JPS604802B2 - anticancer drug - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an anticancer agent containing 4-carbamoyl-5-hydroxyimidazole represented by the general formula or a salt thereof as a main component.

The compound represented by the general formula [1] is a known compound, for example, as described in Journal of the American Chemical Society (J. Am. Chem. SM),
(1952), page 28.

Conventionally, the compound represented by the general formula [1] is simply L-51
Cytotoxicity against 78Y cells was only known;
Although it was not known at all that it had a strong anti-nasal effect, the inventors investigated the anticancer activity of the compound using various Hitomitos, such as Sarcoma 180, Ehritz-Kaba, and MHI Patoma. A detailed study revealed that this compound has a significant anticancer effect, especially against cancerous cancer, which is conventionally considered difficult to treat, and that the effect is sufficiently expressed even when administered orally. prove that
It was discovered for the first time that this compound was a clinically extremely useful anticancer agent.

The anticancer effect, toxicity, etc. of this compound are shown below.

[1' Anticancer effect] The anticancer effect of the present compound on various experimental tumors was investigated according to the method described in Applied Pharmacology, Vol. 4 (1970E), page 521.

The results are shown in Tables 1 and 2. 1 Mouse
, Table 2: Anticancer effect on experimental mouse transplant pupil scar K'2)
Acute toxicity Animals used: Mouse ICR-JCL strain, male, body weight 22-25 mm (n=10).

However, animals were observed for 5 days after administration.

The results are shown in Table 3. Table 3 Acute toxicity value for mice (3- Subacute toxicity test mouse ICR-JCL strain, male, around 25 ta (n=10)
The test animals were individually housed in cages made of wire mesh, and 100 m9/k9 was orally administered by force every day for 21 days.

Animals were sacrificed at 2 hours after the 21st administration, blood test, urine test,
The animals were subjected to anatomical findings, organ weights, and histopathological examination.

The breeding feed was a garden type feed, the intake was measured once every 4 to 5 days, and drinking water was provided ad libitum from a glass water bottle. Body weight was measured every day during the administration period. The results are shown below. [
1} Avoid abnormal weight gain and feed intake.

{2} Blood test results White blood cell count (average) 6,500 cells/Phosphorocyte count ('') 6.0 x 105 cells/pine Hb amount (
″ ) 15.1 evening/d〃 matocrit value ( ″ )
35% GOT activity value ('') 54.4 karmen units As above, no abnormalities were observed.

{3} Urine test Protein 30-100 9/dl back Occult blood negative pH 6.0-6.5 As above, no abnormality detected.

‘4} Anatomical findings No abnormality detected.

[5) Organ weight (% of body weight) Liver (average) 6.24 Kidney (″) 1.50 Torso (″) 0.30 Thymus (″) 0.20 Heart (″) 0.49 Gunmaru (″) 0.38 Lungs (″) 0.81 Due to the above deviation, the corner bran will shrink slightly. No abnormalities were observed other than the presence of a feeling of discomfort.

(6) Histopathological examination The liver, kidneys, bran, thymus, lymph, lungs, heart, and Yukimaru were examined, but no abnormalities were found except for the bran on the buccal side, where the bran was slightly atrophied.

As is clear from the above experimental examples, 4-carbamoyl-5-hydroxyimidazole represented by the general formula [1] is a highly safe anticancer agent with strong anti-caking activity and few side effects.

In particular, there are only a few anticancer drugs that can be administered orally and have the above-mentioned strong effects on solid cancers, which have traditionally been difficult to treat clinically. This drug, which exhibits anticancer effects, can also be used in the treatment of human cancer as an extremely useful and innovative anticancer agent.
This drug is administered by intravenous injection, subcutaneous injection, orally, etc., and when used for treatment of adults, the dosage is preferably in the range of 3 to 10 days per day, depending on the route of administration and the number of administrations.

4-Carbamoyl-5-hydroxy-imidazole represented by the general formula [1] can be prepared for administration by any conventional method by analogy with other orally administrable anticancer agents, such as ftorafur.

Therefore, the present invention also includes a pharmaceutical composition containing at least a compound represented by formula [1] or a pharmaceutically acceptable salt, which is suitable as a human medicine. Such compositions are prepared for use in a conventional manner with any required pharmaceutical carriers or excipients. Desirably, the composition is provided in a form suitable for absorption from the gastrointestinal tract.

Tablets and capsules for oral administration are metered dosage forms and may contain binders such as syrup, acacia, gelatin,
sorbit, tragacanth, or polyvinylpyrrolidone, excipients such as lactose, sugar, corn starch, calcium phosphate, sorbit or glycine, lubricants such as magnesium stearate, talc, polyethylene glycol or silica, disintegrants such as potato starch or as may be acceptable. Excipients such as wetting agents such as sodium lauryl sulfate may also be included. The tablets may be coated by methods well known in the art, and coloring agents, crosslinking agents, etc. may be added as necessary. Oral liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc., or they may be dry products that are redissolved in water or other vehicle before use. Such liquid preparations may contain commonly used excipients such as suspending agents such as sorbitol syrup, methylcellulose, glucose/bran syrup, gelatin, hydroxyethylcellulose, hydroxymethylcellulose, aluminum stearate gel or hydrogenated Edible fats, emulsifiers such as lecithin, sorbitan monooleate or gum arabic, non-aqueous vehicles such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol, preservatives such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate or It may also contain sorbic acid and optionally a dye and fragrance. Compositions for injection may be presented in fixed-dose ampoules or in multi-dose containers with added preservatives and suitable solubility aids.

The compositions may take such forms as suspensions, solutions, emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing, and/or dispersing agents. good. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use. These compositions and their soluble salts can contain 0.1% or more of active substance, preferably 10-60%, depending on the method of administration.

When the composition consists of a fixed dosage, it is preferred to contain from 50 to 2000 9 active ingredients. When 4-carbamoyl-5-hydroxyimidazole represented by general formula [1] is to be administered intravenously, it is preferable to form the compound into a salt form, such as a sodium salt or a hydrochloride.

Some examples of formulations of this invention are listed below. Formulation Example 1 Injection Sterile 4-Carbamoyl-5-Hydroxyimidazole Sodium Salt 250ml was aseptically dispensed into vials and sealed to remove moisture and bacteria.

Before administration, add Lidocaine 0.5% Injection 2' to prepare an injection. Formulation Example 2 Injection Sterile 4-Carbamoyl-5-Hydroxy-imidazole Hydrochloride 250 parts were aseptically dispensed into vials containing 9 parts and sealed to remove moisture and bacteria.

Before use, add Lidocaine 0.5% Injection 2' to prepare an injection. Formulation example 3 Oral tablet 1.4-carbamoyl-5-hydroxyimidazole 250/9
2. mannit
200 servings of potato starch
94 of 47. Magnesium stearate
91 of 3 and 2 were mixed, 3 was added as a 10% starch paste and granulated.

This particle is called a snake. Pass through a 60 mesh (B.S.) sieve and dry to a constant weight. 16 mesh (B.S.
．． ) was sifted with a sieve. The particles were then mixed with 4 to make it smooth and compressed with a 7/I6'' punch to form 500 tablets each.
It was made into 9 tablets. Formulation example 4 Suppositories 1.4-carbamoyl-5-hydroxyimidazole 500 females 2. Tannic acid 30 females 3. Roto extract 20 females 4. Iktamor 200 female 5. ethyl benzoate 96 of 100. Cocoa butter 1500-91-5
and 1/milk volume of 6 to make a suppository mass, then add 2/3 of the amount of 6 melted (at 30-35°C) and stir while stirring just before it solidifies until it becomes sticky rice. The mixture was immediately poured into crab suppository molds and cooled.

Claims (1)

[Claims] 1 An anticancer agent containing 4-carbamoyl-5-hydroxy-imidazole or a salt thereof as a main component.