JPS63190859A - Glycerin derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is higher alkyl; R is tert. amino or quaternary ammonium; n is 2-10). EXAMPLE:4-[2-(Acetoacetyloxy)-3-(octadecyloxy)propyloxy]butyltrimethyl ammo nium bromide. USE:An antitumor agent, phospholipase A2-inhibiting agent and platelet-activating factor antagonist. PREPARATION:A benzyl group in 2-position of a compound expressed by formula II is reductively removed in the presence of a hydrogenation catalyst (e.g. palladium carbon) in a solvent such as methanol, etc., to provide a compound expressed by formula III, which is reacted with diketene in a solvent such as benzene, etc., in the presence of tert. amine (e.g. triethylamine) at -20-150 deg.C to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to glycerin derivatives. For more details,
The present invention provides a formula useful as an antitumor agent, a phospholipase A inhibitor, and a platelet activating factor antagonist. or represents a quaternary ammonium group, and n represents an integer of 2 to 10] or a salt thereof.

BACKGROUND OF THE INVENTION In recent years, it has been disclosed in the scientific and patent literature that among amphipathic glycerolipids, substances with certain structural factors have antitumor activity. For example, JP-A-55-28955
The publication describes a compound represented by the general formula (ff).

CIl, 0COR'CllOR'' (II) These acyl-substituted glycerin derivatives at the 1-position are easily deactivated by enzymatic hydrolysis in vivo, so
It is inferior to 1-position alkylglycerol derivatives in terms of activity strength and persistence. In fact, lysolecithin does not activate macrophages even at a concentration approximately 1000 times that of platelet activating factor (PAF, III), and also reduces antibody production ability (
PFC), 1nvitro and inv
The ivo antitumor activity of the corresponding alkyl ether compound (
It is known that it is significantly inferior to LysoPAF).

In recent years, general formula (III) CHzOCIeH3t (or -C111H33)
PAF, a natural phospholipid indicated by 〇-, was discovered and is attracting attention as an important mediator in living organisms such as inflammation and blood pressure regulation. [C, A, Demopoulos, R,
N.

Dinckard, and D. J. l.
1anahan, J., Biol, Chem.
,.

254, 9355 (1979); Ben J.
uveniste.

M, Tence, D, Varenne,
J., Bidault, C.

Boullet, and J. Dolons.
ky, C, R, Acad, 5ciSer,
D289. 1 037 (1979)
Ko.

Phospholipid compounds having a structure closely related to PAF have actions similar to PAF, such as platelet activation, neutrophil activation, tissue damage, and vascular permeability hyperactivity.

It is known to have a surface pressure lowering effect etc. [J.

T, O'FIaherty et al, R
es, Commun, Chem.

Pathal, and Pharmacol,
39. 291 (1983): P, 1ldv
ary, Thrombosis Res.

30, 143 (1983)]. Additionally, the alkyl lysophospholipid represented by the general formula (IV) below is P
It is known that it has an antitumor effect, unlike I-octadan-2-arachitonoylglycerophosphocholine, which is known as a precursor of AF' and PAF' [1
E, Berdel, 'N, R, E, Baus
ert.

U., Fink, K., Rostetter a.
nd P, G, Munder.

Anticancer Research, l
, 345 (1981); JP-A-52-134027
No. Publication Ko.

C1120C, 8) 13゜□ 0゜However, since this compound has a structure closely related to PAF,
Serotonin release, bronchial stenosis, platelet aggregation.

It is also known to have PAF-like effects, such as antihypertensive effects [see the literature of O'F 1aherty et al., supra.

J. Hanahan et al., Bioc.
hem, Biophys, Res,.

Commun,, 99. 183 (1981)].

In addition to lowering blood pressure, these effects may cause side effects such as cerebral thrombosis, circulatory disorders such as angina, and asthma. Therefore, the use of this compound as a medicine is restricted.

Recently, the general formula (V) [wherein, R1 - an alkyl group having 8 to 22 carbon atoms, R2 - an acyl group having 2 to 5 carbon atoms, X = O(CH2)n-
R'.

It was disclosed that a compound represented by n=1 to 12] has an antagonistic effect on platelet activating factor [JP-A-58-19
No. 8445]. The scope of the claims in the patent publication is that the acyl group at the 2-position is "an acyl group having 2 to 5 carbon atoms, and specific examples of the acyl group include acetyl, propionyl, butyryl, valeryl groups, and isomers thereof. , and preferably an acetyl group. Further, as a specific example of the 2-position acyl derivative, only the acetyl derivative is described.

The problem that the invention aims to solve In recent years, the abnormal proliferative nature of cancer has been linked to structural changes in the cancer cell membrane.

It is becoming clear that it is based on a functional abnormality.

On the other hand, recent research on biological membranes has gradually revealed that amphiphilic lipids have simulative properties and can exert diverse effects on cell metabolism and functions through membranes. The present inventors found that among amphipathic lipids with certain structural factors, there are lipids that act on cancer cell membranes and are involved in regulating the activity of cancer cell membrane functional proteins (e.g., inhibiting the biosynthesis of membrane phospholipids). I estimated that.

It is generally known that tumor cells have lower alkyl ether group cleaving activity than normal cells [R.

L, Wykle and F, 5nyder
, “The Enzymes or Biolog
ical Membranes,” Mo1. 2
．． edited by A. Martonosi
Pleum Press New York.

1976, 87; H, J, Lin, P, C, S
, Ho, and C, tl, Lee, Can
cer Res, 3 Shadows, 946 (1978);
M, Modell, R, Andre
esen, stomach.

Pahlke, [1, Brugger, and
P., G., Munder.

Cancer Res, 39. 4681 (19
79)].

That is, alkyl ether compounds accumulate in large amounts in tumor tissues, whereas they are more rapidly degraded and inactivated in normal cells. Therefore, it was expected that alkyl ether compounds would act more selectively on cancer cells than on normal cells and inhibit their proliferation. Furthermore, it is known that phospholipids are generally easily hydrolyzed by phospholipases C and D in vivo, but the lipid represented by the general formula (1) of the present invention is not stable against these enzymes. Therefore, in combination with the above reasons, it was also expected that the effect would be sustained and enhanced within cancer cells. From the above points of view, as a result of extensive research, we have found that glycerin derivatives represented by the general formula
The present invention was completed based on the discovery that the present invention can be expected to be used for diseases related to the following.

Means for Solving the Problems The present invention provides the following formula: The present invention provides a compound represented by C representing an integer from 2 to 10 or a salt thereof.

In the above general formula (1), the higher alkyl group represented by R1 includes n-octyl, n-nonyl, n-desol, n-undecyl, n-dodecyl, n-tetradecyl,
Linear and 18.18-dimethylnonadecyl such as n-hexadecyl, n-octadenol, n-eicosyl,
+ 9.19-dimethyleicosyl.

Branched carbon number 8-22 such as I9-methyleicosyl
Examples include alkyl groups. The higher alkyl group is 1 to 7
cycloalkyl, allyl, halogen, cyano,
It may have a substituent such as ethynyl. Examples of the cycloalkyl group include 3- to 8-membered cycloalkyl groups such as cyclopentyl and cyclohexyl. Examples of the allyl group include a phenyl group, and the phenyl group may be substituted with lower (CI-4) alkyl, lower (CI-4) alkoxy, hydroxy, nitro, halogen, or the like.

The halogen as a substituent for the higher alkyl group and the halogen as a substituent for the phenyl group include fluorine,
Examples include bromine and chlorine. When R1 is a substituted higher alkyl group, the substitution position may be at any substitutable position of the higher alkyl group, or preferably at the ω (omega) position. Examples of the substituted higher alkyl group include 12-cyclohexyldodecyl, 12-phenyldodecyl, octadecane-17-ynyl, 18-cyanooctadecyl, I8-chlorooctadenyl, 18.18-dichlorooctadecyl, I8.18. 18- To! J Fluorooctadecyl, + 7.17.18, 18.18-
Pentachlorooftadenol, I 6.16.17.17
゜+ 8.18.18-Heptachlorooctadecyl and other groups are mentioned.

The tertiary amino group represented by R' is represented by the formula: [wherein R3 and R4 each represent a lower alkyl group, or R3 and R4 together with the adjacent nitrogen atom form a cyclic amino group] There are groups that can be used.

Examples of the lower alkyl group represented by R3 or R4 include alkyl groups having 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl 1-pentyl, and preferably a methyl group.

Cyclic amino groups include pyrrolitsuno and piperidino.

Examples include 5- or 6-membered cyclic amino groups such as piperazino and morpholino, and these groups further include lower alkyl groups having 1 to 4 carbon atoms (eg, methyl, ethyl.

It may have a substituent such as propyl, butyl), hydroquine group, hydroxyethyl group, aminoethyl group, carbamoyl group, or ureido group.

Examples of the quaternary ammonium group represented by R1 include a group represented by the formula [wherein R3, R' and R5 each represent a lower alkyl group or a cyclic ammonium group].

The lower alkyl group represented by R3, R4 or R5 includes an alkyl group having 1 to 5 carbon atoms (eg, methyl, ethyl, propyl, butyl, pentyl), preferably a methyl group.

Cyclic ammonium groups include pyridinio, oxazolio, diazolio, pyridacinio, and quinolinio.

Isoquinolinio, l-[lower (C,-4)alkyl]pyrrolidinio, 1-[lower (C,-,)alkyl]piperinonio, N-[lower (CI-4)alkyl]morporinio, l-[lower (C, , ) alkylcopiperazinio, and these groups further include lower alkyl groups having 1 to 4 carbon atoms (e.g., methyl, ethyl, propyl, butyl), hydroxy groups, hydroxyethyl groups, aminoethyl groups, It may have a substituent such as a carbamoyl group or a ureido group.

When R2 is a tertiary amino group, compound (1) is a pharmacologically acceptable inorganic acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid) or organic acid (e.g., acetic acid, It may also form salts with lactic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid).

When R3 is a quaternary ammonium group, compound (1)
is a pharmacologically acceptable anion of an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid) or an organic acid (e.g., acetic acid, lactic acid, tartaric acid, citric acid, methanesulfonic acid,
It forms a salt with an anion (X゛) such as an anion of ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid). Preferred anions include halogen ions (eg, chloride ions, bromide ions, iodine ions), methanesulfonic acid anions, and p-toluenesulfonic acid anions.

In the compound represented by formula (I), 2 of glycerin
Since the position carbon is an asymmetric center, there are two types of stereoisomers, R-configuration and S-configuration, but each of them, their racemates, and mixtures thereof are not included in the present invention. It is something that

The compound of the present invention represented by general formula (I) can be produced, for example, by the method shown below.

CHtOR'ClI20R'CIl
OCIl, C@l(,-)CI(OH-shi (1)I Cl1,0(CH,), R' CIl,0
(C11,)nR'(■) (■) [In the formula, the symbols have the same meanings as above] Compound (■) can be obtained by reductively removing the benzyl group at the 2-position of compound (Vl). The reaction is carried out in a hydrogen atmosphere, in the presence of a suitable hydrogenation catalyst (e.g. palladium on carbon, platinum dioxide), in a suitable solvent (e.g. methanol, ethanol, ethyl acetate, acetic acid, water or a mixture of two or more thereof). ) at room temperature to the reflux temperature of the solvent.

Good results may also be obtained if the reaction is carried out under pressure.

Compound (1) is prepared by combining compound (■) and diketene in a suitable anhydrous solvent (e.g., benzene, toluene, dichloromethane, chloroporum, pyridine, etc., or a mixture thereof).
Tertiary amines (e.g. triethylamine).

pyridine, etc.) at -20 to +150°C, preferably -10 to +80°C. Compound (I) also obtained.

(Vl) and (■) are tertiary amino compound (Ia), (
In the case of Via) and (■a), quaternary ammonium compounds (Ib) and (
It is also possible to convert to VTb) and (■b).

(I a, VIa, ■a) (
Ib, VTb, (b) [In the formula, Z represents acetoacetyl, benzyl, or hydrogen, and other symbols have the same meanings as above. Compound (1) obtained in each step above can be separated and purified, for example, by solvent distillation. This can be carried out using known means such as separation, solvent extraction, recrystallization, and gel column chromatography.

Note that compound (V[), which is a raw material for synthesis, can be produced by the reaction shown below.

C1+2OR'CH,OR'CII
OC112C, +45-〉C) IOC112C, H5-
〉 ] ) CIl, Oll C)1. OR(■
)(■) CH,OR'CIl,OR'C11
0C11,C,116-〉Cll0CII2C,I+5
+ (Vl)I CI, 0(CIl,)nOHCH, 0(CH,)nOR
(X) (墾) °X° [Wherein, R is benzenesulfonyl, lower (C, -
5) Alkylbenzenesulfonyl or lower (Ct-S
) represents alkanesulfonyl, other symbols have the same meanings as above] Compound (IX) is compound (■) [1Ielv, C
Him, Acta.

65, + 059 (1982) or a method similar thereto] and a sulfonic acid halide in a suitable anhydrous solvent (e.g., benzene, toluene, dichloromethane,
chloroform, pyridine, etc. or mixtures thereof) in a suitable deoxidizing agent (e.g. triethylamine).

-20 to tertiary amines such as pyridine)
It can be obtained by reacting at +100°C, preferably -10 to +50°C. Examples of the sulfonic acid halide used in the reaction include benzenesulfonyl halide (e.g., benzenesulfonyl chloride), lower (C, -,
) alkylbenzenesulfonyl halide (e.g., p-)luenesulfonyl chloride), lower (C,-5) alkanesulfonyl halide (e.g., methanesulfonyl chloride,
ethanesulfonyl chloride).

Compound (X) can be obtained by reacting compound (IX) with a diol represented by the formula %. The reaction is carried out in a suitable solvent (e.g. benzene, toluene, hexane, dioxane, tetrahydrofuran, etc.)
Medium to strong bases (e.g., sodium hydroxide).

under aqueous conditions, preferably in the presence of a phase transfer catalyst (e.g., cetyl trimedelammonium chloride, benzyltrimethylammonium chloride, etc.).
It is carried out at 0°C, preferably +20 to +100°C.

Compound (X [) is the compound (X
)-It can be obtained in the same manner as the reaction of compound (IX).

Compound (Vl) can be obtained by reacting compound (XI) with an amine represented by the formula [wherein each symbol has the same meaning as above].

The reaction is carried out in an excess of amine or with a suitable catalyst (e.g. water,
Methanol, ethanol, benzene, toluene.

(tetrahydrofuran, dimethylformamide, etc. or mixtures thereof) at -20=+150°C, preferably from 0 to +80°C. Furthermore, if necessary, the reaction can be carried out in a sealed tube at room temperature or under heating.

Furthermore, starting compound (VI) can also be produced by the reaction shown below.

CH20R'(■)->CHOCIl,C,116->(Vl)CH
zO(CIIt)nY (Kari) [In the formula, the symbols have the same meanings as above, and Y is halogen (e.g.
chlorine, bromine, iodine)] Compound (XI[) is obtained by reacting compound (■) with a dihaloalkane represented by the formula Can be done. The reaction can be carried out in the same manner as the reaction of compound (IX)→compound (X), and compound (VI) can be reacted with compound (■
) in the same manner as the reaction of compound ('X1)-compound (Vl).

Moreover, the synthetic intermediate (■) can also be produced by the reaction shown below.

Cl1yOR'Cl1tOR'j (XIIT) (XIV) CIl, OR' Cl10I+ -111 → (■) CIl, 0(CHrin0R (XV) [In the formula, the symbols have the same meanings as above] Compound (XIV) , compound (XIII) [JP-A-56
1 synthesized by the method described in Publication No. 108781 or a method following it, and used in the next step without isolation or with the formula %) [wherein the symbols have the same meanings as above] It can be obtained by reacting with the diol shown. The reaction is carried out in a suitable solvent (e.g. hexane, benzene, toluene, tetrahydrofuran, dioxane, etc. or mixtures thereof).
-2 in the presence of a strong base (e.g., sodium hydride)
It is carried out at 0 to +150°C, preferably at room temperature to the reflux temperature of the solvent.

Compound (XV) is obtained by converting compound (1') to the above compound (
(2) → Compound (IX) can be obtained in the same manner as the reaction, and compound (1) can be obtained from compound (XV) in the same manner as the above-mentioned reaction of compound (XI) and compound (Vl).

When carrying out the above reaction, intermediates produced during the process can be used in the next step without necessarily being isolated.

Furthermore, the synthetic intermediate (X) can also be produced by the reaction shown below.

C1l, ORI (X Vl) CIl, OR'Cll0C112C1lH5->(X)Ct(=O(C
Ht)n 0Tr (X■) [In the formula, Tr represents a trityl group, and the other symbols have the same meanings as above] Compound (XVI) can be obtained by reacting compound (XIV) with trityl chloride. You can do it.

The reaction is carried out in an appropriate solvent (e.g. benzene, toluene, dichloromethane, chloroform, pyridine, etc.) in the presence of an appropriate deoxidizing agent (e.g. triethylamine, tertiary amines such as pyridine) at a temperature of -20 to +150. C1 Preferably carried out at 0 to +80°C.

Compound (X■) can be obtained from compound (XVI) and pendylchloride in the same manner as the reaction of compound (XfV)-compound (XVI).

Compound (X) can be prepared by adding an acid (e.g., hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, etc.) to compound (X) in a suitable aqueous solvent (e.g., methanol, ethanol, dioxane, etc., or a mixture thereof) for 10 minutes. Heat under reflux from °C.
Alternatively, it can be obtained by reacting hydrogen chloride in chloroform at around -1O to +lθ°C. Further, compound (X) can be obtained by heating compound (X) in aqueous acetic acid from +30°C to the solvent reflux temperature.

The compounds obtained in each of the above steps can be separated and purified by column chromatography, if necessary.

Examples of the elution solvent include hexane-ethyl acetate mixture, nochloromethane-ethyl acetate mixture, and the like.

When R2 is a tertiary amino group, the salt of the compound represented by general formula (1) may be obtained by the above production method itself, but if necessary, it may be produced by adding an inorganic or organic acid. Can be done.

When R2 is a quaternary ammonium group, it is also possible to exchange the anion (X-) with another anion using an anion exchange resin or the like, if necessary.

Although typical methods for producing the compound represented by the general formula (1) have been described above, the method for producing the compound is not limited to these methods.

Edan compound (1) shows a remarkable decrease in side effects (eg, platelet aggregation, blood pressure lowering, vascular permeability enhancement, tissue damage, etc.).

Compound (1) has enhanced and sustained main action (eg, antitumor action), and can be administered as a safe antitumor agent to tumor-bearing warm-blooded animals. Method of administration.

The administration route and dosage can be selected as appropriate depending on the subject and symptoms, but the dosage for mammals is usually
) as O, l~I 50 mg/kg (body weight) immediately,
Preferably it is about 2 to 50 mg/kg body weight.

As for the frequency of administration, the drug can be applied about 1 to 3 times a day, or at intervals of 2 to 7 days. It is also possible to administer the drug intravenously over a long period of time in order to maintain the drug concentration in tissues at the required level for a long period of time. If the drug is administered via the parenteral route in combination with serum albumin or various glupurins, the efficacy of the drug will not be affected, and safety can be expected to be further improved by preventing tissue (local) damage.

Compound (1) exhibits a PAF inhibitory effect and inhibits PAF.
It can be administered as a prophylactic or therapeutic agent for circulatory disorders caused by (eg, thrombosis, angina, cerebral infarction, endotoxic shock, anaphylactic shock) or allergy-related diseases (eg, bronchial asthma). As for the administration conditions, the dosage is preferably 0.2 to 20 mg/kg, but the other conditions are as described above.

Furthermore, compound (1) also has phospholipase A inhibitory activity. Since phospholipase A is involved in the release of arachidonic acid from phospholipids, the compound inhibits phospholipase At to inhibit arachidonic acid cascade products (eg, thrompoxane A2 and other prostaglandens).

Preventive or therapeutic agents for various diseases caused by leukotrienes and riboxins (antiplatelet aggregating agents, antiasthmatic agents,
It can also be administered as an anti-allergic, anti-inflammatory, or anti-immunosuppressive agent. The administration conditions and other conditions are the same as those for the prevention and treatment of cardiovascular disorders and allergy-related diseases described above.

Compound (4) and its salts have excellent hydrophilic and lipophilic properties and are low in toxicity, so they can be administered orally to mammals as a powder or as a pharmaceutical composition in an appropriate dosage form. It can be safely administered parenterally.

The pharmaceutical composition used for administration comprises an effective amount of compound (I)
or a salt thereof and a pharmacologically acceptable carrier or excipient.

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 indoralipid, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, and in the case of aqueous injections, adjuvants such as glucose, serum albumin, serum globulin, etc. may exist. These are sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of disinfectants, or by irradiation with ultraviolet light. They can also be prepared as sterile solid compositions and dissolved in sterile water or sterile injectable solvents before use.

Tablets, capsules, etc. can also be prepared according to conventional methods.

In these solid compositions, compound (1) or a salt thereof is at least one inert carrier.

It is mixed with excipients such as lactose, mannitol, glucose, hydroxopropylcellulose, microcrystalline cellulose, starch, etc. The composition may contain, in a conventional manner, additives other than inert carriers and excipients, such as lubricants such as magnesium stearate and disintegrants such as cellulose carunium gluconate.

EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.

Example 1 1-octadecyloxy-3-(2-)lythyloquinethyloxy)propan-2-olstearyl alcohol 27.1 g (100 mmol, 11/), shrimp chlorohydrin 27.8 g (300 mmol), Dissolve 1.3 g (4 mmol) of cedil trimethylammonium chloride in 200 ml of toluene, add 40 g of 50% sodium hydroxide, stir at 60°C for 13 hours, and then add 9.3 g (100 mmol) of shrimp chlorohydrin. 7 hours,
Stir to 60°C. 20 g of sodium hydrogen carbonate was stirred thoroughly, 400 g of hexane was added, and the upper layer was separated by a decanting method. Insoluble matter was filtered off and dried under reduced pressure.
600 g of hexane was added to the residue, insoluble matters were filtered off, and then the hexane was distilled off. Ethylene glycol 93g (1,
5 mol) was dissolved in 250 ml of dioxane, 1.2 g of 60% oily sodium hydride was added, and after completion of hydrogen generation, the above residue was added and stirred at 88° C. for 15 hours. Dioxane was distilled off under reduced pressure, the residue was diluted with a mixed solvent of water and hexane:ether (2:I), and the upper layer was washed twice with 501n1
Washed with water. The solvent was distilled off under reduced pressure. The residue was dissolved in 100 yd of pyridine and 28 g of trityl chloride (
The mixture was stirred at 40°C for 15 hours, and the pyridine was distilled off under reduced pressure. The residue was extracted with dichloromethane, and the dichloromethane layer was extracted with dilute hydrochloric acid and NaH.
After washing with G Os water, dichloromethane was distilled off. The residue was subjected to silica gel column chromatography [Merck & Co., Ltd.
Art, 7734.500g.

Elution solvent: hexane-ethyl acetate (20:I to 5:1)
] to obtain the title compound. Yield: 30g (yield: 4
8%).

I R(nujol)c+++-'+ 3430.14
45,1115.10g5.1075゜7[)0,70
O NMR (90MHz, CD CI3) δ: 0
．． 90 (3+1), L27 (32H), 2.50 (Il
l), 3.20-3.80 (10) 1), 3.03
~4.17(Ill), 7.23~7.60(15+1
) Example 2 2-pennoloxy-1-(2-hydroquinethyluoquine)-3-octadecyloxopropane 1-octadecyloxy-3-(2-trityloxyethyloquine)propan-2-ol 12゜61g (20.0 mmol)
, benzyl chloride 5.06 g (40.0 mmol),
50% sodium hydroxide aqueous solution 16.0g (200,0
mmol), cedyltrimethylammonium chloride 3
20 mg (1.0 mmol) was heated to 70° C. and stirred for 20 hours.

After cooling, hexane was added and filtered, and the organic layer was concentrated to dryness under reduced pressure. Add dioxane to the residue.

40 d of methanol and 6 d of 2N hydrochloric acid were added, heated to 70°C, and stirred for 2 hours. After adding 00M1 of water, the organic solvent was distilled off under reduced pressure and the remaining aqueous layer was extracted with dichloromethane. After washing with water and drying (magnesium sulfate), it was concentrated to dryness. Petroleum ethyl was added to the residue, the precipitated trityl alcohol was filtered off, and the concentrated residue of the filtrate was subjected to silica gel column chromatography [Merck & Co., Art, 77
34.300g.

Elution solvent: hexane-ethyl acetate (9:1 to 2:1).

Hexane-ethyl acetate-acetone (2:I:l)] to obtain the title compound. Yield ff16.65g (yield 7
0%).

TLC: Rf=0.31 (hexane:ethyl acetate-2.
l).

NMR (90MHz, CDC13) δ: 0.87 (3
+1), 1.27 (30H), 1.55 (2+1), 2
．． 27 (IH), 3.37-3.77 (911), 4.
68 (21+), 7.34 (511).

Example 3 1-[2-(Benzyloxy:)-3-(octadecyloxy)propyloxyconityltrimethylammonium chloride 2-hensyloxy-1-(2-hydroxyethyloxy)-3-octadenyloxypropane4. 96g (1
2.97 g (15.54 mmol) of luenesulfonyl chloride and 1.57 g (15.54 mmol) of dry triethylamine were stirred in 25 volumes of dry tetrahydrofuran at room temperature for 3 days. It was concentrated under reduced pressure and the residue was extracted with dichloromethane. washing with water,
After drying (magnesium sulfate), the solution was concentrated to dryness. Residual 2-benzyloxy-3-octadecyloxy-1
-(2-)Nruoxyethyloxy)propane was dissolved in a mixture of 35 parts of tetrahydrofuran and 5 parts of methanol, and 15 d of a 30% trimethylamine aqueous solution was added thereto.
I stirred it for 4 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography [Merck & Co., Art, 7734.80 g, eluent: chloroform-methanol-water (65:15:2)]. Amberlite resin column chromatography (I
RA-410 [CI] type 200 turns.

Eluent: methanol) to obtain the title compound.

Yield: 15.50 g (yield: 96%).

TLC: Rf=0.45 (chloroform/methanol:
water = 65:15:2).

NMR (90MHz, CD C13) δ: 0
．． 87 (311), 1.27 (3011), 1.53 (
2H), 3.38 (911), 3J3~3.61 (9H
), 4.62 (2H, ddj-12and 611z)
, 7.31 (51i).

Example 4 2-[2-(hydroxy)-3-(octadecyloxy)propyloxyconityltrimethylammonium chloride 1-[2-(benzyloxy)-3-(octadecyloxy)propyloxyconityltrimethylammonium chloride 5. Dissolve 45 g (9.80 mmol) in a mixture of 150 70% acetic acid and 50 ethanol.
%Pd-C1,Og was added as a catalyst, and 16
I stirred the time. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure and dried (ptO5) to obtain the title compound. Collection i
4.01 g (yield 88%).

TLC: r(f=0.24 (reaa form; methanol/water -65:15:2).

NMR (90MHz, CDCl3)δ:
0.87 (3) 1), 1.28 (aou), +, 52 (
2+1), 3.4s(9+o, 3.a7~3.93(9
+1), 5.37 (IH).

Example 5 1[2-(acetoacetyloxy)-3-(octadecyloxy)propyloxyconityltrimethylammonium chloride 2-[2-(hydroxo)-3-(octadecyloxy)propyloxyconityltrimethylammonium chloride 2. OOg (4.29 mmol) was dissolved in a mixture of 40 parts dry dichloromethane and 40 parts dry pyridine,
Diketene 41n1 was added and stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [Merck & Co., Art, 7734.3].
0g, eluent: chloroform-methanol-water (65:
15:2)] to obtain the title compound. Collection ff1
2.00 g (90% yield).

TLC: Rf=0.27 (chloroform:methanol:
Water = 65:25:4).

NMR (90M) [z, CDC13) δ: 0.87 (
3H), 1.27 (30+1), 1.52 (2H),
2.27(3)1), 3.33-3.72 (IOH).

3.48 (9+1), 3.98 (2+1), 5.23
(IH).

Example 6 4-[2-(Hydroxy)-3-(octadecyloxy)propyloxycobutan-2-ol 18.02 g (2Q Q mmol) of 1,4-butanediol was dissolved in 50% dry dimethylformamide, and 60% Add 840 mg (200 mmol) of sodium hydride and heat at 60°C.
After stirring for an hour, 6.53 g (20.0 mmol) of 1,2-epoxy-3-octadenyloxypropane was added and the mixture was stirred at 80°C for 2 hours. Dimethylformamide was distilled off, water was added to the residue, and the mixture was extracted with hexane. The hexane layer was washed with water, dried (@magnesium acid), and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Merck & Co., Ar17734.300 g, eluent:
The title compound was obtained by purification using hexane-ethyl acetate (19:1-3:l) and hexane-ethyl acetate-acetone (3:I:I). Yield: 8.07 g (yield: 97%).

TLC: Rf=0.27 (hexane:ethyl acetate=1.
1).

NMR (90MHZ, CD Cli) δ: 0
．． 87 (3+1), 1.26 (3011), 1.65 (
411), 2.55 (111), 3.35-3.70 (
8H), 3.91 (il+).

Example 7 2-benzyloxy-3-(4-bromobutyloxy)
-1-octadecyloxopropane 2-benzyloxy-3-ophtadenoloxopropan-1-ol 7.8
g (18 mmol), l.

28.9 g (134 mmol) of 4-dibromobutane.

8 g of 50% sodium hydroxide, 290 mg (0.9 mmol) of cedyltrimethylammonium chloride
Stir for 22 hours at °C. After cooling, 10 g of sodium bicarbonate was added and stirred. After the lower layer was solidified, 200 g of hexane was added and the upper layer was separated by a decanting method. Hexane was distilled off, and the residue was subjected to silica gel column chromatography [Merck & Co., Ltd.].

Art, 7734.300 g, elution solvent: hexane-ethyl acetate (20.1-5:1)] to obtain the title compound. Yield: 15.2 g (yield: 51%).

l R (film) cm-': Li2S, 1075,
103Q, 1025°N M R (60M HZ, C
D CI Jδ: 0.87 (3+1), 1.23 (3
211), 1.50-1.97 (4H), 3.30-3
．． 73 (11H), 4.70 (2H), 7.33 (5H
).

Example 8 ■-Octadecyloxy-3-[(4=p-toluenesulfonyloxy)butyloxy]propan-2-olstearyl alcohol 18.9 g C70 mmol).

21.4 g (231 mmol) of shrimp chlorohydrin.

Cetyltrimethylammonium chloride 960D (3 mmol) was dissolved in 150 d of toluene, 32 g of 50% sodium hydroxide was added, and the mixture was stirred at 60° C. for 14 hours. 96 g (100 mmol) of shrimp chlorohydrin was added, and the mixture was further stirred at 60° C. for 6 hours. After cooling, 18 g of sodium hydrogen carbonate was added and stirred well, 300 d of hexane was added, and the upper layer was separated by a decanting method. Insoluble matter was filtered off, and hexane and toluene were distilled off under reduced pressure. 400 ml of hexane was added to the residue, the insoluble matter was filtered off, and the hexane was distilled off. Tetramethylene glycol 90σ (1 mol) was dissolved in dioxane 120i, 60% urasui sodium hydride Ig was added, and after the generation of hydrogen gas was completed, the above residue was added and stirred at 88°C for 14 hours. Dioxane was distilled off under reduced pressure, and the residue was partitioned between dilute brine and a methanol-ether mixture (2:1) (a small amount of ethanol was added at this time to speed up the separation of the layers). 5 organic layers
0Tn1. The solution was washed twice with water, and the solvent was distilled off under reduced pressure. The residue was dissolved in 150 d of toluene, 13.4 g (70 mmol) of I)-toluenesulfonyl chloride and 7 g (70 mmol) of triethylamine were added, and the mixture was left at room temperature for 6 days. Toluene was distilled off under reduced pressure, hexane 600% was added to the residue, insoluble materials were filtered off, and hexane was distilled off. The residue was subjected to silica gel column chromatography [
Merck & Co., Art, 7734°, 500 g, elution solvent: hexane-ethyl acetate (5:1 to I:I)] to give the title compound. Yield: 14.4 g (yield: 36%).

IR(film)cm'': 3440,1350
,1190,1175,1120°1095,1015
．． 925°NMR (90MHz, CD CI*) δ: 0
．． 87 (3H), 1.27-1.70 (36+1), 2
．． 43 (3+1), 3.30-3.50 (9tD, 4.
00 (211).

7.33 (2+1), 7.80 (2H).

Example 9. 1-[2-(hydroxy)-1-(octadecyloxy)propyluoquine]butyltrimethylammonium
Promido 2-bennooxy-3-(4-promobutyloquine)
-1-octadenyloxypropane 2.52 g (4,5
30% aqueous trimedelamine was added and left at room temperature for 65 hours.

It was dried under reduced pressure, and the residue was dissolved in 50 ml of 80% acetic acid.
Add 10% palladium-carbon (50% wet product) Ig,
Hydrogenolysis was carried out at room temperature under normal pressure. The catalyst was filtered off and dried under reduced pressure to obtain the title compound. Yield: 12.4 g (yield: constant).

TR(nujol)cm-': 3320,1120
, 1090, 1050, 970°N M R (60M
Hz, CD CI 3) δ: 0.87 (3H), 1
．． 23 (32+1), 1.57-2.00 (4H),
3.10-3.90 (21H).

Example 10 4-(2-Hydroquine-3-(octadecyloxy)propyloxy)butyltrimethylammonium chloridestearyl alcohol l 8.9 g (70 mmol).

21.4 g (231 mmol) of shrimp chlorohydrin.

Cetyl trimedelammonium chloride 960mg (
3 mmol) was dissolved in 150 ml of toluene, 32 g of 50% sodium hydroxide was added, and the mixture was stirred at 60°C for 14 hours. Shrimp chlorohydrin 9.3g (100 mmol)
was added and further stirred at 60°C for 6 hours. After cooling, 18 g of sodium hydrogen carbonate was added, and after stirring well, 300 g of hexane was added, and the upper layer was separated by decanting. Insoluble materials were removed by filtration and dried under reduced pressure. 400 passes of hexane were added to the residue, insoluble matter was filtered off, and hexane was distilled off. 60% oily sodium hydride Ig was added to a mixed solution of 90 g (1 mol) of tetramethylene glycol and 20 d of dioxane, and after hydrogen generation was completed, the above residue was dissolved and stirred at 88° C. for 14 hours. Dioxane was distilled off under reduced pressure, and the residue was partitioned between moderate brine and a hexane-ether mixture (2 liters). The upper layer was washed twice with 50 liters of water, and the solvent was distilled off under reduced pressure. The residue was dissolved in 150 ml of toluene and added with p-toluenesulfonyl chloride + 3.4.
g (70 mmol) and 7 g (70 mmol) of triethylamine were added thereto, and the mixture was left at room temperature for 7 days.

Toluene was distilled off under reduced pressure, 600 g of hexane was added to the residue, insoluble materials were filtered off, and hexane was distilled off. The residue was dissolved in 200 g of ethanol, 50 g of a 12.30% aqueous trimethylamine solution was added, and the mixture was left at room temperature for 7 days. The mixture was dried under reduced pressure, and the residue was dissolved in 300 g of dichloromethane, and the mixture was shaken and separated with moderately salted water. The aqueous layer was further extracted with 40% dichloromethane, and the dichloromethane layers were combined.
Dichloromethane was distilled off under reduced pressure. The residue was dissolved in methanol and dissolved in Amberlite I RA-410 [
It was applied to a column of CI]I00Tnfl and eluted with methanol. Methanol was distilled off under reduced pressure, and the residue was subjected to gel column chromatography [Merck & Co., Art;
7734.200g, elution solvent;
, l horn no +1. rF-I) rffl'7→-tunno, 4-nor-water (65:25:1 to 65:25:4)
] to obtain the title compound. Yield 12.7 g (yield 3I%).

I R (nujol) cm-': 33ri 0.1120
．． 970ON MR (60MHz, CD C+3
) δ・0.87 (311), 1.23 (32H), 1.
60~2.00 (4H), 3.13~LOO (21+1
).

Example 11 4-[2-(Acetoacedyloquino)-3-(octadecyloxy)probyloquino J-butyltrimethylammonium Bromide 4-42-(Hydroxy)-3-(octadecyloxy)propyloxocobutyltrimethylammonium Bromide 1. 06 g (2 mmol) was dissolved in pyrinone 30 I, 2.5 nl of noketene was added thereto, and the mixture was stirred at 500C for 05 hours. 200 g of ethanol was added to the mixture, and the mixture was dried under reduced pressure. The residue was purified by licage gel column chromatography (Merck & Co., Ltd.).

Art, 7734.50 g, purified with elution solvent C70 form-methanol (4:1), chloroform-methanol-water (65:25:I to G'5:25.1) to obtain a compound with a poor surface appearance. . Yield: 1960 mg (yield: 78%).

(R(C1-(C13)cm-': 1740.17
5.1230.1115°970°NMR (60MH2, CDC13-CD30D) δ:0
．． 87 (311), 1.23 (32+1), 1.60~
2.00 (4+1), 2.27 (3H).

3.23-3.73 (19+1), 5.23 (Ill)
Example 12 2-pennoloxy-3-(8-bromooctyloxy)-1-octayleneluoquinopropane 2-benzyloxy-3-octadecyloxypropan-1-ol4.
35 g (10.0 mmol), 25.0 g (9 t, 2 mmol) of 1,8-dibromooctane, 10 g of 50% aqueous sodium hydroxide solution.

400mg of cetyltrimethylammonium chloride
It was heated to 80°C and stirred for 3.5 hours. After cooling, the reaction solution was extracted with ether. Wash the ether layer with water and dry it (
Magnenium sulfate), concentrated under reduced pressure, and subjected the residue to silica gel column chromatography [Merck & Co., Art.
, 7734.200 g, eluate, hexane-ethyl acetate-acetone (50:l:1)] to obtain the title compound (oil). Yield 6.26 g (yield quantitative).

N M RC90M 11 z, CD CI3) δ:
0.87 (311), 1.28 (4411), 1.8
3 (21D, 3.28-3.53 (911), 4.69
(2+1), 7.23 (5+1).

Example 13 s C2(hennooxy)-3-(octadecyloxy)propyluoquine]ocdyltrimethylammonium promid 2-7\endyloxy-3-(8-bromooctyloxy)-1-(octadecyloxy)propane 6.26 g
(10.0 mmol) was dissolved in 40 methanol and 3
Add 30% 0% trimethylamine aqueous solution to 70% in a sealed tube.
Stir at ℃ for 24 hours. After cooling, the mixture was concentrated to dryness under reduced pressure and dried (p, o5) to obtain the desired product as a white solid. Yield: 5.95 g (yield: 86.9%). TLC:Rf=0.
41 (Rioroform 4 Methanol: Water - 65:15:2
).

NMR (90M1(z, CDCl3 CD30D) δ:
0.87 (3n), 1.26 (30H), 1.3
5 (14H), 1.55 (2+1), 3.24
(911).

91 (), 4.68 (2+1), 7 in 3.35-3.7
．． 31 (511) Example 14 8-[2-(hydroquine)-3-(octadecyl roquine)probyloxycooctyltrimethylammonium
Promide 8-[2-(benzyloxy)-3-(octadecyl-oquine)propyloxy]octyltrimedelammonium 5.95 g (8.69 mmol) of promide at 70%
Acetic acid 150+n1. , dissolved in 50% ethanol, 10%
%Pd-C1,oOg was added and stirred in a hydrogen stream for 24 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure.
Drying gave the title compound.

Yield: 5.33 g (97% yield).

TI, C: Rr = 0.26 (R aa polymethanol water = 65:15.2).

NMR (90MH2, CDC1, -CD30D) δ: 0
．． 87 (311), 1.26 (3011), 1
, 35 (1411) , 1.56 (2+1) ,
3.20 (9+1).

3.27-3.93 (111+1).

Example 15 8-[2-(acetoacederoxy)-3-(octadecylruoquine)propyluoquine]octyltrimedelammonium promide 8-El(hennooxy:l-3-(octadecylroquine)propyluoquine)octyltrimethylammonium promide 2.00 g (3.17 mmol) was dissolved in a mixture of 20% dry dichloromethane and 20% dry pyridine, and while cooling in a water bath, diketene 2% was added and stirred at room temperature for 3 hours. Concentrated under reduced pressure. , the residue was subjected to silica gel column chromatography [Merck & Co., Art;
7734. ．． 40 g, eluent: chloroform-methanol-water (65:2, 15:2)] to obtain the title compound. Yield: 95 g (91% yield).

TLC: Rr=0.16c Chloroform: Methanol:
Water-65:15:2).

NMR (90 MI (z, CDC13) δ; 0.88 (
311), 1.26 (3011), 1.34 (1
411), 1.70 (2+1), 2.27 (311
), 3.47 (9H).

3.35-3.68 (8+1), 5.18 (ill).

IR(Neat)cm-': 3430,2930.
2860.1745.1720°16B5.1465.
H60, 1245, 1120, 760° Example 16 2-benzyloquino 3-(10-bromodecyloxy)-1-octadecyloxypropane 2-hensyloxy-3-octadecyloxypropan-1-ol4.
35 g (10.0 mmol), 36.5 g (122.0 mmol) of I,10-dibromodecane, 10 g of 50% aqueous sodium hydroxide solution, and 400 mg of cedyltrimethylammonium chloride were stirred at 80° C. for 4 hours. The reaction solution was extracted with ether, washed with water, dried (magnenoum sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Merck & Co., Ltd.
Art, 7734.200 g, eluent: hexane-ethyl acetate-acetone (50:I:I)] to obtain the title compound as an oil. Yield 5.53g (yield 85%)
.

TLC: Rr=0.23 (hexane:ethyl acetate:acetone-50:l:1).

NMR (90MHZ, CD CI3) δ: 0
．． 37 (311), 1.28 (46H), 1.53 (2
1+), 1.1115 (2+1), 3.30-3.53
(8H), 3.65 (111), 4.70 (21+),
7.35 (5+1).

Example 17 10-[2-(benzyloxy)-3-(octadecyloxy)probyloxycobucyltrimethylammonium promide 2-benzyloxy-3-(10-bromodecyloxy)-1-octadecyloxypropane 5.52 g (8,
41 mmol) was concentrated in a mixture of 30% trimedelamine aqueous solution and 30% methanol, and stirred in a sealed tube at 70°C for 2 days. After cooling, the mixture was concentrated to dryness under reduced pressure to obtain the title compound.

Yield: 6.00 g (yield quantitative).

NMR (90MHz, CD C13) δ・0
, 88 (311), 1, 27 (4g+1), 1.
75 (2+0.3.47 (911), 3.35~3.f
i7 (911), 4.70 (2+1), 7.31 (51
1).

Example 18 10-[1-(hydroquine)-1(octadecyloxy)propyloxy"decyltrimethylammonium bromide 6.00 g (8,41 mmol) to 70%
Dissolve in a mixture of 150% acetic acid and 70% ethanol,
0% Pd-C1,Og was added and stirred for 1 day in a hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound. Yield 4.80g (yield 87%)
.

TLC:Rf=0. I 8 (Riogutrum:Meta/-
Le, Wed-65:15:2).

NMR (90MHz, CD C13) δ: 0
, 86 (3H), 1.27 (4g+1), 1.49 (2
+1), 3.20-3.68 (8H), 3.47 (9+
1), 3.91(ill).

Example 19 10-[2-(acetoacetyloquine)-3-(octadecyloxy)probyloxycobucyltrimethylammonium Promide 10-[2-(hydroxy)-3-(octadecyloxy)propyloxycobucyltrimethyl ammonium
1.50 g (2.28 mmol) of promid is dissolved in a mixture of dry dichloromethane 15>J and dry pyrinone 15yJ, and while cooling in a water bath, Noketene I h& is added.
The reaction was stirred at room temperature for 19 hours. The residue was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography [Merck & Co., Art 7734.50 g, eluent: chloroform-methanol-water (f35:15:2)] to obtain the title compound. Yield: 1.53 g (95% yield).

'I'LC: Rf=0. I 7 (riaa form: meta)
- Le water - 65:15:2).

NMR (90 MI (z, CDCl5) δ: 0.87 (
3+1), 1.27(4g+1), 1.70(2+1
), 2.26(311), 3.44(9)1),
3.34-3.65 (8+1), 5.16 (ill)
.

I n (K I3 r) cm-' : 3450,2
920.2g50.1745.1?20°1630.1
465,1385.1235.1120,965,91
0,720 Example 2O N-[1[2-(hydroquino)-3-(octadecyloxy)propyloxy]butyl 1pi[7linone 14.2 g (200 mmol) of pyrrolidine was dissolved in 1 oad of toluene and heated at 85°C. After stirring, a solution of 5.7 g (10 mmol) of I-ophtadenolokino-3-(4-p-toluenesulfonyloxybutylokino)propan-2-ol in 100% toluene was slowly added dropwise over 2 hours. . After the dropwise addition was completed, the mixture was stirred at the same temperature for 1 hour and concentrated to dryness under reduced pressure. Dissolve the residue in 300ml of ether,
The ether layer was washed three times with 50 ml of sphagnum moss, and the ether was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography [Merck, Art, 7734° 100 g, elution solvent: chloroform-methanol (9:1 to 2.1).
] to obtain the title compound. Revenue! 3 to f'. Og(
yield 63%).

11Bfi1m)cm-': 3400.1115°N
MR (90MI-1z, CDC13) δ: 0.87 (
311), 1.23 (3211), 1, 50-2
．． 00 (8H), 2.27-2.73 (6+1), 3.
30-4.10 (1011).

Example 21 N-[4-[1-(acetoacetyloquine)-3-(octadecyloxy)propyloxy]butylcopyrrolidine N-[4=[2-(hydroxy)-3-(octadecyloxy)propyloxy] ]butyl]pyrrolidine 2.35
g (5 mmol) was dissolved in pyrinone 50g, dandruff was added thereto, and the mixture was vigorously stirred on a water bath at 50°C for 10 minutes. Twenty ounces of ethanol was added to the reaction solution, and the mixture was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography [Merck & Co., Art.

7734.50 g, elution solvent: chloroform-methanol (9;1-2:I)] to obtain the title compound. Yield: 2.2 g (80% yield).

rR(C14CI3)am-': 1740.17
15.1240.1145°1110°NMR (90MI(z, CDCl5) δ: 0.87(
3H), 1.23 (32+1), 1.50-2.00 (
8+1), 2.23 (311), 2.30-2.77 (
6+1).

3.30-3.70 (101), 5.17 (IH)
.

Example 22 N-[4-2-(acetoacetyloquine)-3-(octadecyloxy)propyloquino]butyl]-N-methylpyrrolinonium chloride N-[1-[2-(acetoacetyloquine) )-3-(Octadecyloxo)propyluoquine]butyl]pyrrolidine (1.1 g (2 mmol)) was dissolved in chloroform, 852 mg (6 mmol) of methyl iosite was added,
The mixture was stirred at 40°C for 3 hours. It was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography [Merck & Co., Art, 7734.25 g, elution solvent: chloroform-methanol (4.I).

Chloroporm-methanol-water (65:25:I~65
:25+4)] to obtain the title compound. Revenue 175
0 mg (yield 62%).

IR(CHCI3)cm-': 1745.17
15.1240.1150°1115°NMR (90MHz, CDC13) δ: 0.87 (3
+1), 1.23 (3211), 1, 60-2.
03 (4H), 2.20 (4+1), 2.27 (3++
), 3.23 (3H), 3.30-3.80 (16H)
, 5.13 (IH).

Example 23 12-Cyclohexyldodecylbromide 1.12-Dibromododecane 98 g (0.30 mol) in 300 d anhydrous tetrahydrofuran (THP) are dissolved in 0.5 mol percent dilithium tetrachlorocuprate (L
300 T of cyclohexylmagnesium bromide (0.30 mol) at 10-15 °C in the presence of LCuC1,)
The HF solution was added dropwise over 1.5 hours, and then stirred overnight at room temperature. Add 2N sulfuric acid 16-molar to the reaction mixture and adjust the pH
After the solution was reduced to about 2,000 g of ethyl acetate was added, insoluble matter was filtered off, and the filtrate was washed with water, saturated aqueous sodium bicarbonate, and water in that order, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the resulting oil was distilled under reduced pressure, with a boiling point of 166-167°C (0,
3 mmHg) fraction was collected and 40 g (40%) of the title compound was obtained.
I got it.

I R (N eat) cm''-292G, 285G,
146Q, 144G.

NMR (90MHz, CD CI3) δ: 1
．． 26(261(), 1.45-i, 93(7+1),
3.45 (2H) Example 24 3-(12-cyclohexyldobunoroxy)propane-1,2-diol I2-cyclohexyldodecylbromide 40,. 8g (
0,123 mol), 22.7 g (0,172 mol) of 1,2-isopropylidene glycerin, 1.0 g of cetyl trimedelammonium chloride, and 27.6 g (0,344 mol) of a 50% aqueous solution of caustic soda at 80% ℃
I stirred it for 10 hours. Then add 2 hexane to the reaction mixture.
After washing with water and drying (MgSO,), the solvent was distilled off under reduced pressure. 200 rfl of methanol and 47 rfl of 6N hydrochloric acid were added to the residue, heated under reflux for 10 hours, and then cooled. The precipitated colorless crystals were collected by filtration, washed with hexane, and dried. 10.
1 g of the title compound was obtained. Further cool the mother liquor and prepare the second product 2.
0.8g was obtained. Total yield 30.9g (74%).

IR(KBr)cm-': 3375.29
20.2850.1460. H2S.

1120.1055.935 NMR (90MHZ, CD C+3)
δ: 1.25 (26H), 1.47-1.74
(711), 2.50(ill), 2.85(
ill), 3.37-3.80 (6H).

3.85 (IH) Example 25 2-(benzyloxy)-1(12-cyclohexyldodecyloxy)propan-1-ol 3-(+2-cyclohexyldodecyloxy)propane-1,2-nol 23 .5 g (68.6 mmol), trityl chloride 28.7 g (103 mmol), triethylamine 13
．． 7 g (137 mmol) and dichloromethane 200
After stirring the mixture at room temperature for 2 days, methanol (IO) was added to the reaction mixture and the mixture was further stirred for 3 hours. This product was washed with water, dried (MgSO,), and the solvent was distilled off to obtain 52 g (quantitative) of 3-(12-cyclohexyldodecyloxy)-2-tridyloquine propan-l-ol. . 35 g (4.6 mmol) of this, 8.7 g (69 mmol) of benyl chloride, 0.5 g of cetyltrimethylammonium chloride, 7.4 g (92 mmol) of 50% aqueous sodium hydroxide solution and 'F1-(F
The 50d mixture was stirred at 60°C overnight.

Furthermore, 74 g (92 g) of 50% sodium hydroxide was added to the reaction mixture.
mmol) and 8.7 g (69 mmol) of hensyl chloride were added and stirred overnight. Then, from the reaction solution, T
1-(F was distilled off, 10Lf of hexane was added to the residue, washed with water, and the hexane was distilled off. 120L of dioxane and 60L of IN hydrochloric acid were added to the residue, stirred at 80°C for 5 hours, cooled, and diluted with baking soda. After neutralization, 100% ethyl acetate was added.The organic layer was washed with water.

After drying (MgSO,) the solvent was evaporated and the residue was left overnight at room temperature. A small amount of hexane was added to this mixture, the precipitated trityl alcohol was filtered off, and the filtrate was collected using silica gel (50%
0 g) column and eluted with hexane-ethyl acetate (9:1) to give the title compound as a colorless oil. Yield: 9.0 g (45%).

I n (N eat) cm'': 3420,292
0.2g50,1465,1450゜1115.106
0,735,695 NMR (90MHz, CD C+3) δ: 1
．． 26 (26H), 1.50-1, 78 (7+1)
, 3.37-3.72 (8+1) , 4 , 68 (
2+1), 7.37 (5+1) Example 26 2-benzyloxy-3-(4-bromobutyloxy)
-1-(+2-cyclohexyldodecyloxy)propane 2-(benzyloxy)-3-(12-cyclohexyldodecyloxy)propan-1-ol 3.50 g
, 1 mmol), 1,4-dibromobutane 25.0 g (
] 1 5.8 mmol), 2.0 g (25.0 mmol) of 50% aqueous sodium hydroxide solution, and too mg of cetyltrimethylammonium chloride were stirred at 80° C. for 2 days. After cooling, extract with hexane, wash with water, and dry (M
After g SO4), the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Merck & Co., Ar
Purification was performed using hexane-ethyl acetate (19:I) as an eluent to obtain a curved title compound.

Yield: 13.03 g (yield: 66%).

TLC: Rr=0.22 (hexane: ethyl acetate; acetone-50:l:1).

NMR(90MHz, CDCli)δ:
1.26 and 1.65 (4111), 3.34~
3.53 (1111), 3.63 (ill), 4.69
(2+1), 7.43 (511).

Example 27 1-(12-cyclohexyldodecyloxy)-3-(
4-Dimethylaminobutyloquino)propan-2-ol 3.00 g (5.28 mmol) of 2-benzyloxo-3-(=1-bromobutyloxo)-1-(+2-cyclohexyl!decyloxy)propane was added to 40 Add to 207% aqueous solution of methylamine and heat to 60°C.
Stir for 4 hours. Concentrate to dryness under reduced pressure to give 2-henzyloquine-1-(12-cyclohexyldodecyloxo)
A crude product of -3-(4-dimethylaminobutyloxo)propane was obtained. This crude product was dissolved in a mixture of 50% 70% acetic acid and 25% ethanol, and 10% Pd-C300m
g was added thereto, and the mixture was stirred for 1 day in a hydrogen stream. The filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the ethyl acetate solution was shaken with an aqueous sodium bicarbonate solution, and then several layers were washed with water and dried (@magnesium acid). After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain the title compound. Collection fi1.
77g (yield 76%).

NMR (90MHz, CD C13) δ: 1
．． 27 and 1.60 (3711), 2.24
(611), 2.37 (21+), 3.48 (
811), 3.92 (110゜Example 28 4-[2-hydroquine-3-(12-chlorohexyldodecyloxo)probyluoquine]butyltrimethylammonium Tonrad 1-(12-chlorohexyldodecyloxo)-3- (
674 mg (1,20 mmol) of 4-dimethylaminobutyloquine)propan-2-ol was dissolved in methanol (8Tn)
Dissolve the solution in a mixture of Q and chloroform, add 830 mg (6,00 mmol) of potassium carbonate, stir, add 893 mg (4,80 mmol) of methyl p-toluenesulfonate, and heat the reaction solution at 70°C. Stir for 2 hours. The residue was concentrated to dryness under reduced pressure and subjected to silica gel column chromatography [Merck & Co., Art 7734.30]
g, eluent/chloroporum-methanol-water (65:1
5:2) l was also used to obtain the title compound. Collection 141
0 mg (yield 46%).

NMR (90MHz, CDCl5) δ: 1.26 a
nd 1.65 (3911), 2.33 (311), 3
．． 20 (9H), 3.31-3.46 (811), 3.
85 (111), 7.15 (2+1), 7.75 (2+
1).

Example 29 4-[2-(acetoacedyluoquine)-3-(12-chlorohexyldodecyloxo)propyluoquine]butyltrimethylammonium Tonrad 4-[2-hydroxy-3-(+2-sochlorohexyldodecyloxo) 410 mg (0.65 mmol) of propyloxycobutyl trimedelammonium was added to 4 d of dry dichloromethane, 17 nf of dry pyrinone. 0.5 kura of fuketene was added. After cooling down for a while in a water bath,
Stir at room temperature for 2 hours. After adding methanol, the mixture was reduced under reduced pressure, and the residue was subjected to gel-lamin chromatography.
[Merck, Art 7734.30g, eluent
Chloroform-methanol-water (65:15:2)]
The title compound was obtained by purification. Yield 1360 mg (yield 77%).

TLC: Rr=0.26 (R aa form: methanol,
Water-65:25・4) NMR(90M I(z, CD C+3)δ:1
．． 25-1.63 (39+1).

2, 23 (3) 1), 2.32 (311), 3
．． 27 (9H), 3.47 (811), 5.1
9 (IH).

7.13 (2+1), 7.74 (2+1).

I R (KBr) cm”+ 3450.2925.
28g5, 1745, 1720°1665, 1490.
+445.1410.1360.1200.1035
．． 1010.975°915.820 Test Example I Antitumor Effect ICR mice (5 mice per group) were intraperitoneally implanted with I×10' Sarcoma 180 cells per mouse. Then,
0.33 mg/mouse of compound dissolved in saline
The drug was administered intraperitoneally three times in total, one hour later, one day later, and two days later. Table 1 shows the life extension rate and the number of survivors 600 days after the start of the test compared to the control group in which no drug was administered.

Table 1 Compound of Example 11 352 015 Test Example 2 Antitumor Effect C3H mice (5 mice per group) were given ix+ per mouse.
o' mouse breast cancer cells MM46 were intraperitoneally transplanted, and 0.25 mg/mouse of the compound of Example 11 dissolved in physiological saline was intraperitoneally administered 101 times for 4 days from the second day after transplantation. . Table 2 shows the survival prolongation rate and survival comparison at 60 days after the start of the study compared to the control group to which no drug was administered.

Table 2 Compound of Example 11 137 415 Test Example 3 Platelet aggregation inhibitory effect [Test method] Male rabbits were given a syringe containing 3.15% citric acid (ratio of 1 to 9 blood) as a blood coagulation inhibitor. Platelet-rich plasma (PRP) is obtained by directly collecting blood and centrifuging it at 800 rpm for 10 minutes at room temperature.
(elet rich plasma) was obtained. The remaining blood was further centrifuged at 3000 rpm for 10 minutes to obtain platelet-poor plasma (P P P ) as a supernatant.
etpoor plasma) was separated. The platelet count was adjusted to approximately 500,000/71Q by diluting PRP with PPP.

After stirring this PR1) 250 μg at 37°C for 2 minutes, add the specified amount of the test drug and stirring for another 2 minutes.1) AF I
XI 0-8M was added. Platelet aggregation was measured using an aggregometer (manufactured by Rika Denki). The aggregation inhibitory activity of the test drug was determined from the inhibition rate against the maximum light transmittance (maximum aggregation rate) by PAF' in control PRP.

The results are shown in Table 3.

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is an optionally substituted higher alkyl group, R^2 is a tertiary amino group or a quaternary ammonium group, and n is an integer of 2 to 10] or a salt thereof.