JPH03118317A - Carcinogenesis-preventing agent - Google Patents

Abstract

PURPOSE:To provide a carcinogenesis-preventing agent originated from a living body (a higher animal), exhibiting an excellent carcinogenesis-preventing activity, and no dangerous adverse effect against living bodies employing a specific alpha,beta-diol as an active ingredient. CONSTITUTION:An alpha,beta-diol of the formula (R is H, 1-5C alkyl, especially H or CH3; n is an integer of 3-21, especially 12-16) is employed as an active ingredient to provide a safe carcinogenesis-preventing agent exhibiting a remarkable carcinogenesis-preventing activity, effective not only for preventing general cancers but also for preventing the recurrence of treated cancers and for preventing genetic cancers and having no adverse effect because the active ingredient is a living substance prepared by decomposing a natural substance such as a wax, e.g. wool wax. The active ingredient is administered in a dose of 10-1500mg/kg of an adult a day for parenteral administration agents such as intravenous injections, subcutaneous injections and drips or in a dose of 0.2-50g/kg of an adult a day for oral administration agents such as capsules.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to a novel anti-carcinogenic agent.

[Prior art] The prevailing theory is that carcinogenesis occurs in two stages, involving initiation and promoters, but the mechanism of carcinogenesis in terms of its effects on the human body in daily life is unknown, and prevention is a matter of empirical trial and error. Compared to anticancer drugs, the development of anti-cancer drugs has been significantly delayed.

[Problems to be Solved by the Invention] First of all, anti-cancer agents must be more safe than anti-cancer and must have no side effects. Secondly, there is a need for the drug to be effective orally so that it can be easily administered in daily life.

Third, it is desired that the drug not only be effective against specific experimental cancers, but also show a wide spectrum of cancers that are actually susceptible.

Based on these points, we believe that it is appropriate to develop anti-carcinogenic agents from among the "biological substances" that exist physiologically in the bodies of higher animals, and as a result of searching for sebum-derived substances, we found that
Among these, we found a substance that satisfies these conditions. These substances are thought to be useful not only for general cancer prevention, but also for preventing recurrence after cancer treatment has been completed, and for preventing occupational cancer or cases where cancer is genetically inherited in the family.

The compound of the present invention is chemically stable and resistant to cooking, so it can be put to practical use as a food additive, functional food, or health food.

Furthermore, since the compound of the present invention is a substance originally present in sebum, it is expected that the general public will be able to accept it without any resistance.

[Means for Solving the Problems] As a result of intensive research into anti-carcinogenic agents without side effects, the present inventors found that the general formula is ROHOH CH3CH (Ct(2)II CHClI2),
α, wherein R is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and n is an integer of 3 to 21;

It was discovered that β-diol has a remarkable anti-carcinogenic effect. That is, the present invention provides α represented by the general formula (■): (wherein R represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and n represents an integer of 3 to 21);
The present invention provides an anti-carcinogenic agent containing β-diol as an active ingredient.

[Example] In the present invention, the chain length of the alkyl chain of the α,β-diol is such that n in the general formula (I) is an integer of 3 to 21, and R is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. It is something that is. There is a problem that when n is less than 3, no anti-carcinogenic effect is exhibited at all, and when n is greater than 21, the anti-carcinogenic effect is similarly not exhibited. When R is an alkyl group, there is a problem that if the number of carbon atoms is 6 or more, it does not exhibit the anti-carcinogenic effect. In the general formula (II), the cancer prevention effect increases rapidly when the value of n is 12 to 12.
16, and R is a hydrogen atom or a methyl group. Among these, 16-methyl-1,2-heptadecanediol represented by the formula (■): and 1,2-hexadecanediol represented by the formula (I): exhibit particularly high anti-carcinogenic effects and are particularly preferred.

The α,β-diol used in the present invention can be obtained by decomposing natural products such as wax. The natural products used include waxes such as wool wax, spermaceti wax, beeswax, fresh white wax, and carnauba wax.

The α,β-diol used in the present invention can be obtained, for example, by the following method.

(Saponification reaction) For example, a natural product such as wool grease is suspended in water in the presence of an alkali (NaOH) of 1.18 times rRo1, and a saponification reaction is carried out under pressure at 135±5°C with stirring for 3 hours. (using an autoclave).

(Separation of alcohol and fatty acid) H2O and CH3C0C2Hs (hereinafter referred to as
Add MEK), transfer to a separatory funnel, and heat to 70-75°C.
The alcohol is extracted and separated into MEK by heating to . The solvent of the MEK solution of wool alcohol is removed under reduced pressure to obtain wool alcohol as a solid.

(Molecular distillation of wool alcohol) Solid wool alcohol is molecularly distilled to produce a low boiling point fraction (temperature:
<80°C, pressure crab I X LO-2 Torr) is obtained. This fraction is designated as MDI-/Vc.

(Fractionation of MDI-Mc by reverse phase column chromatography) MDI-Nc is fractionated into 6 fractions by reverse phase column chromatography (oven column).

Fractionation conditions filler: ODS crushed, pore size 60, particle size 80/2
00 mesh (product name: YMC・GEI7, manufactured by Yamamura Chemical Research Institute) CHCR3/ CH30H/ H20= 5/15/1
(Volume ratio) Eluent: The first eluted fraction, in other words, the most polar fraction, is designated as ODS#L.

(HPLC fractionation of 0DStIl: separation/preparation of α9β-diol) High performance liquid chromatography of ODS$11 = (HPLC
) to isolate the target compound.

HPLC condition column: TSK gel 0DS-L20T (product name, manufactured by Tosoh, (21.5 (inner diameter) x aoomm>
) Mobile phase: CI+30 II/820-90/1
0 (capacity ratio) flow rate: 5. Oml/min Column temperature: room temperature α, β-diols may be separated and fractionated by other methods. Other methods include, for example, Satoshi Dekan, Makoto Yamanaka, Kikuhiko Saikimoto and Fumio Cyto, Allergens of Lanolin: Part I
and ■, Part I: Isolation and Identification of the Allergens of Hydrogenated Lanolin, Journal.
of the Society of Cosmetic Chemistry, Vol. 34, pp. 99-116 (1983) (SA
TO3HI TAKANO, MAKOTOYAMANA
K.A.

KIKUIIIKOOKAMOTO, and PUM
IO5AITO, Allergensoflanoli
n: parts I and Il, PART
I :l5OLATION AND IDENTIPI
CATIO) J OF THEALLERGENS O
F IIYDROGENATIED LAN0LIN,
Journalorthe 5ocjcty of C
Osmetic Chemists, 34°p99-1
16.1983).

As the α,β-diol, for example, when R is a methyl group, iso-CI6-(Oll)2[14-methyl1
．． 2-Pentadecanediolco, iso-017-(01
()2 [15-methyl-1,2-hexadecanediol], iso-〇+a -(OH)2 [1[i-methyl-1,2-heptadecanediol], iso-〇+s -
Examples include (OH)2[17-methyl-1,2-octadecanediol], iso-020-(Ol(h[18-methyl-1,2-nonadecanediol], and R is a hydrogen atom). At some point, Cps −(OH)2
[1,2-Pentadecanediol], Cl6-(OH)
2[1,2-hexadecanediol], Cl7-(Ol
l) 2 [1,2-heptadecanediol], Cps
-(OH)2 [1,2-octadecanediol], C
Examples include 19-(Of()2[1,2-nonadecanediolko).

These diols may be used alone or in combination of two or more.

To make the anti-carcinogenic agent of the present invention into a preparation for injection or infusion, Pluronic F-68 (trade name, manufactured by Kyodenka Kogyo ■), l
Add a surfactant such as Ic0-60 (trade name, manufactured by Nikko Chemicals) and disperse it using ultrasound, or make it into liposome or oil-in-water emulsion, and add a preservative such as methyl p-hydroxybenzoate, lecithin, or linoleic acid. stabilizers such as
A non-aqueous vehicle such as coconut oil, a suspending agent such as glucose may be included.

In addition, to make a light-tasting preparation, capsules suitable for intestinal absorption must contain a binder such as gelatin, a stabilizer such as magnesium stearate, an excipient such as lactose, and a disintegrant such as potato starch. Enteric coatings can be formed using cellulose acetate phthalate, methyl acrylate/methacrylic acid copolymers, etc. In addition, it can be formulated as granules, sustained-release implantable capsules, halved capsules, nebulizers, and buccal preparations.

The anti-carcinogenic agent of the present invention is administered parenterally, such as by intravenous, subcutaneous injection, or infusion, at a dosage of the active ingredient (adult body weight 1
kg, per day) 10-1500■, especially 50-4
00II1 g is preferable, and for oral administration agents such as capsules, 0.2 to 50 g1 is particularly preferable, and 1 to Log is preferable.

The anti-carcinogenic agent of the present invention is effective not only against ascites cancer and leukemia, but also against solid cancers, and has a wide range of indications including adenocarcinoma, squamous cell carcinoma, undifferentiated cancer, and sarcoma of various tissues. has. In addition, it is effective against cultured malignant cells of humans, mice, rats, hamsters, etc., as well as animals with cancer transplants, so it has a direct cancer cell killing effect and is not species-specific.
It can be used in medicine and as a cancer chemotherapeutic agent for livestock and animals.

Furthermore, in addition to direct administration to the tumor implantation site, 1 Therapeutic effects are also observed when administered remotely. Toxic LDs.

is 5.4 to 18 g/kg by subcutaneous injection in rats, and 1 to 18 g/kg.
No side effects were observed even after continuous administration of 2 g'/kg for 10 days.

The method for producing α,β-diol, which is an active ingredient of the anticancer agent of the present invention, will be explained below with reference to Examples, but the present invention is not limited to these Examples.

Example 1 200g of wool alcohol obtained by saponifying wool grease was subjected to molecular distillation to obtain a low boiling point fraction MDI-#
c (Temperature: <80℃, pressure crab lX1O-2Tor
I gained 15.2g of r).

MDl#c was subjected to reverse phase column chromatography (open column), and mobile phase Ct (Co3/CH3011/
+20 = 5/15/1 (volume ratio) into 6 fractions.

Among these, the two parts with the highest polarity (ODSIII) are 1.
I got 36g.

0DS41 by high performance liquid chromatography (HPLC)
The target compound was isolated. ■, 2-hexa2-decanediol, 16-methyl-1,2-heptadecanediol, 17-methyl-1,2-octadecanediol, 1,2-octadecanediol, 14-methyl-1
, 2-pentadecanediol, and 1,2-tridecanediol were obtained.

It was then confirmed by capillary gas chromatography that each diol was clearly isolated.

For structure determination, C-NMR and GO-MS were used, and the isolated substance was identified to be a diol group represented by the general formula of the present invention.

■, 2-hexadecanediol is shown in Figure 2.
C-NMR spectrum (100,40MHz, CD
Cl 3) δ (ppm) is shown, and GC-MS data is shown in FIGS. 3 and 4. Also 16-methyl-1,2
-For heptadecanediol, "'C-" is shown in Figure 5.
NMR spectrum (100,40MHz, CDCl
3) δ (ppIll) is shown, and G is shown in Figures 6 and 7.
C-MS data is shown. The data in FIGS. 3 and 6 are based on IEI mode, 70 eV ionization voltage,
The data in Figures 4 and 7 were measured under the condition that the ion source temperature was 250q °C.
Measurements were made under the conditions that the ionization voltage was 200 eV and the ion source temperature was 250°C.

The diol isolated here is used as an anti-carcinogenic agent.
It was subjected to an in vivo test.

Test Example 1 Using 16-methyl-1,2-heptadecanediol as a carcinogenic agent, 90 6-week-old SD female rats)
The following measures were taken.

Non-administration group: 30 animals Oriental yeast as basic feed■
They were fed MP powdered feed manufactured by

Administration group A: 30 animals As a test feed, a mixture of the above carcinogenic agent mixed with Pluronic F-68 at a rate of 50 mg/kg after emulsification was fed to the basic feed continuously (for 7 days).

Administration group B: 30 animals The above-mentioned anti-carcinogenic agent was mixed with the basic feed at a ratio of 1 g/kg of 2501I after emulsification in pull-mouth F-68 and was continuously fed (for 7 days) as a test feed. .

There was no significant difference in the amount of food intake between the administration groups.

After the treatment, 5 mg/mouse of benzanthracene (DMB
A: carcinogen) was administered by subcutaneous injection into the mammary gland at 1 ml/mouse of a 50 mg/ml solution of benzanthracene, and then each of the above-mentioned administration groups was given each of the above-mentioned feeds for 20 weeks.

There was no significant difference in the amount of food intake between the administration groups.

After completion of the above treatment, the test rats were sacrificed and the development of breast cancer was observed. The results are shown in Table 1.

[Margins below] Katana table b Test example 2 Male Wistar rat (8-9 weeks old, weight 110 g) 4
For 0 animals, drinking water and feed (dried pellets CB-2, CLE
(manufactured by A Japan) for 210 days.

After the 210th day, adenoma-like hyperplasia (
hyperplasia) was observed in the stomach.

After day 211, the rats were divided into 5 groups and subjected to the following treatments.

Non-administration group: 28 animals Administration group A: 8 animals Compound A of the present invention (see below, the same applies hereinafter) 25 On + g/kg feed x 126 days continuous oral administration Administration group B: 8 animals Compound B of the present invention 250 mg/kg
Feed x 126 days continuous oral administration Group C: 8 animals Inventive compound C 250 mg/kg feed x 126 days continuous oral administration Group D: 8 animals Inventive compound D 250+ng/k
g feed x 126 days continuous oral administration A: 1,2-octadecanediol B: 17-methyl-1,2-octadecanediol C: 1,2-hexadecanediol D: 16-methyl-1,2-hepta Decanediol 33
On the 70th day, surviving rats were sacrificed, and the stomachs were (1) visually observed and classified according to Borrmann classification and (
2) Histologically observed (hematoxylin and eosin staining or ASAN staining) and classified as follows, and the results are shown in Table 2.

Grade 0: Gastric carcinoma not found Grade I: Gastric carcinoma, intramucosal grade ■: Gastric carcinoma, infiltrating into the submucosal layer ■: Gastric carcinoma, infiltrating into the muscle layer, even the purpura grade ■: Gastric carcinoma, nearby Metastasized to lymph nodes, duodenum, and jejunum8 9 Test Example 3 Initial shake 0 was administered to 6 groups of 6-week-old F344 male rats.
．． 05% (weight%, the same applies hereinafter) N-butyl-N-(4-
Hydroxybutyl) nitrosamine (BBN: bladder photocarcinogen) aqueous solution was administered in a water bottle for 4 weeks, and then for 32 weeks, 5% sodium erythorbate aqueous solution and compounds of the present invention A-E (described below) were administered as promoters (carcinogenic substances). A feed containing 250 mg/kg of MP powdered feed manufactured by Oriental Yeast ■ as a basic feed was administered.

A: 16-methyl-1,2-heptadecanediol B
: 1,2-hexadecanediol C: 14-methyl-
1,2-pentadecanediol D: 1,2-tridecanediol E: 17-methyl-1,2-octadecanediol There was no significant difference in feed intake between each administration group.

After the above treatment, the test rats were sacrificed and the development of bladder mucosal lesions was observed.

The results are shown in Table 3.

[See below for margin 2] [Effects of the invention] The anti-carcinogenic agent of the present invention exhibits an excellent anti-carcinogenic effect, and its active ingredients are derived from living organisms (higher animals).
It does not show any serious side effects to living organisms.

[Brief explanation of drawings]

FIG. 1 is a flowchart showing the method for producing α,β-diol in the present invention. Figure 2 shows 13C-NM of 1,2-hexadecanediol.
It is a chart showing an R spectrum. FIGS. 3 and 4 are charts showing GC-MS of 1,2-hexadecanediol. Figure 5 is a chart showing the C-NMR spectrum of 16-methyl-1,2-heptadecanediol. Figures 6 and 7 are GC-NMR spectra of 16-methyl-1,2-heptadecanediol. This is a chart showing the MS. 3 Procedural amendment (voluntary) 2 Name of the invention Anti-carcinogenic agent 3 Person making the amendment and 1 other person 5 Subject of amendment (1) 6 amendments to the “Detailed description of the invention” column of the specification Contents (1) "Anticancer agent" in line 5 on page 12 of the specification is amended to read "anticancer agent."that's all

Claims (1)

[Claims] 1 General formula (I): ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and n is 3 to 21 α, which represents an integer of
, an anti-carcinogenic agent containing β-diol as an active ingredient. 2. In the general formula (I), R is a hydrogen atom or a methyl group, and n is an integer of 12 to 16. Claim 1
The listed cancer prevention agents. 3. The anti-carcinogenic agent according to claim 1, wherein the active ingredient is 16-methyl-1,2-heptadecanediol represented by formula (II): ▲Mathematical formula, chemical formula, table, etc.▼(I). 4. The anti-carcinogenic agent according to claim 1, wherein the active ingredient is 1,2-hexadecanediol represented by formula (III): ▲Mathical formula, chemical formula, table, etc.▼(III).