JPS6257191B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel carbamate esters useful as medicines or antifungal agents. More specifically, the invention relates to the formula [In the formula, n represents 0 or 1, R ² represents -H or -OCH ₃ , R ⁶ represents an alkyl group or alkenyl group having 17 or 18 carbon atoms, or 9-
(2,3-dimethoxy-6-methyl-1,4-benzoquinon-5-yl)nonyl group, R ³ ,
R ⁴ and R ⁵ represent a lower alkyl group, or [Formula] represents a pyridinio group or a thiazolio group] and salts thereof. Regarding the above formula (), the number of carbon atoms represented by R ⁶ is 17
Examples of the alkyl group of 18 include n-octadecyl and n-heptadecyl. The alkenyl group having 17 or 18 carbon atoms represented by R ⁶ is, for example, 8-heptadecenyl (△
⁸ ),8,11,14 ^- heptadecatrienyl (△ ^8,1
1 , ¹⁴ ), 8,11-octadecadienyl (△ ⁸ , ¹¹ ),
1
-heptadecenyl (Δ ¹ ). Examples of the lower alkyl group represented by R ³ , R ⁴ , and R ⁵ include C _1-3 alkyl groups (eg, methyl, ethyl), and straight-chain alkyl groups are preferred. More specifically, when n is 0, the compound of the above formula () is the compound of the following formula (a) [In the formula, each symbol has the same meaning as above],
When n is 1, the following formulas (b) and (c) [In the formula, each symbol has the same meaning as above]. Further, the compound () may be represented by, for example, the following formula (d),
It may also exist in the form of a salt as represented by (e). [In the formula, X ^- represents an anion such as Cl ^- , Br ^- , I ^- , M represents an alkali metal (e.g., Na, K) or alkaline earth metal (e.g., Ca), and other symbols are as above. Same meaning]. The compound of the present invention () is effective for the proliferation of tumor cells (e.g., murine leukemia cell M1, Laushyavirus-induced murine leukemia cell, Ehrlichi carcinoma, sarcoma 180, B16 melanoma, adenocarcinoma, human myeloid leukemia cell HL60). Warm-blooded animals (e.g., mice, rats, guinea pigs, humans) suffering from malignant tumors, such as leukemia and solid cancers (e.g., gastrointestinal cancer, lung cancer), which exhibit inhibitory effects and can be used as antitumor agents. Administering this drug to patients can have a significant life-prolonging effect. Compound () is usually obtained as a crystalline powder or powder, and has relatively low toxicity and excellent hydrophilicity and lipophilicity. Therefore, when used as the above-mentioned antitumor agent, it can be used in various dosage forms (e.g., injections, tablets, etc.). It can be safely administered parenterally or orally as a pharmaceutical composition (capsules, solutions, ointments). 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 can be administered in dosage unit form depending on the purpose of administration, for example, in the case of injections, parenteral administration such as intravenous, subcutaneous, direct administration to the affected area, and oral administration in the case of tablets, capsules, etc. Used by any appropriate route of administration. The dosage for tumor-bearing warm-blooded animals is generally about 0.1 to 150 mg/Kg (body weight), preferably about 1 to 150 mg/Kg (body weight).
It can be determined as appropriate within a range of about 20 mg/Kg (body weight) depending on the symptoms, route of administration, etc. The frequency of administration is usually 1 to 4 times a day, but in some cases 2 times a day.
Administration at ~5 day intervals is also possible. In addition, the compound () of the present invention has an excellent antifungal effect and a broad antibacterial spectrum, so it can be used as an antifungal agent, such as an antifungal agent, an antitinea fungus agent, an anticandida agent, etc. It is useful for treating and preventing conditions such as athlete's foot (athlete's foot, etc.) and candidiasis. Since the compound of the present invention has low toxicity, it can be used orally for the above purposes, but it is usually preferable to use it parenterally as an external preparation. When used as such an external antifungal agent, the compound of the present invention may be applied as it is in the form of a fine powder, but it is usually preferable to use it in the form of a pharmaceutical composition together with a suitable carrier. Pharmaceutical compositions as antifungal agents can be prepared, for example, by dissolving or dispersing the compound of the invention in a suitable liquid carrier (e.g. a solvent) or by mixing it with a suitable solid carrier (e.g. diluent, filler). or adsorbed thereon, and if necessary, further admixed with suitable additives such as emulsifiers, dispersants, suspending agents, spreading agents, penetrants, wetting agents, etc.
By adding a mucilage, a stabilizer, etc., the formulation can be made into a solution, granule, emulsion, suspension, ointment, powder, spray, paste, poultice, etc. The amount of the active ingredient of the antifungal agent is not limited, but when used for the purpose of treating athlete's foot, the amount of the compound of the present invention is usually about 0.01% of the total formulation.
-70% by weight, more preferably about 0.1-5% by weight. The antifungal agent is administered by applying, spraying, etc. to the affected area once to several times a day in accordance with conventional methods. Furthermore, the compound () of the present invention has strong antibacterial activity against a wide range of plant pathogens, especially fungi, such as rice blast, rice sheath blight, rice micrococcal rot, cucumber anthracnose, and botrytis. It is useful as an agricultural fungicide against plant diseases such as P. aureus. Such agricultural fungicides may be used as solid formulations containing the active ingredients for the purpose of maintaining their efficacy over a long period of time, or they may be dissolved in a suitable liquid carrier (e.g., a solvent) in accordance with conventional methods. or dispersed therein, or mixed with or adsorbed to suitable solid carriers (e.g. diluents, fillers), and further added to emulsifying agents, dispersing agents, suspending agents, spreading agents, penetrating agents, wetting agents, etc. It can be used in appropriate dosage forms such as oils, emulsions, wettable powders, aqueous solutions, suspensions, powders, granules, fine granules, tablets, and sprays by adding agents, mucilages, stabilizers, etc. Good too. The content ratio of active ingredients in agricultural fungicides is
Usually, the appropriate amount is about 10 to 90% for emulsions and wettable powders, about 0.1 to 10% for oils and powders, and about 5 to 50% for granules. In addition,
When using emulsions, hydrating powders, etc., it is preferable to further dilute them appropriately with water (for example, 50 to 5000 times) before spraying. The amount of active ingredients to be used, the combination with other types of chemicals, and the ratio of these combinations depends on various conditions such as the growth stage of the target plant, growth conditions, type of disease, disease onset, and the time and method of application of the medicine. Varies depending on the product, but generally the active ingredients are 10
The amount should be adjusted so that it is about 10 to 300 g per are. In addition, the concentration used is the active ingredient
It should be in the range of 10 to 1000 ppm,
In addition, the methods of use include spraying, dusting, irrigating, coating or dipping seeds on crops, and if it is safe and effective for crops, what amount, concentration, and method of use will be used. However, this does not impose any limitations on the present invention. In addition, the compound of the present invention () generally has a weak action against bacteria, but has an antiprotozoal action, so in addition to the above-mentioned antifungal action, it can be used as an antiprotozoal, antifungal agent, for example, in soil, activated sludge, or animals. It can be advantageously used when examining the bacterial ecology of body fluids. In other words, when separating useful bacteria from soil, or when testing the effects of bacteria other than protozoa or mold in the operation and analysis of activated sludge methods used in wastewater treatment, mold or bacteria living in the sample may be used. 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 an aqueous solution of approximately 10 μg/ml to 100 mg/ml of the compound () is added to each ml of the medium.
Add 0.1ml and culture. The compound of the present invention can be produced, for example, by the following methods A, B, and C. A legal ceremony [In the formula, Y represents Cl, Br or I, and other symbols have the same meanings as above] to a compound of the formula Compound () is obtained by reacting the compound (in the formula, each symbol has the same meaning as above). B legal formula [In the formula, each symbol has the same meaning as above] is reacted with a compound of the formula R ⁶ -NCO () [In the formula, R ⁶ has the same meaning as above], or phosgene is then reacted with the compound of the formula R ⁶ -NH ₂ () [In the formula, R ⁶ has the same meaning as above] is reacted to obtain the compound (). C legal formula [In the formula, X represents Cl or Br, and the other symbols have the same meanings as above] to the compound of the formula [In the formula, X ^- is a halogen ion, OH ^- ,
The compound () is obtained by reacting a compound (representing an anion such as CO ₃ ^-- , sulfate ion, etc., and other symbols have the same meanings as above). Examples of compounds () used in the reaction of Method A, that is, quaternary ammonium formation, include trimethylamine, triethylamine, pyridine, thiazole, oxazole, N-methylmorpholine, N-methylmorpholine, and N-methylmorpholine.
- Examples include methylpiperazine. The reaction is performed by adding a base represented by the formula () to a compound () at 1
The reaction is carried out using an equivalent amount or a large excess (for example, 50 times the mole) at room temperature or under heating (for example, 35 to 200°C) in the presence of a solvent or in the absence of a solvent. Examples of the solvent include methanol, toluene, benzene, ether, dioxane, and tetrahydrofuran. The reaction of method B, that is, carbamate esterification, uses chloroform, dichloromethane,
This is achieved by reacting 1 to 10 equivalents of () with () in the presence of toluene, pyridine, etc. The reaction temperature is preferably about 0 to 150°C. When phosgene is applied to (), phosgene is applied in the presence of a solvent such as toluene, benzene, chloroform, etc. at a temperature of about -20°C to room temperature,
Either as is or after removing dissolved phosgene, () is allowed to react on ice or at room temperature. The reaction of Method C uses a solvent (e.g., chloroform, dichloromethane, pyridine, toluene, dioxane)
In the presence of (), equimolar of () or
This is achieved by applying about 1.5 times the mole at a temperature of 0 to 100°C. In each of the production methods described above, the progress of the reaction can be tracked by thin layer chromatography, and thereby the reaction conditions can be appropriately determined. Purification of the compound produced by the above method is carried out as appropriate by conventional operations, solvent extraction, recrystallization, chromatography, etc. In addition, in the target compound (), n is 1, R ²
When is -OCH ₃ , D-, L-isomers and racemic forms (DL-isomers) exist, all of which are included within the scope of the compounds of the present invention. Each of the raw material compounds in the above methods A, B, and C can be produced, for example, in the following reaction sequence or in accordance with these. [In the formula, each symbol has the same meaning as defined above] The reaction conditions for each of the above steps can be appropriately determined according to the reaction conditions for the above-mentioned methods A, B, and C. In addition, the compound represented by formula () (R ⁶ −
NCO) to the corresponding carboxylic acid
Should Diphenylphosphorylazide be used [K.
Ninomiya, T. Shioiri, S. Yamada: Chem.
Pharm. Bull 22, 1398 (1974)], a method of deriving the corresponding azide from the carboxylic acid and thermal decomposition of this [CFHAllen & A. Bell: Org. Syn., Coll.
Vol. 3846 (1955)], Method of causing phosgene to act on primary amine R ¹ -NH ₂ [NWFarlor: Org.Syn.
, Coll. Vol. 4521 (1963)]. The present invention will be explained in more detail below using Examples and Test Examples, but the scope of the present invention is not limited thereto. Example 1 n-heptadecyl isocyanate 5.68g of stearic acid was dissolved in 50ml of toluene,
Add 5.5 g of diphenylphosphoryl azide (hereinafter referred to as DPPA) and 3.0 ml of triethylamine, and stir at room temperature for 2 hours. After cooling the reaction solution, add 100ml of ether to it.
Add. After washing the ether solution with ice water and separating the organic layer, it is dehydrated using a dehydrating agent and heated under reflux for 2 hours. 5.3 g of the title compound are obtained as a colorless oil. IRν ^film _nax (cm ^-1 ): 2920, 2850, 2270 (-NC
O),
1680. Example 2 3-(N-n-heptadecylcarbamoyloxy)propan-1-ol 5.0 g of n-heptadecyl isocyanate was dissolved in 1,3
-Dissolve in a mixture of 5.7 g of propanediol and 30 ml of methylene chloride, and stir overnight at room temperature. Add 20 ml each of water and chloroform to the reaction solution, separate the organic layer, and concentrate to dryness. Chromatography using a silica gel column (developing solution: chloroform)
The separated solution obtained using water:97:3) was concentrated to dryness to obtain 3.0 g of the title compound as colorless crystals. IRν ^film _nax (cm ^-1 ): 3450, 2920, 2850, 1695
，
1640, 1530. Example 3 3-(N-n-heptadecylcarbamoyloxy)propyl 2-bromoethyl phosphate 2.5 g of the 3-substituted propanol obtained in Example 2 was mixed with methylene chloride-chloroform (5:
2) Dissolve in 14 ml of mixed solution, add 1.72 g of bromoethylphosphoryl chloride, stir overnight at room temperature,
Heat to reflux for 1 hour. After cooling the reaction solution, add water (20ml)
Add and heat for 1 hour. After cooling, extract with chloroform, separate the layers, and concentrate the chloroform layer to dryness to obtain the desired product as a colorless solid. Example 4 3-(N-n-heptadecylcarbamoyloxy)propyl 2-trimethylammonioethyl phosphate The entire amount of the phosphoric acid ester obtained in Example 3 was dissolved in 70 ml of toluene containing 14 g of trimethylamine in an anhydrous state, and 60 ℃ for 48 hours. After concentrating the reaction solution to dryness under reduced pressure, methanol 40
ml, stir vigorously in the presence of 2.7 g of silver carbonate, and heat under reflux for 1 hour. After filtration, the liquid was dried and chromatographed using silica gel (eluent: chloroform-methanol-
After separation and purification with water: 65:25:4), chloroform-
Crystallizes from acetone. 0.9 g of the title compound is obtained as a colorless crystalline powder. IRν ^film _nax (cm ^-1 ): 1690, 1530, 1460, 1230
，
1080, 1050, 950. NMR (60MHZ, CDCl ₃ ): 1.83 (2H, −NH CH ₂
−), 3.13 (2H, −OCH ₂ CH ₂ CH ₂ O−), 3.40
(9H, s, ⁺ ₋ N(CH ₃ ) ₃ ), 3.5 to 1.7 (8H, m,
[Formula]) Elemental analysis: (C ₂₆ H ₅₅ N ₂ O ₆ P・0.37H ₂ O) Calculated value C58.99; H10.61; N5.29 Actual value C58.99; H11.02; N5.35 Implemented Example 5 2,3-dimethoxy-6-methyl-1,4-benzoquinon-5-yl-n-nonyl isocyanate 2,3-dimethoxy-6-methyl-1,4-benzoquinon-5-yl-n-nonanoic acid Dissolve 1.4g in 10ml of toluene, add DPPA1.09g and triethylamine 0.62ml, and stir at room temperature for 3 hours. Ether and ice water are added to the reaction mixture to quickly extract and separate the layers, and the ether layer is dehydrated and concentrated to 5 ml. This is heated under reflux for 3 hours to obtain the desired toluene solution of isocyanate. Example 6 3-[N-(9-(2,3-dimethoxy-6-methyl-1,4-benzoquinon-5-yl)nonyl)carbamoyloxy]propan-1-ol 1,3-dihydroxypropane 3.0 g
(39.5mM) was dissolved in pyridine (6ml), added to the toluene solution of the isocyanate obtained in Example 5, and stirred overnight at room temperature. The reaction solution was concentrated to dryness under reduced pressure, and 20 ml each of water and ether were added to the residue.
Add and perform extraction and separation. After drying the ether extract, it is separated and purified by column chromatography using silica gel (eluent: CHCl ₃ -MeOH, 39:1). Light tan solid, yield
1.3g. Mass spectrum (m/e): 425 (M ⁺ ), 393
(M-OCH ₃ ). IRν ^film _nax (cm ^-1 ): 1700 [formula], 1660, 1650, 1645, 1605 (1,4-benzo-quinone). Example 7 3-[N-(9-(2,3-dimethoxy-6-methyl-1,4-benzoquinon-5-yl)nonyl)carbamoyloxy]propyl 2-bromoethyl phosphate Above carbamic acid-3- Dissolve 12 mg of hydroxypropyl ester in carbon tetrachloride, add 45 mg of bromoethyl phosphorodichloridate, and stir at room temperature for 7 hours. The reaction completed liquid was dried under reduced pressure, a small amount of water was added thereto, and the mixture was stirred overnight in a cool place. Then water and ether were added, and after ether extraction,
This is dried and the target product is purified and separated using silica gel chromatography. Yellow solid, yield 10
mg. IRν ^film _nax (cm ^-1 ): 1700, 1665, 1650, 1645
，
1610, 1530, 1460, 1450NMR (60MHz,
CDCl ₃ ): 1.0−1.7 (16H, m, −CH ₂ ) ₈ −, 2.03
(3H, s, −CH ₃ ), 2.77−3.80 (4H, m), 4.03
(6H,s, _CH3O- ) Example 8 3-[N-(9-(2,3-dimethoxy-6-methyl-1,4-benzoquinon-5-yl)nonyl)carbamoyloxy]propyl 2- Trimethylammonioethylphosphate 10mg of the bromide from Example 7 above was dissolved in 0.5ml of toluene containing 20% trimethylamine, and
Stir for several days. The reaction solution was dried under reduced pressure,
The dry solid is separated and purified by silica gel chromatography (eluent: _CHCl3 -MeOH- _H2O , 60:40:1). Red solid, yield 8 mg. IRν ^film _nax (cm ^-1 ): 1700 ( -CO NH-), 1660
，
1650, 1640, 1610 (1,4-ben-zoquinone),
1550, 1540 (-CONH), 1260, 1230 (CN, P-
O). Example 9 1-N-n-octadecylcarbamoyl-2-
Methyl glycerol Mix 9.7 g of n-octadecyl isocyanate and 3.5 g of β-methylglycerol ether in 20 ml of pyridine and stir overnight at room temperature. Pour the reaction solution into a mixture of 300 ml of ether and 50 ml of water, and neutralize with concentrated hydrochloric acid. The ether layer is separated, washed with water, dried, and concentrated to dryness. Chromatography using a silica gel column (developing solvent chloroform-ether
1:1) gives 8.2 g of colorless crystals. IRν ^Nujol _nax (cm ^-1 ): 3340, 1687. mp 55-56℃ Mass spectrum (m/e): 401 (M ⁺ ), 370 (M
-OCH ₃ ) Example 10 3-(N-n-octadecylcarbamoyloxy)-2-methoxypropyl 2-bromoethyl phosphate 6.0 g of glycerol obtained in Example 9 was dissolved in 30 ml of carbon tetrachloride, and bromoethyl Add 4.0 g of phosphoryl chloride and heat under reflux for 18 hours. After cooling, the solvent is distilled off, 50 ml of water is added to the reaction mixture, and the mixture is heated under reflux for 1 hour. After cooling, ether is added for extraction, and the ether layer is washed with water, dried, and concentrated to dryness to obtain the desired product as a colorless solid. IRν ^Nujol _nax (cm ^-1 ): 3320, 1690 Example 11 3-(N-n-octadecylcarbamoyloxy)-2-methoxypropyl 2-trimethylammonioethyl phosphate Phosphate ester obtained in Example 10 2.0 Dissolve g in 60 ml of toluene containing 10 g of trimethylamine,
Leave at room temperature for 3 days. The reaction solution was concentrated to dryness under reduced pressure, then dissolved in 50 ml of methanol, 2 g of silver carbonate was added, and the mixture was heated under reflux for 1 hour. After filtration, the liquid was dried and subjected to chromatography using silica gel (eluent: chloroform-methanol-water:
65:25:4) and then crystallized from chloroform-acetone to obtain 640 mg of the desired product as a colorless powder. IRν ^KBr _nax (cm ^-1 ): 3350, 1700, 1542, 1470,
1250, 1090, 1060 NMR (60MHz, _CDCl3 ): 0.7~1.8 (35H), 2.9
~4.6 (11H, m), 3.46 (9H, s, Me ₃ N), 3.50
(3H, s, OCH ₃ ) Elemental analysis (C ₂₈ H ₅₉ N ₂ O ₇ P・1.5H ₂ O) Calculated value C56.63; H10.52; N4.72; P5.22 Actual value C56.37; H10 .70; N4.91; P5.38 Example 12 3-(N-n-octadecylcarbamoyloxy)-2-methoxypropyl 2-pyridinioethyl phosphate 2.0 g of the phosphoric acid ester obtained in Example 11 was Dissolve in 20 ml of pyridine and warm at 60°C overnight. Pyridine was distilled off under reduced pressure, 50 ml of methanol and 2 g of silver carbonate were added to the residue, and the mixture was heated under reflux for 2 hours. After that,
The liquid is dried, separated and purified by chromatography using silica gel (eluent: chloroform-methanol-water: 65:25:4), and then crystallized from chloroform-acetone to obtain the desired product. IRν ^KBr _nax (cm ^-1 ): 3340, 1698, 1540, 1470,
1255, 1075, 1050. NMR (60MHz, _CDCl3 ): 0.7-1.8 (35H),
3.44 (3H, s, OCH ₃ ), 2.9-4.8 (9H, m),
5.20 (2H, broad, CH ₂ N〓), 6.16 (1H,
broad, CONH), 8.0-8.8 (3H, m,
pyridinio), 9.58 (2H, m, pyridinio). Elemental analysis (C ₃₀ H ₅₅ N ₂ PO ₇・H ₂ O) Calculated value C59.98; H9.50; N4.63; P5.12 Actual value C59.94; H9.60; N4.61; P5.30 Example 13 3-(N-n-octadecylcarbamoyloxy)-2-methoxypropyl 2-thiazolioethyl phosphate 2.0 g of the phosphoric acid ester obtained in Example 10 and 4.5 g of thiazole were mixed and heated at 60°C for 5 days. Warm up. Thiazole was distilled off under reduced pressure, and methanol 50% was added to the residue.
ml and 2 g of silver carbonate, and heated under reflux for 2 hours.
After filtration, dry the liquid, separate and purify it by chromatography using silica gel (eluent: chloroform-methanol-water: 65:25:4), and crystallize from chloroform-acetone to obtain the desired product. . IRν ^KBr _nax (cm ^-1 ): 3400, 2920, 2851, 1701,
1558, 1246, 1065. NMR (60MHz, _CDCl3 ): 0.7−1.8 (35H),
3.46 (3H, s, OCH ₃ ), 2.9-4.8 (9H, m),
5.08 (2H, broad, CH ₂ N〓), 6.30 (1H,
broad, CONH), 8.55 (1H, broad,
thiazolio), 8.88 (1H, broad, thiazolio), 10.97
(1H, broad, thiazolio). Elemental analysis (C ₂₈ H ₅₃ N ₂ O ₇ PS・1.5H ₂ O) Calculated value C54.26; H9.11; N4.52; P5.00 Actual value C54.30; H8.90; N4.71; P5 .03 Example 14 2-(N-stearylcarbamoyloxy)ethanol 11.8g (40mM) of stearyl isocyanate and 12.4g (200mM) of ethylene glycol were added to 50% of pyridine.
ml and leave at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, and the residue was recrystallized from 100 ml of methanol to obtain 11.38 g (yield: 79.5%) of the desired product. mp81-82℃ Example 15 2-(N-stearylcarbamoyloxy)ethyl 2-trimethylammonioethyl phosphate Dissolve 4.0g (11.24mM) of 2-(N-stearylcarbamoyloxy)ethanol in 12ml of chloroform, and dissolve 2-bromo Ethylphosphoryl dichloride
Add 2.72g (11.24mM) and heat under reflux for 2 hours. Add 40 ml of water to this, heat under reflux for an additional 3 hours, add 40 ml of chloroform, and separate the chloroform layer. This was concentrated to dryness under reduced pressure, and the residue was
% trimethylamine-toluene solution, sealed the tube, and heated at 60°C for 2 days, and the reaction solution was concentrated to dryness under reduced pressure. The residue was dehalogenated using silver carbonate in methanol, then adsorbed onto silica gel (40 g), and the eluent was [chloroform:methanol:water (65:25:4)].
Elute at . The target product fractions are collected and concentrated to dryness under reduced pressure. The residue is dissolved in a small amount of chloroform, and acetone is gradually added to obtain 4.1 g of the target product (colorless powder) (yield: 69.9%). IR (KBr): 3420, 2910, 2850, 1700, 1540,
1465, 1240, 1080, 1050, 965 Elemental analysis: C ₂₆ H ₅₅ N ₂ O ₆ P・H ₂ O Calculated value C57.75; H10.62; N5.18; P5.73 Experimental value C57.72; H10. 64;N5.28;P5.89 Example 16 3-(N-8,11,14heptadecatrienylcarbamoyloxy)propanol Dissolve 5.56g (20mM) of linolenic acid in 50ml of toluene and dissolve 5.5g of diphenylphosphoryl azide.
(20mM) and 3.0ml of triethylamine were added, stirred for 2 hours, concentrated to about 25ml, and heated under reflux for 3 hours. Add this to 6.0g of propanediol
(78.9mM) in 50ml of pyridine and stir overnight. The reaction solution was concentrated to dryness under reduced pressure, the residue was adsorbed on silica gel (50 g), and 2% methanol-
4.0g of target product eluted with chloroform (yield
68.4%). IR (Film): 3350, 3010, 2960, 2930,
2860, 1700, 1540, 1465, 1270, 1140, 1060. Example 17 3-(N-8,11,14-heptadecatrienylcarbamoyloxy)propyl 2-trimethylammonioethyl phosphate 3-(N-8 ,11,14heptadecatrienylcarbamoyloxy)propanol 4.0g
(11.396mM) in 20ml of chloroform and 2-
Bromoethylphosphoryl dichloride 1.74g
(11.396mM) and heated under reflux for 2 hours. After cooling, add 20 ml of water and 20 ml of chloroform, stir vigorously, separate the chloroform layer, concentrate to dryness under reduced pressure, dissolve in 60 ml of 2% trimethylamine-toluene solution, seal the tube, and heat at 60℃ for 2 days. do.
The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in methanol.
After dehalogenation using silver carbonate, it is adsorbed onto a silica gel column (40g). Elute with an eluent [chloroform:methanol:water (65:25:4)], collect the target product fraction, concentrate to dryness, and wash with n-hexane to obtain 3.2 g of the target product in the form of candy (yield 50.9%). obtain. IR (Film): 3350, 3010, 2970, 2935,
2855, 1700, 1540, 1480, 1230, 1140, 1085,
1055, 970. Elemental analysis: C ₂₆ H ₄₉ N ₂ O ₆ P・2H ₂ O Calculated value C56.50; H9.67; N5.07; P5.60 Experimental value C56.40; H9.54; N5.47 ;P5.98 Test Example 1 Mouse spontaneous myeloid leukemia M1 (Resistant clone) of the compound obtained in Example 4, Rausher
The inhibitory effects (ID ₅₀ values) on the proliferation of virus-induced promyelocytic leukemia cells R453 and human myeloid leukemia cells HL-60 were 3-4 μg/ml and 2-4 μg/ml, respectively.
It was 3 μg/ml and 2 to 3 μg/ml. Test Example 2 Tables 1 and 2 show the antiprotozoal and antifungal effects of the compounds of the present invention. Regarding antiprotozoal effects in Table 1, 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 broth dilution assay. Regarding the antifungal effects in Table 1, Cryptococcus neoformans (Cryptococcus neoformans)
neoformans) was used as the test microorganism, and a paper disk (diameter 8 mm) was added to a 2 mg/ml aqueous solution of the test compound.
After soaking and air drying, the cells were placed on an agar medium, cultured at 37°C for 2 days, and the inhibition circle was measured. If the diameter of the blocking circle is 9 mm or less, -, 9 to 11 mm is ±, 12 to 20 mm, +, 20.
A value of mm or more was judged as 〓. Regarding the antifungal activity shown in Table 2, the minimum inhibitory concentration (MIC) was determined by the multiple dilution method using various representative plant pathogenic bacteria as test bacteria using a 1% glucose bouillon agar medium. [Table] [Table] [Table]

Claims (1)

[Claims] 1 formula [In the formula, n represents 0 or 1, R ² represents -H or -OCH ₃ , R ⁶ represents an alkyl group or alkenyl group having 17 or 18 carbon atoms, or 9-
(2,3-dimethoxy-6-methyl-1,4-benzoquinon-5-yl)nonyl group, R ³ ,
R ⁴ and R ⁵ represent a lower alkyl group, or [Formula] represents a pyridinio group or a thiazolio group] or a salt thereof.