JPH03240779A - New hetero-ring derivative and drug containing thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula l [X is methylene, >N-E (E is 1-8C alkyl), O or S; A is carbonyl or methylene; B is single bond, O, S, N or phosphoric group; B is single bond or 1-6C alkylene; O is amino, -NHCOR<1> (R<1> is 1-6C alkyl or phenyl), -NHR<2> (R<2> is 1-6C alkyl), etc.; R is 2-22C alkyl; bonding of ring part and A is a single bond and an optically active substance or racemic modification having alpha- or beta-configuration of A]. EXAMPLE:An N-[N'-(hexadecyl oxycarbonyl)-3-piperidinyl-methylthioethyl] thiazolium chloride. USE:Used as platelet aggregation-inhibiting agent, antiasthmatic agent, antiallergic agent, anti-inflammatory agent, vasodepressing agent, anti-endotoxin shock agent, antinephritic agent, antipancreatic agent, anti-ischemic cerebrovascular disease agent or antitumor agent. PREPARATION:A compound expressed by formula II (Y is halogen, etc.) is reacted with a compound expressed by the formula HO-C-G (G is halogen, etc.), etc., and further reacted with NH(R<2>)2, etc., to afford the aimed compound.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a novel heterocyclic derivative and a drug containing the same.
activating factor, hereinafter abbreviated as PAF. The present invention relates to a novel heterocyclic derivative having an antagonistic effect on PAF-like blood pressure lowering effect, a phospholipase inhibitory effect, and a growth-inhibiting effect or differentiation-inducing effect on tumors, and a pharmaceutical containing the same as an active ingredient.

[Conventional technology, the problem that the invention attempts to solve! I! ] In recent years, research on the leukocyte-dependent release reaction of active amines from platelets has been vigorously pursued. As a result, a very strong substance that causes platelet aggregation was discovered, and P
Named AF [J, I+u+uno1. , 106
Volume, 1244 pages (1971), J, Exp.

Med, Volume 136, Page 1356 (1972)
and Nature.

Volume 249, page 581 (3974) 1゜After that, P
The existence of AF has also been confirmed in living organisms of various animals including humans. In 1979, its structure was determined [
J. Biol, Chew, vol. 254, 9355.
Page (1979) 1, it was found to be a mixture of compounds represented by the following general formula [J, Biol, C
heIjp,.

Volume 255, page 5514 (1980) 1゜0e
CL (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. It became clear. Also, P.A.
F is one of the platelet aggregation factors in humans, and is also thought to be one of the causative agents of allergic reactions and inflammatory reactions (J, Biol, Chew,
, , 2'' Σ4yo 9355-9385 (1979)).

Therefore, it antagonizes PAF (inhibits the action of PAF)
The compound has great potential to become a different platelet aggregation inhibitor, anti-asthma agent, anti-allergy agent, anti-inflammatory agent, etc. Also, by isolating only the antihypertensive effect of PAF, it is possible to improve platelet aggregation. It is also conceivable that it may be used as an antihypertensive agent without any action. Glycerol derivatives are known as compounds that exhibit the above effects, but
Among them, CV-3988 (Life, 5ci, 3
Volume 2, 1975 pages (19B3 L Prosta
grandins, + 30 volumes, 715 pages (198
5 years) + J, Pharwacol, + 109 volumes,
257 pages (1985)> etc. are known.

[Means to solve the problem]

The present invention was completed after extensive research was conducted to find a compound that antagonizes PAF or a compound that has a PAF-like blood pressure lowering effect, and it was discovered that a certain type of heterocyclic derivative achieves the objective.

General formula (1) [In the formula, X is a methylene group, N-N-E group (E is a carbon number of 1 to
(8) represents a straight chain or branched alkyl group, represents an oxygen atom or a sulfur atom. A represents a carbonyl group or a methylene group, B represents a single bond, an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphoric acid group, C represents a single bond or an alkylene group having 1 to 6 carbon atoms, and D represents an amino group. group or formula -NHCOR', -NHR", -NCR")z
Mataha "NCR") IYo (in the formula, R' is a carbon number of 1 to
6 represents an alkyl group or a phenyl group, Hl represents an alkyl group having 1 to 6 carbon atoms, and ye represents an acid anion. However, if multiple R2s are bonded, they are not the same. In this case, the bond between the ring part and A is a single bond, and A is in an optically active form in which the coordination is at the α- or β-position, or a racemic form in which the combination of both coordinations is present. ] Heterocyclic derivatives represented by or acid addition salts thereof, and platelet aggregation inhibitors, anti-asthmatic agents, anti-allergic agents, anti-inflammatory agents, hypotensive agents, anti-endotoxic shock agents, anti-nephritis agents containing the same as active ingredients, The present invention provides an anti-pancreatitis agent, an anti-ischemic cerebrovascular disorder agent, and an anti-tumor agent.

In the compound represented by the above general formula (1), "alkyl group" and "alkylene group" are linear or branched "
"alkyl group" and "alkylene group". moreover,
In the compound of general formula (1), when R is an alkyl group having 2 to 22 carbon atoms, the alkyl group is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and nonyl.

Examples include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nanodecyl, eicosyl, Henriicosyl, tocosyl groups, and isomers thereof, preferably an alkyl group having 14 to 18 carbon atoms, and particularly preferred The group is a hexadecyl group.

In the compound of general formula (1), when C is an alkylene group having 1 to 6 carbon atoms, the alkylene group is methylene,
Examples include ethylene, triethylene, tetramethylene, pentamethylene, hexamethylene groups and isomers thereof, preferably ethylene and trimethylene. Further, in the compound of general formula (1), D is of the formula (-NHCOR',
-NHR", -N(R")zmataha-ΦN(R"), Y
e) Tealtoki, R' * Tahap" indicates carbon number 1
~6 alkyl groups include methyl, ethyl, propyl,
Examples include butyl, pentyl, hexyl groups, and isomers thereof, and any group is preferred. In addition, in the compound of general formula (1), when E is an alkyl group having 1 to 8 carbon atoms, examples of the alkyl group include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and isomers thereof. are mentioned, preferably a methyl group.

Next, in the compound represented by general formula (1), ye
When is an acid anion, it means the anion of pharmaceutically acceptable inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid.

Inorganic acids such as phosphoric acid, nitric acid or acetic acid, lactic acid.

Tartaric acid, benzoic acid, citric acid, methanesulfonic acid.

Anions of organic acids such as ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid may be mentioned, preferred anions are halogen ions, i.e. chloride ion, bromide ion, iodide ion or methanesulfonic acid, p-toluene. It is an anion like sulfonic acid.

(2) Contains only one nitrogen atom, or one nitrogen atom and one or two other nitrogen, oxygen, or sulfur atoms, provided that the total number of complex atoms is 3 or less shall be. ), and at least 2 carbon atoms; (3) monocyclic or bridged bicyclic; (4) with or without double bonds in the ring; or aromatic or It is a non-aromatic heterocyclic group, and (5) any position (preferably a nitrogen atom) in the ring is substituted with an alkyl group having 1 to 6 carbon atoms, preferably 1 to 5 methyl groups. It means a good heterocycle.

Furthermore, in the case where such a heterocyclic group has a quaternary ammonium ion in the ring itself or a nitrogen atom in the ring is substituted with alkyl to become a quaternary ammonium ion, the appropriate can form salts with the anion of the acid.

Examples of such heterocyclic groups include the following.

and isomers and partially saturated forms thereof, and N-alkyl substituted forms thereof. In addition, when a heterocyclic group becomes a quaternary ammonium ion, the anion (Y-) which forms a salt with them is the same as Y- mentioned above.

The compound of the present invention represented by the general formula (1) has at least one asymmetric carbon (carbon of the heterocycle to which A is bonded), and various substituents represented by R, C, R' and R2. When the alkyl moiety of represents a branched chain, other asymmetric carbon atoms may occur.

However, the compound represented by the general formula (1) of the present invention also contains each isomer generated by an asymmetric carbon and a mixture thereof.

The compound represented by the above general formula (1) can be produced using any of the following methods.

Method A general formula (II) (morpholino group) and their isomers and partially or completely saturated or unsaturated forms, -OR [wherein R has the same meaning as above, and Y represents a halogen atom (e.g. , nitrogen, iodine) or an alkylsulfol group, preferably a methanesulfonyl group (ie, mesyl group) or a substituted or unsubstituted arylsulfonyl group, preferably a p-)luenesulfonyl group (ie, tosyl group). ] and general formula (DI) HO-C-G (III) or general formula (IV) R3-C-G (IV) [wherein, C has the same meaning as above, and G is a halogen atom , represents a hydroxyl group, a mercapto group, or an alkylsulfonyl group. ] can be easily produced by alkylsulfonylation and halogenation using conventional methods.

The general production reaction of Method A is as follows.

Starting material is 4-piperidine methanol, 3-piperidine methanol or 2-piperidine methanol, which is combined with sodium hydroxide and reacted with chilled chloroformate in an alcohol solvent, preferably methanol or ethanol, and then H ooc 61 (ff3 Method B) A compound represented by the general formula (V) [wherein R and Y have the same meanings as above] is reacted with the general formula (I[I) and (IV) in the same manner as in the method. The general formula (V) can be easily manufactured by
The compound represented by
harm, Bull, 33(9) 3766 (1 or J, Che+*, Soc, Perkin,
Trans, I 2: (1985)) to produce 2-substituted or 3-substituted moroline, which can be easily produced in the same manner as method A. In the case of an optically active form, glycerin or light? Optical deglycidol can be produced by a conventional method using a basic amino acid as a starting material, and can be converted to optically active (V).

The general reaction formula of Method B is as follows.

ooc H33 ooc H33 COOC1&)133 COOC+1lhi NAE1 COOC+hHsz 3-substituted product CH2Ph C00C1683:1 COOC16H33 COOC1&H33 ttzph COOC+dhz COOC+J z3 C method general formula (VI) [wherein R and Y have the same meanings as above. ] It can be easily produced using the compound represented by the general formula (I[I) or (IV) in the same manner as in Method A. Note that the compound represented by the general formula (V[) can be easily produced using cysteine, which is an amino acid, as a starting material.

The reaction formula of the general production method of Method C is as follows.

C00C16833 COOC+J33 C00CI&H3:1 COOC+Jh:+ C00CI&)133 D-method general formula (■) [In the formula, R and Y have the same meanings as above. It can be easily produced using the compound represented by formula (In) or (IV) in the same manner as in Method A. The general formula (■) is based on the method described in literature (Helv, Chen+, Acta, etc.).

2383 (1962)).

The general reaction formula of Method D is as follows.

Among the compounds represented by the general formula (1) of the present invention, preferred examples include the following compounds.

N-(N''-(hexadecyloxycarbonyl)2-piperidinyl-methylthioethyl phthiazolium halide or mesylate N-(N'-(hexadecyloxycarbonyl)3-piperidinyl-methylthioethyl phthiazolium halide or mesylate N- (N'-(hexadecyloxycarbonyl)4-piperidinyl-methylthioethyl]thiaturium halide or mesylate 11- (N'-(hexadecyloxycarbonyl)-
2-Piperidinyl-methyloxyethylcutiazolium halide or mesylate N-(N'-(hexadecyloxycarbonyl)=3-
Piperidinyl-methyloxyethylcutiazolium halide or mesylate N-CN'-(hexadecyloxycarbonyl)-4-
Piperidinyl-methyloxyethylcutiazolium halide or mesylate halogenation N-(N'-(hexadecyloxycarbonyl)-2-piperidinyl-methylthio]ethyltrimethylammonium or mesylate halogenation N-[N
"-(hexadecyloxycarbonyl)-3-piperidinyl-methylthio]ethyltrimethylammonium or mesylate halogenated N-(N'-(hexadecyloxycarbonyl)-4-piperidinyl-methylthio]ethyltrimethylammonium or mesylate N-( N“
-(hexadecyloxycarbonyl)-2-morphonyl-methylthioethyl phthiazolium halide or mesylate N-(N'-(hexadecyloxycarbonyl)-3-
Morphonyl-methylthioethylphthiazolium halide or mesylate halogenation [N-(hexadecyloxycarbonyl)
-2-morpholinyl-methyloxyphethyl-trimethylammonium or mesylate N-[N'-(hexadecyloxycarbonyl)-3-thiomorpholinyl-methylthionityl]thiazolium halide or mesylate N-(N'-methyl-N "-(hexadecyloxycarbonyl)-2-piperazinyl-methylthioethyl phthiazolium halide or mesylate N-(N'-(hexadecyloxycarbonyl)-2-indolinyl-methylthioethyl phthiazolium halide or mesylate N-(N ``-(hexadecyloxycarbonyl)aminomethyl-2-ethylthioethyl]thiazolium halide or mesylate In addition, the compound represented by formula (I) of the present invention may be in the form of a pharmacologically acceptable acid addition salt. I can do it.

Examples of pharmacologically acceptable acid addition salts include acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as p-)luenesulfonic acid and maleic acid. .

The compound of the present invention represented by general formula (1) is as described above (
It has an antagonistic effect on PAF and a PAF-like blood pressure lowering effect, but it also has a phospholipase (phospholipase) effect.
1pase) was found to also inhibit the effects of A and C. In vivo calcium-dependent phospholipases A2 and C are involved in the mechanism of arachidonic acid release from phospholipids. Arachidonic acid released by physiological stimulation is incorporated into the prostaglandin metabolic pathway,
It is known that it is eventually metabolized into thromboxane A2 and other prostaglandins, which have a strong platelet aggregation effect, and into various leukotrienes, which are important bronchoconstrictors during asthma attacks.

Therefore, compounds that inhibit phospholipases A and C, which are involved in the release mechanism of arachidonic acid, have a different mechanism of action than PAF antagonists, and moreover, compounds that inhibit cyclooxygenase such as aspirin, It is thought that the drug may become a platelet aggregation inhibitor, an anti-asthmatic agent, an anti-allergic agent, or an anti-inflammatory agent based on inhibiting different holipases A2 and C.

Furthermore, the compound of the present invention represented by the general formula (1) exhibits a tumor cell growth-inhibiting effect or a culture-inducing effect, and therefore can be expected to be used as an antitumor agent.

To use the heterocyclic derivative represented by general formula (I) of the present invention or its acid addition salt for the above-mentioned purpose, it is usually administered systemically or locally, orally or parenterally. The dosage varies depending on the age, body weight, symptoms, therapeutic effects, administration method, treatment time, etc., but it is usually an Ig-
1 g, preferably in the range of 20 to 200 μg, administered orally once to several times a day, or 10 μg to 100 μg per dose, preferably 1 to 10 μg per dose per person.
It is administered parenterally once to several times a day.

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 objects for oral administration according to the present invention include tablets, powders, granules, and the like. In such solid compositions, one or more active substances may be present in at least one inert diluent such as lactose, mannitol, dextrose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminate metasilicate. Mixed with magnesium.

The compositions may contain additives other than inert diluents, such as lubricants such as magnesium stearate and disintegrants such as cellulose and 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, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc., or may be coated 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. - inert diluents used in boating, e.g. Contains water and 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 and suspensions.

Includes emulsifying agents. Examples of aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol and polyethylene glycol.

These include vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. They are rendered sterile, 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, containing one or more active substances, are formulated according to methods known per se. These include liquid preparations for external use, liniments such as soft creams, suppositories for intrarectal administration, and pessaries for intracavitary administration.

〔Example〕

EXAMPLES Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited to these Examples.

In addition, rNMRJ, rlRJ, [αIn
represent "nuclear magnetic resonance spectrum", "infrared absorption spectrum", and "specific rotational hardness by sodium D line", respectively. NMR was measured using a deuterated chloroform (coc 1 g) solution.

Example 1 Lithium aluminum hydride (2.2g, 58n+a
+ol) was suspended in tetrahydrofuran. After refluxing for 15 minutes, 3-piperidinecarboxylic acid (57) (5
g, 39 hours) was added. After refluxing for 1 hour, potassium hydroxide solution (20 μl) was added. After filtering out insoluble substances, the mixture was concentrated under reduced pressure to obtain 4.0 g (yield 100x) of 3-piperidine-methanol as an oily substance.

3-piperidine methanol (1,2g, 10mm+o
ffi) was dissolved in 10 d of 2N sodium solution (20 sso j!) containing 2.4 d of methanol, and cooled with water.
hexadecyl chloroforme) (3.0g, 10m
moi) was added dropwise. The mixture was stirred for 2 hours under water cooling and further stirred for 1 hour at room temperature. After adjusting the pH to 3 with IN hydrochloric acid, the mixture was extracted with ethyl acetate. After drying the extract over magnesium sulfate, it was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography.
N-(hexadecyloxycarbonyl)piperidine 3-
3.7 g (yield 96z) of methanol was obtained as a colorless oil. The physical properties of this compound are shown below.

IR: (νneat)cm-' 3420.1680.
'H-NMR: δ (CDCf 3) 0.88 (38,
t J = 6.23Hz), 1.26 (28H, br),
1.46J, 94 (5H, m), 2.57-4.27 (
7H, m), 3.48 (2H, d, J=5.12
Hz) N-(hexadecyloxycarbonyl)piperidine-3-methanol (3.3g, 8.6+w+wo 1
) and triethylamine (1.7 g, 17sso j
2) was dissolved in dichloromethane. While stirring under water cooling, 4-toluenesulfonyl chloride (2.5 g, 13sI
lo l) was dissolved in dichloromethane 10- and added dropwise. After stirring at room temperature overnight, the mixture was washed with water and saturated brine. After drying the dichloromethane layer with magnesium sulfate, it was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography.
Remove to volume with hexane-ethyl acetate, N-(hexadecyloxycarbonyl)-3-piperidinyl-methyl-P-
3.4 g (yield 73z) of toluene sulfate was obtained as a white powder.

IR: (v KBr) cw, -' 1705.
'H-NMR: δ(C[lCf j)0.88(3H,
t J = 5.62Hz), 1.26 (28H, br)
, 1.52-2.03 (5H4).

2.45 (3H, s), 2.40~3.02 (28
, m), 3.71-4.26 (4H, s+).

7.34 (2H, d, J=8.31 Hz), 7.
79 (2H, d, J=8.31 Hz).

Sodium hydride (480■, 12++no l)
After washing with hexane, it was suspended in 10 d of tetrahydrofuran. After stirring under water cooling, 2-mercaptoethanol (700 μ, 9.0 m5 o i!) was added dropwise, and the mixture was stirred for 30 minutes. Under water cooling, N-(hexadecyloxycarbonyl)-3-piperidinyl-methyl-p-)luenesulfate (3.2 g, 6.0 mmo 12
) was dissolved in 10 ml of tetrahydrofuran and added dropwise. 6
After stirring at 0°C overnight, the mixture was allowed to cool, then ice water was added and extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluting with hexane-ethyl acetate to obtain 2.4 g of N-(hexadecyloxycarbonyl)-3-piperidinyl-methylcothioethyl alcohol as an oil (yield 68x) obtained.

IR: (νneat)aI-' 3440.1685.
'H-NMR: δ(CDCj! ri 0.88 (3H,
tJ=5.49Hz), 1.26(28EI, br
), 1.40-2.04 (5H, a+), 2.30-3
．． 09 (6H, a+), 3.51-4.26 (711
,s) [N-(hexadecyloxycarbonyl)-3piperidinyl-methylcothioethyl alcohol (1.8g
, 4. Oauwo 12 ) and triethylamine (800 μ, 8+++s+ol) were dissolved in dichloromethane. Methanesulfonyl chloride (700 μ, 6.0 m+no1) was added dropwise with stirring under water cooling. After stirring overnight at room temperature, dichloromethane was distilled off, and the residue was subjected to silica gel chromatography eluting with hexane-ethyl acetate. hexadecyloxycarbonyl)-3
1.7 g (yield: 92x) of -piperidinyl-methyl-chloroethyl sulfide was obtained as an oily substance.

IR: (νneat)cm-' 1700. ')l-
NMR: δ(coc i ,)0.88(3H,t
J=5.62Hz), 1.26 (288, br), 1.
46-2.07 (6H, m).

3.50-4.50 (68,s).

N-(hexadecyloxycarbonyl)-3-piperidinyl-methyl-chloroethyl sulfide (1.0 g,
2.1 mmo j! ) with thiasol (1.9g,
22m5of) and reacted in a sealed tube at 100°C overnight. After distilling off the thiazole, the residue was subjected to silica gel chromatography, eluted with chloroform-methanol water, and N-rN'-(hexadecyloxycarbonyl)
-3-Piperidinyl-methylthioethyl]thiazolium chloride as pale yellow powder 80k (yield 66z)
Obtained.

Example 2 Commercially available 2-piperidimethanol (1.2 g, 10
++no1) was reacted in the same manner as in Example 1, and the target substance N-(N'-(hexadecyloxycarbonyl)-
600 ml of 2-piperidinyl-methylthioethyl]thiazolium chloride was obtained as a pale yellow powder (yield: 5 oz).

Example 3 Lithium aluminum hydride (2.2g, 58smo
ffi) was suspended in tetrahydrofuran and refluxed for 15 minutes.

4-Piperidinecarboxylic acid (5B) (5g, 39s
So j! ) was added. After refluxing for 1 hour, potassium hydroxide (20-■Ol) was added. After filtering the insoluble Kansho,
Decompression! By condensation, 2.0 g (yield: 45x) of 4-piperidine methanol was obtained as an oily substance.

4-piperidine methanol (1,2 g, 10 saof
fi) was reacted in the same manner as in Example 1, and the target substance N
4.0 g (yield: 93z) of (N'-(hexadecyloxycarbonyl)-4=piperidinyl-methylthioethyl phthiazolium chloride) was obtained as a white bundle.

Example 4 Sodium hydride (0.45g, 11m5+o l
) was washed with hexane, and then N,N-dimethylformamide 10- was added under ice cooling. Furthermore, dimethylaminoethanol (0.75 g, 8.3 wmo j!) was added under water cooling.
was added dropwise, and the mixture was stirred for 30 minutes. N-(hexadecyloxycarbonyl)-3-piperidinyl-methyl-p-toluenesulfate (3.0 g) obtained in Example 1 under water cooling.
, 5.6v++o 1 ) was dissolved in 10 yd of N,N-dimethylformamide and added dropwise. After stirring at 50°C for 8 hours, the mixture was allowed to cool, then ice water was added and extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with chloroform-methanol to give 1.2 g of N-(hexadecyloxycarbonyl)-3-piperidinyl-methyldiaminoethyl ethyl ether as a pale yellow powder (yield). A rate of 47χ) was obtained.

IR: (νKBr) cs-' 1705. 'H-N
MR: δ(CDCj! ri0.87(3H,t, J=
5.9882), 1.26 (28H, br) 1
．． 49”2.04 (4H, m).

2.29 (6H, s), 2.51 (2H, t,
J=5.86Hz), 40-3.70 (28, m)
.

3.29 (28, d, J=5.99Hz), 3
．． 52 (2H, t, J=5.62Hz), 3.
78-4.27 (2H, m), 4.05 (2B, t, J
=6.47tlz).

N-(hexadecyloxycarbonyl)-3piperidinyl-methyldiaminoethylethyl ether (780■,
1.7 ml of the solution was dissolved in ether 5d and added dropwise to methyl iodide (48 ml, 3.4 mmoffi).

- After stirring overnight, filter the insoluble matter and iodide [N-(hexadecyloxycarbonyl)-3-piperidinyl-methyloxy]
Ethyltrimethylammonium as pale yellow powder 7
80μ (yield: 76z) was obtained.

Example 5 N-(hexadecyloxycal; i: nyl)-3-piperidinyl-methyl-chloroethyl sulfide amine <6.5y1mol) obtained in Example 1 was dissolved in 5m of toluene and heated to 100°C in a sealed tube. - Reacted overnight. After distilling off the toluene, the residue was subjected to silica gel chromatography and eluted with chloroform-methanol-water to give N- (N'-
(Hexadecyloxycarbonyl)-3-piperidinyl-methylthioethyl] 20 ml of trimethylammonium chloride was obtained as a pale yellow powder (yield: 6x).

Table 1 shows the structural formulas and physical properties of the compounds obtained in Examples 1 to 5.

Example 6 2-benzyloxymethylmorpholine (1.0 g, 4.
8ma+of) in 2N sodium hydroxide solution containing 1.2I11 methanol 5d (10++s+o l )
Dissolved in n-hexadecyl chloroformate (
1.6 g, 4.8 mmof) was added dropwise. The mixture was stirred for 2 hours under water cooling and further stirred for 1 hour at room temperature. After adjusting the pH to 3 with IN hydrochloric acid, the mixture was extracted with ethyl acetate. The extracted product was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography to obtain 1.9 g of N-(hexadecyloxycarbonyl)-2-benzyloxymethylmorpholine.
(Yield: 72) A colorless oil was obtained.

IR: (v neat) cm-' 1703. 'H-
NMR: δ(CDCl3)0.88(3H,t),
1.26 (288, br), 2.7 (1~4.0
4 (IIH, w), 4.48 (78°s), 7
．． 25 (5B, s).

N~(hexadecyloxycarbonyl)-2benzyloxymethylmorpholine (120μ, 2s+mol) and palladium hydroxide on carbon (20μ) were dissolved in ethanol and replaced with hydrogen. After stirring at room temperature for 2 hours, it was filtered and the filtrate was was concentrated under reduced pressure to obtain N-(hexadecyloxycarbonyl)-2-
100μ of morpholinyl-methanol (yield 100%)
Obtained as a white powder.

IME (Kbr) cm-' 3425.1702. '
H-NMR: δ (CDc 123) 0.88 (3H,
t), 1.26 (28H, br), 2.90-4.40
(12H, a).

N-(hexadecyloxycarbonyl)-2-morpholinyl-methanol (10 g, 2.7 mmol) and triethylamine <0.4 g, 4.0 s+t*ol) were dissolved in dichloromethane. 4-Toluenesulfonyl chloride (0.57 g, 3.0 vsoj) was stirred under water cooling.
! ) was dissolved in 10M1 dichlorothane and added dropwise. After stirring at room temperature overnight, the mixture was washed with water and saturated brine. The dichloromethane layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluted with hexane-ethyl acetate to obtain N-(hexadecyloxycarbonyl)-2-morpholinyl-methyl-p-toluene sulfate as white. 640 mg (yield 44x) was obtained as a powder.

IRE(Kbr)CI-' 1702. 'H-NMR
: δ(CDCj! ri 0.88(31,t).

1.26 (281, br), 2.42 (3H, -), 2
．． 70-4.20 (118, s), 7.25 (2H, d
), 7.73 ((2H, d).

Sodium hydride (80 g, 2.0 mmoj!) was washed with hexane and then diluted with N,N dimethylformamide 1
01d. After stirring under water cooling, 2-mercaptoethanol (120 ml, 1.5 mmof) was added dropwise, and the mixture was stirred for 30 minutes. Under water cooling, N-(hexadecyloxycarbonyl)-2-morpholinyl-methyl-p-toluene sulfate was dissolved in N,N dimethylformamide (10j).
d and added dropwise. After stirring for 2 hours, the mixture was allowed to cool, then ice water was added and extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluting with hexane-ethyl acetate and using [N-(hexadecyloxycarbonyl)-2-morpholinyl-methyl]thioethyl alcohol as an oil for 500 μl.
(yield: 90x).

IR: (νneat)cm-' 3405,1700.
'H-NMR: δ(CDCl:l)0.88 (
38,t), 1.26 (28H,br), 2
．． 50-4.20 (16H, m).

(N-(hexadecyloxycarbonyl)-2-morpholinyl-methylcothioethyl alcohol (46011g)
, 1.1 mmof) and triethylamine (200 mmof)
.

2 mmof) was dissolved in dichloromethane. methanesulfonyl chloride (230 μl) while stirring under water cooling.

2.0tstmol) WK was lowered. After stirring overnight at room temperature, dichloromethane was distilled off, and the residue was chromatographed on silica gel, eluting with hexane-ethyl acetate.
3500 Ig (yield 69z) of N-(hexadecyloxycarbonyl)-2-morpholinyl-methyl-chloroethyl-sulfide was obtained as an oily substance.

IR: (!I neat) cm-' 1693. ')
I-NMR: δ (CDC13) 0.88 (3H, t)
, 1.26 (28H, br) , 2.45-4.25
(15B, m).

N-(hexadecyloxycarbonyl)-2-morpholinyl-methyl-chloroethyl-sulfide (350g
, 0.75 mao l) and thiazole (1.0 g,
12B1 mol) was dissolved in a sealed tube at 100″C-
The reaction was carried out in the evening. After distilling off the thiazole, the residue was subjected to silica gel chromatography and eluted with chloroform-methanol-water to remove N-(N'-hexadecyloxycarbonyl)-2-morpholinyl-methylthioethyl]thiazolium chloride. 150 ml (yield 36 z) was obtained as a yellow powder.

Example 7 Sodium hydride (0.34g, 8.5++v+of
) was washed with hexane, and then 10M1 of N,N dimethylformamide was added under water cooling. Furthermore, dimethylaminoethanol (0.57g, 6.4gmoffi) was added under water cooling.
) was added dropwise, and the mixture was stirred for 30 minutes. N-(hexadecyloxycarbonyl)-2-morpholinyl-methyl-p-tolsulfite (2.3 g, 4.3 mmo) under water cooling.
Il) was dissolved in N,N dimethylformamide 101d and added dropwise. After stirring at 50°C for 8 hours, the mixture was allowed to cool, then ice water was added and extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluting with chloroform-methanol [N-
(Hexadecyloxycarbonyl)-2-morpholinyl-methyltudimethylaminoether was used as an oily substance to obtain 200 μl (yield: 10).

IR: (y KBr) ell-' 1702. 'H
-NMR: δ(CDCl3)0,88(31,t)
, 1.26 (28H,br) , 2.30 (6
H,s), 2.45-4.25 (158, m).

(N-(hexadecyloxycarbonyl)-2-morpholinyl)-dimethylaminoether (180■, 0.4
IllIIIol) to ether 5111i! and added dropwise to methyl iodide (131 g, 0.8 mmof). After stirring overnight, the insoluble matter was filtered to obtain 150 ml of iodized [N-(hexadecyloxycarbonyl)-2-morpholinyl-methyloxylaethyl-trimethylammonium] as a pale yellow powder (yield 63z).

Example 8 2-benzyl-1,3-peropanediol (32g).

180vgtaol) to vinyl acetate (34.6g,
400m+so 1 ). Lipase P (
After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using dilormethane:methanol (70:
When eluted with 1), (S)-1-acetoxy-2-benzyloxy-3-propatol was obtained as an oily substance at 35.
3 g (yield: 8B%, optical purity: 91Xee) was obtained.

(S)-1-acetoxy-2-penzyloxy-3-propatol (20 g, 90 mmol) and triethylamine (14 g, 135 mmol) were dissolved in dilormethane.

After stirring under water cooling, 4-toluenesulfonyl chloride (21
g, 108 mmo 1) was dissolved in dilormethane LT.
dripped. After stirring at room temperature overnight, the mixture was washed with water and saturated brine. After drying the diclmethane layer with magnesium sulfate,
After concentration under reduced pressure, the residue was chromatographed on silica gel and eluted with hexane:ethyl acetate (10:1) to give (R).
33 g of -3-acetoxy-2-hensyloxy-1-tosyloxypropane (yield 97x) was obtained.

(R) -3-acetoxy-2-hensyloxy 1-tosyloxypropane (33g, 87imo j2)
Sodium hydroxide (3.8g, 96mmo 1)
was dissolved in an ethanol solution of The mixture was stirred for - hours under water cooling. After neutralizing with 6N hydrochloric acid, the ethanol solution was distilled off, and the dichloromethane layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from isopropyl ether to obtain 20 g (yield: 68z) of (R)-1-hydroxy-2-benzyloxy-3-tosyloxypropane as a white powder.

(R)-1-Hydroxy-2-benzyloxy-3-tosyloxypropane (20 g, 60 mmol I!,) was dissolved in ethanol. Palladium on carbon (2 g) was added and the mixture was replaced with hydrogen. Stir overnight at room temperature. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to obtain 15 g of (R)-3-)siltoxy-1,2-propanediol as a white powder.
(Yield 100X) was obtained.

(R)-3-) Siltoxy-1,2-propanediol (15 g, 60 mmol) in methanol 25. I
dl and ether 12d. Under water cooling, sodium (1.4 g, 60 mmol) was added dropwise over a period of - hours. After stirring for an additional hour, the reaction solution was concentrated under reduced pressure. After adding ether to the residue and filtration, the filtrate was concentrated under reduced pressure.

The residue was added with chloroform and concentrated under reduced pressure to obtain 4.4 g (yield: 100 Z) of (R) glycidol as an oily substance.

Sodium hydride (3.2g, 80nuwo l)
After washing with hexane, it was suspended in tetrahydrofuran.

While stirring under water cooling, (R)-glycidol (3,
7g.

60 mmo i) was added dropwise. Immediately, hensyl bromide (12.6 g, 74 ol) was added dropwise. Under water cooling,
- After stirring overnight, ice water was added. After extraction with ether, drying over magnesium sulfate, and concentration under reduced pressure, the reaction mixture was subjected to silica gel chromatography, and hexane-
Elution with ethyl acetate (10:1) gave 7 g (yield 71z) of (S)3-benzyloxy-1,2-epoxypropane as an oil.

2-Aminoethylsulfonic acid (30g, 215mmo
i) with 70χ sodium hydroxide solution 25ad! dissolved in (S)-3-benzyloxy-1, at 50°C
2-Epoxypropane (7g, 73v++ol)
was dissolved in methanol 401d and added dropwise. After stirring for 1 hour at 50°C, 40ad of 70x sodium hydroxide solution was added.
was dripped. The mixture was further stirred at 50°C for 16 hours. 300
Water from step d was added and extracted with toluene. The toluene layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography.
0:1), 3.8 g (yield 43z) of (S)-morpholine-2-methanol was obtained as an oily substance.

Thereafter, in the same manner as in Example 6, (S)-(+)-N [N
'-(hexadecyloxycarbonyl)-2-morpholinyl-methylthioethyl]thiazolium chloride was obtained.

Example 9 (S)-1-acetoxy-2-benzyloxy-3 propazuramine (13 g, 100 mmo j!) was dissolved in dichloromethane. Methoxymethyl chloride (6.5 g, 81 wmol) was added dropwise while stirring under water cooling. After stirring overnight at room temperature and drying, reduce the pressure! When it shrinks (S)
-1-acetoxy-2-benzyloxy-3-methoxymethylpropane as an oily substance (18 g (yield 100z)
) obtained.

(S)-1-acetoxy-2-benzyloxy-3-methoxymethylpropane (18 g.67 mmof) was dissolved in an ethanol solution of sodium hydroxide (2.7 g, 67++nof). The mixture was stirred for an hour under water cooling, neutralized with 6N hydrochloric acid, ethanol was distilled off, and the residue was extracted with dichloromethane. The dichloromethane layer was dried over magnesium sulfate and concentrated under reduced pressure to give (R)-1-hydroxy-2-
15 g (yield: 100%) of benzyloxy-3-methoxymethyloxypropane was obtained as an oily substance.

(R)-1-Hydroxy-2-hensyloxy-3-methoxymethyloxypropane (15g, 67+s+++
offi) and triethylamine (Log, 100m5
o l) was dissolved in dichloromethane. Under water cooling and stirring, 4-toluenesulfonyl chloride (15 g, 81
a+mo 1 ) was dissolved in dichloromethane and added dropwise. After stirring at room temperature overnight, the mixture was washed with water and saturated brine.

The dichloromethane layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified with hexane by silica gel chromatography.
Elution with ethyl acetate (5:1) gave 15 g (yield 98z) of (S)-1-)yloxy-2-benzyloxy-3-methoxymethyloxypropane.

(S)-1-Tosyloxy-2-benzyloxy 3-methoxymethyloxypropane (25g, 65*so
1) was added to a methanol solution containing 15d with 6N hydrochloric acid and stirred at 60°C for 8 hours. After neutralizing with 2N sodium hydroxide solution, methanol was distilled off and the residue was extracted with dichloromethane. The dichloromethane layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain (S
21 g (yield: 98z) of -1-tosyloxy-2-benzyloxy-3-propatool was obtained as a white powder.

Thereafter, in the same manner as in Example 8, R-(-)-(N"(hexadecyloxycarbonyl)-2-morpholinyl-methylthioethyl)thiazolium chloride was obtained.

Example 10 (S)-(-)-3-morpholinemethanol (115
) (7001 g, 6.0 asol) in 6 dl (12
*so i! ), and n-hexadecyl chloroformate (1.8 g, 6.0 sumol) was added dropwise under water cooling. The mixture was stirred for 2 hours under water cooling and further stirred for 1 hour at room temperature.

After adjusting to p)13 with IN hydrochloric acid, the mixture was extracted with ethyl acetate. After drying the extract over magnesium sulfate, it was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography.
(-)-N-(hexadecyloxycarbonyl)-3-
1.9g of morpholinyl-methanol (yield 81χ)
Obtained as a colorless oil.

IR:(νneat)c++-' 3450.1700
．． 'H-NMR: δ(CDCf,)0.88(3H
, t), 1.26 (28B, br), 2.90-4.
40 (12H, w).

S-(-)-N-(hexadecyloxycarbonyl)-
3-morpholinyl-methanol (1.8g, 4.7ta
Tao I! ) and triethylamine (0.7g,
7.0+wmol) was dissolved in dichloromethane. After stirring under water cooling, 4-toluenesulfonyl chloride (1
, 1 g, 5.6 mmof) was dissolved in 101 d of dichloromethane and added dropwise. After stirring at room temperature overnight, the mixture was washed with water and saturated brine. The dichloromethane layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate to obtain 5(-
)-N-(hexadecyloxycarbonyl)-3-morpholinyl-methyl-p-)luene sulfate was obtained as a white powder in an amount of 400 μm (yield: 16×).

IRE(νKBr) 3-' 1705. 'H-NM
R: δ (CDCj!s) 0.88 (3H, t), 1
．． 26 (28H,br), 2.40 (3H,s
), 2.80-4.40 (IIH, s), 7.20
(2H, d), 7.68 (2H, d).

Sodium hydride (64 cm, 1.6 questions) was washed with hexane and suspended in N,N dimethylformamide l〇-.While stirring under water cooling, 2-mercaptoethanol (9011 g, 1.2 n + mo) was added to the solution. ) was added dropwise and stirred for 30 minutes. Under water cooling, S-(-)-N-
(Hexadecyloxycarbonyl)-3-morpholinyl-methyl-P-toluenesulfate (400 ml.

0.8 tamo Il) was dissolved in N,N' dimethylformamide 10- and added dropwise. After stirring for 2 hours, the mixture was allowed to cool, then ice water was added and extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluting with hexane-ethyl acetate.
S-(-)-(N-(hexadecyloxycarbonyl)
-3-morpholinyl-methyl)thioethyl alcohol was obtained as an oily substance in an amount of 300 ml (yield: 84 z).

IR: (νneat)cm-' 3395.1695.
'H-NMR: δ(CDCj!z)0.88(3B
, t) , 1.26 (288,br) , 2.3
0=4.40 (16H, s).

S-(-)-(N-(hexadecyloxycarbonyl)
-3-morpholinyl-methylcothioethyl alcohol (
300M, 0.7s+mof) and triethylamine (
130■, 1.3nuwo I! ) was dissolved in dichloromethane. Methanesulfonyl chloride (110 cm, 1.0 mmol) was added dropwise while stirring under water cooling. After stirring overnight at room temperature, dichloromethane was distilled off and the residue was chromatographed on silica gel eluting with hexane-ethyl acetate to give S-(-)-N-(hexadecyloxycarbonyl)-3-morpholinyl-methyl- Chloroethyl sulfide in oil form! #J quality 150 ml (yield 48 z) was obtained.

IR: (νneat)cm-' 1698. 'H-N
MR: δ(CDCffi ff)0.88(30,t)
, 1.26 (28H, br), 2.70-4.20 (1
58, m).

S-(-)-N-(hexadecyloxycarbonyl)-
3-morpholinyl-methyl-chloroethyl sulfide (
15011 g, 0.3 mmoj of thiazole (1,
0g + 12smo 1 ) and heated at 100° in a sealed tube.
C - Reacted overnight. After distilling off the thiazole, the residue was subjected to silica gel chromatography and eluted with chloroform-methanol-water to give S-(-)-N-(N'-(hexadecyloxycarbonyl)-3-morpholinyl-methylthio 20 ml of ethylphthiazolium chloride was obtained as a pale yellow powder (yield 12x).

Example 11 The reaction was carried out in the same manner as in Example 10, and the target substance R-(+
)-N-(N'-(hexadecyloxycarbonyl)-
3-morpholinyl-methylthioethyl phthiazolium chloride was obtained.

The structural formulas and physical properties of the compounds obtained in Examples 6 to 11 are shown in Table 2.

/ Example 12 4-Methylpiperazine-2-methanol (130μ.

Dissolve 1.0 mmoj2) in dichloromethane and cool with water to dissolve n-hexadecyl chloroformate (300 mm, 1.0
mmojl! ) was added dropwise. The mixture was stirred for 2 hours under water cooling and further stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography to obtain 250 μl (yield: 63×) of hexadecyl 2(hydroxymethyl)-4-methylpiperazine-1-carboxylate as a colorless oil.

R: (J/neat)cyr-' 3230.17
00. 'H-NMR: δ(cociL:+)
0.88 (3H, t), 1.26 (28H, br), 2
．． 9 (1-4.40 (128, m).

Hexadecyl 2-(hydroxymethyl)-4methylbiperazine-1-carboxylate (400■, 1.0
mmol) and triethylamine (0,2 [, 2,0 ml
1+ol) was dissolved in dichloromethane. 4-Toluenesulfonyl chloride (23011 g,
1.2 mmol) was dissolved in 10-dichloromethane and added dropwise. After stirring at room temperature overnight, the mixture was washed with water and saturated brine.

After drying the dichloromethane layer with magnesium sulfate, (3H
,t), 1.26(28H,br), 2.20
(3H,s), 2.47-4.23(158,m
).

Hexadecyl 2-(((2-chloroethyl)1,000]methyl]-4-methylpiperazine-1-carboxylate (220111 g, 0.48 mmo j2) was dissolved in thiazole (400 g, 4.8 questions o1) and sealed in a tube. The mixture was reacted overnight at 100°C. After distilling off the thiazole,
The residue was subjected to silica gel chromatography, eluted with chloroform methanol and water, and N-(N'-(hexadecyloxycarbonyl)-N-methylpiperazine-2-methylthioethyl phthiazolium chloride was obtained as a pale yellow powder for 40 μm). (Yield 15χ) was obtained.

Example 13 N-(hexadecyloxycarbonyl)-N-methylpiperazine-2-methanol (1,2 g) described in Example 12
, 3.0simol) and 2-bromoethylphosphoric dichloride (860cm, 3.6wa+ojl!) were dissolved in benzene, and while stirring under water cooling, pyridine (290cm) was dissolved.
3.6+uio iL) was added dropwise, and the mixture was further stirred for 12 hours. After adding 20 d of water, the mixture was refluxed for 1 hour. After cooling, it was extracted with ether. The extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain an oily residue. Add this to thiazole (2.6g, 30a+mof)
and stirred overnight at 90°C in a sealed tube. After concentrating the reaction mixture under reduced pressure, the residue contained silver carbonate (1.2 g, 4.5++
30 d of methanol were added, and the mixture was stirred at room temperature overnight. After filtering off insoluble materials, the insoluble substances were concentrated under reduced pressure, and subjected to silica gel chromatography, eluting with chloroform-methanol-water to remove N-(hexadecyloxycarbonyl)-N-methylpiperazine-2-methyl(thiazolium)ethyl phosphate. 170 μm (yield: 102) was obtained as a yellow powder. (See Table, 11) Example 12
．． The structural formula and physical properties of the compound obtained in 13 are shown in Table 3.

Example 14 L-(-)-cysteine ethyl ester hydrochloride (123) (1.0 g, 5.4 mmof)
and diitopropylethylamine (3.5g, 27sm
oI! ) was dissolved in dichloromethane. Bromoacetylpropyrode (1.6g, 8.1o) was stirred under water cooling.
nof) was added dropwise. After stirring overnight at room temperature, the mixture was washed with water and saturated brine. The dichloromethane layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluted with chloroform-methanol to give ethyl-(S)-(-)-5-oxothiomorpholine-
7190 mg of 3-carboxylate as an oily substance (
A yield of 19X) was obtained.

MS (s+/e): 189 (M”), IR: (νnea
t) as-'1738,1660°'H-NMR:
δ(CDCj! ri 1.30(31,t, J-9,4
0Hz), 2.92=3,50 (411,m),
4.26 (2H, q, J-7, 42Hz), 4
．． 79 (1B, s).

6.74 (18,br).

Ethyl-(S)-(-)-5-oxothiomorpholine-3-carboxylate (1,9 g, 10snoj!
) was dissolved in tetrahydrofuran. Under ice cooling, Red
- A 1 (1,5d, 5 questions) was dropped. After stirring overnight at room temperature, potassium 402 hydroxide solution was added until no more bubbles appeared. After saturated with potassium carbonate, the mixture was extracted with ethyl acetate. Depressurize the extract I! Shrink, (S)-(-)-
Thiomorpholine-3-methanol as oil 95
0■ (yield 71z) was obtained.

MS (m/e): 133 (M”), IR: (νneat
) am-' 3400° (S)-(-)-thiomorpholine-3-methanol to methanol IJII! 2N including
Dissolve n-Hexadecylchlororofo in 3 m (6 g moj!) of sodium hydroxide solution and cool with water.
rmate (70011g, 2.3mmol)
was dripped. The mixture was stirred for 2 hours under water cooling and then overnight at room temperature. After adjusting the pH to 3 with IN hydrochloric acid, the mixture was extracted with ethyl acetate. After drying the extract over magnesium sulfate, it was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography to obtain hexadecyl (S)-(-)-3-(hydroxymethyl).
Thiomorpholine-4-carboxylate was obtained as a colorless oil in the form of 120 μm (yield 13z).

IR:(y neat)cig-' 3425.168
0. 'H-NMR: δ (CDCj! 3) 0.88
(3H, t), 1.26 (28H, br),
2.16-3.50 (6H, @), 3.80-4
．． 77 (6H, a+).

(S)-(-)-3-(hydroxymethyl)thiomorpholine-4-carboxylate (2.3g, 5.1mm
o l ) and triethylamine (1.2 g, 11a+
The a+oil mixture was dissolved in dichloromethane. After stirring under water cooling, 4-toluenesulfonyl chloride (1.6 g, 8.5
mmoit) was dissolved in dichloromethane 10- and added dropwise. After stirring at room temperature overnight, the mixture was washed with water and saturated brine. After drying the dichloromethane layer with magnesium sulfate,
It was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluted with hexane-ethyl acetate, and hexadecyl (S
)-(-)-3-(chloromethyl)thiomorpholine 4-
360 mg of carboxylate as oil (yield: 1
5z) Obtained.

IR: (νneat)cm-' 1702. 'H-N
MR: δ (CDCf:l) 0.88 (38, t)
, 1.26 (28H, br) , 2.20J, 6
5 (6H, m), 3.65-4.80 (5H, m
).

Sodium hydride (40■, 1.0 +uaoj!)
After washing with hexane, it was suspended in 10-N,N dimethylformamide. 2-Mercaptoethanol (60 ml, 0.8 n+mof) was added dropwise while stirring under water cooling, and the mixture was stirred for 30 minutes. Under water cooling, hexadecyl (S)
(-)-1-(chloromethyl)thiomorpholine 4-carboxyle) (200 mg, 0.5 mmo I!
) was dissolved in 10-N,N dimethylformamide and added dropwise.

After stirring for 2 hours, the mixture was allowed to cool, then ice water was added and extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography.
With ethyl acetate? Discharge, hexadecyl (S)-(-)-
3-C((2-hydroxyethyl)thio]memel]thiomorpholine-4-carboxylate as an oily substance at 1
50μ (yield: 65χ) was obtained.

IR: (νneat)cm-' 3430, 1700.
'H-NMR: δ(CDCl:+)0.88(
3H, t), 1.26 (28H, br), 2.
23-4.67 (16H, m).

Hexadecyl (S)-(-)-3-((2-hydroxyethyl)thio]memel)thiomorpholine 4-carboxylate (150 µ, 0.3111 mol) and triethylamine (60 µ, 0.6 mmo 42) Dissolved in dichloromethane.Methanesulfonyl chloride (70μ, 0.6mmof) was added while stirring under water cooling.
dripped.

After stirring at room temperature overnight, dichloromethane was distilled off, and the residue was chromatographed on silica gel with hexane-ethyl acetate to give hexadecyl (S)-(-)3-(((
2-chloroethyl)thio]methyl]thiomorpholine-4
- Carboxylate as oily substance 110 μ (yield 7
1χ) obtained.

R: (v neat)cub-' 1700. 'H-
NMR: δ (CDC13) 0.88 (3H, t), 1.
26 (28H, br), 2.47-4.61 (15H,
m).

Hexadecyl (S)-(-)-3-C((2-chloroethyl)thio]methyl]thiomorpholine-4carboxylate (11011 g, 0.23 m+aol) was dissolved in thiazole (1.0 g, 12n+a+o l) and sealed in a tube. After distilling off the thiazole, the residue was subjected to silica gel chromatography, eluted with chloroform-methanol-water, and (S)-
(-) -N [N”-(hexadecyloxycarbonyl)-3-thiomorpholine methylthioethyl] thiazolium chloride as pale yellow powder, 15 g (yield 12X)
Obtained.

The structure and physical properties of the compound obtained in Example 14 are shown in Table 4.

Example 15 Lithium aluminum hydride (1.7 g, 46++ u
wof) was suspended in tetrahydrofuran. ■ After refluxing for 5 minutes, indole-2-carboxylic acid (5 g, 31
+mol) was added. After refluxing for 1 hour, potassium hydroxide solution (16 mmol) was added. After filtering out insoluble materials, the mixture was concentrated under reduced pressure to obtain 74.8 g (yield: 1002) of 2-indoline methanol as an oily substance.

2-Indoline methanol (1.5g, 10 questions)
was reacted in the same manner as in Example 1, and the target substance NCN'
-(Hexadecyloxycarbonyl)-2-indolinyl-methylthioethyl]thiazolium chloride was obtained as a pale yellow powder in the form of 50 μl (yield: 132).

The structural formula and physical property values of the compound obtained in Example 15 are shown in Table 5.

Example 16 Commercially available 2-acinoethanol (1.2 g, 2O
n+mo Il was reacted in the same manner as in Example 1 to obtain the target substance N(N'-(hesdecyloxycarbonyl)-
380 mg (yield: 53z) of amino-2-ethylthioethyl]thiazolium chloride was obtained as a pale yellow powder.

The structural formula and physical property values of the compound obtained in Example 16 are shown in Table 6.

) Example 17 N-(N'-(hexadecyloxycarbonyl)2-morpholinyl-methylthioethyl]thiazolium chloride 5g, cellulose calcium gluconate (disintegrant) 20
0 ■, magnesium stearate (lubricant) 100 ■ and crystalline cellulose 9.7 g were mixed and compressed into tablets using a conventional method.
Tablets were obtained containing 50 μ of active ingredient in the tablet.

The pyrrolidine derivative represented by general formula (I) and its acid addition salt of the present invention have an antagonistic effect on PAF and
It has anti-hypertensive effects, phospholipase inhibitory effects, and anti-proliferative effects on tumor cells, so it is used as a platelet aggregation inhibitor, anti-asthmatic agent, anti-allergic agent, anti-inflammatory agent, anti-hypertensive agent, anti-endotoxic shock agent, and anti-nephritis agent. drugs, anti-pancreatitis drugs,
It is useful as an anti-ischemic cerebrovascular disorder agent and an anti-tumor agent.

These effects have been confirmed through laboratory experiments.
For example, the antagonistic effect on PAF was confirmed by the screening system described below.

AFtfE Blood collected from male rabbits and 3.13χ sodium citrate aqueous solution were mixed at a ratio of 9:1 (v/v), and platelet-rich plasma obtained by centrifugation (120G) for 10 minutes at room temperature was used. , P A F 4 Xl0-”
Platelet aggregation by M was measured by absorbance method using a Born aggregometer (J, Physiol
,, Volume 162, Page 67 (1962)].

The results are shown in the table below, where the concentration of the compound of the present invention that suppresses or inhibits 50% of the effect ■CS. It was shown in

As shown by the above results, the compound represented by formula (I) of the present invention was found to be a substance that exhibits a PAF-induced platelet aggregation action and has an antagonistic action against PAF.

/ Table 7 Antagonism of novel heterocyclic derivatives against PAFPAF in rabbit blood.

PAF-like blood pressure lowering effect.

It has an induced platelet aggregation effect, a phospholipase inhibitory effect, and an antiproliferative or differentiation-inducing effect on tumor cells, and is useful as a pharmaceutical.

Claims (1)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, ~8 straight-chain or branched alkyl group) represents an oxygen atom or a sulfur atom. A represents a carbonyl group or a methylene group, and B represents a single bond, an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphoric acid group. C represents a single bond or an alkylene group having 1 to 6 carbon atoms, D represents an amino group or the formula -NHCOR^1,
-NHR^2, -N(R^2)_2 or -^■N(R
^2)_3Y^■ (In the formula, R^1 represents an alkyl group having 1 to 6 carbon atoms or a phenyl group, and R^2 represents an alkyl group having 1 to 6 carbon atoms.
represents an alkyl group, and Y^■ represents an acid anion. However, when multiple R^2's are bonded, they may be the same or different. ) or a heterocyclic group ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼. R represents an alkyl group having 2 to 22 carbon atoms. Further, the bond between the ring part and A is a single bond, and an optically active substance in which A is coordinated at the α-position or β-position, or a racemic body which is a mixture of both coordinations is shown. ] A heterocyclic derivative or an acid addition salt thereof. (2) A platelet aggregation inhibitor comprising the heterocyclic derivative according to claim 1 or an acid addition salt thereof as an active ingredient. (3) An anti-asthmatic agent containing the heterocyclic derivative according to claim 1 or its acid addition salt as an active ingredient. (4) An antiallergic agent containing the heterocyclic derivative according to claim 1 or its acid addition salt as an active ingredient. (5) An anti-inflammatory agent containing the heterocyclic derivative according to claim 1 or its acid addition salt as an active ingredient. (6) An antihypertensive agent containing the heterocyclic derivative according to claim 1 or an acid addition salt thereof as an active ingredient. (7) An anti-endotoxin shock agent comprising the heterocyclic derivative according to claim 1 or its acid addition salt as an active ingredient. (8) An anti-nephritis agent containing the heterocyclic derivative according to claim 1 or its acid addition salt as an active ingredient. (9) An anti-pancreatitis agent comprising the heterocyclic derivative according to claim 1 or its acid addition salt as an active ingredient. (10) An anti-ischemic cerebrovascular disorder agent comprising the heterocyclic derivative according to claim 1 or its acid addition salt as an active ingredient. (11) An antitumor agent comprising the heterocyclic derivative according to claim 1 or an acid addition salt thereof as an active ingredient.