JPS60146894A - Phospholipid - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is 10-24C alkyl; R<2> is (substituted) imide group; A<+> is cyclic ammonio] or its salt. EXAMPLE:3-Octadecyloxy-2-phthalimidopropyl 2-pyridinioethyl phosphate. USE:A thrombocyte activation factor-inhibiting agent. It has excellent hydrophilic and oleophilic property, and low toxicity. PREPARATION:The objective compound can be produced e.g. by reacting the compound of formula II (Y is Cl, Br or I) with a cyclic amine compund (e.g. pyridine) in a solvent such as methanol or in the absence of solvent. The amount of the amine compound is 1 equivalent or large excess (e.g. 50 times mol) based on the compound of formula II.

Description

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

More specifically, the present invention relates to the formula % formula % [wherein R1 is a C10-24 aμkyl group, R2
represents an optionally substituted cyclic imide group, and A+ represents a cyclic ammonio group] and its salts.

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

Conventionally, adenosine diphosphate (ADP) and arachidonic acid metabolites, particularly thromboxane A2 (TXA2), have been known as representative 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, platelet activating factor (PLATELET ACTIVATIN) has been recently discovered as a substance that causes a stronger platelet aggregation effect with a different mechanism of action than ADP and TXA2.
gFactor (P AF )) has been elucidated, and its structure is 1-0-amyl-2-acetyl-5n-glyceryl-3-phosphoryl! It turned out to be lecolin [Nature, vol. 285, 193 (1980)]. P
AF' has a different mechanism of action than ADP, 'I'XA2,
It has been found to have strong activity at low intensities.

In addition, PAP is a strong chemical messenger for allergies; for example, when measuring bronchial stenosis as Merckmar μ,
Known to have the strongest activity among known compounds (European Journal of P
hermacology, u, 185-192(1
980)). Therefore, if we can find a compound that has an inhibitory effect on PAr, it could serve as a more effective inhibitor against platelet aggregation in living organisms, and could also be used to treat other PAF-induced diseases, such as ( It can be used as an effective suppressant for allergic diseases.

In addition to platelet aggregation, PAF has a strong antihypertensive effect, and is thought to act as a shock inducer [1 Imropean J
Our own of Pharmacology, 8
6.

403-413 (1983)). Shock can occur due to various causes such as trauma, bleeding, and resistance to the nine rules of heart thickness.

However, although the causes are different, the pathology of shock is almost the same.
Circulatory abnormalities such as a drop in blood pressure and decreased cardiac output, and circulatory abnormalities such as transgenic acidosis, hyperkalemia, and lactic acidemia are observed. For example, bacterial shock is particularly likely to occur due to infection with Gram-negative bacilli (E. coli, Bacillus aeruginosa, Klebsiella, etc.), and endotoxin, a cell wall component of these bacteria, is thought to be the cause. Shock can actually be induced in animals by injecting them with endotoxin. Despite advances in antibiotics and 'itk fluid therapy, there has been no improvement in the mortality rate due to shock. Therefore, when shock is expected, drugs to prevent endotoxic shock are used in combination with antibiotics. Adrenocortical hormones such as hydrocortiscin and dexamethasone are frequently used, but since they are used in shock, the side effects of adrenocortical hormones pose a problem. °Anti-inflammatory drugs such as indomethacin are still being used, but they are not foolproof and have side effects such as sun formation, and their effects are not very effective.

The present inventors have intensively investigated methods for suppressing the action of PAF' involved in various circulatory disorders and shock, and have discovered that the compound represented by formula (I) has a strong anti-PAF effect. completed.

Regarding the formula (I), C represented by R1. -24μ
The kill group may be linear or branched, such as decyl, dodecyl, tridecyl.

Tetwodecyl, Pentadecyl, Hexade VIV, Hebutade VA/, Octadecyl, Nonadecyl, Icosani,
Examples thereof include dokosani, fanesi, and dihydrofichi p, among which C□4-20 alkyl group is preferred.

Examples of the cyclic imide group represented by R2 include a phthalimide group, a succinimide group, and a maleimide group.
, propyl, isopropyρ, butyμ, isobutyl, lower argy/L/ groups, lower alkoxy groups such as methoxy, ethoxy, halogeno groups such as chloro, brome, nitro h1 panacetiμ groups, etc. .

Cyclic ammonio group represented as A+, such as pyridinio group, oxazinio group, thiazolio group, isothiazolio group, pyridacinio group, quinolinio group, isoquinolinio group, N-methypmophorinio group, N-methylpiperidinio group, N -Methylpyrrolidinio group, etc. are rejected.

Further, compound (I) is, for example, (Ia), (Ib)
It may also exist in the form of pharmacologically acceptable salts such as those represented by

H2OR1 ■ H2OR1 [In the formula, X- is C1, Br, I, OH, COi,
anion such as sony, M is an alkali metal (e.g. N
a,

In compound (1), there are two types of stereoisomers, R-coordination and S-coordination, with respect to the carbon at the 2-position, and each of them, a mixture thereof, and a racemate are within the scope of the present invention. It is included in.

Compound (I) and its salts are excellent platelet activating factors (
PAF), and more specifically, it strongly suppresses platelet aggregation, shock (lower blood pressure, death, etc.) and allergies caused by PAF. Therefore, the compound (I
) and its salts are used to treat circulatory disorders caused by platelet activating factors in mammals, such as thrombosis, stroke (eg, cerebral hemorrhage, cerebral thrombosis), myocardial infarction, angina pectoris, and thrombophlebitis.

Glomerulonephritis, shock (e.g., endotoxin shock,
It can be used to prevent and treat diseases such as intravascular blood coagulation syndrome caused by endotoxin (anaphylactic shock) and bronchial asthma related to allergies.

Compound (I) and its salts have excellent properties in both hydrophilicity and lipophilicity, and have low injection rates, so they can be administered orally or parenterally as a powder or as a pharmaceutical composition in an appropriate dosage form. can be safely administered to Although the dosage varies depending on the subject, symptoms, administration route, etc., for example, when orally administered to prevent or treat thrombosis in adults, the dosage of Compound (I) is usually about 0.1 to 0.1 to 1.
It is convenient to administer about 20M9/kg body weight, about 1 to 34 times a day. More specifically, when the purpose is to prevent thrombosis, the equivalent amount is about 0.5 to 4 eq/kg, and when the purpose is treatment, the equivalent amount is about 4 to 10 eq/kg.
It is preferable to administer about 1 to 34 doses per day.

In addition, when used for the prevention or treatment of shock, for example, in the case of adults, when administered intravenously, compound (I) is usually administered in a single dose of 01 to
20-. It is convenient to administer 1 to 34 times a day, preferably 1 to 10 times a day, 1 to 3 times a day. In addition, compound (1) was added once (#) 0.07 to 0.7
It can also be administered by drip injection at a rate of about Mfl/k1 body weight/min for about 1 hour, about 1 to 34 times a day. Similar amounts are administered for other parenteral administrations and oral administrations. If the symptoms of shock are particularly severe, the dose may be increased depending on the symptoms.

The pharmaceutical composition used for the above administration contains an effective amount of Compound (I) as an active ingredient or a salt thereof and a pharmacologically 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 or liquid dosage forms, specifically tablets (including M-coated tablets and film-coated tablets), pills, granules, powders,
Capsules (including soft capsules), syrups,
Examples include emulsions, ζ distribution IC agents, and the like. 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 milk, starch, sucrose, and magnesium stearate.

Compositions for parenteral administration include, for example, injections,
Examples include suppositories, and injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, and one-drop injection. Such injections are prepared by a method known per se, ie, by dissolving, suspending or emulsifying Compound (I) or a salt thereof in a sterile aqueous or oily liquid commonly used for injections. Aqueous fluids for injection include physiological saline, isotonic solutions containing grape moat and other adjuvants, and suitable solubility aids, such as alcohol (e.g., ethanol-1v), polyalco-/I/( Examples, propylene glycol-yv, polyethylene glycol)v), nonionic surfactants [e.g., polysorbate 80, HCO-5Q
(polyoxyethylene (5Q mol
) adduct of hydrogenated
castor oil] etc.

Oil-based liquids include sesame oil and soybean oil, and solubilizing agents such as benzyl benzyl and benzyl alcohol may be used in combination. The prepared injection solution is usually filled into suitable ampoules. Suppositories used for rectal administration are
It is produced by mixing compound (1) or a salt thereof with a common crude drug 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/I/), suppositories, etc.
It is preferred that the compound (I) contains 500q, especially 5 to 10 (1) for injections, and 10 to 250M9 for other dosage forms.

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).

Compound (I) can be produced, for example, by the method shown below.

Method A HOR1 2 Jtl [In the formula, Y represents CI, Br, or engineering, and the other symbols have the same meanings as above] is reacted with a cyclic amine compound A (11[) corresponding to A+ Compound (I
).

Compound (1) is obtained by reacting an active derivative of an optionally substituted cyclic imide with a compound of B method % formula % [in the formula, each symbol has the same meaning as above].

C formula % Formula % [In the formula, X' represents C1 or Br, and the other symbols have the same meanings as above] For the compound of the formula % Formula % () [In the formula, X- represents an anion, and other symbols Compound (I) is obtained by reacting a compound with the same meaning as above].

Examples of the compound (I[) used in the reaction of method A above include pyridine, thiazole, oxazo-〃, quinoline,
Examples include inquinoline, isothiazole, pyridazine, N-methylmorpholine, N-methylpiperazine, and N-methylpyrrolidine. In the reaction, base (I[) is added to compound (IF) by 1 part or in large excess (e.g., 50 times mole).
The reaction is carried out at room temperature or under 7yil heat in the presence of a solvent or under the ayu-melting method. The methanol,
Examples include toluene, benzene, ether, dioxane, and tetrahydrofuran.

Examples of active derivatives of optionally substituted cyclic imides used in the reaction of method B include N-ethoxycarbonyl phthalimide, di-methoxycarbonyl phthalimide, N-ethoxycarbonyl succinimide, and N-ethoxy carbonyl phthalimide. Examples include μbony-maleimide. Compound(
The reaction between IV) and these active derivatives can be carried out according to widely known conditions for reactions between amino compounds and these active derivatives. It also promotes the reaction f
The reaction may be carried out by adding a base such as triethylamine or pyridine to the 7'c point.

The reaction of method C is carried out in the presence of a solvent (e.g., chloroform, dichloromethane, pyridine, toluene, dioxane), or equivalent mole of compound (VT) to compound (V).
．． This is achieved by applying about 5 times the A/m degree at 0 to 100C.

In each of the above-mentioned production methods, the progress of the reaction can be monitored by 14-cycle chromatography, which allows the reaction conditions to be determined promptly.

Purification of the compound produced by the above method involves normal operations,
It is suitably clarified by solvent extraction, recrystallization, chromatography, etc.

The present invention will be explained in more detail below using examples, performance examples, and formulation examples, but the scope of the present invention is not limited thereto.

Example 1 3-0-octadecyl-2-0-)/l/-1-〇-tritylglycerol 3-0-octadecyl-1-〇-tritylglycerol 5.0 Q (8,52 mmiv) 9 ml of pyridine
Toshi chloride A/1.95g (10.22ml 7p) dissolved in
) was added thereto, stirred overnight at room temperature, and then concentrated to dryness under reduced pressure. Dissolve the residue in 50a/w of water and 50+w/w of dichloromethane, stir, and separate the dichloromethane layer. The organic layer was concentrated to dryness under reduced pressure.
(193 Near) to obtain 5.3 g of colorless needle crystals (yield: 83.9%).

mp 52° to 53°C Example 2 3-octadecyloxy-2-phthalimido-1-trityloxypropane 5.3 g of tosyl compound obtained in Example 1 (115 mm/L/
) Dissolved in 53 ml of dimethylspoxyte, added 10.69 ml of potassium phthalimide, and heated to a bath temperature of 115 tE.

Stir for 35 hours. The reaction solution was poured into 500*t of water, extracted with ether)v50011It, and the ether)V layer was dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified using a silica gel column (50 g), a developing solvent of n-hexane, and ethyl acetate/L' (193 nia) to obtain a colorless oily substance. (1 (yield 58.6%)) was obtained.

TLC (5ilicaqel, n-Hexane
, EtOAc (9:1)] Rf=0.25 s
ingle 5pot.

Example 3 1-Hydroxy-3-octadecyloxy-2-phthalimidopropane 3.0 g (4,19 mm!J mol) of the trityl compound obtained in Example 2 was soaked in 50 ml of 70 ml of vinegar, The mixture was heated under reflux for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column (4(1) n-hexane, ethyl acetate/I/(4:
1) to obtain 1.17 g of colorless needle crystals (yield: 511
L9%) was obtained. mp(iQ'-51t: T L CC
Silicagel, n-Hexane, EtOA
c (4:1)) Rf=0.16 ER(KBr)am 1: 3500.3450.29
10. 2850°1765, 1700.1465.
1390.1150.1060°75 Example 4 3-octadecyloxy-2-phthalimidopropyl lv
2-bromoethyl phosphate 1.8949 (4 mmA/) of the hydroxy compound obtained in Example 3 was mixed with benzene 8
Dissolved in wt, 1.45 g (6 mmol) of 2-bromoethyl phosphorodichloridate, 0.475 g of pyridine.
(6 mm 7) v> was added dropwise and stirred at room temperature for 4 hours.
The reaction solution was concentrated to dryness under reduced pressure, and the residue was poured into 100 y/ml of water and heated to 50° C. for 30 minutes while adjusting the pH to 7.0. After further heating and centrifuging for 30 minutes, after cooling, ether 1v6CLttl was added for extraction, and ether M was concentrated to dryness under reduced pressure to produce a colorless solid. ．． 64 g (yield 100%) was obtained.

Example 5 3-octadecyloxy-2-phthalimidopropyl/L
/2-Pyridinioethyl phosphate 127 g (3.55 mm/L/) of the bromide obtained in Example 4 is dissolved in 20 x l of pyridine and heated at a bath temperature of 60 tE for 2 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column (
20g) Purified with methanol to give 740wI of light brown solid
(yield 33.3%).

TLC (silicagel, CHCl3,
MeOH, H2O (65: 25: 4)'] Rf
=0.21 aingle 5pot.

Engineering R (film) cu+ 1: 3400.2930.
2850.1775°1?10.1635. 1490
．． 1465. 1395.1250°1100, 10
75.1050. 760. 72ON MR(60
MO, CDCl5) δ: 0.88 (3H), 1.27 (
32H), 3°40 (2H).

3.80 (2H), 4.22 (4H), 4.60 (xr
I), 4.73 (2H), y, 7z (4H), s, o7
(2a), s, 42(xn), 9. os(tu) Example 6 3-octadecyloxy-2-phthalimidopropyl)v
2-Thiazolioethyl phosphate 2.27 g of the bromide obtained in Example 4 was dissolved in a mixture of thiazo-AI (5 liters) and toluene (5 wt) and heated at 65C for 7 hours. The reaction solution was IM concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column Chromadog "7F" to obtain the desired product 540
I got two.

TLC(ailicagel, CHC131Me
OH, H2O (65:25:4))Rf=0.22 The following compound can be synthesized in the same manner as in the example.

3-octadecyloxy-2-succinimidoprovil 2-pyridinioethyl phosphate 3-octadecyloxy-2-succinimidoprovil 2-thiazolioethyl phosphate 3-octadecyloxy 2-
Maleimidopropyl/I/2-pyridinioethyl phosphate 3-octadecyloxy-2-maleimidopropyl/L/2-thiazolioethyl phosphate 3
-hexadecyloxy-2-phthalimidopropyl/
2-pyridinioethyl phosphate 3-hexadecyloxy-2-phthalate! Imidobrohy/I/2-thiazolioethyl phosphate 3-octadecyloxy-2-phthalimidopropy/L/2-isoquinolinioethyl phosphate 3-octadecyloxy-2-phthalimidopropyl
2-quinolinioethyl phosphate 3-octadecyloxy-2-phthalimidopropytv 2-(1i-methylpyrrolidinio) x th)v phosphate 3-octadecyloxy-2-phthalimidopropy/L
/ 2-(N-Methylpiperazinio)ethyl phosphate (normal example) PAF inhibitory effect PAF inhibitory effect on platelet aggregation [Test method and results] 3.15% citric acid ( Blood was collected directly using a syringe containing 1 to 9 parts of blood. Then at room temperature, 1.000 rpm
Collect platelet-rich plasma (P) by centrifuging for 10 minutes at
RP: PLatelet rich plasma
) was obtained. 15 more PRP at 1.40 Orpm
Centrifugation was performed for a minute to obtain a Platelet pellet, which was then transferred to Ca free T7rOde (gelat
Washed in 0.25%)
PRP was prepared. This Washecl PRP 2
50111 at 37℃ for 2 minutes, 0.2-0.5m
25 ttl of M's Ca+-1- solution was added, and the mixture was further stirred for 30 seconds. Next, the compound of Example 5 was added in an amount of 3X10 M, and after stirring for an additional 2 minutes, PAF 3X10'
Added M. Blood l) Pseudo-agglutination was measured using an aggregometer (manufactured by Rika Denki). The activity of the first drug was determined by PA in control PRP.
The suppression rate for the maximum light transmittance (maximum aggregation rate) due to F was calculated to be 70%.

Formulation example 3-octadecyloxy-2-phthalimidopropyl
2-Pyridinioethyl phosphate 1 (l distilled water,
1. Dissolve in OJ, pass through a sterile filter, dispense 1 wt each into 1000 vials under aseptic conditions, freeze-dry, and seal tightly after drying.

On the other hand, 2 containing xylitol or manni) -/&100t! After aseptically dispensing 2 txt of distilled water for injection into the injection amplifier p, melt and seal it to make 1,000 bottles.

When using, xylitol solution for injection (still mannitol solution)
Dissolve one vial of the former powder in and use.

Procedural amendment (spontaneous) December 22, 1920, Mr. Commissioner of the Japan Patent Office 1, Indication of the case, Patent Application No. 4080 of 1982, 2, Title of the invention: Phospholipid 3, Relationship with the person making the amendment Patent Applicant Address 2-27 Doshomachi, Higashi-ku, Osaka Name (29
3) Takeda Pharmaceutical Co., Ltd. Representative Iku Kurabayashi Division 4 Agent Address 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka City Takeda Pharmaceutical Co., Ltd. Osaka Factory Name Patent Attorney (6022) Saku Amai Next Tokyo contact information (Patent Laws and Regulations Division) Tel: 278-2218/22196,
Contents of amendment (1) The following statement is inserted between lines 11 and 12 on page 19 of the specification.

(Kucho Yosu) [Example 7 3-octadecyloxy-2-amino-1-trityloxypropane 6.4 g of 3-octadecyloxy-2-phthalimido-1-trityloxypropane was dissolved in 50xt of isopropyl alcohol, and hydrazine Eiwa Add 4ml of
Heated at 0°C for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and ethyl acetate was added to the residue to remove insoluble matter. The filtrate was concentrated to dryness and purified by silica gel chromatography. (Eluent n-hexane-ethyl acetate 3:1). 4.41 g (84%) of the target product was obtained as a light brown solid.

NMR (90M) Iz, CDC1a) 1. 0.
87 (8H.

1) 1.25 (82I-10m) 8.0-8. ．． 5
6 (7I-1°m) 7.2-7.5 (15H, m) Example 8 3-octadecyloxy-2-(2-carboxyethylcarbonylamino)-1-)lythyloxypropane obtained in Example 7 2-amine compound 2.849 (4 mmol
e) in 10 m/chloroform, 2 ml of triethylamine, 0.489 mmol of succinic anhydride (4.8 mmol)
le ) was added thereto, and the mixture was heated under reflux overnight. The reaction solution was concentrated to dryness and purified by silica gel chromatography.The eluent was chloroform-methanol-20:1). 2.88 g (85%) of a one color solid was obtained.

Ding R (KBr, cm) 8265, 8060, 2925
゜2850.17'80,1680,1648,155
0°1490.1470,1455,1400,125
5゜1088.1020.705 NMR (90Ml-1z, CDCeB) J, 0.8
7' (81(.

tl i, 25(82H, sl 2.25-2.75(
4H0ml' 8.0-8.75 (6H, m) 4.2
2 (IHom) 5.95 (IHo d) 7.15-7
．． 50 (15 tons 1.m) Example 9 3-Octadecyloxy-2-succinimidepropertool The carboxylic acid form 2.21Q obtained in Example 8 and 045 g of sodium acetate were heated at 100°C for 2 hours in 10 g of acetic anhydride. did. The reaction solution was concentrated under reduced pressure, n-hexane was added, and insoluble materials were filtered off. The filtrate was concentrated to dryness to obtain a crude product of 3-octadecyloxy-2-succinimide-1-trityloxypropanol.

This crude trityl compound was added to 20 rsl of 70% acetic acid at 100°C.
Heated for 2 hours. The reaction solution was concentrated to dryness, and the residue was purified by silica gel chromatography to obtain the desired product as a colorless powder, 1.316'7 (95
%) was obtained.

IR (KBrlcm)8525, 2970, 2925
゜2850.1768,169R,1470,L192
゜1180.1122, 1060.725NMR (90
MHz, CnC13) 1.0.87 (aH.

t) x, 2 5 (s 2 H, m) 2.7 1 (
4H, S) 2.9 (IH, br ) 3.40 (2H
,m) 165-4.0(4I(,ml 4.48<LH
, m) m, I), 76-78°C Example 10 3-occudecylogycy 2-succinimide propatool J, Hajdu Lano method [J, Org,, Che
m, 4.8°1197-12112. (1988)], 343 g (10 mmole) of 3-occudecyloxy-2-aminopropatool, and 1.789 g (10 mmole) of carboethoxysuccinimide.
) The mixture was stirred in dichloromethane for 50°C to obtain 1.019ml of triethylamine while cooling with water. 3 at room temperature
After stirring for 0 hours, the reaction solution was concentrated to dryness, and the residue was purified by silica gel chromatography.

The desired 2-succinimide compound 894M1 was obtained.

The spectral data were consistent with that obtained in Example 9.

Example 11 3-octadecyloxy-2-succinimide globil 2-bromoethyl phosphate 3-octadecyloxy-2-succinimide propatool 688”f (1,
5 mmole) was dissolved in 20 mt of toluray, and when cold, bromoethylphosphocycloresort 786 mg (8
, 25 mmole) and triethylamine 101 da (8
, 25 mmole) and stirred at room temperature for 4 hours. After adding 20% of water and 05% of concentrated hydrochloric acid and stirring at 80"C for 1 hour, the solvent was distilled off. The residue was dissolved in ether, washed with water, concentrated, and dried to obtain the desired bromine compound 939 da. .

Example 12 3-octadecyloxy-2-succinimidopropyl 2-thiazolioethyl phosphate 030 g of the crude bromine compound obtained in Example 11 was dissolved in thiazole 1 mtI and heated at 80° C. for 26 hours.

The reaction solution was concentrated to dryness, and the residue was purified by silica gel chromatography. (Eluent: methanol; chloroform - meta/-water 65:25:4) to obtain the desired product 121jv as a colorless solid.

rR (KBr9cm)8410.2850.1?75
゜1550.1470,1400,1240,1200
゜1065.88O NMR (90MHz, CDCβ8) δ, 0.87 (8H
.

t) 1°25 (f32H, m)'2.69 (4H.

S) 3.2-1.5 (2H, m) 8.5 4.054
H, m) 4.2 (2H, br) 4.5 (IH, m) 4.
88 (2H, m) 8.20 (IH) 8.49 (IH
) 10,4(tH) TLCRf=0.24(CH(43-MeOH=H20
65:26:4) Example 18 3-Octadecyloxy-2-maleimidopropertoolmaleimide 495-(5 mmole) and triethylamine O, TOyd7 were dissolved in dichloromethane 5*l, and under water cooling, ethyl chloroformate 542-(5 mmole)
) in dichloromethane (5 ml) was added dropwise. After stirring for 1 hour at room temperature, 3-octadecyloxy-2-
Minobanol 1.30 (4 mmole), dichloromethane 10 ml and triethylamine 70.55
ml (4 mmole) to 7XI engineering.

Stir at room temperature for 4 hours. The reaction solution was concentrated to dryness, and the residue was purified by silica gel chromatography (eluent: n-hexane-ethyl acetate 8:1).
- Recrystallize from hexane to obtain colorless needle-like object 6
I got 75 da.

I R (KBr, cm') 8548. J960
．． 2925°2852,1768.1700,1498
,1470°1408.1390,1120,1058
, 880°0O NMR (90Ml-1z, CDC47B) J, 0.
87 (814°t) 1.25 (82H, br-s)
2.51 (IH.

014 ), 8.89 (2H, +n) 8.78 (
2H, d) 8.92 (2H, t ), 4.41 (I
H, m) 6.68 (2H, S, maleimide) TLCRr=o, 17 (n-hexane:ethyl acetate-3
:1) m, I), 58-60°C Example 14 3-octadecyloxy-2-maleimidofurovir 2
- Thiazolioethyl phosphate 3 obtained in Example 1a -
Octadecyloxy-2-maleimidopropanol (6
84#) and 2-bromoethylphosphoryl chloride (
5411f) in the same manner as in Examples 11 and 12 to obtain the desired product 7.

NMR (CDCh) δ: 0.87 (81-
1,t) 1.2 5(82H,m) 8.2-4.
0 (6H, m) 4.2 (2H, m) 4.4 (IH
, m') 4.8 (2'H.

m) 6.7 (21-1, s), 8.2. 8.
5. 10.481-1. Th1azolio) IR (KBrlcm') 2925, 2850. I'1
72°1702.1550,1470,1,240.1
065'' (2) The following statement is inserted between page 21, line 17 and line 18 of the specification.

"Experimental Example 2 Platelet aggregation inhibitory effect [Test method] Blood gJ7 from male rabbits. 315% as an anticoagulant.
Blood was drawn directly using a syringe containing citric acid (9 parts blood to 1 part). 1 at 800 rpm at room temperature.
Platelet-rich plasma (PRP) was obtained by centrifugation for 0 min.
: platelet rich plasma) was obtained. The remaining blood was further centrifuged at 8000 rpm for 10 minutes to obtain platelet-poor plasma (PPP) as a supernatant.
let poor plasma) was separated.

Dilute PRP with PPI) to reduce the platelet count to approximately 500,000/l.
Adjusted to tl. This PRP250μ! 2 at 37℃
After stirring for 8 minutes, the test drug was added and the mixture was further stirred for 2 minutes, after which 1×1 OM of PAF was added. Platelet aggregation is caused by aggregation needles (
The measurement was made using a bureau (manufactured by Denki). The aggregation inhibitory activity of the test drug was determined by the inhibition rate against the maximum light transmittance (maximum aggregation rate) caused by PAP in control PRP.

[Result 1 Table 1 (shown in Table 2).

Table 1: Inhibitory effect of rabbit platelet aggregation by PAF ” that's all

Claims (1)

[Claims] Formula % Formula % [In the formula, R1 is an alkyl group having 10 to 24 carbon atoms, R2
is an optionally substituted cyclic imide group, ? represents a cyclic ammonio group] or a salt thereof.