JPS58154512A - Agent for suppressing blood platelet activation factor - Google Patents

Abstract

NEW MATERIAL:The glycerol derivative of formulaI(R<1> is 15-18C alkyl; R<2> is H or methoxy) and its salt. EXAMPLE:3-Hexadecyloxy-2-methoxypropyl 2-pyridinioethyl phosphate. USE:An agent for suppressing the blood platelet activation factor. It suppresses the activity of 1-O-alkyl-2-acetyl-n-glyceryl-3-phosphoryl choline which is a blood platelet activation factor (PAF) causing coagulation of blood platelets, and is useful also as an agent for suppressing the allergic diseases caused by PAF. PROCESS:The compound of formulaIwherein R<2> is OCH3 can be prepared by (1) reacting the compound of formula II with the compound of formula III (X and Y are halogen), (2) reacting the reaction mixture with water and (3) reacting the resultant compound of formula IV with pyridine. When 1,3-propanediol is used in place of the compound of formula II, the compound of formulaIwherein R<2> is H can be obtained as the product.

Description

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

Blood smallness and aggregation are thought to be the cause of various cardiovascular disorders, and platelet aggregation inhibitors occupy an important position as medicines.

Hitherto, adenosine diphosphate (ADP) and afric acid substitutes, particularly thromboxane A2 (TM11), have been known as representative compounds that cause platelet aggregation. Therefore, conventional platelet aggregation inhibitors have been tested using the inhibition of the effects of these compounds as the first screening method.

However, recently, platelet activating factor (pl&t61stAat1vatin) has been discovered as a compound that causes a stronger platelet aggregation effect with a different mechanism of action than MuDP and TXMu2.
g F'aotor (P A If' )) was elucidated and its structure was found to be 1-0-alktv-2-acetyl-n-glyceride/L/-3-7 osphorylcholine [Nature, Volume 285, 193 (1
980)). PAF is ADP, TM11
They have been found to have different mechanisms of action and strong activity at low concentrations. In addition, PAli' is a powerful chemical mediator of allergies, and is known to have the strongest activity of any known compound when measuring, for example, bronchial stenosis. Fa Makoroshi Volume 65, 185-
192 (1980)). Therefore, if a compound can be found that has an inhibitory effect on P A k', it could become a more effective inhibitor of platelet aggregation in living organisms, and could also be used to treat other diseases caused by PAF, such as It can be used as an effective suppressant for ALA/A/Gy disease. As a result of extensive studies, the present inventors discovered that the novel 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 15 to 18 carbon atoms, B2
represents a methoxy group or hydrogen] The glycerin derivative 1+ is related to a blood 11\platelet activating factor inhibitor containing a salt thereof.

Regarding the above formula (I), the number of carbon atoms represented by R1 is 15-18
The alkyl group of may be either linear or molecular, and examples thereof include pentadecy~, hex+deVμ, he1tadacil, octadecyρ, etc. 1 Note that the alkyl group of compound (I)ti is a physiologically acceptable salt. Such salts may be used in the form of, for example, the formula % [wherein X- represents chloro, bromo, M-do, )$/A/ion] and the formula % [ In the formula, M+ is an alkali metal (eg, sodium.

Potassium) ion #:, ti alkaline earth metal (e.g., μsium, magnesium) ion] salts are prepared.

In compound (I), there are two types of stereoisomers, R-coordination and S-coordination, with respect to the second element at the 2-position, and each of them, a mixture thereof, and BS as a whole are included in the present invention. The range includes turtles.

The glycerin derivative (I) and its salt in the present invention are novel compounds] and are excellent platelet activating factors (PAF).
It exhibits an inhibitory effect, and more specifically, it strongly inhibits platelet aggregation and allergies 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 for the prevention and treatment of diseases such as glomerulonephritis and allergy-related asthma.

Glycerin derivative (I) and its salts have excellent properties in both 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 route, etc., for example, when administered orally for the prevention and treatment of thrombosis in adults, the usual dose of Compound (I) is 0.1 to 20 Ij per dose.
It is convenient to administer IlkQ about 1 to 3 times a day, about the same amount as body weight. More specifically, when the purpose is to prevent thrombosis, the same amount of 1 is about 0.5 to 4 kg/ky body weight, and when the purpose is treatment, the same dose is about 4 to 10 kg/ky body weight, respectively. It is preferable to administer about 1 to 3 times a day.

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

That is, for example, rounded compositions for oral administration include solid or liquid dosage forms, specifically tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders,
Power 1 cell preparation (including soft capsules), syrup preparation,
Can be used for emulsions, clouding agents, 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,
Examples include sucrose and magnesium stearate.

Compositions for parenteral administration include, for example, injections,
Examples include skewers, etc., and injections include fan-shaped injections such as pulse injections, intramuscular injections, and intravenous drip injections. It is prepared by dissolving, suspending, or emulsifying it in a sterile aqueous or oily liquid used for injections. Aqueous solutions for injection include physiological saline, isotonic solutions containing glucose and other adjuvants, and suitable solubilizing agents,
For example, alcohol-1v (e.g., ethanol), polyalco-A/(e.g., propylene glycol, polyethylene glycol-1v), nonionic surfactants [e.g., borithobate 80. HCO~50 (pOlyoxyyeLhyLen
e (5Qo+ol) adduat ofhydr
oaster oil ))
It may be used in combination with Sesame oil, soybean oil, etc. are used as oil-based liquids, and benzyl benzoate is used as a solubilizing agent.

Benzyl alcohol-μ or the like may be used in combination. The injection solution prepared by #Il is usually filled into a suitable container.

The skewer used for rectal administration is prepared by mixing compound (I) or its salt with a common herbal medicine base3. Conveniently, it is made into a fan-shaped dosage unit that fits the dosage unit of 14. As a sector of such a dosage unit,
Examples include tablets, round bars, 1-cell preparations, injections (Amp A/), and skewers.
It is preferable that the compound (I) contains 500 Wv, especially for injections, 5 to +00 Wv, and 10 to 250 Wv in other fan shapes.

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

Among the compounds (I) of the present invention, compounds in which R2 is methoxy can be produced, for example, by the following method.

Method A: 2-0-methy/Mgj, which is a production intermediate in this method
An example of J Sepul is the Journal of the Chemical Society (J, CheI! 1.800.).

IQ, j4,1234 or Ann, -'j-09,
2421 (1967). Sodium salt (II) of 2-0-methylglycerol is prepared, dissolved or suspended in an inert solvent under anhydrous conditions, and given the formula RIQC, where R1 is the same as above and Q is halogen. , sulfate, and sulfonate] to obtain compound (V) [wherein R1 has the same meaning as above].

+1 C) II20HCH20H (II) (IV)
(V) The neglected intermediate (V) has the formula [where X and Y are halogens (e.g., chlorine, bromine, iodine)]
] is reacted, and after the reaction, water is reacted to obtain a compound of the formula % [wherein Hl and y have the same meanings as above].

By reacting this with pyridine, a compound (I) in which - is a methoxy group is obtained.

Method Compound (V) is reacted with an active derivative of formula. Activation methods include, for example, DCC, Avance-honylimidazolide (e.g.
2,4,6-drimethylbenzene phonylimidazofide, etc.), allenesulfonitriasifide (e.g., 2
,4.6-)diiso10biμbenzenesulfony/L'-
3-nitrotriazolyte F), allenesulfony/i
Coupling reagents such as ''': fY bovine' = 7) and do (e.g., 8-quinolinesulfonyltetofusofide) can be used.

Method C The starting material in Method A, 2-0-methylglycerol, was replaced with 1,3-propanediol, and the reaction was carried out in almost the same manner as described in Method A below, to ensure that r<2 is hydrogen. A certain compound (I) is obtained.

In the method, the starting material is changed to a compound of the formula % formula %: () 1, where R1till is the same as above], and this is reacted with a compound of the formula (Vl), and the same operations are performed thereafter to obtain the formula ( In I), compounds are obtained in which R2 is hydrogen.

Purification of the compound produced by the above method is carried out using normal operations.
For example, it is suitably purified by solvent extraction, recrystallization, chromatography, etc.

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 inhibitory effect (1) PAF inhibitory effect on platelet aggregation [Test method and results] Male rabbits were given a syringe containing 3.15% citric acid (ratio of 1 part to 9 parts blood) as a blood coagulation inhibitor. Blood was collected directly using the Then, at room temperature, at LOOOrpm of 1
Platelet-rich blood* (PR
P: Platelet rear plasma)
I got it. PRP was further centrifuged at 1+400 rpm for 15 minutes and plated.
and convert it into Qa+” free Tyrode
(gelatino, containing 25%), Waah
edP RP was prepared. This @ashea P R
Stir 250μl of P at 37℃ for 2 minutes, 0.2-0
．． Add 25 μl of 5 mM Ca solution and stir for an additional 30 seconds. Then, the test drug was added in an amount of 3xlOM, and after stirring for an additional 2 minutes, 3xlOM of PAF was added. Platelet aggregation was measured using an aggregometer (Rika Denki 1m). The activity of the test drug was determined from the inhibition rate of the maximum light transmittance (maximum aggregation rate) by PAli' in control PRP.

The results are summarized in Table 1.

Table 1 Test compound BI B2 inhibition rate (%) I C15H310CH3462
Cl8H37υCH387 Formulation example 1 3-octadecyloxy-2-methquinpropyl/L/2
-1 Of pyridinioethyl phosphate to 1 part distilled water
．． After 0IKi@ is dissolved and aseptically filtered, it is dispensed into 1,000 vials in 1 d portions under aseptic conditions, freeze-dried, and after drying, the solution is sealed.

On the other hand, 21 distilled water for injection containing xylit-t or mannitol 100f is aseptically dispensed in 2 wrl portions into the injection amplifier μ, the bath is closed, and 1000 bottles are prepared.

When using, dissolve one vial of the former powder in xylitate solution for injection (or mannitol solution).

Formulation Example 2 Usage amount per tablet: (1) 3-hexadecy~oxyV-2-methoxyVpropyl 2-pyridinioethyl phosphate 004 (2) Milk m 200qF (3) Cornstarch 51"1
(4) Hydroxypropylcellulose 9
11F was mixed and granulated in a conventional manner, and cornstarch (
81q), mixed with magnesium stearin (2wI) and compressed into one tablet (3701F, diameter 9.5mrt).

Formulation Example 3 Acetone-ethano/L is prepared by dissolving hydroxy-10-vinylmethylcellulose phthalate (34wf) and castor V oil (111fI) in a solution having a concentration of 7 arcs, using the tablets in 2 above as a stool dose per tablet. /(4:6) mixture 1& is applied to form an enteric coating.

Production Example 1 3-pentadecyloxy-2-methoxypropy~2-
Pyridinioethyl phosphate 1) 3-pentadecyloxy-2-methoxypropan-1-ol 2-methylglycero-/'+09f and 1-bromopentadecane 101''h: dimethylsulfoquine (DM
S O) 30 liters of moromi and tetrabuhydrofuran (THF)
KOI dissolved in a mixed solution of 30st and powdered at room temperature
(Added 7.7f and stirred vigorously for 30 minutes.

After heating under reflux for an additional 3.5 hours, the mixture was poured into 400 g of water, and neutralized with concentrated hydrochloric acid while cooling with water. Extracted with ethyl acetate (
3 times), washed with water, dried, concentrated to dryness, and left an oily residue (10F
) to silica gel chromatography (silicage/L/1
1 (using l, developing solvent n-hexane-chloroform, 2
:3) to obtain the desired alcohol compound 4.6f.

IR(111)cil: 3430,2920.285
0°1460.1110,750 TLC: Rf=0. +2 (V licagel, developing solvent, chloroform) 11) 3-pentadecyloxy-2-methoxyV propyl 2-pyridinioethyl phosphate 3-ventada V/L/oxy-2-methquine propano-
/L/4.6f and 5.6f of 2-bromoethyl phosphorodichloridate were dissolved in 40-benyne, and 1.8f of pyridine was added dropwise with stirring at room temperature. After further stirring at room temperature for 3 hours, it was concentrated to dryness, and the residue was mixed with 40% of water.
1 and heated under reflux for 1.5 hours. After cooling, concentrated hydrochloric acid 6°C was added, extracted with ether, washed with water, and concentrated to dryness. Residue (3
-Bentadey)voxy-2-methoxy10 pills 2-
Pyridine (20) was added to Procethane Phosphineton and heated under reflux for 1.5 hours, stirred overnight at room temperature, pyridine was distilled off, 50 sJ of methanol and 15.2 f of carbonic acid were added to the residue, and the mixture was heated under reflux for 1.5 hours. The mixture was filtered while hot, the first solution was concentrated to dryness, and the residue was purified by silica gel chromatography twice. 1st time, using 150f of silica gel, developing solvent methanol ~, 2nd time, 60ftft of silica gel!
Developing solvent: chloroform-methanol-water, 65:2
The product was dissolved in 5:4% proform and acetone was added to powder it to obtain the desired product 3.761.

I R (KBr) 01” 3420.2920.28
50 e1630.1489.1460.1240.1
07ONMR (107ON, CDC13) δ: 0.89
(3H).

1.24 (26H, 8), 3.42 (3H, 8), 3.
63-4.52 (9H, m), 4.92-5.19 (2
H.

brOaa), 8.06-8.65 (3H, m),
9.45 (2H, I T L C: ) if = 0.26 (V licagel, C
HCL3-MIIIOH-H2O, 65: 25:
4) Elemental analysis: CHNo P-H20 26486 Calculated value: C,60,09IH29-70+ 42-
70! P, 5.96 Dormitory measurement: C, 60,031H, 9,40! N, 2
471P, 5.75 Production Example 2 3-hexadecyloxy-2-methoxypropyl 2-
Pyridinioethyl phosphate 1) 3-hexade￥~oxv-2-methoxypropan-1-ol 2-methylglycero-*1G, 6# and 1-bromohexadecane 15F are reacted according to Production Example 1-1), i9 of the desired alcohol form 9.4f.

11) 3-Hexade\oxy-2-methoxyV globil 2-pyridinioethyl phosphate 3-hexadecyloxyv-2-methoxyV propane-1-
Production Example 1-11)
The reaction was carried out in accordance with VC to obtain 7.4 f of a professional human body. This professional human body 3.7f is mixed with 40sJ of pyridine and construction example 1-11)
The reaction was carried out according to the latter half of the procedure and purified to obtain the desired product 1.251.

TLC: Rf-Q, 28 (V Likage A', C
HC13-MeOH-H2O, 65:25:4) NMR (60MH2, CDC13) #: 0.83
(3H).

i, 22 (28H), 3.44 (3H, a, OMe)
, 3.1-4.7 (9H, m), 4.95 (2H, br
oad).

7.74-8.60 (3H, m, pyridin
io), 9.22 (2H, pyridinjo) Elemental analysis: C2wa H5oNO6P・H20 calculated value c,
60.76 pieces H, 9, 82; N, 2.63+P, 5.
80 East side - C, 60, 92+ H, 9, 72+ N, 2.5
8+P, 5.74 Production example 3 3-he1 tadecyp oxyV-'l-methoxyV propyl 2
-pyridinioethyl phosphate j) 3-to1
Tadecyloki V-2-methquine 10-pan-1-o-2-methylglycero-/'10.6I and 1-bromoheptadecane 10.7F were reacted according to Production Example 1-1) to obtain the desired alcohol compound. 5.2ft-obtained.

11) 3-heptadecyloxyv-2-methoxypropane-1
-O#5.18f and 2-10moethyl-phosphorodichloroliso-)4.72f were reacted according to Production Example 1-11), and 3-heptadecyμoV-2-methoxyV10biIv 2-bromoethyl ~ Phosphate 7, 1 F obtained 9. This prohair body 3.55 ft-pyridine 50 resistant was reacted with the latter half of Production Example 1-11) and purified to obtain the desired product as a colorless powder.

TLc: Rr-0,28 (silicage A', CHCl
3-MeOH-H2O, 65: 25: 4) Engineering R
(Nujol) CM, 2920 (CH), 2850
(ea), J460.1240(P-0),! 07G(
p-o-c.

C-0-C) Elemental analysis: 028H52NO6P rumor H20 calculated value c,
61.40+H, 9,94+N, 2.5f+p,
5.66 Actual value C, 61,81+ H, 9,92+ N, 2°51! r, 5.62 1H example 4 3-octadecyloxy-2-methoxy 10 pA/2-
Pyridinioethyl phosphate 3-octadecyloxy-2-methocynebanol 391 and 2-bromoethyl phosphorodiclo! JP-) 2.9f was dissolved in 20ml of back tetrachloride and heated under reflux for 25 hours. The solvent was distilled off, 30 ml of water was added, and the mixture was heated under reflux for 1 hour. After cooling, the mixture was extracted with ether, dried over Glauber's salt, and then the solvent was distilled off to obtain 4.5 lt of an intermediate (brominated). This intermediate 1.
Of was dissolved in 10 mK of pyridine and heated at 60'C overnight. Pyridine was distilled off under reduced pressure, and silver carbonate 1f and methanol, I%'25w1 were added to the residue and stirred for 1 hour.

Remove unnecessary substances and concentrate the p solution to dryness.
! MmL, <
Effluent solvent: CHCl3: MeOH: H2O11=
65:25:4), the target product 0.5F was obtained.

TLC: Rf-0,28 (CHC13: Me
OH: H20=65'25:4) Infrared absorption spectrum/v (KBr)all, 291G
.

2845.1490, 1465.1230.107ON
MB(107ON,cDcx3)J:0.89(3H,
m).

1.23 (32H), 3.45 (31), 3.2-4.
6 (9H, in), 5.10 (2H, broaa, CH
2N).

8.0-8.8 (3H, tn, pyrlaini
o), 9.5 (2H.

tr+, pyridinio)

Claims (1)

[Scope of Claims] A platelet activating factor inhibitor containing a glycerin derivative or a salt thereof represented by the formula [wherein R1 is alkyl IL/1& having 15 to 18 carbon atoms and R2 is methoxy or hydrogen] .