JPS5835116A - Blood platelet active factor inhibitor - Google Patents

Abstract

PURPOSE:The titled inhibitor that contains a specific glycerol derivative or its salt, thus being used as a remedy or preventive for circulatory disorders relating to blood platelet coagulation and broncheal asthma relating to allergy. CONSTITUTION:The titled inhibitor contains a glycerol derivative of formulaI (R<1> is 10-24C alkyl; R<2> is 1-4C alkyl, or an aralkyl (e.g. benzyl); A<+> is heterocyclic ring having a quaternary nitrogen atom) or its salt such as 3-(N-octadecylcarbamoyloxy)-2-methoxypropyl 2-thiazolioethyl phosphate as an active ingredient. The chemical inhibits strongly blood platelet coagulation and allergy caused by the blood platelet active factor (L-O-alkyl-2-acetyl-Sn-glyceryl-3-phosphorylcholine). The compound of formulaIis obtained, e.g., by reaction of a compound of formula II (Y is Cl, Br, I) with another compound of formula A.

Description

[Detailed description of the invention] The present invention relates to a novel platelet activating factor inhibitor.

Platelet aggregation is considered to be the cause of various cardiovascular disorders, and platelet aggregation inhibitors occupy an important position as pharmaceuticals.

Hitherto, adenosine diphosphate (ADP) and aphchidonic acid metabolites, particularly trympoxane A2 (TXA2), have been known as typical compounds that cause platelet aggregation. Therefore, conventional platelet aggregation inhibitors have been searched for using inhibition of the effects of these compounds as a primary screening method. 'However, recently, ADP, TXA2
Platelet activating factor (Platθle) is a compound that causes a stronger platelet aggregation effect with a mechanism different from
tAotivating Factor (PAF
)) was elucidated, and its structure was 1-0-AμK〃-2-
It was found to be acetyl-8n-glyceryl-3-7 osphorylcholine [Nature. Volume 285, 193
(11$80)), PAF is ADP, TXA2 and t
It has been found that it has an action mechanism of 1L and strong activity at very low concentrations. In addition, PAF is a powerful chemical mediator with no allergy; for example, it is known to have the strongest activity among known compounds when measuring bronchial stenosis with Merckmarker. μmacology.

Kage I, 185-192 (1980)). Therefore, P.A.
If we can find a compound that has an inhibitory effect on PAF, it may become a more effective inhibitor against platelet aggregation in living organisms, and may also be used to treat other PAF-induced diseases, such as allergy to allergy. It can be an effective suppressant for diseases such as cancer. As a result of intensive studies, the present inventors discovered that the compound represented by formula (I) has an excellent PAF inhibitory effect, and completed the present invention.

That is, the present invention relates to the formula % formula % [wherein R1 is an alkyl group having 10 to 24 carbon atoms, R2
is an alkyl group having 1-4 carbon atoms,
A+ represents a heterocyclic group having a quaternized nitrogen.

Regarding the above length CI), the carbon number represented by R1 is 10-24
The alkyl group may be linear or molecular, such as decyl, dodecyl, trideyl, tetofdenyl, pentadecyl, hexadeyl, hegtadecyl, octadecyl, nonadecyl.

Icosanil, docosanil. Examples include dihydrophytyl, especially alkyl J&I with about 14 to 20 carbon atoms.
II& is preferred.

Examples of the alkyl group having 1 to 4 carbon atoms represented by R include methyl, ethyl, propyl, iso-10-vinyl, butyl, and isobutyl, among which methoxy is preferred. Examples of the aralkyl group represented by R2 include phenyl-C1-3alIIP~ groups (e.g., benzy); , isopropyl).

cl-4 alkoxy groups (e.g. meFoxy, ethoxy.

prophoki V), halogeno groups (e.g. chloro, bromo).

2) It may have a substituent such as a group or an acetyl group. Note that the compound CI) in which R is an aralkyl group is a new compound.

Examples of the heterocyclic group having a quaternized nitrogen represented by +A include a pyridinio group, an oxazolio group, an isoxazolio group, and a thiazolio group.

Examples include an isothiazolio group, a pyridacinio group, a quinolinio group, an isoquinolinio group, and these heterocyclic groups further include a Cl-4 alkyl group (eg, methyl.

ethyl), hydroxy group, hydroxyethyl group.

aminoethyl group, amino (imino) group, force ~ bamoi fi
It may have a substituent such as / group or ureido group.

Compound (I) may also be used in the form of a physiologically acceptable compound, such as, for example, the formula % [wherein f is chloro, bromo, iodo, toxin, etc.] ] and CH20C (OR2(Ib) [wherein M is an alkali metal (e.g., sodium.

Examples include salts represented by a potassium (potassium) ion or an alkaline earth metal (eg, sium, magnesium) ion.

In compound (I), R-coordination and S-coordination with respect to carbon at the 2-position! Although various stereoisomers exist, each of them, a mixture thereof, and RS as a whole are included within the scope of the present invention.

The glycerin derivative CI) and its derivatives in the present invention exhibit an excellent platelet activating factor (PAF) inhibitory effect, and more specifically, strongly inhibit allergies during platelet aggregation caused by PAF. Therefore, the platelet activating factor inhibitor of the present invention can be used to treat circulatory disorders related to platelet aggregation in mammals, such as thrombosis, stroke (e.g., cerebral hemorrhage, cerebral thrombosis), myocardial infarction, angina pectoris, thrombophlebitis, It is used to prevent and treat diseases such as glomerulonephritis and bronchial asthma related to allergies.

Glycerin derivative (I) and its salts have benign properties with excellent hydrophilicity and lipophilicity, and are low in toxicity, so they can be used as a powder or as a pharmaceutical composition in an appropriate dosage form.
It can be safely administered orally or parenterally.

Dosage is subject to administration.

Although it varies depending on the symptoms, administration, etc., for example, when administered orally for the prevention and treatment of thrombosis in adults, a single dose of Compound CI) is usually administered at CLI ~201.
It is convenient to administer about 117 kQ body weight about 1 to 3 times a day. More specifically, when the purpose is to prevent thrombosis, the body weight is approximately 0.6 to 41,117 times the body weight.
For therapeutic purposes, approximately 4 to 10 IIF/49 per infusion
It is preferable to administer each drug about 1 to 3 times a day, depending on the body weight.

The pharmaceutical composition used for the above administration contains an effective amount of Compound (I) or its compound as an active ingredient, and a pharmaceutically acceptable carrier or excipient. Such compositions are provided in dosage forms suitable for oral or parenteral administration.

That is, for example, as a composition for oral administration,
Solid forms include liquid dosage forms, specifically tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules), syrups, emulsions, and suspensions. etc. Such compositions are produced by methods known per se and contain carriers or excipients commonly used in the pharmaceutical field. For example, carriers and excipients for tablets include lactose, starch, sucrose, and magnesium stearate.

Compositions for parenteral administration include, for example, injections,
Injections include dosage forms such as intravenous injections, intramuscular injections, and single-drop injections. Such injections are prepared by a method known per se, ie, by dissolving, suspending or emulsifying Compound (I) in a sterile aqueous or oily liquid commonly used for injections. Aqueous solutions for injection include physiological saline, isotonic solutions containing dextrose and other adjuvants, and suitable solubilizing agents, such as alcohol (e.g., ethanol/I/), polyalcohols (e.g., 10 pyrene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 6
g, HC○-50 (p'pxyoxyethylene
e (60mO engineering) adduct cfhydro
It may be used in combination with generated caster oi, l)), etc. Examples of oil-based liquids include sesame oil and soybean oil, and benzyl benzoate is used as a solubilizing agent.

Benzyl alcohol or the like may also be used in combination. The prepared injection solution is usually filled into a suitable amplifier.

Half-open tablets used for rectal administration are prepared by mixing compound (I) or a salt thereof with a conventional herbal base.

The oral or parenteral pharmaceutical compositions described above are conveniently prepared in dosage unit form to suit the dosage of the active ingredient. Examples of such dosage unit dosage forms include tablets, pills, capsules, injections (amp fi/), half-open tablets, etc., and each dosage unit usually contains 5 to 50 mg per dosage unit dosage form.
It is preferable that the compound CI) contains 500 m'f, particularly 5 to 100 m'f for injections, and 10 to 250 m'f for other dosage forms.

Note that each of the above-mentioned compositions may contain other active ingredients as long as they do not cause undesirable interactions when mixed with compound (I).

Glycerin derivative (I) used in the PAF inhibitor of the present invention
) can be produced, for example, by the following method.

A formula % Formula % [In the formula, Y stands for C1, Br or Br, and the other symbols have the same meanings as above] to the compound of formula A (11) (
A#-tl! Compound (I) is obtained by reacting a compound (heterocyclic ring having an element).

B formula % formula % [In the formula, each symbol has the same meaning as above] to the compound of the formula R-NC
The compound ( To obtain I), a compound of the formula % formula % [wherein XFiClt or Br is shown, and the other symbols have the same meanings as above] is added to the compound of the formula % formula % () [wherein, X- is a halogen ion, ○ H-, COl''-.

An anion such as a sulfate ion, and other symbols have the same meanings as above] are reacted to obtain a toyoshi compound (I).

Examples of the compound (1) used in the reaction of method A, that is, the quaternization reaction, include pyridine tthiazole, isothiazole, oxazole, pyridazine, quinoline, and isoquinoline. These heterocyclic rings further include the above A
It may have the substitution positions exemplified for K. The reaction is carried out using a base represented by formula (1) in an amount of 1 equivalent or in large excess (used as a solvent) relative to compound (II) K, at room temperature or under heating (e.g. 35 to 200°C), in the presence of a solvent or Use methanol as a solvent without any solvent.
μ, toene, benzene, ether.

Examples include dioxane and tetrahydrofuran.

The reaction of method B, ie, carbamic acid enetherization, uses chloroform and dichloromethane as the solvent.

1 to (IV) in the presence of toluene, pyridine, etc.
This is achieved by applying 10 equivalents of (V). The reaction temperature is preferably about 0 to 150°C. (IV)
When reacting with phosgene, phosgene is reacted in the presence of *[ such as toluene, benzene, chloroform, etc. at a temperature of about -20 to room temperature, and the tt4ht, < is once dissolved phosgene is removed, then (Vl) t' Remove the water cooling and allow the reaction to occur at room temperature.

In the reaction of method C, in the presence of a solvent (e.g. chloroform, dichloromethane, pyridine, toluene, dioxane)
This is achieved by allowing the same amount or about 1.6 times the mole of (2) to act on (2) at a temperature of θ to 100°C.

In the above-described production method, the progress of the reaction can be tracked by thin layer chromatography, which allows the reaction conditions to be appropriately determined.

Purification of the compound produced by the above method usually involves O operation,
It is suitably purified by molten extraction, recrystallization, chromatography, etc.

Each of the raw material compounds in the above methods A, B, and C can be produced, for example, by the reaction routes shown below or according to these.

CH20HCH20H The present invention will be explained in more detail by showing experimental examples, formulation examples, and manufacturing examples below, but the scope of the present invention is not limited thereto.

Experimental example PAF suppression effect (1) j! ! PAF inhibitory effect on Kosaka aggregation [Test method and results] Blood was directly collected from male rabbits using a syringe containing 3.15≦citric acid (10 ratio to 9 blood) as a blood coagulation inhibitor. Then 1 at room temperature and 1 at OOO rpm.
Dissolve platelet plasma (PRP) by centrifugation for 0 min.
: Plctelet riqhplasma)
I got it. The PRP was further centrifuged at 1.40 orpm for 15 minutes to obtain a platelet pellet.
This is pr+free Tyl”Ode (gela
Washed P
RP f Preparation Nine, Cono Washed PRP
After stirring 260μJ at 37℃ for 2 minutes, 0.2-0.5
25 μl of m M OCa solution was added, and the mixture was further stirred for 30 seconds. Then, the test drug was added in an amount of 3x10-M, and the mixture was further stirred for 2 minutes@PAF 3xlO-7M was added. Platelet aggregation was measured using an aggregometer (Seikaden m1m1). The activity of the test drug was determined from the inhibition rate of the maximum light transmittance (1 major aggregation rate) by PAF in the control PRP.

(Left below) (2) Effect of suppressing PAF in airway stenosis Male and female Hart''Ley peaches weighing around 4,009 pounds were used.

Urethane (1,5f / 9, lp,)
Fixed in the dorsal position under anesthesia, a cannula (four legs) was inserted into the trachea, and two of the other three legs were placed on a ventilator (Harva).
rd apparatus rodent ye
spirator). Transducer 7 of the remaining leg (lateral branch)
Mourning connected to G20 (TJgo b<1L611e). 11! ] Air supply amount, 6 to 7 sJ, number of air supply 70 times/m'
xn + negative back pressure to the lungs 10 as H2O and over
The amount of air flowing through the transaucer is
BS, recorded on Sanei Sokki.

Gallamine triethodi(le(1)
81/91V) After treatment (histamine,
2HC1 (10 μg/#) was administered intravenously to examine the reactivity of the animals. Physiological saline was administered intravenously to the group.
When FO, 3 μg/intravenous administration, the maximum airway constriction reaction was observed 30 seconds later, and when the complete occlusion was assumed to be 100%, the value was 72.8 ± 4.3%, (mean +Se, n-
6) is 6 nine. The compounds of Production Example (■) are 0.3 and 111.
Intravenous administration 2 minutes before y/#0 inhibited the above reactions of PAF by 49 and 82%, respectively.

Formulation Example 1 3-(N-OctadeV~Power~Paramyloxin-2-methquinepropyl~) 1 of 2-thiazolioethyl phosphate was dissolved in distilled water, 1.Ol, and sterile-extracted for 1 d under aseptic conditions. Dispense into ~1000 pipes, freeze-dry, and seal tightly after drying.

On the other hand, Xylit Maku is prepared by dispensing 21 distilled water for injection containing mannitol toyt into amp μ for injection in an aseptic manner and melting and sealing it to make 1000 bottles.

When using, dissolve 1 vial of powdered xylitate (or mannitol) solution for injection.

Formulation Example 2 The usage amount for 1 tablet is (1) 3-(N-octade VJ'&!Carbamoyloxy V)-2-methoxypurupia v 2-thiazolioethyl μ
phosphene) 100W100W lactose
200'f (3) Cornstarch 61 Cape (4)
HydroxyV propiμ7~loose 911IfI
Mix and granulate using a conventional method, and add corn starch (84).
, magnesium stearate C2Mfl) and then compressed into tablets each weighing 370 Hg and having a diameter of 9.5 g.

Formulation Example 3 Using the amount of each tablet in 2 above, hydroxy V propy-methy-seμ rhonupthalate (141F) and mustard oil (IMI) should be added to a concentration of 7%.
The tablets are coated with a mixed acetone-ethanol-μ (4:6) solution to obtain enteric coated tablets.

Production Example 1 3-(N-Octade V/I/Force~Bamoi μOki V)-2
-Methoquinpropy~ 2-pyridinioethyl phosphate 1), n-octadecyl isocyanate i, 7f, β
-Methyl~glycerol ether lW3.6ft pyridine2
Mix it in 0wt and overnight in Tomion! ! Mix. The reaction solution was poured into a mixture of ether fi/300m and water 50M1, and neutralized with concentrated hydrochloric acid. After separating the ether layer, washing with water and drying,
Concentrate to dryness. Chromatography using a silica gel column (developing solvent: chloroform-neetile 1:1)
8.2f of colorless crystals of 3-(N-octadeV-carbamoyloxy)-2-methquin-1-propano- are obtained.

IR (infrared %lt yield x hex)* ) yNujol(c
s*-"): ax 3340, 1687゜mp ss~56℃ Y Snubect lv (m/e): 401 (M), 37
0(M-OCH3) 2), 3-(N-octadeVμkarpamoi~okiV)-
2-Methoxy-1-propano-/L/6. of and 2
-bromoethylphosphorodichloride4. Of is heated to reflux in 3 Oat of tetrachloride for 18 hours. After cooling, the solvent is distilled off under reduced pressure, 50 ml of water is added, and the mixture is heated under reflux for 1 hour. After cooling, the mixture is extracted with ether, dehydrated with Glauber's salt, and the solvent is distilled off to obtain intermediate (prohuman body) 7.1 f. This intermediate 1.6f was dissolved in pyridine 16 and heated at 60η overnight. Pyridine was distilled off under reduced pressure, and the residue contained 2 silver carbonates.
F. Add 60seg of methanol and heat under reflux for 2 hours. Insoluble matters were removed by filtration, the filtrate was concentrated to dryness, and the resulting residue was purified by V Rikage μ chromatography. Effluent solvent; (:jHC13:MeOH:H2O-65
:25:4) Reprecipitation from -chloroform-acetone yields the desired product 393q.

TLO (thin layer chromatography): Rf 0.2 (CHCL3:
MeOH: H2O-65:25:4) Engineering R (KBr)
5I: 3340.169g, 1540°147G, 1
256.1075.10105ON (6G MHz
, coa13)': 0.7-1.8 (35H)
13.44 (3H, 8, 0CH3), 2.9-4.8
(9H, m).

6.20 (2H, broad, CH2N), t
ie(IH.

'broad, C0NH) w 8.0~8.8
(3H, m.

pyriclinio), 158 (2H, m
, pyridinio) elemental analysis 203°H55N2
07P-o, 5H2° calculation i [C, 60, 48, H, 9
,48,N,4.70゜P,5.20 Dormitory measurement C,60,20i H,9,28,N,4.7
7; P, 5.30 Production Example 2 3-(N-octadecylcarbamoyloxy)-2-methquinpropyl 2-thiazolioethylphosphate 3-(N-octadecylcarbamoyloxy)-2-methoxy-1-glopanol 20 .1 F and 2-bromoethylphosphorodichlor! J) Dissolve '14.5F in Hensen 25C1s/ and dropwise add 4.74F of pyridine while cooling with water. After the addition, the mixture was further stirred at room temperature for 6 hours. Under reduced pressure (distill the solvent, add 200 s of water to the residue and heat under reflux for 1 hour. After cooling, extract with ether to obtain 29 ff of the intermediate.
get t. Thiazole 20F and toluene 25
mK71! Dissolve and heat at 60°C for 3 days. The solvent was distilled off, the residue was dissolved in methanol/L 1500-
Add 0F and stir at room temperature for 1.5 hours. Insoluble materials were removed by filtration, the liquid was concentrated, and the residue was purified by silica gel chromatography.
OH:E (20-65: 25: 4) Target 5
．． 1 f tul.

TLC:Rf-0,2(CHCL3:MeOH:H2O
-65:25:4) Engineering R (KBr) C1l” :3400,2920.28
51゜1701.1558.1246.1065N M
R(60MHz, CDCl3)J: 0.7
-1.8 (35H).

3.46 (3H, 8, OMe), 2.9-4.8 (9H
, m).

5.08 (2H, broad), 55.30 (IH
, broacl.

C0NH), 8.55, 8.88 & 10.93
(Thiazoli elemental analysis; C28H53N20.
PS-1,5H20 calculated value C,54,26+H,9
,11B N,4.52+P,5.00*,m value C,54,3(l H,8,90+N,4
．． 71sP, 5.03 Production Example 3 3-(N-decylcarbachoyloxy)-2-methoxyV
7″ Robi/v 2-thiazolioethyl phosphate 1), n-undecane @ 259 dissolved in toluene 220 L, diphenylhonupoly-azide 51.6f.

Add 28.3 ml of triethylamine, stir at room temperature for 3.6 hours, then concentrate the reaction solution to 70 ml, and heat under reflux for 1.6 hours. After cooling, β-methylglycerol ether~6
Add a, 3f, and pyridine 165, stir at room temperature, and concentrate to dryness. Remove the residue with chloroform (dissolve and wash with water,
Drying, concentration, and chromatography on silicage yielded 20.7 g (63%) of 3-(N-decylcarbamoyloxy)-2-methoxy-1-propano-μ.

Engineering R (F/L'mu) 3340.2920.285
0°1700.1255.1065.955.7482
), 3-(N-decylcarbamoyloxy)-2-methoxy-1-globanol ~ 289.4 q (1, Qmm
Ole), 2-bromoethylphosphoryl dichloride 36
2.8 Wf (1.6 mmole) to benzene 2.1
Melt mK, viridiyl 18.71f (1,5mmo
) and stir at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, 41 t of water was added to the residue, and the mixture was heated at 90°C for 1
Heat for an hour, add 10 seconds of cold chloroform, stir vigorously, separate the organic layer, and discard the aqueous layer. The organic layer was concentrated to dryness under reduced pressure, a 1 wt tube of thiazo-A' was added to the residue, stirred at 50°C for 3 days, and concentrated to dryness under reduced pressure. Add 2220 q of methanol to the residue and leave at room temperature for 1 hour. After filtering off insoluble matter, the mother liquor is concentrated to dryness under reduced pressure. This was added to the silica gel column (C8f), developing solution chlorophor, methanol, water (65:26:4).
The target product was colorless powder 147M1 (yield: 3
2%) tli.

IR(fj-Lm)rxl: 332G, 3080,2
930°2850.1700,1546.1460,1
240°109G, 1060.95O NMR (60MC, CDC13) J: 0.93 (3H)
, 1.23 (16H), a, 13 (2H), a, 38 (
3H), 8.70-4.67 (7H), 4.96 (2H
), 6.17 (IH).

8.33 (IH), 8.67 (IH), 10.70 (I
H) TLC: riproform, methanol, water (65:2
5:4) Rf-0,21 (1 spot) Production Example 4 3-(N-octadecylcarbamoyloxy)-2-methoxypropyl/L/2-(4-methyl-5-hydroxyethyl, A/)thiazolioethyl phos Phate [3-(N-octadecylcarbamoyloxy)-2-methoxypropy/L/2-promoethylphosphate obtained with ifu 1 - phosphate 294 (0.5 mmol 1θ).

4-Methyl-5-hydroxythiazole 28
L4W (2, Ommole) t), u=c7
Melt at 0.5 dK and heat at 75°C for 3 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue was transferred to a silica gel column (8F).

Developing solution: chloroform, methanol, water (65; 25:4
) to produce a colorless powder of 85”f (yield 26.2%).
get the results.

Engineering R(fllm)ag+, 3300.2920,2
850°17G0.1540.1460.1230.1
090°1060.1055,930,86O NMR (60MC, CDCl3)': 0.9
0 (3H).

1.28 (32H), 2.57 (3H), 8.08 (6
H).

a, 43 (3H), a, 83 (6H), 4.10 (2)
().

4.33 (IH), t77 (LH), 5.78 (I
H).

10.57 (IH) TLC: Chloroform, methanol, water <65:26:
4) Rf=0.33 (15pot) UV (ultraviolet "A absorption"): λmaxM00H
! 22m voice, 282mμ Production Example 6 3-(N-octade Vlucarpamoyl)-2-methoxypropyfi/2-isoquinolinioethyl phosphate Prohuman body obtained in Production Example 1, that is, 3-(N- Octade V
fi/force~bamoyloxy)-2-methoxypropy~
2-bromoethyl phosphate 294IIf (0,
6mmole), I'/Ki/! Jn258.3”IF
(L Oxsole) 'to A/ x 70.5
ml and heated at 75°C for 3 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue was transferred to a V ricagel column C3f) and a developing solution.

Purification using chloroform, methanol A/water (65:25:4) gives colorless powder 1409 (yield 44%).

Engineering R (film)! -”: 3320, 2920
, 2850.

1700.1640.1530.1460.1240゜1095.1060.930.82O NMR (60MC, CDC13) J: 0.88 (3H
).

1.27 (35H), 3.13 (2H), 8.32 (3
H).

3.3-8.8C2H), 8.93 (IH), 4.07
(8H).

4.63 (IH), 6.30 (LH), 6.0O (IH
).

8.00 (3H), 8.50 (IH), 8.57 (IH
).

9.10 (IH), 10.70 (IH) TLC: Chloroform, methanol, water (65:25:4) Rf-
0,47 (15pot) eOH UV: λmax 233m11.279
m voice, 340 mμ Production example 6 3-(N-octadecylcarbamoyloxy)-2-benzylokinlopi-2-thiazolioethyl phosphate 1), 1,3-benzylidene glycero-tv27f*benzyl chloride 45f, Et, N engineering 3001F , 50
%NaOH6G- and benzene 240- are mixed and 40
Heat to reflux for an hour. Separate the benzene layer and add 50% NaO
Add H60-, Et, N engineering 30011 and add 20 more
Heat to reflux for an hour. Separate the benzene layer, wash with water, and concentrate. The residue was purified by silica gel chromatography (f#, benzene).

1.3-benzylideneglycerol β-penzyl ether ~36f (yield 89%) is obtained. mp 73-75°C 2), ether compound 339 obtained by the method described above is dissolved in a mixture of 3611kt of water and 14G of acetic acid, and heated under reflux for 1 hour in a nitrogen stream. The residue was distilled off under reduced pressure, and the residue was purified by silica gel chromatography.
IIIg, ether), β-benzylglycero, a/
196F (yield: 88 hers) was obtained.

NMR (CDCl5) J:a, 14(2H,OH), 8
．． 3-8.9 (6H), 4.60 (2H, phca2-
), 7.34 (6H1ΣdanCH2-)- 3), β-benzylglycero-fi/a, 6441 was dissolved in pyridine O-, to which wasoV anoic acid octadecyfi6.91 was added, and the mixture was dissolved at room temperature. Stir overnight. Pyridine is distilled off, and dilute hydrochloric acid and chloroform are added to the residue. Separate the chloroform layer, dry and concentrate. The residue was purified using a silica gel chromatograph (eluent solvent: chloroform-ether, 10:1), and the main product was recrystallized from n-hexane to form 3-(N-octadecyp-pamoyloxy). -2-benzyloxy-1-propano-IM
4.11 is obtained. ml) 52-54°C 4), 3-(N-octadecyl 〃bamoyloxy]-
3.1 g of 2-benzyloxy-1-7' lovanol and 2.9 f of 2-promoethyl phosphorodichloritate were dissolved in 50 g of benzene, and 0.96 g of pyridine was added under water cooling.
Drop t. After further stirring at room temperature for 1.6 hours, benzene was distilled off, 50 sJ of water was added to the residue, and the mixture was heated under reflux for 46 minutes. After cooling, it is extracted with chloroform and concentrated to dryness to obtain a white powder (bromine compound) 6.3f.
Take F, dissolve it in thiazo-6-, and heat at 60°C for 3 days. The solvent was distilled off, methano-N4 Gm and 3.1 f of silver carbonate were added, and after stirring at room temperature for 1 hour, the insoluble matter was removed, the furnace solution was concentrated to dryness, and the residue was chromatographed on V lyca gel. Effluent solvent for purification: CHCl3: MeO
H:H2O-65:25:4) to obtain the target product 8111II.

Engineering R (KBr) ffi, 3340, 292
0.2850.

1695.146L 1230,1055N MR(
60MHz, CD013) I: 0.7-1.8
(35H).

19-4.9 (11H, m), t62 (2H, s.

-CH2Ph) -6,0(IH, broad, 0
ONH).

7.30 (6H, s, Ph), 8.21.8.44&1
0.73 (3H, thiazolio) Elemental analysis: C54H N20F SP/2H20 calculated value
C, 57,93 irises H, 8,72 toads N, 3.97+P,
4.39 Actual measurement C, 58,00 H, 8,91; N, 3.9
7! P, 4.22 Production Example 7 3-(N-octadeV ~ Kaμpai 4th xy-2-benzylokiV) propylv 2-viridinioethyl! 2.3f of the intermediate (bromine compound) obtained in Phosphate Production Example 6 is dissolved in 12ggl of pyridine and heated at 60°C for 16 hours.

Pyridine was distilled off under reduced pressure, and 2.3 f of silver carbonate and methanol-μ3C)xl were added to the residue, followed by heating under reflux for 1 hour. Insoluble matter was removed, the filtrate was concentrated to dryness, and the residue was purified by silica gel chromatography. Eluent solvent: CHCl3
: MeOH: H2O-65: 25:4) Target 7
7011f is obtained.

TLC: Rf = 0.35 (CHCl3:
MeOH: H2O-65:25:4) Infrared absorption spectrum * (KBr) as+: 291G,
2840°16116.1245.1010 7ON (6fMHz, CDCl3) J: 0.8
-1.8 (36H).

2.7-6.1 (13H), 6-10 (IH,
broad.

C0NH), 7.27 (5H, 8, Ph), 7.6
6-8.47 (3H, broad, pyridini
o), 9.10 (2H.

'broaa, pyridini, o) Elemental analysis:
C36H59N207P・1.5H20 calculated value C,6
2,68+ H, 9,06t N, 4.06 actual value C
,62,80+ H,8,80s N,4.47 Production example 8 3-(N-toco S/, A/force μ pamoi Oki V)-2-
Meshiki V10 biμ 2-thiazolioethyl phosphate 2 1), tricosanoic acid 7.08f (2X10 mo/L/
) was filtered into a mixture of 70 Wt of anhydrous toluene and 8°6 of triethylamine, and diluted with diphenylphosphor 9 at room temperature.
*A5FF41.6f (L4xlO''-t, u) was added dropwise. After stirring at room temperature for 3 hours, the reaction solution was concentrated to a volume of A under reduced pressure. The reaction solution was refluxed for 1.5 hours, and after cooling. , pyridine 30m and 2-methoxy-1,3-p20pyrene glyco-μ7.84f (7,4xlOmofi/
) and stir at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After washing the chloroform layer with water, it is dried with Na2SO4. The solvent is distilled off, and the residue is purified by column chroma-side chromatography using Vlikage fi/(10(1)).

The chloroform effluent fraction was concentrated to dryness to give 3-(N-y
4.3F (47%) of colorless powder of -2-methoxy-1-purpanol is obtained.

Engineering R (KBr): 3360 (NH, OH), 292
0 (CH).

285G (CH), 1685 (-NHCOO-), 15
30(-NHCOO-) 2), 3-(N-docoxy-carbamoyloxy)-2-
Metquin-1-propano-1%/174 f and 2-
Promoethyl phosphorodichloridate was dissolved in 1.89 tt/20 g of benzene, 0.62 F of pyridine was added dropwise, and the mixture was stirred at room temperature for 2.6 hours. Benzene was distilled off, water was added, and the mixture was heated under reflux for 1 hour and 30 minutes. Extract with cold chloroform and concentrate to dryness.

Thiazo-6.4d was added to the residue and heated at 60°C for 77.6 hours. The reaction solution was dried and the residue was mixed with 80 sJ of methanol.
Then, 2.15 F of silver carbonate was added, and the mixture was heated under reflux for 1 hour.

Filter while hot and concentrate the p solution to dryness to obtain a crude product. Effluent was purified by chromatography using Vlikage/1/CHCL3-MeOH420°65:26:4
), and recrystallized from a chloroform-acetone mixture to obtain the desired product 0.411 (10,6 times).

Engineering R(KBr)es, 2920. 2850. 1
700°1246, 1065 Elemental analysis C32H61N 207 PS・2H20 calculated value C,56,12+ H,9,57i N,4.0
9+P, 4.52〼 8.4.68 Actual value C, 56,14; H, 9,47; N, 4.
071P, 4.68; S, 4.24 Production Example 9 3-(N-tetofdecyl-bamoyloxy)-2-methoxyderrohyde A/2-thiazolioethyl phosphate 1) 20f of pentadecanoic acid was dissolved in dry toluene 200s (K
jll solution L, diphenylphosphoryl azide 27.3f,
) Add 149m of riethyμamine and stir at room temperature for 5 hours.
The reaction solution was concentrated under reduced pressure and heated under reflux for 1 hour. Cold machine, β
- Add 3L8f of Methi μglycerol ether and 124d of dry pyridine, and stand at room temperature overnight or t! Mix. Concentrate to dryness, dissolve in chloroform, wash with water, dry, and purify by chromatography on silica gel (IIII eluate; chloroform) to obtain 2-methoxy-3-(N-tetofudecy ~ force μ) (hair Iyvttrv>- 1-prot<1-1v9.
43 t (33%).

Br Engineering Rvmax (cs) 1695 2), 2-methoxyV-3-(N-tetotudecyμcapamoyloxy)-1-propano-Iv5.18F and 2
- Dissolve 5.41 t of phosphorodichloridate in 73 ml of benzene, dropwise add 1.78 ft of pyridine, and stir 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. Extracted with cold chloroform,
Concentrate to dryness.

Thiazo-7- is added to the residue and heated at 60°C for 60 hours. The reaction solution was dried and 90d of methanol and 8f of silver electorate were added to the residue, and the mixture was heated under reflux for 1 hour.

Filter while hot, concentrate the p solution to dryness, and purify the residue by chromatography using silica gel. Chloroform-
Recrystallization from an acetone mixture yields the desired product 0.4f (6%).

Engineering R (KBr) am”-2920, 2850, 170G
.

1230, 1050 Elemental analysis: C2, H45N20. PS・2H20 needle count @ C, 50, 33; H, 8, 27; N, 4.8
9+P, 5.41i S, 5.60 actual measurement @ C+50.35; El, 8.20. N,
4.76°P, 5.38. S, 4.84

Claims (1)

[Scope of Claims] Formula [wherein, R1 is an alkyl group having 10 to 24 carbon atoms, R2
is an alkyl group or aralkyl group having 1-4 carbon atoms, A
represents a heterocyclic group having a quaternized electron; or a salt thereof.