JPS5835194A - Carbamic esters - Google Patents

Abstract

NEW MATERIAL:A compound (salt shown by the formulaI[n is 0 or 1; R<1> and R<2> are H, -OCH3, -OCONHR<6>(R<6> is 8-26C aliphatic hydrocarbon residue), at least one of R<1> and R<2> is -OCONHR<6>; R<3>-R<5> are H, lower alkyl, or cyclic ammonio group as a group shown by the formula II]. EXAMPLE:2-(N-n-Dodecylcarbamoyloxy)ethyl 2-trimethylammonio-ethyl phosphate. USE:An antitumor agent against leukemia, solid cancer, etc., antifungal agent, antifungal substance. Having low toxicity. Orally (parenterally) medicated and its dose is 1-20mg/kg-weight. PROCESS:For example, a compound shown by the formula III (Y is Cl, Br, or I) is reacted with a compound shown by the formula IV to give a compound shown by the formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel carbamate ester, A/ll11K, which is useful as a medicine or an anti-imaging agent.

More specifically, the present invention relates to the formula [where n#'i0 [the circle represents 1, R1 and R1! Ha-
H, -0CH3 represents 10CONHR6 (R6 represents an aliphatic hydrocarbon residue having 8 to 26 carbon atoms), and relates to its woodcutter.

Regarding the above formula (1), as the aliphatic hydrocarbon residue having 8 to 26 carbon atoms represented by H6, linear or branched saturated or unsaturated groups such as alkyl A/'&, alkenyl N These groups include substituents such as hydroxyl group, mercapto group, amino group, oxo1&, carbamoyl group, carboxyl group, halogen eC3-7 cycloalkyl group, phenyl group, 2,3- It may have a $'methox/-6-methyl-1,4-benzoquinon-6-yl group, etc. More specifically, R6 is a cig-gg alkyl group (e.g., n-octadecy~
.

n-Hedetade Vru) Bentade $/A/, Tetofude ysy
, tride S/#, dodey)v, icosanil, docosani-, dihydrophytyl) e Czz-zt Aμkeni-group [e.g., phytyl, 8-he1-tadecenyl (△8),
8-tetofdecenyl (80), 8-)9decenyl (Δ8
), 3-tridecenyl (△3), 8,11.14-hebutadecatrienyl (Δ8・11.14), f3, 1
1- Otaku! Decajenil (△8・11), 4,7,10
．． 13-nonadecatetopheny A/(Δ4,7,10゜1
3), 1-to-1 tadecenyl (△l), 12-(2゜3-
V clopentenyl→-dodashi#, 12-(2,3-cyclobenteny~)-dodecane-6-enyl, 11-hydroxyS/-? -737decenyl.

3.7-dimethy*-2-(2,a,a-)limethy A/-
1-5/Kurohetosen-1-Il&/)-2,riζ,r
7/natetophenyl], C16-26 aph-kyl group [e.g., 15-(4-n-butylphenoxy)pentadecifiz, (Ml-p-)ruyl-hetade VA
/1.9-(2,3-dimethoxy,-5-methyl-1,
4-benzoquinon-6-yl)nonanyl group, 4.7,1
0.13-nonadecatetophynyl group, heptadecane-8
-ynyl group, etc.

The lower alkyl μ group represented by R3, R4 and R5 is, for example, a C1-31 group (e.g. methyl, ethyl
/), [alkyl group whose chain alkyl group is 01-4 (e.g., methyl, ethyl A/), hydroxyethyl group,
Amino group, μ-pamoyl group.

It may have a substituent such as a ureido group, and
! The cyclic ammonio group is specific when it is R1, R4 and a group (eg, methyl, ethyl A/).

In the definition of each group in the above formula (1), n is 1, R1 is 10CONHR6 (R6 is an alkyl group having 10-18 carbon atoms, alke is a cyclic ammonio group (especially a pyridinio group).

thiazolio group) are preferably used.

More specifically, when KFin is 0, the compound of the above formula (1) is represented by the following formula (I&) [wherein, each symbol is uniquely expressed as above]; when n is 1, it is represented by the following formula (lb ), (io) and (ld) CH20
CONHR6 CH20CONHR6 ■ H2R1 [In the formula, each symbol has the same meaning as above].

In the above compound (1), when R3, R4 and R5 are aqueous, formula (1) can also be expressed as the following formula (le).

H2R1 n The migratory compound (1) is, for example, the following formula (If).

It may also exist in the form of a filler as shown in (1g).

H2R1 1 H2ft1 [In the formula, X- represents an anion such as C1'-, Br, I-, etc.; The symbol is curvature and 1iiiit! II! ).

Representative examples of the compound &(1)O of the present invention include the following compounds.

2-(N-n-dodeFA/Force~Bamoi poxy)eth,
4'2-trimethymuammonioethylphosphate),
a-(M-n-dodes/fi/forceμbamoyloxy)-
2-Methoxyzolo'A/2-)limethylammonioethylphosphate), 3-(M-n-dodecyl-pamoyoxy)propyl A/2-aminoethylphosphate),
3-(1-n-dodeVcarbamoy-oxy)propyl 1
4/2-trimethylanthonioethyl σ), 3-
(11-n-tridecyμcarbamoyμoxyS/)-2-
Methoxypropyl 2-)limethylammonioethylphosphate, 3-(N-n-)lysoy)vcarbamoyloxy)propyfi/2-)limethylammonioethylphosphate), 3-(N-n-)lyso Decyl Kalpamoiy
oxy)-2-methoxypropyl 2-pyridinioethyl phosphate), 3-(M-n-trideVlucarpamoyloxy)-2-methoxypropyl 2-thiazolioethyl phosphate), 3- (M-n-)lysoV~carbamoy~oxy)propyl 4/2-pyridinioethyl phosphate), 3-(N-n-)libsylcarbamoyl oxyV)
Propyl A/2-(4!-Carbamoylviridinio)ethylphosphe-), 3-(N-n-tetofdecylcarpasoyloxyF)-2-methoxypropyl 2-trimethylammonioethylphosph21), 3 -(N-n-tetofdecylcarpamoy~oky)-2-methoxyV noropiA'
A' Power, 4/A Moi〃Oki S/)-2-MeF
? r￥NoropylL/2-thiazolioethylphosphate)
, 3-(N-n-tetofude Vlucarpamoy-oxy)propyl 2-trimethylammonioethylphosphate
), 3-(M-n-tetowodeshiivybamoiloki￥)
Professional? "A/ 2-aminoethyl phosphate, 3-
(M-n-tetofdecylcarpamoyloxyV)propyf
i/2-pyridinioethyl phosphate, 3-(N-n
- Tetofudecy Carbamoyl Oki V) Propyi I&/2-
(Ghiaminopyridinio) Ethyl Honsufuni? , 3-(
N-n-tetofdecylcarpamoyloxyp)propyl
2-thiazolioethyl phosphate, 3-(N-2-8
-heptadecenyl force N bamoyl oki V) propyl 2-
Trimethylan amount nioethyl sphni), 3-()i
-2,2-8,11-hebutadecagenyl rupamoi μ
Oxy) Propyl 2-trimethylammonioethylphosphate.

3-(N-n-to 1 Polygonum V Carbamoyl Oki V)-2
-Methoxypropyl -n-octadecylcarba(yloxyl V)-2-methoxypropyl N
2-pyridinioethyl phosphate, 3-(carbamoyloxy to M-n-otata fS7)-2-methoxyprohyA/2-thiazolioethyl phosphate This @light compound (1) is a leucoid cell M
l. Mouse leukemia NIMIM8.
Ni-Ritsuhika nanoma, sarcoma 180. B16
In addition to inhibiting the growth of Mefunoma, Azotsuka V-tinoma, and human myeloid leukemia (HL60), it also induces differentiation and promotes immunostimulation. Bleeding animals suffering from oval ulcers (
For example, mice, rats, mofi/set, humans) When administered as an antiswine tumor field, K can have a significant survival effect.

When used as the above-mentioned anti-stick Mk-, the pharmaceutical composition of various dosage forms (e.g., injection 9 tablets, turnip 7-tablet, liquid field, #plasty) is obtained. It can be safely administered parenterally or orally as a drug. Steel production of injections and the like is carried out in accordance with conventional methods using, for example, physiological saline or a water bath solution containing glucose and other auxiliary agents. Vil sardines, capsules, etc. can also be produced according to conventional methods. These fields are administered in the form of injection units depending on the purpose of administration, for example, in the case of injection steel, intravenous administration, subcutaneous administration, parenteral administration such as direct administration to the affected area, tablets, T1 drug, etc. In this case, it is used by an appropriate projection path, such as by evacuation of the pus. The dosage range for tumor-bearing warm-blooded animals is generally about 0.1 to 150 kg/kg (body weight), preferably about 1 to 2 oq/kg (body weight), to reduce symptoms,
It can be determined as appropriate depending on the route of administration, etc. The frequency of administration is usually 1 to 4 times a day, but in some cases 2 to 4 times a day.
Administration at 5-day intervals is also possible.

In addition, the compound (1) of the present invention has an excellent effect on L1
The Makurazaki spectrum is wide, so it is used as an antifungal agent, an antifungal agent, an antiwhitening agent, an anticandida fungus, etc. for the treatment and prevention of candidiasis (e.g., athlete's foot, etc.), and candidiasis. It is useful for

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 used 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 anti-inflammatory agents can be prepared, for example, by dispersing or dispersing the compound of the invention in a suitable liquid carrier (e.g. HA&I) or in a suitable solid carrier (e.g. diluent, bulking steel). ), or adsorbed thereon, and if necessary, further adsorbed thereto with suitable additives, such as emulsifiers, dispersants, clouding agents, spreading agents, penetrants, moisturizers, etc. For example, by adding mucilage, stabilizer, etc., it can be made into a solution.

Granules, emulsions, suspensions, ointments, powders, sprays.

It can be made into dosage forms such as pasta fields and poultices.

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 to 70% by weight, preferably about 0.01 to 70% by weight based on the entire preparation. It is about 0.1 to 5% of electric power. Antiviral vMfd
4 is administered according to a conventional method by applying or spraying one to several liters per day on the affected area.

Furthermore, the compound (1) of the present invention has strong antibacterial activity against a wide range of plant pathogenic bacteria, especially fungi, such as rice blast, rice sheath blight, rice subregion #i nuclear blight, and cucumber leg rot. It is useful as an agricultural fungicide against plant diseases such as botrytis blight and gray mold.

Such agricultural fungicides may be used as solid formulations containing the active ingredients for the purpose of maintaining efficacy for a long period of time, or
In addition, a suitable liquid carrier (for example, agent #I) can be added according to a conventional method.
K is dissolved or dispersed therein, mixed with or adsorbed to a suitable solid carrier (e.g. diluent, filler), and further added with an emulsifier, dispersant, suspending agent, spreading agent, etc. Penetration solution, wet pigeon agent, slime field, stabilizer, etc. are added, oil M, emulsion, wettable powder, bath agent, suspension field, powder 2
It may be used in an appropriate form such as granules, I1 granules, tablets, and propellants.

The content of active ingredients in agricultural offset IJIIIAIIK is usually about 10 to 90% for emulsions and hydrating agents, and about 0.1 to 10% for orchid powder, powder, etc.
Appropriate Vi for granules is about 5 to 50%. In addition, when using milk powder, hydrating powder, etc., dilute it with water, etc.
For example, 50 to 5000 times) and spraying is recommended. The amount of active ingredients to be used, combinations of mixtures with other drugs, and their mixing ratios are based on the growth stage of the target plant, growth conditions, disease IUI, disease state, time of application of the drug, application method, etc. Generally, the amount of active ingredient may be adjusted to about 110 to 300 g per 10 ar, although it varies depending on the conditions. In addition, the concentration of the active ingredient may be in the range of 10 to IQOOppm, and the method of use may be by spraying, dusting, irrigating, or coating or soaking the seeds. As long as it is used safely and effectively, it does not impose any restrictions on the present invention, regardless of the amount, concentration, or method of use.

In addition, although the compound (1) of the present invention generally has a weak action against #iK, it has an antiprotozoal action, so the above-mentioned O
! In addition to fL fungal action, it can be used as an antiprotozoan, antifungal agent, for example, in soil, activated sludge, animal body fluids, etc.
It can be used advantageously when examining the order of birth. 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, molds living in the sample are used. Alternatively, it is possible to selectively grow other bacteria without growing protozoa. Specifically, a test sample is added to a liquid or solid medium, and compound (1) is added per 1 wt of the medium.
About 10 μg/d-100 μg/d of an aqueous solution is added for 0.1 d and cultured.

The compounds of the present invention can be produced, for example, by the following methods.

A method % Formula % ([In the formula, Y indicates C1, Bri or Engineering, and other symbols are the same as in the d period: ta) to the compound of the formula [In the formula, each symbol has the same meaning as above] Compound (1) is obtained by reacting the compound (1).

B formula % formula %) [In the formula, each symbol has the same meaning as above] to the compound of formula R6-N
GO (Ma) [In the formula, R6 has the same meaning as above] by reacting the compound, or by reacting phosgene with a compound of the formula % () [In the formula, the same meaning as the Ra unit] Compound (1'') Yt is obtained.

C method dog H2R1 [wherein,
Compound (1)
get.

Examples of compounds used in the reaction of method A above, i.e., 4-test ammonium formation, include trimethylamine, triethylamine, pyridine, thiazo-, oxazo-
Examples include I/, M-methyl 77-holin, N-methylbibefudin, and the like. The reaction is carried out by adding one group represented by formula (1) to compound (1) in an amount of 1 equivalent or a large amount (e.g., 50 times
) K at room temperature or under heating (e.g. 35-200
°C) in the presence of a solvent or without a melt rope. Examples of the solvent include methanol, toluene, benzene, ether, dioxane, and tetofhydrofuran.

The reaction of Method B, ie, the esterification of chlorine and pamine, uses chloroform and dichloromethane as the M strategy.

(W&) or (lb) in the presence of toluene, pyridine, etc.
) This is achieved by applying 1 to 10 equivalents of (ma) to K. The reaction temperature is preferably about 0 to 150°C. When phosgene is allowed to act on (ffa) or (IVb), phosgene is made to act in the presence of a solvent such as toluene, benzene, chloroform, etc. at a temperature of about -20 to room temperature.
Either as is or after removing the phosgene present in the bath,
(W) is reacted under water cooling or room temperature.

In the reaction of method C, (
This is achieved by allowing approximately 7 to 1.6 times the mole of (2) to act on (2) 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 using normal operations.
It is suitably clarified by # line extraction, recrystallization operation, chromatography, etc.

In addition, in the target compound (1), n is 1. R2 is 10C
R3 or 1000N! D- for lR6.

Although the L-isomer and the TS-isomer (DL-isomer) exist,
All of these are included within the scope of the compounds of the present invention.

Each of the starting compounds in Methods M, B, and C above can be produced, for example, by the following reaction routes or in accordance with these.

ill (M) b) [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 of the above-mentioned M, B, and C methods.

In addition, the compound (B&-H) represented by formula (ma) is the corresponding carboxylic acid 11c Diphenylphoap
Let hory-1gglde act (H,)i
inomiya,? .

8hioiri, 8. Yamada: Chem, Pha
rm, Bul122, 1a9s(1sy+)), a method of deriving the corresponding azide from the bonic acid and thermal decomposition of this [C, F, H, A11en & M, Bs1l
: Org, 8yn, .

Co11. Vol. 3, 846 (1955)), Method of acting with primary amine R1-11H2K phosgene ()
j, W.

F'ar1or: Org, Syn,, Co11. Vol.
, 4,521 (1963)) K.

When 116 has an active substituent such as an amino, hydroxyl, or carboxyl group, it is protected with a commonly used protecting group, and then converted to the formula (1) through the reaction described above.
) After synthesizing a compound having one protective group, the protecting group is removed by a conventional method.

The present invention is described below as 9i! The present invention will be explained in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.

9! Example/n-hedetade VA/incyanate 5.68 g of stearic acid was dissolved in 50 d of toluene, and diphenylphosphoryl azide ((C6H60)2PN3.hereinafter referred to as DPP) was prepared.5. e$g,) ethylamine 3. Add Od and stir at room temperature for 2 hours.

After cooling the reaction solution, 00 mg of Ede μm is added thereto. After washing the ether solution with ice water and separating the organic layer,
Dehydrate with a dehydrating agent and heat under reflux for 2 hours.

6.3 g of the title compound is obtained as a colorless oil.
, fA bar"(oi-'): 2920.2850.22
70 (-NGO), 1680° Example 23-(N-n-heptade Vlucarpamoi/L/
) Okitapropan-1-ol n-heptadecy~isoV
6.0 g of anate as 1.3-propanedio-Iv5,
7 g, dissolved in a mixture of jJI methylene 301iI,
Stir overnight at room temperature. 20m each of water and chloroform in the reaction solution? was added, the organic layer was separated, and this was concentrated to dryness. Chromatography using V licage gel color five (1
The separated solution obtained by 1651M chloroform-water (97:3) was concentrated to dryness to give 3.0 g of the title compound as colorless crystals.
get t.

IRQ≦: Bar” (cm”-'): 3450.2920
．． 2850゜1695.1640.1530゜dorjlNj 3-(N-XI-heptadeVcarbamoyloxy)noropi A/2-promoethyl p phosphate Example λ Substituted derobano A/2 obtained in the a-position
．． 5gt methylene chloride-chloroform (6:2) mixture 1
4m? After dissolving the IC, 1.72 g of Promoethyl A/*Scholicrophyte was added, and after stirring overnight at room temperature, the mixture was heated under reflux for 1 hour. After cooling the reaction solution, water (20 s/) was added and heated for 1 hour. After cold chloroform extraction and liquid separation, the chloroform layer was tab dried to obtain the desired product as a colorless solid.

Example 3-(N-n-heptadeVlucarbamoyloxyV)noropiA/2-trimethylammonioethyl phosphate The entire amount of the phosphoric acid ester obtained in Example 3 was added to an anhydrous M solution containing 14 g of trimethylamine. 70dt
Melt with 1C and heat to react for 60t:, 4aFi&.

After condensing the reaction solution to dryness under reduced pressure, methanol was added for 40 m? [The mixture was vigorously stirred in the presence of 2.1 g of dissolved Hirotani silver and heated under reflux for 1 hour. After that, the furnace solution was solidified, and this was separated by chromatography using silica gel (#eluent: chloroform-methanol-water: 65:25:4).
After IllflIII, it is crystallized from chloroform-acetone. 0.9 g of the title compound is obtained as a colorless crystalline powder.

I RX/::: (0 meals-'): 1690.
1630. 1460°1230.1080,10
50,950°NMR (60M) lx, CDC13):
1.83 (2H, -NH(517), 3.13
(2H, -0CH2CH2CH20-), 8.40
1'1Xil C58,99; H10,61i N
5.29 Dormitory 1114I C58, 99s H11,
02i M 5.35 Example i 2,3-dimethoxys
/-6-methyl-1,4-benzoquinone-6-yN-n
-nonyl isocyanate 2.3-dimethoxy-6-methyll'a/-1,4-benzoquinone-6-yl&'-n-nonanoic acid 1.4 g
Dissolve the mixture in 10d of Ene, add 1.09g of DPPl and 0.62sf of triethylamine, 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. After dehydrating the ether layer, the mixture is concentrated to 5d, and heated for 3 hours to obtain the desired toluene solution of isocyanate.

Example 4 3-(N-(9-(2,3-s/me)key ¥-
6-methyl-1,4-benzoquinon-5-yl)nony~
) carpamoy~oxy]propan-1-ol 1,3-dihydroquine propane 3.0 g (a9.53I
M) was dissolved in pyridine (6m) and added to the above reaction solution,
Room temperature - stir at night. The inverted liquid was concentrated to dryness under reduced pressure, and 20 d each of water and ether were added to a colander to perform extraction and liquid separation. Dry the needle extract (i! i11? & cuff chromatography using silica gel (bath solution: CHCL)
3-MeOH139: 1) Make K, minute #1@. Light yellowish brown solid, yield: 1.3g.

Mass spectrum (wV/@): 425 (M+),
39.31660, 1660. 1645. 160
5 (1,4-benzo-quinone).

Example 7 3-(-N-C9-(2,3-sllttr
6-Methyl-1,4-benzoquinone-6-y~)nonyl)carbamethyloxy]propyl 2-bromoethyl phosphate The above carbamine-3-hydroxypropyl ester 1
Dissolve 2 ml in carbon tetrahydride, add 45 mg of 10 ml phosphorodichloridate, and stir at room temperature for 7 hours. The reaction-completed solution was evaporated to dryness, a small amount of water was added thereto, and the mixture was stirred at night in a cool place.

Next, water and ether are added, and after ether extraction, this is dried and the desired product is separated by silica gel chromatography (manufactured by WI). Yellow solid, yield 1011g0IRvfll”
(cm-'): 1700.1666, 1660aX, 1645. 1610. 1530. 1460
．． 14501fMR (60MH2, CDC13):
1.0-1.7 (16H.

m, -(CH2)B-), 2.03(3H, Im
, -CH5), 2.77-3.80<, 4TI, xa
), 4.03C6H,s, CT130-) Example 3
-CN-(9-(2,3-dimethoxy-6-methy#-1
, 4-benzoquinon-5-yl)nonyl)carbamoyl ookine]propy/%/2-trimethylammonioethyl phosphate Bromide of Example Z above 10■2
0.5ml of toluene containing 0X-trimethylamine? J
After stirring at room temperature for 3 days, the fcQ reaction solution was dried under pressure, and the dried solid was silica gel chroma) (la[:CH
CL3-MeOH-H2O, 60:40:1)
Minute #1111ifl111. Red solid, yield 8 drops.

IRQ story "x"(cm-'): 1yoo(-corH
-).

1660, 1650. 1640. 1610 (1,
4-ben-zoquinon@), 1550.
1540(-CONH).

1260.1230 ((J, P-0).

Example 9.1-N-n-off-tagged silcarbamoyl-2
-Methyl glycerol, 9.7 g of n-octadecyl incyanate, and 3.5 g of β-methylglycerol ether are mixed in 20 d of pyridine and stirred overnight at room temperature. The reaction solution was diluted with 30 M ether.
Pour into a mixture of 50% water and neutralize with all Asahi #.

Separate the ether layer and wash with water.

After drying, evaporate to dryness. When purified by chromatography using a silica gel column (pIll open solvent chlorophore-mouede-1:1), colorless crystals were obtained.8.
2g is obtained.

I RJN'uj01(cii-'): 3340.
1687゜ &
370 (M-OCH3) Example 103-103-(Octade Vlucarpamoyl Oki V)-2-methquinepropyl 2-bromoethyl phosphate Nine glycero-A/6.0 g obtained in Example 1 was dissolved in carbon tetrachloride. 30 w1 and added 4.0 g of bromoethylphosphoryl crophyte for 18 hours.

Heat to reflux. Cold welding, the solvent was distilled off, and 50 d of water was added to the reaction solution.
and heated under reflux for 1 hour. After cooling, extract with ether, wash the ether layer with water, dry and concentrate to dryness to obtain the desired product as a colorless solid.
): 3320. 1690 °a
Ammonioethyl phosphate phosphoric acid ester obtained in Example 10/L/2.0g toluene containing 10g of trimethylamine 60si? Dissolve in and leave at room temperature for 3 days. After condensing the reaction solution to dryness under reduced pressure, methanol 50
M! Add m2g of hydrochloric acid and heat under reflux for 1 hour. After drying the filtration ridge and the furnace liquid, it is separated and purified by chromatography using y lyca gel (l# eluate: chloroform-methanol-water: 65:25:4), and then crystallized from chloroform-acetone to achieve the purpose. 640% of the product is obtained as a colorless powder.

IRX/KB"(as-'): 3350.1700.
1542°11&1 1470.1250,1090,1060°N M R
(60MHz, CDC13): 0.7-1.8 (35
11), 2. r4.6 (IIH, m), 3.46 (9
H, s, Mo2N), 3.50 (3H, a, 0CR
3).

Elemental analysis (C28H59N207P・1.5H, 20)
tV calculation tIC56,63s H10,52! M4
．． 72SP 5.22 #! I value c 56.37! H10,70; M4
．． 91$p 5. Phosphate ester obtained in aa Example/λ 3-()in-octagVlucarbamoyl-oquine)-2-methoxypropyl/l/2-pyridinioethylphosphate Example//2. Dissolve Og in Viridi 720Iit and warm at 60° C. overnight. Pyridine was distilled off under reduced pressure, and methanol was added to the residue for 50 seconds. , *# Add 2 g of silver and heat under reflux for 2 hours.

- After filtration, the filtrate was dried and chromatographed using V-lica gel (eluent: chloroform-methanol-
After separation and purification with water (66:25:4), the desired product is obtained by crystallization from chloroform-acetone.

IRQ"r(cm-'): 3340.1698,1
540゜Peng 5LX 1470, 1255. 1075. 1050゜M
MR (60MHz, CDC13): 0.7-1
．． 8 (35H), 3.44 (3H, a, 0CR3)
, 2. g, 8 (911°I11), 5.20 (2
H, broad, CH21F-i), 6.16 (IH
, broad, C0NH), 8. (,8(3H,m
.

pyridinio), 9.513 (2F!, m,
pyridinio).

Elemental analysis (C30H55N2PO7・H2O) calculation il
C50,58; H9,50-N 4.63; P
5.12 1*IjA koshiki Cfi9.94g H9,60i
N 4.61; P 5.30 Run fl'4/3 3-(N-n-octadecylcarbamoyloxy)-2-methoxypropyl A/2-thiazolioethyl-phosphate Phosphate ester obtained in Run e4J/Q Mix 2.0 g and 4.5 g of thiazole and heat at 60°C for 6 days.

Under reduced pressure, remove thiazole and add methanol to the residue for 50s.
Add 2 gt of /J acid silver and heat under reflux for 2 hours. After filtration, the filtrate was dried and chromatographed using VY Kagel (eluent: chloroform-methanol-water: 6
After separation and purification (5:25:4), the desired product is obtained by crystallization from chloroform-acetone.

IRQKBr (cm-'): 3400. 2920
．． 2851゜1a&X 1701, 1558. 1246. 1065゜M
MR (60MHz, CDC13): 0.7-
1.8 (35H), 3.46 (311, a, 0CH
3), 2. Te→, 8 (911゜), 5.08 (2
1, broad, ClI21fEE), 6.30 (IH
, broad, C0NH), 8.55 (IH, broa
d.

thiizolio), 8.88(1!I, bro
ad, thia-zolio), 10.97 (IH, b
road, thiazo-1io).

Elemental analysis (C28H53N207PS・1.5H20)
Calculation [CI54.26s H9,11s N 4.52
sP 5゜OO Actual measurement III CM, 301 H8,90 蕃N 4
．． 71P 6.03 ★Example/g 11.8g (40mM) of 2-(N-stearylcarbamoyloxy)ethanol stearyl isocyanate, 12.4g (200mM) of ethylene glyco-Az were dissolved in 50dKII of pyridine, and Leave it alone overnight. The reaction solution was concentrated to dryness under wave pressure, and the residue was dissolved in methanol-A'100s.
Recrystallized from P to obtain 11.38 g of the target product (yield 79.6%).
). Otori p81-82℃.

WAIN/j, 2-(N-stearylcarbamoyloxy)ethyl 2-trimethylammonioethyl phosphate 2-CM-stearylcarbamoyloxy)ethano-J
4/4.0g (11,24M) in chloroform 12d
KM Kashi, 2-10 moethylphosphoryl dichloride 2.
Add 72g (11.24mM) and heat under reflux with W for 2 hours. Add 40s of water to this, and after heating and refluxing for 3R,
Add 40 liters of chloroform cod and separate the chloroform layer. This was concentrated to dryness under reduced pressure, the residue was dissolved in a 20% trimethylamine-toluene solution, the tube was sealed and heated for 2 days at 60'C, and the reaction solution was concentrated to dryness under reduced pressure. The residue was dehalogenated using silver carbonate in methanol and then purified with silicage μ (40
g) K: adsorbed, bath sensitive [chloroform: methanol A
/: water (65:25:4)). After collecting the target product fractions and drying them under reduced pressure, the residue was gradually added to a small amount of chloroform, and 4.1 g of colorless powder of the target product was obtained (yield: 69 .9%).

I R (KBr): 3420.2910.2850°1700, 1540. 1465. 1240. 1
080°10150, 965° elemental analysis: c26n55N2o6p-n2° calculation i1
C57,76IH10,62t M 5.18 black P fs, 73 Sice # value C57,724H10,64 stone N 5.28
IP 5.89 Example/&3-(II-8,11,14-hebutadecatrieni~carbamoyloxyV)propano-,ru' 5.56 g (20M) of phosphoric acid was dissolved in toluene aomKj
l or L diphenylphosphoryl azide 6, ISg (20
Add 3.0% of triethylamine and stir for 2 hours, concentrate at about 25 s/l, and heat under reflux for 3 hours. This is propanediol 6, Og (78,9!aM)
Add 60 dK of pyridine and stir overnight. Concentrate the reaction solution to dryness under reduced pressure.
) to obtain the target product +,og (yield 68.4%), which was eluted with 2% methanol-μm chlorophosate.

IR (film): 3350, 3010, 2960°2930.2860, 1700, 1δ40. 1465
゜1270, 1140. 1060° Example/7 3-(N-8,11,14-heptadecatrienylcarbamoyloxy)propyl 2-trimethylammonioethyl phosphate 5-(x-s, 11.
4.0 g (11,39611 IM) of 14-hedetadecatrie di-carbamoyloxy)propanol is dissolved in 20 mg of chloroform, 1.74 g (11,396 mM) of 2-bromoethylphosphoryl dichloride is added, and the mixture is heated under reflux for 2 hours. Cold water 2011! , chloroform 20
After stirring vigorously, the chloroform layer was separated and dried under Kal pressure.
After sealing the toluene solution in a tube, heat it at 60° C. for 2 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue (containing the target substance in BBr) was dehalogenated using methanol and *acid silver, and then adsorbed onto a silica gel cuff (40 g). Eluate [chloroform:methanol-A/:water (65:25:
4) Collect the target substance eluted in step 4), concentrate to dryness, and wash with n-hexane to obtain 3.2 g of candy-like target substance (yield 60.9%).
get.

IR (film): 3350. 5olo, 2
970°2935, 2855. 1γ00. 1540
．． 1480°1230, 1140. 1085.
105+5. 970° elemental analysis: C2611149
N206P・2H20 calculation [C56,50 black H9,67
; M 6.07sP 5.60 Experimental value C56,40 black H9,54 black N 5.47 KaP 5.98 5*L Example #: 3-(8,11,14(Z, Z, Z
)-heptadecatrienylca~bamoyloxy]propano~ Rirun 11g1BS, 56g (20m*M), s/fz
Dissolve 6.0 g (22 mM) of Nilf-Osfufus azide in 50 s of toluene, gradually add 3.3 d of triethylamine, and stir at room temperature for 2 hours.

Approximately 25m of reaction solution? The reaction mixture was heated under reflux for 2 hours until 1 lall, then poured into a 50 wt solution of pyridine containing ~6.0 g of 1,3-propanedio-, and stirred overnight at room temperature. The reaction solution was concentrated to dryness under reduced pressure, and 50w1.
#Add 50ml of ethyl acetate, stir vigorously, and separate the ethyl acetate layer. This is V pressure KaliAlf, tA L
, ysttl'fiy < 50g) Nocuff AK adsorbed, eluted with chloroform, thin potato chroma) (Vsub
GeA/) Rf-0,50(CHCL3)O min w4t-Collect. Yield 4, 0 ga IR (film) cm 1: 3330,300
0°2960, 2930. 2850. 1700.
1540°1460, 1260. 1140. 1
0fS5゜Example/Ta 3-[8,11,14(Z,
Z, Z)-heptadacatrienylcarpamoyl oxy V]
Propyl A/2-aminoethyl phosphate 3-[8,1
1,14(Z,Z,Z)-7''1decatrienylcarbamoy~oxy]propatool(1)+,2+g(t2
．． Dissolve O+Otori M) in 30 s of benzene and 4.82 g of 2-(phthalimido)ethylphosphoryl dichloride.
(15,65EIM), pyridine 1.24g (15,6EIM), pyridine 1.24g (15,6EIM),
5) was added dropwise and stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and the r4 residue was hydrolyzed with 70% pyridine-water, and then concentrated to dryness under reduced pressure again.
-HCl is added and extracted with ether. The extract was soaked in a methanol solution containing 3.0 g of hydrazinohydrate,
Heat to reflux for 0 minutes. Insoluble matters precipitated during heating are filtered off, and the mother liquor is concentrated to dryness under reduced pressure.

A sample of 1 m was prepared using silica gel cuff chromatography, and finally reprecipitated with chloroform-acetone to obtain the target product as a dark-colored powder.

Thin pigeon ama) (S/Rikage A/, CHCL3-Me
OH-H2O (65:25:4))Rf-0,26I
R(KBr)cs+-1: 3350. 30 (BS,
2930°2850, 1690. 1540.
1260. 1240°1210, 1140. 10
80. 1000. 915.830°30 Elemental analysis: C23H43NO6P-1120 calculated value
CI56.08 Iris H9,2HM 5.69; P 6
．． 29 Experimental value C56,08i II 9.01 M!
5.79iP 6.07 Example Q 3-(8,11(Z,Z)-hebutadienylcarbamoyloxy]propyl A/2-)limethylammonioethylphosphate Synthesized according to Example/Y 3-(8,11(2,2)butadiene-carbamoyloxy)propano-A/1.8g (5,3mM) to chlorophor A6.5sfK# or L, 1.28g of 2-10 muethylphosphoryl dichloride (5.3mM) and heated under reflux for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, 20ml of water was added to the residue, heated under reflux, and extracted with 20wt of chloroform. was concentrated to dryness under reduced pressure, and the residue was dissolved in 50 ml of 20% trinothiamine-toluene (1K) and heated in a sealed tube at 65°C for 48 hours.The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in methanol-v25.
1.8 g of Mug2CO3 was added thereto, heated to reflux, and the solution after heating was dried under reduced pressure. The residue was purified using a V-Rikage to Kahum chromatograph to obtain 0.6 g of the desired product as a colorless solid.

IR (film) cs-1: 3350. aot
o.

2960.2940, 2860, 1700, 1540°1460.1230, 1140, 1090, 1060,
970° elemental analysis: C261H61N206P・2■
20 Calculation II C56, 291H9, 79i N 5
．． 051P 5. fi8 Experimental value C56,22&119.631M 6.18P 5.48 Dice m example/: 2-(8,11(Z,Z)-to 7'#
2-(8,11(2,2)-butadecadienylcarpamoyloxy) synthesized by applying it to Shidaka Ichimisaki enylcarpamoyloxyethyl A/2-trimethylammonioethyl phosphate★m. Kin] Ethanol 1.8g (5,
6 (jaM) in chloroform, 1.38 g of 2-proethylphosphoryl dichloride (55.69 m
Add M) and heat Rfk for 3 hours. Purification was performed according to Example Q to obtain the desired product as a colorless solid. 250s is also I
R (film) oi-1: 3460, 3000° 2950, 2920. 1700. 1540. 1
460°1225, 1080. 1050. 960
゜Elemental analysis: CgaH49NgOaP・2H20 calculated value C55,541H9,881N 5.18iP
5.73 Experiment [C55,53; III 9.976 N 5.
29蓚P 5.59 Example-λ 3-(8,11(Z,Z)-Hebutade force dienylcarbohydrate-BamoyloxyV]propyl 2-aminoethyl-Nesphate 3-[8,1l-(Z,Z)- Butade Power Jenni~ka~
Bamoyloxy]propano-A/2.8g (8,3!I
M), Dissolve 3.32 g of 2-(phthalimido)ethylphosphoryl dichloride in benzene, and dissolve 0.8 g of pyridine.
Add 5g (10.8mM) and react at room temperature for 2 hours. Example/? Hydrolyzed and defthaloylated according to
The product was purified by chromatography on V-Rikage to obtain 2.1 g of the desired product as a colorless powder.

IR (film) I:m-1: 3350.3000
゜2960, 2920. 2850. 1690.
1630°1540, 1460. 1240. 12
10. 1140°1080, 1000. 920° elemental analysis: Cz3H+aNzOaP・2H20 needle calculation i
1 C57,54; H9,60s M 5.96
Black P 6.45 Experimental value C57,53i H9,53; N 5,83
蓚P 6.49 Example-, 23-(ml-) Rizo V/L/Calva hair ~
9.12 g of myristic acid (40
4.0 g (13-27 sM) of 3-(M-)lysoVμ carbamoyloxy)propano-* (13-27 sM) and 4.82 g (19
, 90mM) in benzene at 28s/K11, 1.57g of pyridine (19°90mM) was added dropwise, and the mixture was stirred at room temperature. The reaction solution was hydrolyzed according to Example-OK, and 4g
m-ization.

The product is dehalogenated and purified using a V licage gel kafmutaromat to obtain the desired product as a colorless solid. Yield: 3.5g.

IR (film) C1l-1: 2830. 293
0°2850, 1700. 1530. 1460.
1240°1120, 1080. 1055. 96
5. 920.830° 160° Elemental analysis 2c22u47N2o6p・o, 6n2° Calculated value C55,35 H10,18; N 51.8
7; P 6.49 Experimental value C55,32; H10,34; N 5.8
1iP 6.51 Example 2 Kyu 3-N-tetofdecyl carpamoyl oxychloride V
-2-Methylglycero-~ Pentadecanoic acid 2ogt-Dry toluene 200dK#N
L, diphenylphosphoryl azide 21.3g, )
9:cchi47mi714,9g1tlEL,Wlm
The reaction mixture was stirred for 5 hours, concentrated under reduced pressure, and heated under reflux for 1 hour. Cold welding, β-methylglycero-μ ether 432.8
g, dried Viridi 7124s/ and stir overnight at room temperature. Concentrate to dryness, dissolve in chloroform, wash with water, dry, and purify with Taromatofufui using V Rikagel (eluent: chloroform) to obtain 9.43 g (33%) of the desired product.

I RJKBr (cm-') 1695m & , 2-(phthalimido)ethylphosphoryA/dichloride 5.4 g, dry pyridine 1.6 g'
and stir at room temperature for about 4 hours. l! Dry the 11i ring, add 19s/70% pyridine water bath solution to the residue,
Stir at 0°C for 1.3 hours.

Cold contact, acidification with hydrochloric acid, extraction with ether, washing with water, drying, and concentration. The residue was dissolved in methanol-A/.
Add 1g of the reaction solution and stir for 30 minutes at room temperature.The reaction solution was condensed to dryness, separated and purified by V□Kagel chromatography, and then recrystallized from methanol to obtain 2.4γg of white powder (
46%).

IRυ"rcm-': 3325. 2920.
2851.

1LX 1689, 1550. 1460. 1240. 1
21!5゜1079゜P: 185-190℃ Elemental analysis: C! l! 1H45N207P calculation @ C
53,83 gates H9,68; N 5.98! P
6.61 Dormitory #@C53,61; H9,f59IN 5.9
5; P 6.68 *Example-Otsu 3-(M-tetofude VI4/carbasoyloxyV)-2-methoxypropyl/L/2-)limethylammonioethyl phosphate Example-9 obtained by rot 6.4 g of glycerol was dissolved in 25 dK of benzene, and 4.
Add 9 g and 1.6 g of pyridine, and stir at room temperature for 3 hours. After drying with tmIm, water is added to the residue and heated under reflux, chloroform is extracted with cold mixed acid, washed with water, and dried.

Concentrate to dryness, dissolve the residue in toluene containing 10 g of trimethylamine, and heat at 60° C. for 48 hours. The reaction solution was concentrated to dryness, dissolved in methanol-μ, added with 6 g of silver legate, heated under reflux for a while, then filtered while hot. The filtrate was condensed to dryness, and then separated and purified by chromatography using silica gel. Then, recrystallization is performed from a chloroform-acetone mixture to obtain 2.0 g (25%) of the desired product.

IR (film) 3325, 2920, 2850
゜1699, 1530. 1460. 1228.
1080° elemental analysis (c324n51a2o7p-n2
o) Calculation g C54,52: H10,11s N
5.30+P 5.86 Dormitory 11g@c 54.48; H10,06; N
5.1 Iris P 5.88 Example core 3-M-deVA/force〃Bamoi~Dissolve 25 g of oxy-2-methylglycerol n-undecanoic acid in 220 m of toluene,
Added 51.6 g of diphenylphosulfur azide and 28.3 ml of triethylamine, stirred at room temperature for 3.5 hours, concentrated the reaction solution to 10 ml, and heated for 1.6 hours.
l flow. Cold welding, β-methylglycerol ether 53
Add 1 g and 155 d of pyridine, stir overnight in WLM, and concentrate to dryness. The residue was dissolved in chloroform, washed with water, dried, concentrated, and subjected to chromatography on silica gel to obtain 20.7 g (53X) of the desired product.

XR(yi#A) 3340.2920.2B6
0°1700, 1255. 1065. 955.
748゜Real IMIiJ2J7 a -(N-decylcarbamoyloxy)-2-methoxypropyl/L/2-aminoethylphosphate chloride 7.5g and pyridine 2.03g were added, 3#&
Stir at room temperature for a while. The solvent was distilled off, 70% pyridine aqueous solution ffI21d was added, and the mixture was stirred at 70°C for 1°5 hours. A cold ether extraction is carried out, and hydofucine decomposition and work-up are carried out in the same manner as in Example Cj. V Likage A/
Perform aliquoting w4# using a chromatography system, and then recrystallize from ethanol to obtain 2.6 g (37
%).

I RuKBr(cll-') 3324.2925.
2851°! 1&x 1689, 1550. 1460. 1240. 1
215° 1080° Elemental analysis (C17H37N207P) Total ILm C49,48s III 8.66; N
6.86 蓓P 7.61 夾廁value C49.5 (HH9.04; M 6.79
Toad P 7.51 Example 2 3-(N-decylcarbamoyloxy)-
2-Methoxypropyfiy 2-) Limethylammonioethyl phosphate Example 7 g of glycero/L obtained from the core and 7.6 g of bromoethylphosphoryl talolide were dissolved in benzene, 2.5 g of pyridine was added dropwise, and the mixture was heated to room temperature. Stir for 3 hours. For concentration, add 50 sZ of water to the residue, heat to reflux, and after cooling, perform ether extraction. Wash with water, dry, and distill off the solvent.
Add a toluene solution containing 14g of triethylamine,
Warm at 60°C. The reaction solution was concentrated to dryness, and methanol #K
Dehalogenation was carried out using 9.3 g of silver carbonate. After separation and purification by chromatography using V rica gel, recrystallization is performed from a mixture of seven tons of chloroformam to obtain 1.0 g (9%) of the desired product.

Elemental analysis (C24HC24H51N”H20) calculation [C
54,48t H10,06$ M 5.15+P
5.88 Dice@@c 54.52; H10,11+ N
5.30; P 5.86 I Rv/K”r(ra-”) 2920.
1695. 1230゜Feng &

Add 3.1st triethylamine and stir for 2 hours under a room strainer. The reaction solution was concentrated to 20 m/ml and heated under reflux for 1 hour. After 6 hours, 50% of a pyridine solution containing 56 g of trimethylene glyco-IL/4 was added and stirred overnight. The solvent was distilled off, dissolved in chloroform, washed with water, and dried. (by silica gel chromatography), 3.88 g of target product (79,6
%).

IRJ"r((2+-") 16851a & Dissolve 2.86 g of globileste and 3.53 g of bromoethylphosphoryl chloride in befin,
．． 191 (dropwise. After stirring at room temperature, # rope is distilled off, water is added to the residue and refluxed for a while. Cold ether extraction is carried out, ether is distilled off, and the residue is diluted with toluene bath solution 2bdKII containing 20% trimethylamine. The mixture is heated to 70°C. After distilling off the solvent, it is dissolved in methanol-A/2, dehalogenated with 2.07 g of silver chloride, separated and purified by V silica gel chromatography, and further purified with chloroform. Recrystallize from acetone mixture to obtain the target product 2.72
g (60%).

Elemental analysis (C2xHa5NgOaP・2BaO) calculated value C51,62 (H10,10$N 5.73;P
6.34 Contamination value C51,57; II 9.88; N
5.751P 6.53 xau::; (cm-') 3420. 29
20. 1695°1530.1470,1235.
1080゜Example 32 3-N-dodecy~carbamoyloxyS/7'lopyl 2-trimethylammonioethyl
Carbamic acid 3-hydroxyVfropiester/L/970I1g, 2-(phthalimide) obtained in Example 30
Ethylphosphoryl dichloride 1.66g 1 benzene 20
m, and 400 ag of pyridine was added dropwise. After stirring at room temperature, the mixture was concentrated to dryness, a little pyridine and water were added, and the mixture was stirred at 80°C.

The solvent was removed, water was added and extracted with ether, washed with water, concentrated to dryness, the residue was dissolved in methanol, 3M of hydrofusine hydrate was added, and the mixture was heated under reflux. The solvent was distilled off and V
Separate M using chromatography using Rikage A/vr and recrystallize (from ethanol) to obtain 560 mg of the target product (3
6%).

I R (KBr, I1) 33150, 2920.28
50°1690.1530,1462,1240.10
80°1000, 920° Elemental analysis (Cx5II39N206P) calculated value C52
,671H9,58; N 6.82SP 7.65 1! $111 C52,59i K 9.37
; M 6.96 蓚P 7.54 Example 33 2-Methoxy-3-N-) Ribcyl Rubamoyluoquine Probanol Tetofdecanoic Azodore, 99 g (35 mmol), DPI) A 10.45 g (38 mmol) ) was treated according to Example 30, and β-methylglycerin 11.13
(105 mm/L/) of pyridine 44@t to obtain 7.0 g of the target alcohol. TLC(
M・OH:CHCl3 (1:19)) Rf-0,
55 NMR (6ONC, d5-DMSO): 0.7-
1.6 (25H), 3.01 (2H), 3.3
5-4.3 (811), 4.70 (111), 7
．． 10(IH) Example 3 Modification 2-methoxyV-3-N-) Ribcyl RubamoyoxyVpropy~ 2-Trimethylammonioethylphosphate 1.53 g (6.34 mmol) of the alcohol obtained in Example 33 benzene y, adKl, pyridine 0
．． Add 5g directly and stir vigorously at room temperature.

This was subjected to hydrolysis, quaternization with trimethylamine, and dehalogenation according to Example 2, and 1.2 g of the desired product, colorless powder, was obtained using silica gel chromatography.

111 (film) C1l-13450, 2930°2
850, 1700. 1545. 1460. 13
00°1080, 1055. 960. 760° elemental analysis (c23n4gN207-0.711 [20) calculation [C54,25 black H9,981M 5.50 pieces P
6.08 Experimental value C54,32 H10,03: 115.93
aP 6.07 ★mNjj: 3-x-tetofdecyl rupamoyl oxy V propano- ~ Dissolve 20 g of pentadecane in 200 g of toluene, 34 g of diphenylphosphoryl azide, )-ethylamine 1
Add 8 and 7@t and stir at room temperature for 3.6 hours. 1. Concentrate the reaction solution under reduced pressure to 70 s/d and heat under reflux for 1 hour. After cooling, trimethylene renge! J Co-Ay 23.6g,
Add 9s/124TId and stir overnight at room temperature. The reaction solution is concentrated to dryness and chromatographed using silica gel to obtain 10 g of the desired product.

I RvKBr (cm-'') 169011 & Dissolve 26gt benzene 40sZKjll and add pyridine 2.
Add 37g dropwise. After stirring at room temperature for 1 hour, the solvent was distilled off, 50 ml of water was added, and the mixture was heated under reflux for 1 hour. After 6, extract with ether and concentrate to dryness to obtain 10 g of triethylamine.
Dissolved in a toluene bath solution containing 60 s/ml and heated at 60°C for 2 days. The solvent was changed to methanol, dehalogenation was carried out with silver envyate, purification was performed by talomadography using silica gel (eluent: methanol), and further recrystallization was performed from a mixture of 7 tons of chloroformam to obtain 4.8 g of the desired product ( 50%
).

Elemental analysis (C23H+9N206H-BgO) calculation @
C55,40 series H10,31+ N 162;P
6.21 Actual measurement [C55,10i H10,51; N 6.4
HP 6.36 IR (KBr, ci+-1) 292FS, 1
700. 1240° 1085, 1065° Example 77 3-! i-tetofuda VA/kakarmoi-oxypropyl A/2-aminoethyl phosphate Example 3
3 g of the alcohol obtained in step i and 3.8 g of 2-7 thalimidoethylphosphoryl dichloride were mixed with ben (74
0- and added dropwise to 1 gt. After stirring at room temperature for 3 hours, it was concentrated to dryness to obtain a residue [70%
Add 16d of pyridine aqueous solution and stir at 70°C for 1.5 hours. The reaction solution was again dried to aI-dryness and extracted with chloroform under acidic hydrochloric acid. The solvent was changed to methanol, 1.4 g of hydrazine hydrate was added, and the mixture was heated under reflux for 30 minutes. After removing the solvent, it was purified by chromatography using silica gel, and further recrystallized from methanol to obtain the desired product 2.
Obtain 2 g (53%).

Elemental analysis (C20H4312061”H20) calculated value
C54,52 collection H10,08; N 6.19IP
7.13 Liao Ding-C54,78 Ban II 9.88; N 6.3
9th grade P 7.06 I R (KBr cm-1) 1690,1520,
1413°1213. 1080. 1010゜Example jf, 3-(N-dodecylcarbamoyloxy V
)-2-Methoxypropano- ~ 8.46 g of tridecane iV was dissolved in 100 dlC of toluene and 12.1 g of phosphoryl azide.

Add 4.44 g of triethylamine and stir at room temperature for 2 hours. The reaction solution was concentrated to 60 g Itt and heated under reflux for 1 hour. After 6, glycerol β-methyl ether*10.
Add 6 g, 100 mg of pyridine and stir overnight. f
After distilling off iIMX, washing with water, and drying, chromatography using V licagel (#eluent penyne-#ethyl acid 7
:3) to obtain the p objective log.

I RXJKB"Cc■-') 1690°!IJ
L! Implementation elJj9! 3-(N-dodecylcarbamoyloxyV)-2-methoxypropy~2-trimethylammonioethylphosphate 9i! 6 g of glycero-A/derivative obtained in Example 3 g,
Using 86 g of 2-promoethyl phosphoryl and 2.24 g of pyridine, phosphoric acid ester μ was synthesized in the same manner as in Example 3 B. Additionally, 8g of triethylamine
Y remethylamination with 40sZ of a toene solution containing 40sZ and dehalogenation with silver #2 acid were carried out in the same manner as in Example 3B, and 4.0 g of the target product was obtained by chromatography using V rica gel.

Elemental analysis (C22H47N207F- to H20) Calculated value C53,75 Toad H9,8 IJ5.7QsP6.30 East survey value C53,5B9 El 9.99. )I 5
．． 63 turns P6.21 TLc: Rt-o, 34 (Silikage A/.

CHClMeOH1120,65:25:4
) Example 4 IQ 3-(1-hedetade Vμ force μ pamoi μ oxy) propyμ
2-thiazolioethyl phosphate 3-(M-he1tadey)vforceybamoiμokiV)-1-propano-,le-
357. 6'f (1,0 mmole)
/, 2-gp moethyl phosphoryl chloride 362.8q
Dissolve 1afK of benzene and 118.71ft of pyridine.
- Add dropwise and stir at room temperature for 5 hours. The reaction solution was diluted with concentrated lIr! under reduced pressure. Solidify the bag, add 4 d of water to the residue, and heat at 90℃ for 1
Stir the time. After 6 days, the precipitated solid was collected by filtration and dried. The solid was dissolved in thiazo-A/2s/ and heated at 75°C for 3 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in methanol-μ. After dehalogenation using silver chloride 275Iv,
Concentrate to dryness again. The residue was dissolved in chloroform, methanol,
Dissolve in 4 d of a mixture of water (65:25:4), adsorb K with V9 Kag μOhum (5 g), and elute with the same mixture to obtain the desired product as a colorless solid. Yield 25 osv (yield 45.
6%) TLC (CHCl3.MeO!I, H2O-65:
25:4) Rf-0, 21, single spot IR (film) cm, 3350, 2920, 28
50.1700, 1550.146G, 1240.10
90,1060,940,830.755NMR(CD
Cl2.60MC)J: 0.9 (3H).

1.27 (3QH), 3.13 (2H), 3.4-4.
6 (6H), 4.91 (4H), 6.0r (III),
8.43 (嘗1.L 7G(13YO[), 10.6
7 (13 Yol) Example 4t1 3-(M-deV/L/carba7ipoxyS/)-2-methoxypropy~ Sulfate 3-(N-decylcarbamoyloxy)-2- in 2-thiazolioethyl Metoki V
-1-10 bar/-v289.4Iv (1°Q n+n+
ole), 2-gromoethyl-phosphorylv citarolide 362. asv (1.5 mmole) was dissolved in benzene 2.1 s/, and pyridine 118.71 f (1,
5! Add IIIIIO16) and mix at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, 4 d of water was added to the residue, heated at 90°C for 1 hour, 10 s of cold water was added, and the mixture was vigorously shaken. The organic layer was separated, and the aqueous layer was separated. Throw away. The organic layer was concentrated to dryness under reduced pressure, and the residue was
Add IIIt, stir at 50°C for 3 days, and concentrate to dryness under reduced pressure. 75g of methanol in the residue? , Ag2C
Add O322011v, stir for 1 hour at room temperature, filter out insoluble matter, and concentrate the mother liquor to dryness under reduced pressure. This is purified using a V9 Kagel column (8 g) and JIM liquid chloroform, methanol, water (65:25:4) to obtain the desired colorless powder 1471F (yield 32%).

IR (fllm) cm-1: 3320.3Q110
,29H1,2850,1700,1545,1460
,1240,H190,10@0,156N MR(6
0MC, CDCl5) δ: O, 193 (311).

1.23 (16H), 3.13 (21), 3.38 (3
)1),3. TO~4.67 (rfl), 4. ! 16(
2H), 6. IT (IH), 8.33 (IH), a, 6
7 (fg), +o.

70 (IH) TLC: chloroform, methanol, water (65:25:
4) if-o, 21 (lx bo)) Example λ S-<W-octadeVlucarpamoypokyen)=2-methoxypropy~ 2-(4-methyA/-5-hydroxyethyl)thiazolioethyl phosphate 3-(M-octade S/A/carba
-methoxyVpropyl/I/2-gp moethyl phosphate 2944 (0,5 mmole), 4-methyl-5-
Hydroki V Echiμ Thiazo-μ286゜4'f (2,0
mmole ) ~ en 0.5 dK @ 75℃
, heat for 3 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified using a V1 Kagel column (8 g) and a developing solution of tarolophorf, methanol, and water (65:25:4) to obtain a colorless powder of 85 kg (yield: 2S, 2%).

IR (film) cml: 33G0.292G, 2
850.1700, 154G, 14・0.1230.1
090,1080,1055.930.10 111MR (60MC, CDC13) J: 0.9
0 (311).

1.28H32M>, 2.57 (3H), 3.08 (6
1), 3.43 (3H), 3.83 (6H), 4.10
(21), 4.33 (IH), 4.77 (III), 5
．． 78 (IB), 10.57 (III) TLC: Ripa*vum, ip no, u, water (65:25
:4) Rf-0,33 (1apot) υma (w7: external absorption spectrum fiy): l wax"0H22
2u, 262u Example 3 3-(N-OK!DE S/J&/Karubamari IμOKI V)-
2-methoxyVbipbi~ 2-isoquinolinioethylv*
Sufeto 3-(N-Ota! De VA/Power p Pa 3 Iruoki ¥) -2-
Methoki vf 騨hifi/2-Glomoethyl phosphene) 2
9411g (0.5mmole), Isoquino 9y2
58.3111i (2, Ox screen〃) toμen0,5
gg and heated at 15°C for 3 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified using a V9 Kage V column (l1g) developing solution, chloroform, methanol, and water (65:25:4) to give 140WIg of colorless powder (yield: 44%). ).

IR(film)cs+1: 3320,2920.
2B50, 170G, 1640, 1530, 1460.
1240,1095.106G, 930.80 M MR (60MC, CDCl5) δ: 0.88 (
311).

1.27 (35H), 3.13 (2H), 3.32 (3
11), 3.3-3.8 (211), 3.93 (IM)
, 4.0r (81, 4, 63 (IH), 5.30 (IH)
), fi, 00 (lil), 8.00 (3B), 8.5
0 (IH), 8°57 (IH), 9.10 (1M), 1
0.70 (IH) TLC: Chloroform μm, methanol! ,
Water (65:25:4) Rf-0,47 (lapot)
enu υv:λwax 2331&u, 27 ss
.

340 Refreshing Example 4t (3-(N-Octade Vμ Carbamoyl Oxide S/)-2-
Methoxyglobi/L/2-(2-methylimidazoli μ
) 3341F (1 mmole) to ethyl phosphate 3-(M-octade Vμ carpamoi ~ ox V)-2-methoxypropano-1,
2-promoethylene μphosphoryμ chloride 242 μ was dissolved in benzene 1sfKiil, pyridine 120 Da was added, and 3
The reaction solution was stirred at room temperature for an hour and concentrated to dryness under reduced pressure. 5 d of water was added to the residue and heated under reflux for 30 minutes. After 6 hours, the precipitated colorless powder was filtered and dried.

Add this to 1F IMt, 2-methylimidazole 128
．． Dissolve in a mixture of 4'lF (4 mmole) and heat at 75°C.
, heat for 3 days. The reaction solution is treated according to Example 4 to obtain the desired product as a colorless powder. Yield: 176 Da (yield: 29.8 Da) TLC: (￥9*Gelk', CllICl3,
MeOH, H2O-32:25:4) Rf-0,40
Single 2/7) R (film) cm”: 3325
,2920.285G,1700.1540,1485
,1240.1100,1070.1040.960,
70 MMR (CDCl2.60MC) a: o, 9 (3H
).

1.23 (35H), 2.43 (3H), 3.42 (3
H), 2.8-4.8 (1111), 5.113 (IH
), 6.92 (211) Example Lt 3-(N-docoxy~capamoyloxy$')-2-methoxypropyfi/2-thiazolioethylphosphe-F 1) Tricholic acid? , O41g (2 x 1O" mol) was dissolved in a mixture of anhydrous toluene 70- and triethyl amine 3.6-
i, @g (2,4xlO-2 mol) is added dropwise. 3
After stirring at room temperature for an hour, the reaction solution was concentrated to 173 volumes under reduced pressure. The reaction solution was refluxed for 1.5 hours, and after 6 hours, 30 d of pyridine was added.
and 2-methoxy$'-1,3-propylene glyco-t
Add 7.84 g (7.4 x 10~) and stir at room temperature. 6. The reaction solution is concentrated to dryness under reduced pressure, water is added to the residue, and extracted with proform. After washing the five layers of taloloform with water, it is dried with Na2SO2. The solvent was distilled off and the residue was
Purify by column chromatography using Rikage* (100 g). Chloroform effluent Ili! 1gI was concentrated to dryness to give 3-(M-tocosilka μpamoi μoki F
)-2-MeF xy 1-Globano μ colorless powder 4.3
g (47N) is obtained.

IR (KBr): 3350 (NH,Ol, 2920
(CH), 2850 (ca), 1685 (
-aacoo-), 1530 (-Nucoo-) r 2) 3-(M-tocoVrupamoylukiF)-
2-methoxyv-1-propano-#2.74g and 2-
1.811 g of rodicrylidate in bromoethylphos was dissolved in 20 sJK of benzene, 0.82 g of pyridine was added dropwise, and the mixture was stirred at room temperature for 2.5 hours.

Benzene was distilled off, water was added, and the mixture was heated under reflux for 1:5 k and 130 minutes. After 6 days, the mixture was extracted with chromium and chromium and concentrated to dryness. Thiazo-pyL 4d was added to the residue and heated to 71.5 at 60°C.
The reaction solution heated for 0 hours was dried and the residue was mixed with methanol-14/
Rod and 2.15 g of silver carbonate are added and heated under reflux for 1 hour. After heating, the solution was concentrated to dryness to obtain a crude product. V
Purified by chromatography using silica gel Effluent solvent: CHCL3-MeOH-H2O,s5:
25:4) and recrystallized from a chloroform-acetone mixture to obtain 0.41 g (10.5%) of the desired product.

IR (KBr) cml: 292G, 2850.1700
．． 1245. liri65 Elemental analysis: c32a61a2o7ps・2H20 calculated value C56,12; H9,57s N 4.09 蕃P
4.52i S 4.68 Actual value C56, 14 蓚H9, 47 蓚M4.07iP4
．． 68 Toad 84.24 Example 41'& 3-(II-Tetofude VfiI force ~ Pamoi μoki V)-
2-methoxy-3-(1-tetradecy-μ-pamoy-oki-V)-1-propyl 5.18 g and 2-bromoethyl phosphorodichloridate 5 .44g of benzene 7
3jK was dissolved, 1.78 g of pyridine was added dropwise, and the mixture was stirred at room temperature for 2 hours. Benzene was distilled off, water was added, and the mixture was heated under reflux for 1 hour and 30 minutes. After 6 hours, extract the mixture using a rolling mill and concentrate to dryness.

Thiazo-A/7yd was added to the residue and humidified at 60°C for 60 hours. The reaction solution was dried and the remaining ff1K methanol, l&'l
.

d and 8 g of reconstituted silver were added, and the mixture was heated under reflux for 1 hour.

The filtrate is concentrated to dryness while hot, and the residue is purified by chromatography using a V9 cage. Chloroform-
Recrystallization from an acetone mixture yields 0.4 g (5%) of the desired product.

IR (KBr) cml: 2$12G, 2850.17
00,1230.1050 Elemental analysis: C24H,5M, 07PB-2B, 0 calculated value C50,33 toad H8,274M 4.89 compilation
5.41&8 5.60 Sou IRfli 05G, 35G H8,208M
4.76 + P5.38 Act 84.84 Example Z 2-(N-Octade V14/Carbamoyl Oxide V) Ethyl 2-Thiazolioethyl Phosphate 2-CM-Otatadecyl Carbamoyl Oxide S/) Ethano-, &3.57
g (10 mmole), 3.63 g (15 mmole) of 2-proethylphosphoryl chloride was mixed with 10 mg [ll of benzene, and 1.4 g of pyridine was added to give 2.5
Stir at room temperature for an hour.

KfiJii! reaction solution under reduced pressure! Dry and add 30ml of water to the residue.
was added, heated under reflux for 1.5 hours, and subjected to cold precipitation. Collect colorless powder on filter 4 and dry it. Thiazole r, s*
The mixture was heated at 60° C. for 3 days, and the reaction solution was concentrated to dryness under reduced pressure. The residue was treated according to Example 40 to obtain the desired product as a colorless powder.

TLC: ($/Likage A', CHCl3.MeOH, H
2O-65:25:4) Rr-o, 28 single sub FIR (KBr) cm, 3400, 2910.28
50.1700, 1540.146G, 1230.10
90,1060. ! 150,790 Test Example 1 Mouse spontaneous myeloid leukemia M1 (Re5istant clone) of chemotaxis obtained in Example 2.

Rauaher virus induction - promyelocytic Hakuoh disease JI
JIiR453 and human myeloid leukemia cells HL-60
The inhibitory effects (5o values) on 70 proliferation were 3 to 4 μV, 2 to 3 μv, and 1 μC, respectively.

In addition, Example 2j, 1:F myeloid leukemia cells HL of 2≦
-60 IDbo values showed 2-3 μgld, respectively.

Regarding the antiprotozoal action in Table 1, see Tetofhymena bilihon/
%/Miss (Tetraphymena pyrlfor
mia) W strain was used as the test strain, and a test medium [20 g of tryptose/peptone (Difco 11), #ft extract Ig, 2 g of glucose, 100 G@t of distilled water, 1 molar phosphoric acid i1 buffer pH 7.0, 10 sJ) was used. 1/k, 28
℃ for 44 to 48 hours, and the bioinhibitory ability (MIC) of the metal compound of the present invention was determined by liquid dilution assay.

Regarding the anti-IlI action in Table 1, Cryptoaoacua neof.
or-mna) as the test microorganism, and the test compound's 2'
A vapor disk (8 diameter) was immersed in the l/i//d aqueous solution, air-dried, placed on an agar medium, and cultured for 3TC for 2 days to define its inhibition zone. If the diameter of the blocking circle is 9- or less, it is judged to be good, 9 to low is judged to be poor, 12 to 2o1 is judged to be +, and 2° or more is judged to be bad.

Regarding the antifungal activity shown in Table 2, various representative plant diseases were tested, and the minimum inhibitory concentration (MIC) was determined using multiple dilution method 1 using a 1% glucose bouillon agar medium.

Table 30 Antiwhite II! Regarding 1 effect, the minimum growth inhibitory concentration (MIC) of each compound against white fungi was determined using the multiple dilution method using an agar medium. The test medium was a Sabouraud agar medium, and each metal compound was dissolved in methanol-μ and diluted with sterilized water to adjust the concentration in the medium.

Each test bacterium was cultured at 28°C using the liquid chemistry method.
Do three days of questions.

Intermediate exam white -- DT-66: Tryohophyton men
tagrophytesIFO51109 DT-63: Trychophyton rub
rumI)'0 546T Table 3 Anti-white soda action of example compounds-885-

Claims (1)

[Claims] Formula [wherein n is 0 or 1, R1 and R2 are one irises,
= oca3 t or 10CO) IHR6 (116 represents an aliphatic hydrocarbon residue having 8 to 26 carbon atoms), and R1
and at least one of R2 is 10CO)I)! R6
[representing an ammonio group] The force expressed by pbamic acid ester ~lI4 is its filler.