JPH0358331B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel organic compounds of selenium that exhibit substantial antitumor activity. More specifically, the present invention relates to an organic compound of selenium obtained by reacting metallic selenium and eleostearic acid. Eleostearic acid has the formula: _CH3- ( _CH2 ) ₃ -CH=CH-CH=CH-CH=CH
It refers to 9,11,13-ocdadecatrienoic acid represented by -( _CH2 ) _7- COOH. The eleostearic acid is a fatty acid,
The main component (80%) is tung oil,
"China wood oil"
Also called. A preferred method for producing the compounds of the present invention is to use tung oil as a raw material for eleostearic acid. By reacting metallic selenium with eleostearic acid, more preferably tung oil, at 200-250°C, selenium itself can be converted into various forms (e.g., perselenide, hydroperselenide) in the side chains of fatty acids. Hydroperselenide, episelenide, etc.) disappear with the formation of adducts. The proportion of selenium in the compounds obtained as described above may vary within a wide range depending on the consumption, e.g.
It may vary within the range of 0.1 to 5% by weight. However, to use the compound therapeutically, selenium
Compounds containing ~2% by weight are particularly useful. The invention also relates to a process for preparing the novel compounds of the invention by reacting selenium and tung oil under heating until the metallic selenium disappears and the mixture becomes clear. EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples. Example 3 g of fine gray or red selenium powder was gradually heated in 100 g of tung oil and thoroughly stirred. about
The reaction mixture began to become clear at 230°C and became completely clear at about 248°C. The reaction up to this point required about 2 to 3 hours. The reaction mixture was then heated with good stirring for an additional hour and a half, then cooled and the selenium that had reacted and collected as a single mass was decanted. The resulting liquid exhibits atomic absorption (atomic absorption).
It was determined that it contained 2.03% by weight of selenium. The obtained compound (hereinafter,
The ultraviolet spectra of TSel) showed an absorption maximum typical of conjugated dienes and conjugated trienes. This fact was consistent with the results of quantifying free iodine in the reaction between TSel and potassium iodide in acetic acid using sodium thiosulfate. In addition, in this determination, the number of iodine is determined by the presence of selenium bonded to the carbon atom adjacent to the double bond of triene in the form of a hydroperselenide group (=C-C-Se-Se-H) and the perselenide group.

Indicates the presence of selenium added to a double bond in the form: However, the novelty of the present invention is not limited to how selenium is attached in the form of TSel. The TSel obtained as described above may be administered in the form of drops or 50% diluted with sesame oil, and in unit dosage form in gelatin capsules or phthials for injection. You may. Contains 2% by weight of selenium obtained as described above.
Acute toxicity, subacute toxicity, chronic toxicity, and carcinogenic activity were investigated using TSel. The method and results are shown below. (Acute toxicity) The acute toxicity of TSel was investigated using male and female mice and rats. TSel was administered subcutaneously, intraperitoneally, or intragastrically to test animals in increasing doses. For subcutaneous administration, up to 1 c.c. of TSel was administered to female mice weighing 26-32 g and male mice weighing 28-34 g, and to female rats weighing 150-220 g.
The test animals did not die even when administered up to 2 c.c. to male rats weighing 170-230 g. For intraperitoneal administration, the maximum dose that does not cause death is 0.2 cc for female mice and 0.5 cc for male mice.
cc, and in rats, it was 0.8 cc in both sexes.
When 1 c.c. was administered to mice and 1.5 cc was administered to rats, at least 50% of the animals tested died. However, female mice were significantly more susceptible than other test animals. An autopsy revealed atrophy of the adrenal glands with almost total disappearance of sudanophilic material. On the other hand, when administered intragastrically, the amount of sudanophilic substances decreased in the adrenal glands when high doses were administered to mice of both sexes up to 1 c.c. and to rats up to 2 c.c. No other toxicity was observed. (Subacute toxicity) Subacute toxicity was investigated by administering TSel to male and female mice and rats by subcutaneous and intragastric administration, and to guinea pigs by intragastric administration for 6 consecutive days. In the case of subcutaneous administration, 1 out of 10 female mice and 2 out of 10 male mice died at the maximum dose of 0.3 cc. On the other hand, no pathological symptoms were observed when rats were administered up to 0.3 cc per 100 g of body weight. For intragastric administration, the maximum dose (in mice)
No symptoms of toxicity were observed other than slight gastritis (0.3 cc, 0.5 cc for rats). In addition, when guinea pigs were used, the tolerance to TSel was extremely good at the maximum dose (0.4cc). (Chronic toxicity) TSel was subcutaneously administered to mice weighing 30 g at a dose of 0.1 cc per day, three times a week for three consecutive months. The test animals showed no abnormal reactions compared to the controls, and no pathological changes were observed at autopsy after killing. Similar results were also obtained when rats were administered 0.2 cc per 100 g of body weight. Even when TSel is orally administered over a long period of time to rats or mice using a tether, no symptoms of toxicity are shown, and even when 1% by weight of TSel is added to the diet and administered to the same test animals, no symptoms of toxicity are shown. I didn't show it. As stated above, the compound of the present invention had no toxicity in practical use. This is surprising considering the well-known fact that selenium compounds are toxic. (Carcinogenic activity) 30 male mice weighing 23 to 27 g and 30 female mice weighing 28 to 31 g were each given a pelleted diet containing TSel0.1c.c. for one year. At the end of the study, no tumor status was observed in any of the test animals. (Pharmacological testing) The concept of anabolic/catabolic dualism and related definitions described below are introduced in E. Revici, Research in Physiopathology, Van.
It has been extensively described in terms of both animal and human experiments in Van Nostrand, Princeton, 1961. However, the novelty of the present invention is not based on the correctness of the theory stated in the paper. The compounds of the invention exhibit significant catabolic activity as shown in a series of tests. When the compounds of the present invention are administered orally to humans, or orally or parenterally to rats, mice, guinea pigs or rabbits,
Corresponding to the catabolic effects, leukopenia (less than 6000/mm ³ ) was accompanied by eosinophilia (less than 60/mm ³ ).
Moreover, in animals, serum potassium always increases with a decrease in red blood cell potassium, corresponding to catabolism. TSel and other compounds of the invention specifically caused changes in human urine. In summary, the surface tension was not lower than 66 dyne/cm, the specific gravity was higher than 1.016, and the pH was lower than 6, indicating catabolic activity. According to atomic absorption spectrometry, selenium was uniformly distributed in the body and rapidly decreased during 48 hours after administration. Note that selenium itself is mainly transported by red blood cells and excreted through stool and urine. When TSel was administered to animals with tumors, atomic absorption showed that 75% of the selenium was fixed in the tumor itself.
Furthermore, when the test animals were killed 1 to 2 weeks after TSel administration and autopsied, the same amount of selenium was found in the tumor. Cytochemical analysis showed that most of the selenium was present in the cytoplasm of cancer cells. Histological examination showed pycnosis of cancer cells with areas of necrosis and a substantial increase in cellular carhiorexi. In the ascites oxygen uptake test of mice with cancer and the yeast oxygen uptake test, the compounds of the invention increased oxygen uptake commensurate with their catabolic effects. When administered orally or injected into rats, the compounds of the present invention will cause an increase in the scab of one-day-old wounds.
This caused a change in the pH value. That is, the PH value of the animals in the control group was 7.62 to 7.64, whereas the PH value of the animals administered with the compound of the present invention was 7.62 to 7.64.
The value increased to 7.80, indicating substantial catabolism. Furthermore, when the effects of the compounds of the present invention on the regeneration curve of epidermal wounds in mice or rats were investigated, a substantial catabolic effect was also observed in this case, indicating that the peak in the regeneration curve was substantially This was evident from the increase and the extension of the regeneration period. When the compound of the present invention was orally administered to mice of FC ₁ origin, 45% of mice in the control group developed spontaneous cancers during the 1-year observation period, whereas spontaneous cancers were observed in 45% of mice in the control group. The incidence of cancer was reduced to about 8%. In other experimental groups, 0.2 cc per pellet of Purina diet
When TSel was orally administered for one year,
In the control group, spontaneous cancer was observed in 40.6%.
It decreased to 3.3%. When the compound of the present invention was administered to mice or rats implanted with various tumors, the tumor incidence rate was reduced to an average of 4%, taking the tumor incidence rate in the control group as 100%. Administration of the compounds of the invention to animals bearing implanted tumors consistently caused growth inhibition and, when implanted intramuscularly, caused tumor disappearance to an extent of over 60%. For example, Ehrlich for ascites cancer.
The results obtained in mice to which cells were administered intramuscularly are shown below. Test animals were intramuscularly injected with TSel in the amounts shown in the table below for 6 days.

[Table] (Clinical test) Humans, who were found to have anabolic effects by administering TSel in the range of 0.25 to 3 c.c. two to four times a day, that is, eosinophils in the blood. was administered to humans with high levels of urinary chloride, high urinary surface tension, high chloride index, high PH, and low specific gravity. A reduction or virtually complete disappearance of symptoms, especially pain, was observed 2-3 days after administration. This phenomenon followed the progressive decline of the tumor. The results obtained by administering selenium-containing compounds of the invention, alone or in combination with other anabolic agents, to tens of thousands of patients with various types of tumors have shown particularly good effects in terms of clinical disappearance of tumors. However, no tumor regeneration was observed even after several years. The only drawback to such treatment is that
Very high doses of selenium caused breath to smell like garlic. Below are some of the most important clinical examples. Clinical case 1 (Patient CB, 39 years old, descending intestinal cancer) Resection. Hepatic coma. Serum bilirubin 120. Urine analysis: Anabolic insufficiency 5 drops of TSel were administered 3 times a day. After one month, the hepatic coma disappeared and the liver became insensible. After one and a half years, the patient returned to normal without recurrence. Clinical case 2 (Patient HD, 48 years old, descending colon cancer) Surgery was performed. Descending colon cancer was removed. Ascites, numerous transplants into the lymphatic glands of the peritoneal cavity. Biopsy result is positive. 10 drops of TSel was administered 4 times a day. Treatment was discontinued after 18 months. Clinical case 3 (Patient CS, 50 years old, left breast cancer) Positive axillary lymph nodes. One year later, ascites increased rapidly. After administering 10 to 20 drops of TSel four times a day for 10 months, the symptoms subsided without the need for trepanation. No recurrence was observed during the subsequent 3 years. Clinical case 4 (Patient GB, 28 years old, brain tumor) Surgery was performed. Recidivsm. Positive scan. 10-20 drops of TSel were administered 4 times a day for 1 year. Over the past two years, I have had repeated negative scans. Clinical case 5 (Patient AH, 17 years old, pituitary tumor) Surgery was performed. Habitual tumors of large size. Right arm paralyzed. headache. After TSel administration, all symptoms progressively disappeared. After 18 months, the patient was completely back to normal. Clinical case 6 (Patient NJ, 44 years old, pancreatic cancer) Surgery was performed. Biopsy and cholecyst-yeyunumstomia. After administering 10 drops of TSel 3 times a day for 6 months,
Clinical disappearance of the tumor was observed, and optimal general condition was achieved. Clinical case 7 (Patient CA, 54 years old, ovarian cancer, multiple peritoneal metastases,
Ascites) 15 drops of TSel was administered daily. Ascites and palpable tumor mass disappeared. There was no metastasis for 3 years. The present invention also relates to the industrial application of the medicament of the present invention as an antitumor agent. The anti-tumor agents of the invention contain a predetermined amount of the compound of the invention and may be formulated in a form suitable for oral or parenteral administration, such as gelatin capsules, phthials for injections,
Examples include syrups.

Claims (1)

[Claims] 1. An organic compound of selenium obtained by reacting metallic selenium and eleostearic acid under heating. 2. The organic compound according to claim 1, wherein the eleostearic acid is present in tung oil. 3 Heat selenium metal and tung oil to about 230℃,
3. The organic compound according to claim 2, which is obtained by reacting the mixture until it becomes clear. 4. The organic compound according to claim 1, which contains 0.1 to 5% by weight of selenium. 5. The organic compound according to claim 4, which contains 1 to 2% by weight of selenium. 6. A method for producing an organic compound of selenium by reacting metallic selenium with eleostearic acid or tung oil under heating until the metallic selenium completely disappears and the mixture becomes clear. 7. The production method according to claim 6, which comprises heating a mixture of metallic selenium and eleostearic acid or tung oil to about 230°C. 8. An antitumor agent whose active ingredient is an organic compound of selenium obtained by reacting metallic selenium and eleostearic acid under heating. 9. The antitumor agent according to claim 8, wherein the eleostearic acid is present in tung oil. 10. The antitumor agent according to claim 8 or 9, which contains an organic compound of selenium containing 1 to 2% by weight of selenium as an active ingredient. 11. The antitumor agent according to claim 8, 9, or 10, which is in a unit dosage form.