prepared using a suppository mold. Example 5 Compound 3 (1.8m) at 12.5% (w/v)
Witebusol W containing dimethyl β-type cyclodextrin
-35 Suppository base (approximately 45 cm) was heated and dispersed to prepare suppositories. Example 6 Compound 3 was dissolved in polyethylene glycol 400 (PEG400) to a concentration of 20 ml/sl, and the mixture was prepared using a conventional method [edited by Kyosuke Tsuda et al., Basic Course on Pharmaceutical Development X: Drug Manufacturing Methods (Part 1), p. Soft gelatin capsules (average weight: 1,600 cm) were prepared according to the method of Soft gelatin capsules (average weight: 1,600 cm). Example 7 In place of PEG400 in Example 6, purified soybean oil, refined sesame oil, or purified safflower oil containing 5% (W/V) Pluronic F31 was used, and the same procedure was performed to prepare soft gelatin capsules. did.

Example 8 Compound 3 (4g) and dimethyl β-type cyclodextrin 1
A small amount of water is added to 25 g, kneaded, granulated by extrusion granulation method, filled into hard gelatin capsules, and oral capsules are made into AJ! Manufactured.

Example 9 Magnesium stearate was added to the granules obtained in Example 8.
% and compressed into tablets to prepare oral tablets.

Example 10 Compound 3 (50 ■), purified egg yolk phospholipid 1K500 ■ Oyohi α-tocopherol 0. 5 mg to chloroform 1
(After dissolving in 1+1, chloroform was distilled off by heating under reduced pressure using a rotary evaporator to form a thin film of phospholipid containing Compound 3.

10 parts of physiological saline solution was added to this thin film, and immediately after shaking vigorously at room temperature for 20 minutes, a sonicator (Brans
on Sonic Power, Cell Dis
Ultrasonication was performed for 1 hour while cooling on ice using a router (Rutor 1350, output 60 W). Furthermore, centrifugation M (25,000 g, 1 hour) was performed at room temperature, and the resulting bottom layer sediment was collected, centrifugally washed several times using the above-mentioned physiological saline, and then sterilized and filtered. A phospholipid complex of the shape was obtained.

Example 1l The turbid preparation obtained in Example 10 was freeze-dried to obtain 520 ml of a dried phospholipid complex preparation.

Example 12 Preparation of a complex of penzoylurea compound (compound 3) and human serum albumin. Human serum albumin Ig was extracted with 100 d of 5% glacial acetic acid monoisooctane solution dried with dehydrated sodium sulfate by standing at 0°C for more than 6 hours without shaking, and the extract was decanted and extracted with isooctane. 2 more extraction operations
Repeatedly, the isooctane and glacial acetic acid were removed by vacuum drying, and the dried human serum albumin was dissolved in purified water, dialyzed against purified water at 1'C for 3 days, and then the fatty acids were removed by freeze-drying. Obtain large serum albumin free. Add this to phosphate mild solution pl 17.4, ionic strength 0.1.
6 to make a 1% solution. Add 1 of compound 3 to 10 m2 of this solution 4. 7 9■DM SO 0. 2
Add the dissolved ingredients to m and mix. This mixture was stirred at room temperature for 2 hours, and then left at 4°C for at least 6 hours. The solution thus obtained was dialyzed at 1 °C for 2 days against phosphate buffer pH 7.4, ionic strength 0.16 to remove free compound 3 and DMSO, and the resulting complex The body solution can be stabilized by dialysis against a 0.5% sodium chloride-1% glycose solution at 1°C for 2 days. The solution thus obtained is lyophilized to obtain the desired complex. The composition ratio of the complex was 20 molecules of penzoyl urea compound (compound 3) per molecule of albumin. Experimental Example 1 {Ha Test animals include BDF, mouse (male, weight 18
−2 2 g, n=6) was used. intraperitoneally of mice
IXIO' l210 cells were transplanted, and drugs were administered on the first day after transplantation. Six anticancer compounds were administered intraperitoneally,
In addition, a penzoyl urea compound (compound 3) was administered orally. Follow-up was performed until 60 days after transplantation of the II tumor. The anti-II tumor effect was determined from the survival rate compared with the physiological saline administration group, and the results are shown in Table 1. Table 1 Life extension rate (%) Experimental example 2 The test animals were BDF, mouse (m, weight 18-2
2g, n=6) was used. IXIO' L1210 cells were intraperitoneally transplanted into mice, and drugs were administered from the first day after transplantation. Six anticancer compounds were administered intraperitoneally for 4 consecutive days, and a penzoylurea compound (compound 3) was administered orally only on the first day. The antitumor effect was determined from the survival rate compared with the physiological saline administration group, and the results are shown in Table 2. Table 2 Life extension rate (%) 2. Name of the invention Anticancer agent 3. Relationship with the case of the person making the amendment Patent applicant name Midori Juji Ishihara Sangyo Co., Ltd. 4, Agent 541 Address 3-3-9 Hirano-cho, Chuo-ku, Osaka (Yumoto Building) - (06) 227-1156 Experimental Example 2 The test animals were BDFI mice (male, body weight 18-2
2g, n=6) was used. IXIO' L1210 cells were intraperitoneally transplanted into mice, and drugs were administered starting one day after transplantation. Six anticancer compounds were administered intraperitoneally for 4 consecutive days, and a penzoylurea compound (compound 3) was administered orally only on the first day. The antitumor effect was determined from the survival rate compared with the physiological saline administration group, and the results are shown in Table 2. Table 2 Life extension rate (%)

Claims (1)

[Claims] (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X is a halogen atom or a nitro group, Y is a hydrogen atom, a halogen atom, a nitro group, or a trifluoromethyl group, and Z_1 is a The active ingredient is a benzoylurea compound represented by a halogen atom or trifluoromethyl group, Z_2 is a hydrogen atom or a halogen atom, and A is a CH or nitrogen atom), and is used in combination with other types of anticancer compounds. Anticancer drug for.