JPH0259834B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel antitumor agents and ethylene glycol derivatives. More specifically, the invention relates to the formula [In the formula, R ¹ represents an aliphatic hydrocarbon residue having 8 to 26 carbon atoms, and A ⁺ represents a cyclic ammonio group] or a salt thereof; and ethylene glycol represented by the above formula (). The present invention relates to an antitumor agent containing a derivative or a salt thereof. Regarding the above formula (), the number of carbon atoms represented by R ¹ is 8
-26 aliphatic hydrocarbon residues include linear or branched saturated or unsaturated groups, such as alkyl groups and alkenyl groups, and alkenyl groups include Z and E configurations. . These groups have substituents such as hydroxyl group, mercapto group, amino group, oxo group, carbamoyl group,
It may have a carboxyl group, halogen, C _3-7 cycloalkyl group, phenyl group, etc. More specifically, R ¹ includes, for example, a C _10-20 alkyl group [e.g., n-dodecyl, n-tridecyl, n-tetradecyl, 3,7,11-trimethyltetradecyl, n-pentadecyl, n-heptadecyl, n- −
octadecyl, n-icosanyl, n-docosanyl, dihydrophythyl], C _10-20 alkenyl group [e.g., 8-tridecenyl (△ ⁸ ), 3,7,11-trimethyl-2,6,10-dodecatrienyl, 8-
Tetradecenyl (△ ⁸ ), 8,11-tetradecadienyl (△ ^8,11 ), 8-heptadecenyl (△ ⁸ ), 1-
Heptadecenyl (△ ¹ ), 8,11,14-heptadecatrienyl (△ ^8,11,14 ), 8,11-octadecadienyl (△ ^8,11 ), 4,7,10,13-nonadeca Tetraenyl (△ ^4,7,10,13 ), phytyl, 12-(2,3-cyclopentenyl)dodecyl, 12-(2,3-cyclopentenyl)-5-dodecenyl, 11-hydroxy-8-heptadecenyl, 3,7-dimethyl-9
-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenyl, C _14-24 aralkyl group [e.g., 15-(4-n
-butylphenoxy]pentadecyl, ω-(p-
tolyl)heptadecyl, 6-(4-n-pentylphenoxy)hexadecyl, others, 4,7,
10,13-nonadecatetraenyl, heptadecane
Examples include 8-ynyl. Cyclic ammonio group as A ⁺

[Formula] includes, for example, a pyridinio group, an oxazolio group, a thiazolio group, a pyridazinio group, a quinolinio group, an isoquinolinio group, and these groups can further be replaced by a C _1-4 alkyl group (e.g., methyl, ethyl), hydroxyl group, etc. group, hydroxyethyl group, aminoethyl group, amino (imino)
It may have a substituent such as a group, a carbamoyl group, or a ureido group. The above cyclic ammonio group has
When any two groups of R ² , R ³ , and R ⁴ form a ring with a quaternary nitrogen atom, and the remaining one group is, for example, a C _1-4 alkyl group (e.g., methyl, ethyl), Specifically, it includes cases where groups such as N-methylmorpholinio group and N-methylpiperazinio group are formed. Note that the compound () is, for example, the formula [In the formula, X ^- represents an anion such as chlorine, bromine, or iodide ion] and [In the formula, M ⁺ represents an alkali metal (eg, Na, K) ion] It may also exist in the form of a salt. Also alkaline earth metals (e.g. Ca,
K) Forms salts with ions. The above compound () can be produced, for example, by the following method. formula [In the formula, R ¹ has the same meaning as above] [In the formula, X and Y mean halogen (e.g. chlorine, bromine, iodine)] By reacting the compound, the formula [In the formula, R ¹ , A compound represented by the formula [wherein R ¹ and Y have the same meanings as above] is obtained. By reacting this with a compound of the formula A () [wherein A has the same meaning as above], a compound () is obtained. In this case, the compound of formula () can be prepared by known methods,
For example, Yoshiro Abe, Shoichiro Watanabe: Industrial Chemistry Magazine 66
1842-1844 (1963), Ryohei Oda, Kazuhiro Teramura, "Synthesis of surfactants and their applications," Maki Shoten, p141-143, or Wrigley et al.: Journal of Organ Chemistry (J.Org.Chem), 25 , 439 (1960) )
It can be produced by the method described in . Compound () which is an active ingredient of the antitumor agent of the present invention
and its salts have anti-proliferative and differentiation-inducing (cancer-eliminating) effects on tumor cells (e.g. mouse spontaneous myeloid leukemia cells MI, mouse Lauscher virus-induced leukemia cells R-453, human myeloid leukemia cells HL-60). shows. It also exhibits antitumor activity even in tumor systems with relatively slow growth rates (in vivo). In this case, host-mediated antitumor effects such as activation of macrophages are observed in addition to cell killing and differentiation-inducing effects on tumor cells. Specifically, spontaneous cancers in mice or rats, solid cancers induced by carcinogens, breast cancer-derived cells MM46, and Ehrlitsu
It shows a survival effect when administered to animals bearing tumors such as carcinoma and sarcoma 180, or to nude mice transplanted with human cancer. Compounds () have relatively low toxicity, and the hemolytic properties of these compounds are generally low. In these compounds, the influence of the chain length of R ¹ changes depending on its combination with other parts of the molecule. Generally, the bactericidal effect on tumor cells is strong at C ₁₆ - C ₁₉ , and the host-mediated antitumor effect such as immunostimulation is strong at C ₁₂ - _{C 15} due to the differentiation induction effect at C ₁₉ - C ₂₆ . . Further, when R ¹ contains a double bond or when A ⁺ is a cyclic ammonio group such as a pyridinio group, the hemolytic property is further reduced. The antitumor agent of the present invention is suitable for leukemia, solid cancer (e.g.
When administered to warm-blooded animals suffering from malignant antitumor diseases such as gastrointestinal cancer and lung cancer, it can have a significant survival effect.
Compound () is usually obtained as a crystalline powder or powder, and exhibits sufficient hydrophilic and lipophilic properties. Therefore, the dosage forms of antitumor agents include injections, tablets, capsules, liquids, ointments, etc. These include various pharmaceutical compositions, which can be safely administered parenterally or orally. Formulation of injections, drip injections, etc. is carried out in accordance with conventional methods using, for example, physiological saline or an aqueous solution containing glucose and other adjuvants. Tablets, capsules, etc. can also be prepared according to conventional methods. These dosage forms are used in dosage unit form depending on the purpose of administration, for example, in the case of injections, by an appropriate administration route such as intravenous, subcutaneous, or direct administration to the affected area. The dose for tumor-bearing warm-blooded animals is usually about 0.1 to 100 mg/Kg (body weight) of the compound ().
It is preferably in the range of about 0.5 to 30 mg/Kg (body weight) and can be appropriately determined depending on the symptoms, administration route, etc. As for the frequency of administration, the drug can be applied daily or at intervals of 2 to 7 days. In addition, in order to maintain the drug concentration in tissues at the required level for a long time,
Administration 1 to 3 times a day or intravenous drip infusion over a long period of time is also possible. Furthermore, the compound () has antifungal action. Such antifungal effects include, for example, anti-trinea, anti-Cryptococcus neoformans, and anti-yeast effects, and are useful in the treatment and prevention of diseases caused by these bacteria (eg, ringworm). The antifungal agent is formulated according to a conventional method, and the amount of the active ingredient is not limited, but when used for the purpose of treating tinea, for example, the amount of the compound of the present invention is usually about 0.01% of the entire formulation. -70% by weight, more preferably about 0.1-5% by weight. It is convenient to administer the antifungal agent by applying it to the affected area once to several times a day in a conventional manner, such as by applying it or spraying it. In addition, the compound () has antibacterial activity against plant pathogens, especially molds, and is effective against plant diseases such as rice blast, rice sesame flake, rice micrococcal rot, gray mold, and cucumber anthracnose. It is also useful as a concentrated industrial disinfectant. Concentrated industrial disinfectants are formulated according to conventional methods, and the active ingredient content is usually about 1 to 90% for emulsions and wettable powders, and 0.1 to 10% for oils and powders. For granules, the appropriate amount is about 5 to 50%.
Note that emulsions, hydrating agents, and the like are preferably further diluted (for example, 50 to 5,000 times) with water and the like before being sprayed. Concentrated industrial fungicides can be applied by various application methods known per se, and generally it is sufficient to apply the active ingredient in an amount of about 10 to 300 g per 10 ares.
It is desirable to apply the amount within the range of ~1000ppm. Furthermore, although the compound () generally has a weak effect on bacteria, it has an antiprotozoal effect (e.g., anti-Tetrahymena effect). It can be advantageously used when examining the bacterial ecology of activated sludge or animal body fluids. In other words, when useful bacteria are to be separated from a soil pot, or when the action of protozoa or bacteria other than mold is to be tested in the operation and analysis of an activated sludge method used for wastewater treatment, mold living in the sample is used. Alternatively, it is possible to selectively grow other bacterial organisms without allowing protozoa to develop.
Specifically, a test sample is added to a liquid or solid medium, and about 1 ml of the compound () is added to the medium.
Add 0.1 ml of 10 μg/ml to 100 mg/ml aqueous solution and culture. The present invention will be explained in more detail below using production examples, test examples, and formulation examples, but the scope of the present invention is not limited thereto. Production example 1 2-pentadecyloxyethyl 2-pyridinioethyl phosphate 4.4 g of 2-pentadecyloxyethanol and 5.7 g of 2-bromoethylphosphorodichloridate were dissolved in benzene, and 1.86 g of pyridine was added dropwise while cooling on ice. and stir at room temperature. Benzene is distilled off, water is added, and the mixture is heated to reflux. After cooling, extract with ether,
Concentrate to dryness. The residue was dissolved in pyridine, heated to reflux, and then stirred. After the reaction is completed, it is concentrated to dryness. Add methanol to the residue, add 5.3 g of silver carbonate, and heat to reflux. After heating, the solution was concentrated to dryness to obtain a crude product. The product was purified by chromatography using silica gel and recrystallized from a chloroform-acetone mixture to obtain 3.41 g (57%) of the desired product. Elemental analysis: C ₂₄ H ₄₆ NO ₅ P・0.25H ₂ O Calculated value C62.11; H10.10; N3.02 Actual value C62.03; H10.06; N3.13 Production example 2 2-tetradecyloxyethyl 2-Pyridinioethyl phosphate 5.1 g of 2-tetradecyloxyethanol and 7.6 g of 2-bromoethylphosphorodichloridate are dissolved in benzene, then 2.5 g of pyridine is added dropwise and stirred at room temperature for 3 hours. The solvent is distilled off, water is added, and the mixture is heated to reflux. After cooling, extract with ether and concentrate to dryness. Add the residual pyridine and dissolve.
After heating to reflux, stir at room temperature and concentrate to dryness. Add methanol to the residue, add 7.06 g of silver carbonate, and heat to reflux. After heating, the solution was concentrated to dryness to obtain a crude product. Separated and purified by chromatography using a silica gel column, chloroform-
Recrystallize from acetone mixture to obtain 4.3g of the target compound.
(49%). NMR (CDCl ₃ ) 0.87 (3H), 1.23 (24H), 3.26-4.56 (8H), 4.91
~5.17 (2H), 8.10~8.63 (3H), 9.56 (2H, J=
6.0Hz) Elemental analysis: C ₂₃ H ₄₂ NO ₅ P・0.55H ₂ O Calculated value C62.04; H9.58; N3.10; P6.84 Actual value C60.92; H9.85; N3.11; P6 .63 Production Example 3 2-Octadecyloxyethyl 2-pyridinioethyl phosphate 2-octadecyloxyethanol 2.73g and 2-bromoethylphosphorodichloridate
3.16g was subjected to reaction purification according to Production Example 1 to obtain 840mg (19.3%) of the desired colorless powder. Elemental analysis: C ₂₇ H ₅₀ NO ₅ P Calculated value C64.90; H10.09; N2.80; P6. 2 Experimental value C65.03; H10.19; N3.07; P5.74 Infrared absorption spectrum (KB ) cm ^-1 : 2910, 2850,
1220, 1090 NMR δ ( _CDCl3 ): 0.88 (3H), 1.27 (32H), 3.27
~4.07 (6H), 4.33 (2H), 4.97 (2H), 8.03
(2H), 843 (1H, 9.28 (2H) Test Example 1 Human myeloid leukemia cell HL-60 using the compound of the present invention
Table 1 shows the growth inhibitory effect (GD ₅₀ ) and differentiation-inducing activity. The measurement method is, for example, R. Gallo et al.
The method described in Blood, Vol. 54, No. 3713 (1979) was used.

[Table] Test Example 2 Table 2 shows the antiprotozoal and antifungal effects of the compounds of the present invention. Regarding antiprotozoal effects in Table 2, Tetrahymena
Pyriformis (Tetraphymena pyriformis) W
The strain was used as the test microorganism, and the assay medium [tryptose
Peptone (manufactured by Difco) 20g, yeast extract 1g,
2g of glucose, 1000ml of distilled water, 10ml of 1M phosphate buffer PH7.0] at 28℃ for 44 hours or 48 hours.
After culturing for a period of time, the microbial growth inhibiting ability (MIC) of the compound of the present invention was examined by liquid dilution assay. Regarding the antifungal effects in Table 2, Cryptococcus neoformans (Cryptococcus neoformans)
neoformans) as the test microorganisms, and a paper disc (diameter 8
mm), air-dried, placed on an agar medium, cultured at 37°C for 2 days, and the inhibition circle was measured. An inhibition circle with a diameter of 8 mm or less was judged as -, 8 to 10 mm was judged as ±, 10 to 20 mm was judged as +, and 20 mm or more was judged as +.

[Table] 3 4...

Claims (1)

[Claims] 1 formula An antitumor agent containing an ethylene glycol derivative or a salt thereof represented by the following formula: [wherein R ¹ represents an aliphatic hydrocarbon residue having 8 to 26 carbon atoms, and A ⁺ represents a cyclic ammonio group]. 2 formulas An ethylene glycol derivative or a salt thereof represented by [wherein R ¹ represents an aliphatic hydrocarbon residue having 8 to 26 carbon atoms, and A ⁺ represents a cyclic ammonio group].