JPS59112961A - Glycerol derivative, its preparation and drug containing said derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is 8-22C alkyl, or phenyl- substituted 2-5C alkyl; R<2> is H, 1-6C alkyl, group of formula II (R<5> is H, halogen, methoxy, etc.) etc.; R<3> is 1-8C alkylene; R<4> is amino, -NHCOR<7> (R<7> is 1-4C alkyl), NHR<7>, etc.] and its salt. EXAMPLE:( 2RS )-1-O-Hexadecyl-2-dehydroxy-2-methylthio-3-O-[4-(dimethylamino)- butyl]glycerol. USE:A blood platelet coagulation inhibitor, antiasthmatic agent, anti-allergic agent, anti-inflammatory agent, hypotensor, or antitumor agent. PROCESS:The compound of formula V (R<2a> is 1-6C alkyl, etc.) is prepared by reacting the compound of formula III [R<8> is alkylsulfonyl or (substituted) arylsulfonyl; R<4a> is -NHCOR<7>, -N(R<7>)2, etc.] with the compound of formula HS-R<9> (R<9> is 1-6C alkyl) or formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel glycerin derivatives. More specifically, platelet activating factor (VLA, telet).

activating factor, hereinafter P A
It is abbreviated as F'. ), PAF-like hypotensive action, phospholipase (Dhosphorinase)
) The present invention relates to novel glycerin derivatives having an inhibitory effect, as well as a growth-suppressing effect or a differentiation-inducing effect on tumor cells, a method for producing the same, and a pharmaceutical containing them as an active ingredient.

In recent years, research on the leukocyte-dependent release reaction of active amines from platelets has been vigorously pursued, and as a result, a very strong substance that causes platelet aggregation was discovered and named PAF [J ,Immunol,,
Volume 106, 1244, Ichiji (1971), J, Ex
T3. Med, Volume 136, Volume 1356 (19
72) and Nature, vol. 249, p. 581 (1974). ]. Subsequently, the existence of PAF was confirmed in the living bodies of various animals including humans. In 1979, its structure was determined [J,B
iol-Chem, Volume 254, 9655 (1
979) and C-R, Acad, Sci, S'θ
See rie D (Paris), vol. 289, 10j7 Baichi (1979). [J, Biol
,Chem,.

255, 5514 (1980).

].

(In the formula, n represents 15 or 17.) The physiological effects of PAF include not only the initially known strong platelet aggregation and secretion effects, but also extremely strong hypotensive and bronchoconstrictive effects. has become clear. Also, P
AF is one of the platelet aggregation factors in humans, and is further thought to be one of the causative agents of allergic reactions and inflammatory reactions. Therefore, it antagonizes PAF (PA
Compounds that inhibit the action of F have great potential to become unprecedented platelet aggregation inhibitors, anti-asthmatic agents, anti-allergic agents, or anti-inflammatory agents. Furthermore, if only the antihypertensive effect of PAF is isolated, it is possible that K would result in an antihypertensive agent that does not have platelet aggregation effects.

The present inventors conducted extensive research in order to find a compound that antagonizes PAF or has a PAF-like blood pressure lowering effect, and as a result, they found that a compound represented by the general formula +II described below achieves the objective, and the present invention was made. completed.

Furthermore, the compound of the present invention represented by the general formula (Il) has phospholipase A2 and C
It was also found that it inhibits the action of In vivo calcium-dependent phospholipases A2 and C are involved in the mechanism of arachidonic acid release from phospholipids.

Arachidonic acid liberated by physiological stimulation is taken up by the prostaglandin metabolic pathway, and is eventually converted into other prostaglandins such as thromboxane A2, which has a strong platelet aggregation effect, and is also important during asthma attacks. It is known that it is metabolized into various leukotrienes, which are bronchoconstrictor substances. Therefore, compounds that inhibit phospholipases A2 and C, which are involved in the release mechanism of arachidonic acid, have a mechanism of action that is different from that of PAF antagonists, and are also different from conventional nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase, typified by aspirin. different,
It is thought that it will be a platelet aggregation inhibitor, an anti-asthmatic agent, an anti-allergic agent or an anti-inflammatory agent based on inhibiting phospholipases A2 and C.

Furthermore, the compound of the present invention represented by the general formula +Il exhibits an effect of suppressing proliferation or inducing differentiation of tumor cells 1, and therefore can be expected to be used as an antitumor agent.

The present invention is based on the general formula [wherein R represents an alkyl group having 8 to 22 carbon atoms or an alkyl group having 2 to 5 carbon atoms substituted with a phenyl group, R is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms] The group or formula R represents a hydrogen atom, ).rogen atom, a methoxy group, or an alkyl group having 1 to 4 carbon atoms, and R represents an alkyl group having 1 to 6 carbon atoms or a phenyl group. ), R represents an alkylene group having 1 to 8 carbon atoms, and R represents a group represented by
represents an amino group. However, when a plurality of R's are bonded, they may be the same or different. ) represents a group represented by ] and their acid addition salts.

In the explanation of each symbol in this specification including the claims, the words alkyl group and alkylene group are
It refers to straight-chain or branched alkyl groups and alkylene groups.

The alkyl group having 8 to 22 carbon atoms represented by R in the general formula III includes octyl, nonyl, decyl, undecyl, hitecyl, tridecyl, tetradecyl, antadecyl, -
\Xadecyl, heptadecyl, octadecyl, nonadecyl, eicobucyl, heneicosyl, tocosyl groups and isomers thereof, and preferred groups are those having 14 to 1 carbon atoms.
8 is an alkyl group, and a particularly preferred group is a hegisatecyl group.

Examples of the alkyl group having 2 to 5 carbon atoms substituted with a phenyl group represented by R1 include ethyl, propyl, butyl, intyl leather, and isomers thereof in which any one hydrogen atom is substituted with a phenyl group.

Examples of the alkyl group having 1 to 2 carbon atoms represented by R in the general formula III include methyl, ethyl, propyl, butyl, pentyl, hexyl groups and isomers thereof, and any group is preferable, but particularly preferable groups are mentioned. is an alkyl group having 1 to 6 carbon atoms. The formula is hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methoxy group and methyl group,
Examples include ethyl group, propyl group, butyl group and isomers thereof, preferred groups are hydrogen atom, chlorine atom, methoxy group or methyl group, and particularly preferred group is hydrogen atom. In addition, the group represented by R in formula -03-0-R is:
Examples of methyl, ethyl, propyl, butyl include butyl, hexyl groups, isomers thereof, and phenyl groups, and preferred groups are alkyl groups having 1 to 3 carbon atoms, and more preferred groups are ethyl groups.

Preferred R groups are alkyl groups having 1 to 6 carbon atoms, or all symbols in the formula have the same meanings as above. ) are mentioned.

The alkylene group having 1 to 8 carbon atoms represented by R in the general formula III includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene groups, and isomers thereof; preferred The group is an alkylene group having 6 to 6 carbon atoms, and a particularly preferred group is a tetramethylene group.

Among R in the general formula (Il), examples of the alkyl group having 1 to 4 carbon atoms represented by R include methyl, ethyl, propyl, butyl groups, and isomers thereof, and any of these groups is preferred, but particularly preferred. Anions are pharmaceutically acceptable anions of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, and hydroiodic acid. , inorganic acids such as sulfuric acid, phosphoric acid, nitric acid,
Or acetic acid, lactic acid, tartaric acid, benzoic acid, citric acid, methanesulfone I'! ! ? , ethanesulfonic acid, hanzensulfonic acid, tolueisulfonic acid, and isethionic acid. Preferred anions are halogen ions, that is, chloride ions, bromide ions, and iodine ions, with particularly preferred anions. The ion is an iodine ion.

All symbols have the same meaning as above. ), and a particularly preferred R group has the same meaning as in formula -N(R)2. ).

Compound I11 of the present invention has at least one asymmetric carbon (
carbon atom at the 2-position of glycerin), and further R, R
, R and the various substituents represented by R represent a branched chain, other asymmetric carbon atoms may occur. However, the compound represented by the general formula i11 of the present invention also contains each isomer caused by an asymmetric carbon and a mixture thereof.

According to the present invention, R, an alkyl group having 1 to 5 carbon atoms, or all symbols in the formula have the same meanings as above. ) indicates the same meaning as above. ) A compound represented by the general formula (II), that is, a symbol represented by the general formula [wherein R is an alkyl group having 1 to 6 carbon atoms, and all symbols have the same meanings as above] has the same meaning as above.), and other symbols have the same meanings as above. ] The compound represented by the general formula (wherein R represents an alkylsulfonyl group or a substituted or unsubstituted arylsulfonyl group, and the other symbols have the same meanings as above) is a compound represented by the general formula % It is produced by reacting with a compound represented by the formula %( ) (wherein R represents an alkyl group having 1 to 2 carbon atoms, and the other symbols have the same meanings as above).

The reaction between the compound represented by the general formula (IIA) and the compound represented by the general formula (IIQ or general formula (IV)) can be carried out using an inert organic solvent, such as an ether such as tetrahydrofuran, diethyl ether, or dioxane, or dimethylformamide. or hydrogenation in a mixed solvent)
The reaction is carried out in the presence of IJum at room temperature to the reflux temperature of the solvent.

Also, compounds represented by general formula (ITA) and general formula (V)
The reaction with the compound represented by is carried out in an inert organic solvent such as hexamethylphosphaamide 8, dimethylformamide, or dimethyl sulfoxide at a temperature from room temperature to 100°C.

R2 represents a group represented by R2'L, R is an amine group,
Alternatively, a compound represented by the general formula TII representing a group represented by the formula -NHR (wherein R has the same meaning as above), that is, a compound represented by the general formula b [wherein R is an amino group or a group represented by the formula -NHR (the formula (R7 has the same meaning as above.), and the other symbols have the same meanings as above. ] The compound represented by the general formula [wherein R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, 2 represents a tert-butoxycarbonyl group (hereinafter abbreviated as a boc group), vanzil It represents an oxycarponyl group (hereinafter abbreviated as cbz group) or an 0-nitrophenylthio group, and other symbols have the same meanings as above. ] The compound represented by the general formula (III),
Reacting with a compound represented by general formula (IV) or general formula (M) to remove the protecting group Z of the resulting compound represented by general formula (in which all symbols have the same meanings as above) Manufactured by

The reaction between the compound represented by the general formula (IIB) and the compound represented by the general formula (IV) or the general formula (V) is carried out in order to produce the compound represented by the general formula (IA-1). It is carried out by the method described above.The general formula (■
The reaction for removing the protecting group 2 of the compound shown in 1) is well known. For example, when (1) Z is a boa group, an inert reaction such as ethyl acetate, methylene chloride, chloroform, or lower alkanol is used. It is carried out by using hydrochloric acid in an organic solvent at a temperature between room temperature and 50 °C, or by using trifluoroacetic acid at room temperature (i.e., when Z is a cbz group, catalytic reduction is carried out in the presence of acetic acid or hydrochloric acid. or in acetonitrile at room temperature, and in the case of Z or 0-nitrophenylthio, in an inert organic solvent such as ethyl acetate or methylene chloride It is carried out using hydrochloric acid at room temperature.

Further according to the invention, the general formula I in which R represents a hydrogen atom
The compound represented by 11, that is, the compound represented by the general formula (in which all symbols have the same meanings as above), is the compound represented by general formula (lIA) or the general formula (in which all symbols have the same meanings as above). has the same meaning as above) with sodium thioacetate or potassium thioacetate in an inert organic solvent such as dimethylformamide, dimethylsulfoxide or hexamethylphosphaamide 9 at a temperature of 408C to 60C. represents a group represented by the general formula (in the formula, all symbols have the same meanings as above), and other symbols have the same meanings as above. ] By hydrolyzing the compound represented by under alkaline conditions, for example using a hydroxide of an alkali metal such as sodium or potassium in a lower alkanol such as methanol or ethanol, at a temperature above room temperature, preferably 50°C. It can be produced by reacting at a temperature of 60°C to 60°C.

Compounds represented by general formula (IIIA) and general formula (II
The compounds represented by B) are prepared by converting the compounds represented by the general formula (in which all symbols have the same meanings as above) into methylene chloride in the presence of a trivalent amine such as pyridine or triethylamine. in an inert organic solvent such as (11) in pyridine at -60°C.
It is prepared by reacting with an alkylsulfonyl chloride such as mesyl chloride or an arylsulfonyl chloride such as tosyl chloride 9 at a temperature of 9 to 50°C.

A compound represented by the general formula (JIG) is a compound represented by the general formula (IIB
) of the compound represented by general formula (IA-2)
In order to produce the compound represented by It is produced by reacting with trifluoroacetic anhydride in an organic solvent or without a solvent in the presence of a tertiary amine such as triethylamine at a temperature of 50° C. or lower.

Compounds represented by the general formula (■) and the general formula (IX) were prepared according to the method described in Japanese Patent Application No. 57-79179. Manufactured from the compounds shown.

The compound represented by the general formula (XI) is
No. 179, but can also be obtained by the series of reactions shown in Scheme I below.

In the formula, THP represents a tetrahydropyran-2-yl group, and R has the same meaning as above.

Schema I Each step in the diagram is performed by a known method.

For example, step [α] is THP conversion, which is carried out in methylene chloride in the presence of a small amount of T)-)luenesulfonic acid at room temperature using an equimolar amount of 2,3-dihydropyran; ] in dry dimethylformamide in the presence of sodium hydride at a temperature from room temperature to 100°C.
ITT> and argyl bromide represented by the formula Br-R (wherein R has the same meaning as above), step [c] is THP removal, A mixture of tetrahydrofuran, acetic acid and water, p
-) It is carried out at room temperature or under heating using a mixture of toluenesulfonic acid and anhydrous methanol or a mixture of dilute hydrochloric acid and tetrahydrofuran.

e Furthermore, according to the present invention, a general group in which R represents a group represented by the formula -N(R)3.Y (in the formula, Y represents a halogen atom, and the other symbols have the same meanings as above) formula il
A compound represented by l, that is, a compound represented by the general formula (in which all symbols have the same meanings as above), is a compound represented by the general formula (in which all symbols have the same meanings as above). The indicated compounds can also be prepared by reacting with an alkyl halide such as methyl iodide in a lower alkanol such as methanol or ethanol at room temperature to the reflux temperature of the solvent.

4 ■ 7 θ2 θ2 R is a N(R)3.Y group (wherein, Y represents an acid anion other than the halogen ion J″J, and R represents the general formula lit
After neutralizing in an aqueous solution of IJum,
It can be produced by reacting with a desired inorganic or organic acid.

R is an amino group or the formula -NHR or -N(R7)2
The glycerin derivative represented by the general formula +Il representing the group represented by (wherein, R7 has the same meaning as above) can be used as an acid addition salt thereof. Preferably, the acid addition salt is a non-toxic salt and is water-soluble. Suitable acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, nitrate, or acetate, lactate, tartrate, benzoic acid. Examples include organic acid salts such as citrate, methanesulfonate, ethanesulfonate, benzenesulfone salt, ) luenesulfonate, and isethionate. Acid addition salts can be prepared by adding a compound represented by the general formula +I+ in which R represents an amino group or a group represented by the formula -NHR or -R7)2 with a desired acid in stoichiometric amounts in a suitable solvent. Obtained by reaction.

Glycerin derivatives represented by the general formula (Il) and their acid addition salts have an antagonistic effect on PAF, a PAF-like blood pressure lowering effect, a phospholipase inhibitory effect, and a growth suppressive effect on tumor cells, so they can be used as platelet aggregation inhibitors, It is useful as an anti-asthmatic agent, an anti-allergy agent, an anti-inflammatory agent, an antihypertensive agent, and an anti-tumor agent.These actions have been confirmed by laboratory experiments, but for example, the antagonistic action against PAF is described below. Confirmed by screening system.

Inhibitory effect on PAF-induced platelet aggregation Whole blood from male guinea pigs and 6.8% sodium citrate aqueous solution were collected at a ratio of 9:1 (v/v) and centrifuged (120,?) for 10 minutes at room temperature. Using the obtained platelet-rich plasma, platelet aggregation with 10 nM PAF was measured by absorbance method using a Born aggregometer [J, Physiol, Vol. 162.

67 see J. (1962). ] The results were expressed as the concentration of the compound of the present invention required to inhibit platelet aggregation by 50% (■C3o).

Table ■ To use the glycerin derivatives represented by the general formula (II) or their acid addition salts for the above purpose, they are usually administered systemically or locally, orally or parenterally. Although it varies depending on the symptoms, therapeutic effects, administration method, treatment time, etc., it is usually 1 to 1 dose per adult.
-1 g, preferably in the range of 20 - 200 g, once a day
Orally administered once to several times or per adult,
100μg~100~, preferably 1m2~ per time
It is administered parenterally once to several times a day for ages 10 to 10 years.

Of course, as mentioned above, the dosage varies depending on various conditions, so there are cases where it is sufficient to use an amount smaller than the above-mentioned dosage range, and there are also cases where it is necessary to administer the dosage beyond the range.

Solid compositions for oral administration according to the present invention include tablets, powders, granules, and the like. In such solid compositions, one or more active substances are present in at least one inert diluent, such as lactose, mannitol, dextrose, human 90-xypropylce-luulose,
Mixed with R crystalline cellulose starch, parivinylpyrrolidone, magnesium aluminate metasilicate. The compositions may contain additives other than inert diluents, such as lubricants such as magnesium stearate and disintegrants such as fibrin calcium gluconate, in accordance with conventional methods. Tablets or pills may be coated with a film of gastric or enteric substances such as sucrose, gelatin, hibiloxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, or with two or more layers, if necessary. . Also included are capsules of absorbable materials such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified water. , including ethanol. In addition to inert diluents, this composition may contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents,
It may contain aromatics and preservatives.

Other compositions for oral administration include sprays containing one or more active substances and formulated in a manner known per se.

Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of aqueous solutions and suspensions include distilled water for injection and physiological saline.

Examples of non-aqueous solutions and suspensions include propylene glycol, sZ++ ethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Examples include gum arabic and sodium alginate. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These are sterilized, for example, by filtration through bacteria-retaining filters, by incorporation of disinfectants, or by irradiation. They can also be prepared as sterile solid compositions and dissolved in sterile water or sterile injectable solvents before use.

Other compositions for parenteral administration include topical solutions, liniments such as ointments, pessaries for rectal administration and intracavitary pessaries, which are formulated by known methods. Contains a challenge.

Among the compounds represented by the general formula (II) included in the present invention, preferable ones include, for example, N, (2R8)-1-0-hexadecyl-2-dehydro or syrin, N, Phosphorus, (2R8)- 1-0-hexadecyl-2-dehydroxy and acid addition salts thereof.

Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples, but the present invention is not limited to these Examples. In addition, [T L CJ "NMRJ," I
Rj and "MassJ" represent "thin layer chromatography", "nuclear magnetic resonance spectrum", "infrared absorption spectrum" and "mass spectrometry", respectively.

The solvent in parentheses listed in the section for separation by chromatography indicates the developing solvent used.

Unless otherwise specified, IR is measured by the liquid film method, and N
MR is measured using deuterium chloroform (CD (J3) solution)
).

Example 1 50 m of sodium hydride (containing ft: 64.1%) suspended in 4 d of dry tetrahydrofuran under an argon atmosphere
Add 0.144 phenylmethanethiol to 9 and stir for 15 minutes at room temperature.
(2R3)-1-0-hexadecyl-2- dissolved in
0-Mesyl-37o-[a-(dimethylamino)butyl]glycerin (compound described in Reference Example 7 of Japanese Patent Application No. 196849/1984) 1571n9 was added, and the mixture was refluxed overnight. 501 rL of chloroform was added to the reaction mixture, washed with water, dried over potassium carbonate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform, then a mixture of chloroform, methanol and triethylamine) to obtain the title compound 165.■ having the following physical properties.

TLC (ethyl acetate: acetic acid: water = 3:1:1): RJ'
= 0.64; NMR: δ = 7.17C5H9hs), 3.77 (2
H, -r), 3.7-3.1 (8H, m), 3.0
~2.7 (IH, m), 2.5~2.0 (2H,
m and 6) I,, p), 1.9-0.7 < 358
.

m); ■R Niji==2910.2850.1460.1450
．． 1110CrlL.

Mass: m/e=521 (M), 460,39
8゜In the same manner as in Example 1, using ethanethiol instead of phenylmethanethiol used in Example 1,
The following compound was obtained.

TLC (ethyl acetate: acetic acid: water = 31:1): Rf = 0
．． 59; NMf-1: δ=3.8-3. I C8H, 7F,
), 6.0-2.8 (IH, 7B).

2.7-2.5 (2H, m), 2.4-2.0 (
2H, and 6H, J'), 1.8 to 0.8 (38H, 7
7L);MaSs: m/e=459(M), 4
30.698゜Example 2 Under argon atmosphere, N,N-dimethylformamide)-”
Dissolved in 1 mJ (2F(S)-1-0-8-subyl-2-0-mesyl-3-0-['4-(dimethylamino)butyl]glycerin Patent Application 1984-1984)
Compound described in Reference Example 7 of the Specification) 1107i# and potassium 0-ethyl dithiocarbonate (i.e. [C2
H3O-03-3IK) 100μ was added and stirred at 70°C overnight. Water was added to the reaction mixture, extracted with ethyl acetate, and the extract was washed successively with water and saturated brine, dried, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: a mixture of chloroform and methanol).
The title compound 19~ having the following physical properties was obtained.

TLC (ethyl acetate:acetic acid:water=3:1:1)2Rf=
0.69; NMR: δ = 4.67-3.25 (8H, 7FL), 6
．． 26-2.93 (IH.

nL), 2.87-2.45 (2H, q), 2.4
5-2.10 (2H, ml 2.33 (6H, r), 1
．． 87-0.63 (38H, 77L); IR Niji = 2940.2870.1. ! 160,13
70.1115-1 + c'IrLj Mas : mJe ~490.460.698.6
85.116.1000 Example 6 2-Bandylthio 3-0-[4-(dimethylamino)
Butyl]glycerin compound (produced in Example 1) 1
60■, methyl iodide 0.2d, potassium hydrogen carbonate 50
A mixed solution of ~ and 107 m of methanol was stirred at room temperature for 1.5 hours, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: a mixture of chloroform, methanol and water) to obtain the title compound 188.5■ having the following physical properties.

Melting point: 58-62°C; TLC (ethyl acetate:acetic acid:water, ~3:1:1):I
(f = D, 57; NMR: δ = 7.3 (5H, 77L), 3.82 (2H
,,t), 3.75-3.4 (10H, m), 3.36
(9H,,r), 3.0-2.8(IH,m), 2.0
~1.79 (2H, m), 1.79~1.6”+(
2H, rIL), 1.62-1.45 (2H, m)
, 1.25 (26H, m), 0.88 (3H, t); I
R (KBr method) Niji=3600-3100.2920.
2850.1470.1110 Sieve.

Mass: m/e = 521,460,698° 2-indylthio-6-〇-[4-(
The following compounds were obtained in the same manner as in Example 6 except that various glycerin compounds were used in place of the t-methylamino)butyl]glycerin compound.

Starting material: Example 1 (2-ethylthio- prepared in α1)
3-0-[4-(dimethylamino)butyl]glycerin compound; melting point = 56-60°C.

) T'LG (ethyl acetate:acetic acid:water=3:1:1):Rf
De0.48; NMR: δ=3.9-3.3 (19H, 7yt), 3
．． 05-2.88 (IH.

77L), 2.63C2H,q)', 2.04-1.8
3 (2H.

m), 1.83-1.65 (2H, m), 1.65
~1.45 (2H, 77L), 1.26 (26H, fi
), 0.88 (3H.

77L); IR (KBr method): L/=3600-31 Do,
3010.2910.2840.148o, 1460
, 1120-1° Inj Mass: m/e = 459,460,698° Starting material: 2-[ethoxy(thiocarbonyl)thio)-3-0-[4-(dimethylamino)butyl prepared in Example 2] ] Glycerin compound, but potassium hydrogen carbonate was not used; Melting point = 69-72°C; TLC (ethyl acetate: acetic acid: water = 3:11): Rf = 0
．． 77; NMR: δ=3.66-6.36C10H, m), 3.
44 (9H, s) 3.18~s, oci-(1H, m>
, 2.71 (2H, q), 2.04~1.4s (sH,
m), 1.45-1.16 (26H, m), 1.3
2 (3H, t), 0.88 (3H, I!); IR
(KBr method) Niji = 2925.2855.162o, 1
48o, 1460.111'l! 1cm.

Mass: m/e=490.430.698.685.
142.116.100゜Example 4 (2R3)-1-0-hexadecyl-2-dehydroxy-2-[ethoxy(thiocarbonylcothio)-3-0-
(4-()limethylammonio)dutyl]glycerin.
Yosito 5L Cellulose Calcium Gluconate (Disintegrant) 2
00yny, magnesium stearate (lubricant) 10
0 mg and crystalline cellulose 97 g were mixed and compressed into tablets using a conventional method to obtain tablets containing 50 m9 of the active ingredient in one tablet (and 6 other people) Procedural amendment dated August 1, 1982, and case description 1982 Patent Application No. 224699 2, Name of the invention: Glycerin tombstone, its manufacturing method, and a drug containing its derivatives 3, Relationship with the person making the amendment ° Patent applicant name: Ono Pharmaceutical Co., Ltd. (2) ) Insert the following Bunka in lines 1 to 2 of page 44 of specification i, and Hj+ in line 1 of lower blade S.

Actual Example 1↑ Phenylmethanethiol The following compound was obtained in the same manner as in Actual M flJl except that 4-chlorophenylmethanethiol was used.

(b) (2IIS)-1-0-hexadecyl-2-
Dehydroxy-2-(a-chlorophenyl)methylthio-6-○-[4-(dimethinoge≧])butylcog-”serine TLC (ethyl acetate:acetic acid;water=3:1:i)
:Rf=0.64;N. MR: δ=7.17 (4H,
s), 3.77 (2H, s), 3.7-3.1 (8.
H, m), 5.0-2.7 (IH, i),
2.5-2. [l(2H.m and 6)I,S), 1.9
-0.7 (35H, ffl):.

IR: ν=29 1 0, 2850, 1460, 14
50, 1110cffl-1; Mass: m/e=55
5(M+), 464, 432.

(2RS)-1-O-hexadecyl- used in Example 1
(2RS)-1-Q-hexadecyl-2-〇-mesyl-3-0-(8- (dimethylamino)
The following compound was obtained in the same manner as in Example 1 using octyl]glycerin (produced by the method described in Japanese Patent Application No. 196849/1984) and pentanethiol.

(c) (2R8)-1-Q-hexadecy/L;-2-dehyProxy-2-pentylthio-3-Q- (
8-(dimethylamino)octyl]glycerin TLC: (ethyl acetate:acetic acid:water-5:1:1
) :Rf=D. 41; 'NMR: δ=6
．． 75-3.4 (8H, m), 6. 0 4-2.
95 (IH, m), 2, 58-2.4
6(2H,t), 2.55-2.18(2H,y+ and 6I(,S), 1.65-1.45(8H,m), 1
．． 26 (IH, m), 0.88r6H, In); 11 (
:l'=2930, 2850, 1460, 1120cm
';Mass: m/e= 557 (M+)
-l(3) Insert the following sentence between the 4th and 5th lines of No. 46 Tei.

"The following compound was obtained in the same manner as in Example 2 except that potassium O-phenyldithiocarzenate was used in place of the potassium O-ethyldithiocarzenate used in Example 2.

(a) (2RS)-1-Q-hexadecyl-2-
Dehydroxy-2-[phenoxy(thiocarbonyl)]
thio]-3-0-(4-(dimethylamino)butyl)glycerin TLC (ethyl acetate:acetic acid:water=3:1:i
): Rf=0.72; NMR: δ=7.6-6, 8
(5H, m), 4, 67-3.23 (8I-I, m),
3, 23-2.93 (IH, m), 2.45-2.10
(2H.

m), 2.33 (6H, s), 1.87-0.63 (3
5H.

7 liters); IR: l/=2940, 2870, 1460, 1370
, 1 1 1 5 cm-1; Mass: m/e=
4 9 0, 450j9B. 1(
4) Insert the following sentence between the 7th and 8th lines of the 49th member r(c) (2RS)-1-0-hexadecyl-2-dehydroxy-2-(4-10lofenyl)methylthio- 3-0-(4-()limethylammonio)butyl]glycerin yossite. Starting material: 2-(4-) prepared in Example 1(b)
chlorophenyl)methylthio-3-0- ( 4- (
dimethylamino)butyl]glycerin compound; TLC (
Ethyl acetate:acetic acid:water-3:1:1):IL
f=0.57; NMR=δ-7.5(4H,7n), 6
．． 82 (27-1, S), 3. 7 5-3.
4 (10H, 7n), 3.36 (91-1, s), 3
．． 0-2. 8(IH, m'>, 2.o-179
(2H, m), 1. 7 9 -1, 63 (21-1,
m), 1. 6 2-, 1. 4 5 (21-
1, Ill), 1, 25 (26H, m), 0.
88 (3H, m); IR: I/=4450, 2920,
2850, 1470, 1110c7n.

Mass: m/e=5 5 5, 464, 462.

(d) (2RS)-1-Q-hexadecyl-2-dehydroxy-2-pentylthio-6-+Q-(a-()
Limethylammonio) ocnal] glycerin yosito. Starting material: Example 1 (C) ↑Prepared 2-pentyl naor 3-O-(8-(dimethylamino)octyl)
Glycerin compound; TLC (ethyl acetate:acetic acid:water-6:1:1)
:Rf=0. 9; NMll, : δ=3.80. -6
．． 43(10)(,m),3. +2 (9H,s')
, 6, os-2, 94 (1) 1. m), 2.58-2.
46(2I(.

t), 1.85-1.45 (8I-I, m), 1.26
(58H.

m), 0.88 (6H, 771); ■R Niji = 29
20.2850.1480.1120cm-1; Mas
s: m/e=557°(e) (2R8)-1-0-hexadecyl-2-dehydroxy-2-(phenoxy(thiocarzenyl)thio']-3-(7-(4-()limethylammoni) e) Butyl]glycerin/yoshito starting material: 2-(phenoxy(thiocarzenyl)thio'3-5-O-44-(dimethylamino)butyl)glycerin compound prepared in Example 2(a); TLC (ethyl acetate) :Acetic acid:Water-11:1):Rf
= 0.69; NMIt: δ = 7.6-6.8 (5H, m
), 6.66-5.36 (1oH, m), 5.44 (9
H,s), 6.18-3. OO (I H, R), 2.
04-1.45 (6H, m), 1.45-1.16 (2
6H.

rrL), 0.88 (6H, rrL); IR; ν=29
25.2855.1620.1480.1460.11
10cJ.

Mass: m/e=49[], 460°
] 1-40 Moriyama, Tomino Koza, Joyo City

Claims (1)

[Claims] 1. General formula [wherein R represents an alkyl group having 8 to 22 carbon atoms or an alkyl group having 2 to 5 carbon atoms substituted with a phenyl group, B is a hydrogen atom, The alkyl group having 1 to O, or the formula R represents a hydrogen atom, a halogen atom, a methoxy group, or an alkyl group having 1 to 4 carbon atoms, and R represents an alkyl group having 1 to 4 carbon atoms or a phenyl group. ), R represents an alkylene group having 1 to 8 carbon atoms, R is an amino group, or is a group represented by the formula -NHCOR, -NHCO,
-NHFI. (2) Represents an alkyl group with a prime number of 1 to 4, and Y represents an acid anion. However, when a plurality of R's are bonded, they may be the same or different. ) represents a group represented by ] Glycerin derivatives or acid addition salts thereof. 2. The compound according to claim 1, wherein R is an alkyl group having 14 to 18 carbon atoms. 3. The compound according to claim 1 or 2, which is Fl or a hexadecyl group. 4. The compound according to claim 1, 2 or 6, wherein R is an alkylene group having 6 to 6 carbon atoms. 5. The compound according to any one of claims 1 to 4, which is Fl or a tetramethylene group. 6. R or amino group or formula -M state, -N(R)2
■ θ Also, yo-N(R7)3. Claims 1 to 3 (wherein all symbols have the same meanings as in claim 1) representing a group represented by Y (in the formula, all symbols have the same meanings as in claim 1) The compound according to any one of claims 1 to 6, which represents a group represented by (having the same meaning as described in claim 1). 8. The compound according to any one of claims 1 to 7, wherein R2 is an alkyl group having 1 to 6 carbon atoms. 9. The compound according to any one of claims 1 to 8, wherein R is an alkyl group having 1 to 6 carbon atoms. 10, the compound is (2R8)-1-0-hexadecyl-2
-dehyde90xy2-ethylthi,t-3-0-[4-
The compound according to claim 9, which is (dimethylamino)butyl]glycerin. 11, the compound is (2R8)-1-0-hexadecyl-2
-dehyde90xy-2-ethylthio-3-0'-[4-
()! The compound according to claim 9, which is J methylammonio)butyl]glycerol halide. It has the same meaning as stated in claim 1. ) The compound according to any one of claims 1 to 7, which represents a group represented by the following. Represents a hydrogen atom, a chlorine atom, a methoxy group or a methyl group. ) The compound according to any one of claims 1 to 7 or claim 12, which represents a group represented by the following. 14, the compound is (2R8)-1-0-hexadecyl-2
-dehydroxy-2-benzylthio-6-〇-[4-(
17. The compound according to claim 16, which is dimethylamino)notyl]glycerin. 15, the compound is (2R3)-1-〇-hexadecyl-2
-dehyde90xy-2-indylthio-6-〇-(4-
17. The compound according to claim 16, which is ()limethylammonio)butyl]glycerol halide. 16. Claims 1 to 7 in which R represents a group represented by the formula -as-o-R (wherein R has the same meaning as in claim 1) A compound described in any section. 17, R has the formula -as-o-R (wherein R has 1 to 6 carbon atoms
represents an alkyl group. ) or any one of claims 1 to 7 or claim 16 representing a group represented by
Compounds described in Section. 18, the compound is (2R8)-1-0-hexadecyl-2
-Dehydroxy-2-(ethoxy(thiocarbonyl)thio]-3-0-[4-(dimethylamino)butyl]glycerin. 19. The compound is (2R8)-1- 0-hexadecyl-2
-Dehydroxy-2-[ethoxy(thiocarbonyl)thio]-3-0-[4-(,1-limethylammonio)butyl]glycerin halide 9. 20, represents a group represented by the general formula (wherein R represents an alkylsulfonyl group or a substituted or unsubstituted atomylsulfonyl group, and has the same meaning as described in claim 1), and other The symbol represents the same meaning as described in claim 1. ] A compound represented by the general formula % formula % ( ) (wherein R represents an alkyl group having 1 to 6 carbon atoms, and other symbols have the same meanings as described in claim 1.) Represents a group represented by the general formula [wherein R is an alkyl group having 1 to 6 carbon atoms, and all symbols have the same meanings as above], which is characterized by reacting with a compound represented by The symbol represents the same meaning as above. ] A method for producing a compound represented by. 21. General formula [wherein, R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, Z represents a tert-butoxycarbonyl group, benzyloxycarbonyl group, or o'-nitrophenylthio group, and R represents a It has the same meaning as in claim 20, and other symbols have the same meaning as in claim 1. [In the formula, R4b is an amino group or the formula -NHR (in the formula, R
has the same meaning as described in claim 1. ), and other symbols have the same meanings as above. ] A method for producing a compound represented by. 22, represents a group represented by the general formula (wherein R represents the same meaning as described in claim 21, and other symbols represent the same meaning as described in claim 1), Other symbols have the same meanings as described in claim 1. ] Production of a compound represented by the general formula (wherein all symbols have the same meanings as stated in claim 1), which is characterized by hydrolyzing the compound represented by the formula under alkaline conditions. Method. 26. A compound represented by the general formula (wherein, all symbols have the same meanings as described in claim 1) with an alkyl halide, represents a halogen atom, and other symbols have the same meanings as above. 24. Platelet aggregation inhibitors and antiplatelet aggregation inhibitors containing glycerin derivatives or their acid addition salts represented by the general formula (in which all symbols have the same meanings as described in claim 1) as an active ingredient. asthma medicine,
Anti-allergic, anti-inflammatory, hypotensive or anti-tumor agents.