JPH0797329A - Carcinostatic auxiliary - Google Patents

Abstract

PURPOSE:To obtain a low toxic carcinostatic auxiliary having activity to significantly improve the efficacy of existing carcinostatics, containing a specific ribofuranose derivative as an active ingredient. CONSTITUTION:This auxiliary contains, as active ingredient, a ribofuranose derivative of the formula [R is a 1-6C (branches) alkyl] (e.g. 5-deoxy-5- methylthio-D-ribose, 5-deoxy-5-ethylthio-D-ribose, 5-deoxy-5-n-propylthio-D-ribose). The carcinostatic to be used in combination with this auxiliary or by containing in a formulation together with this auxiliary includes an anthracycline compound such as adriamycin, a platinum compound such as cis-diaminodichloroplatinum (II) or a fluoropyrimidine compound such as 5-fluorouracil.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a carcinostatic auxiliary agent containing a ribofuranose derivative as a useful ingredient.

[0002]

2. Description of the Related Art Cancer accounts for about one-fourth of Japanese deaths, and it is expected that the number of cancer patients will continue to increase. Due to advances in cancer treatment methods, the long-term survival rate of cancer patients is 50%. It's over. The main treatment methods are surgery, radiation therapy, and chemotherapy, which are combined treatments. However, all of the existing anti-cancer agents have strong side effects, cause great pain to patients, and cannot administer a sufficient amount of the agents, thus reducing their effectiveness.

For example, anthracycline anticancer agents such as daunomycin and adriamycin are acute leukemia,
It has effects on various cancers such as hematological cancers such as malignant lymphoma and lung cancer, breast cancer, and solid tumors such as osteosarcoma, and is widely used, but the anticancer agent of this system is myelosuppression such as thrombocytopenia, stomatitis, In addition to side effects commonly seen in anticancer drugs such as digestive disorders and hair loss, they also have myocardial toxicity. Also, cis-diaminedichloroplatinium (II) [Pt (NH ₃ ) ₂ C
In a toxicity test using Beagle dogs and squirrel monkeys, carcinostatic agents composed of platinum compounds such as [1 ₂ ] are toxic to various organs such as digestive organs, kidneys, lymphatic system, liver and bone marrow, and are clinically associated with nausea. , Digestive disorders mainly due to vomiting, general malaise,
Side effects such as hematopoietic disorders, renal dysfunction and hearing dysfunction are known. Furthermore, fluorinated pyrimidine-based carcinostatic agents such as 5-fluorouracil are effective in a wide range of clinical cancers, and are used for the treatment of gastric cancer, liver cancer, colorectal cancer, and in combination with other carcinostatic agents or radiation, the esophagus. It is also used to treat cancer. However, the side effects are strong, and the main ones are digestive disorders, stomatitis, diarrhea, nausea, loss of appetite, and pharyngitis, esophagitis, gastritis, enteritis, etc., which may be accompanied by mucosal ulcer and bleeding. In addition to this, leukopenia, thrombocytopenia, hair loss, dermatitis, pigmentation, etc. appear.

Although many compounds having an anti-cancer effect have been found in this way, the original effects of the drug have not been fully utilized due to their side effects. For this reason, while the development of new anticancer agents is currently being actively pursued, it is possible to directly reduce the side effects of existing anticancer agents, or to lower the dose by increasing the effects of anticancer agents and reduce the side effects. The development of an auxiliary agent for the anticancer drug possessed is also in progress.

[0005]

DISCLOSURE OF THE INVENTION As a result of intensive investigations by the present inventors to obtain a compound that reduces the side effects of an anticancer drug, some ribofuranose derivatives have low toxicity and the effects of existing anticancer drugs. The present invention has been completed by finding that they have an activity that can be significantly improved.

[0006]

Thus, according to the present invention, the general formula (1)

[Chemical 2] (In the formula, R is an optionally branched alkyl group having 1 to 6 carbon atoms) A carcinostatic agent auxiliary agent is provided, which comprises a ribofuranose derivative represented by the formula as a useful ingredient.

In the above general formula (1), R is methyl group, ethyl group, n-propyl group, isopropyl group, n-
Butyl group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, n-hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2 -Methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethyl It shows a C1-6 optionally branched alkyl group such as a butyl group, preferably a C1-4 optionally branched alkyl group. Specific examples of such compounds include 5-deoxy-5-methylthio-D-ribose, 5-deoxy-5-ethylthio-D-ribose, 5
-Deoxy-5-n-propylthio-D-ribose, 5
-Deoxy-5-isopropylthio-D-ribose, 5
-Deoxy-5-n-butylthio-D-ribose, 5-
Deoxy-5-isobutylthio-D-ribose, 5-deoxy-5-s-butylthio-D-ribose, 5-deoxy-5-t-butylthio-D-ribose, 5-deoxy-5-n-pentylthio-D -Ribose, 5-deoxy-5-isopentylthio-D-ribose, 5-deoxy-5- (2-methylbutylthio) -D-ribose, 5
-Deoxy-5-neopentylthio-D-ribose, 5
-Deoxy-5-n-hexylthio-D-ribose, 5
-Deoxy-5- (4-methylpentylthio) -D-ribose, 5-deoxy-5- (3-methylpentylthio) -D-ribose, 5-deoxy-5- (2-methylpentylthio) -D -Ribose, 5-deoxy-5-
(3,3-Dimethylbutylthio) -D-ribose, 5-
Deoxy-5- (2,2-dimethylbutylthio) -D-
Ribose, 5-deoxy-5- (1,1-dimethylbutylthio) -D-ribose, 5-deoxy-5- (1,2
-Dimethylbutylthio) -D-ribose, 5-deoxy-5- (1,3-dimethylbutylthio) -D-ribose, 5-deoxy-5- (2,3-dimethylbutylthio) -D-ribose, etc. Is exemplified. These compounds can be reacted with an alkylmercaptan by a conventional method, for example, inactivating the 1,2-, and 3-position hydroxyl groups of D-ribose with an appropriate protecting group, and then activating the 5-position hydroxyl group with tosyl chloride. It is manufactured by

The carcinostatic agent used together with the carcinostatic agent auxiliary agent of the present invention may be any known compound having a carcinostatic action,
Specific examples of such compounds include anthracycline compounds such as adriamycin, platinum compounds such as cis-diaminedichloroplatinium (II), and 5
-A fluorinated pyrimidine-based compound such as fluorouracil is exemplified.

The carcinostatic agent auxiliary agent of the present invention is usually prepared using a conventional formulation means, and can be used in combination with or mixed with a carcinostatic agent. The dosage form is not particularly limited and may be appropriately selected and used as necessary. Oral preparations such as solutions, powders, granules, tablets, enteric agents and capsules, parenteral preparations such as injections and suppositories may be used. Can be mentioned. In order to exert a desired effect as an oral agent, it varies depending on the age, body weight, and degree of disease of the patient, but it is usually used in adults in combination with an anticancer agent in the range of 10 to 500 mg / kg per day as the useful ingredient amount of the present invention. can do. In order to exert the desired effects as a parenteral agent such as intravenous injection, subcutaneous injection, intramuscular injection, it depends on the patient's age, body weight and degree of disease, but it is usually 1 in adults.
1 to 200 mg / day of the adjuvant of the present invention can be used in combination with the anticancer drug.

[0010]

EXAMPLES The anticancer drug auxiliary agent of the present invention will be specifically described, but the present invention is not limited to the compounds used here.

Test Example 1 Combined effect of 5-deoxy-5-methylthio-D-ribose with an anti-cancer agent The animals were 6-week-old male BDF ₁ (C57BL / 6xDB).
A / 2) A mouse was used. Mice have a constant temperature (22-2
The animals were raised in an environment of 6 ° C., and food and water were freely ingested. As the tumor, mouse leukemia L1210 cells (hereinafter referred to as L1210) passaged intraperitoneally in DBA / 2 mice were suspended in physiological saline. Anticancer agents include adriamycin (hereinafter referred to as ADM) and 5-fluorouracil (hereinafter referred to as 5-Fu) manufactured by Kyowa Fermentation Co., Ltd., and cisplatin (hereinafter referred to as CDDP) as bristol.
A clinical drug manufactured by Myers Co., Ltd. was used and suspended in physiological saline. 5-deoxy-5-methylthio-D
-Ribose was dissolved in saline.

Under the above conditions, the effect of the present invention as a carcinostatic agent auxiliary agent was confirmed by the following test method. L1210
After intraperitoneally transplanting about 1 × 10 ⁵ tumor cells of 6 cells per mouse (6 mice per group), a carcinostatic agent was administered once a day for 5 days from the day after the transplantation of tumor cells for 5 days with 5-deoxy-5-methylthio. −
D-ribose was intraperitoneally administered once a day at a concentration shown in Table 1 for 30 days from the day after the tumor cell transplantation.

The life extension effect was evaluated as follows. Mean survival days (hereinafter, referred to as MST) of the L1210-transplanted mice of each group were administered with a test compound and an anticancer agent.
I asked. In addition, the life extension rate (%) is ((MST of drug-administered group-MS of control group without drug)
T) / MST of control group without drug) × 1
It asked from 00. The results are shown in Table 1.

[0014]

[Table 1]

From these results, it was found that the survival rate increases when the anti-cancer agent auxiliary agent of the present invention is used in combination.

Test Example 2 Combined effect of 5-deoxy-5-ethylthio-D-ribose with an anti-cancer agent Test Example 1 except that the administration period of 5-deoxy-5-ethylthio-D-ribose was changed to 9 days. Tests and evaluations were performed by the same method. The results are shown in Table 2.

[0017]

[Table 2]

From these results, it was found that the survival rate increases when the anticancer agent auxiliary agent of the present invention is used in combination.

Test Example 3 Toxicity test To 6-week-old BDF1 male mice, 3000 mg / kg of 5-deoxy-5-methylthio-D-ribose was intraperitoneally administered once or 200 mg / kg of the same compound for 30 days (total amount). 6 g / kg) was intraperitoneally administered daily. No abnormal symptoms were observed until day 30 in both administration groups, and no individual died. On the 30th day, laparotomy was performed and pathological observation was performed, but no abnormality was observed. Similarly, 5-deoxy-5-
Ethylthio-D-ribose and 5-deoxy-5-isobutylthio-D-ribose give 400 mg / kg of 1
It was administered once a day for 9 consecutive days. When observed for 60 days after administration, no abnormal symptoms were observed and no individual died. From this, it was found that the anticancer drug adjuvant of the present invention is a compound having extremely low toxicity.

Claims (1)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R is an optionally branched alkyl group having 1 to 6 carbon atoms) A carcinostatic agent auxiliary agent comprising a ribofuranose derivative as a useful component.