JPH01104036A - Glycerol derivative - Google Patents

Abstract

NEW MATERIAL:A glycerol derivative expressed by formula I [R<1> is higher alkyl; R<2> is H, lower alkyl, lower alkanoyl or lower alkylthiocarbamoyl; R<3> is N-oxide-tertiary amino; X is -(OCH2CH2)m- (m is 1-4) or -O(CH2)n- (n is 2-12)]. EXAMPLE:4-[3-(12-Cyclohexyldodecyloxy)-2-methoxypropyloxy]butyl bromide. USE:A medicinal agent, having antitumor action, selectively acting on cancerous cell membranes, capable of exhibiting controlling activity of cancerous cell membrane function protein, e.g. inhibitory action on biosynthetic enzyme of membrane phospholipid, without side effects, such as blood platelet agglutination or hypotensive action. PREPARATION:For example, a compound expressed by formula II is reacted with a sulfonyl halide to provide a product, which is then reacted with an amine and then hydrogen peroxide reagent to afford the aimed 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,
Formula % useful as an antitumor agent and platelet activating factor antagonist [wherein RI is an optionally substituted higher alkyl group, R2 is hydrogen, an optionally substituted lower alkyl group,
It represents an optionally substituted lower alkanoyl group or lower alkylthiocarbamoyl group, R3 represents an N-oxyto-tertiary amino group, and X represents the formula (OCH2CH2)m- (wherein, m represents 1 to 4 It relates to a divalent group represented by the formula %) or a divalent group represented by the formula % (in which n represents an integer from 2 to 12).

Conventional technology In recent years, among amphipathic glycerolipids, substances with a ridge structure factor have been shown to have antitumor activity or platelet activating factor (
It has been disclosed in academic and patent literature that it has an antagonistic effect on the formula (1) (hereinafter abbreviated as PAF). for example,
A natural phospholipid represented by the formula (2), ie, PAF, was discovered relatively recently and is attracting attention as an important mediator of inflammation, blood pressure regulation, etc. in living organisms. C, A,
Demopoulos, R.N., Pinka
rd, and D, J., Hanahan, J.
Biol, Chem, 254.9355 (19
79); J, Benveniste, M, T
ence, P. Varenne.

J, Bidault, C, Boullet, a.
nd J, Po1onsky.

C,R,Acad,Sci,(D),289.1
037 (1979).

Phospholipid compounds that are structurally related to PAF have effects similar to PAF, such as platelet activation, neutrophil activation, tissue damage, vascular permeability enhancement, and blood pressure lowering effects, although there are differences in strength. It is known. [J,T,
O'Flaherty et al, Res.

Commun, Chem, Pathol &
Pharmacol, 39°291 (19H)
; P, Hdvary, Thrombosis
Res.

30, 143 (1983)] Furthermore, the alkyl lysophospholipid represented by the formula (■) has an antitumor effect, unlike l-octadecyl-2-arachitonoylglycerophosphocholine, etc., which are known as PAF and PAF precursors. It has been known. [11, E. Berdel, W.
R, E, Bausert, U, Fink,
K., Rostetter, and P.G.
Munder, Anticancer Re
5earch, l, 345 (1981),
JP-A-52-134027] However, since this compound has a structure closely related to PAF, it is also known to have PAF-like effects such as serotonin release, bronchial stenosis, platelet aggregation, and antihypertensive effects. [O'Flaherty, supra.
References in and Tori, J.

Hanahan et al, Biochem, Bi
ophys, Res, Commun.

99, HI3 (1981) Therefore, in addition to lowering blood pressure, these substances may cause cerebral thrombosis, circulatory disorders such as angina pectoris, and asthma. In addition, it exhibits local irritating effects, and these side effects limit the clinical use of the compound.

(III) (I%') Recently, glycerolipids IV without phosphate ester groups (R' = long chain alkyl, R1 = short chain or long chain alkyl or carbon number 2
~5 acyl.

It has been disclosed that X=O (CHJ R', n=1-12) has a PAP antagonistic effect and has the potential to be a therapeutic agent for disorders involving PAF, such as anaphylactic shock. [JP-A-60=100544; JP-A-58-198445; T, Miyamoto
et at,, Kyoto Conference
of Prostaglandins, Nov.
26-28, 1984. Abst.

p99]. However, in actual use, it is desired to improve the durability of the action and further improve the therapeutic coefficient.

Further, there is no specific disclosure regarding antitumor effects.

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 amphipathic lipids have simulative properties and can exert diverse effects on cell metabolism and functions through membranes. . The present inventors have discovered that some amphipathic lipids with certain structural factors act selectively on cancer cell membranes and are effective in controlling the activity of cancer cell membrane functional proteins (e.g., inhibiting membrane phospholipid biosynthesis enzymes). It was assumed that there was something involved.

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

[Wykle, R.L. and 5nyder,
F., The Enzymes of Biolo
gical Membranes, Marton
osi, A.

Ed, Vol. 2. Plenum Pres
s, New York, 1976°87; Li
n, H, J,, tlo, F, C, S,, an
d Lee, C, L, H,.

Cancer Res, 38. 946 (1
978); Modelell.

M., Andreesen, R., Pahlke.
L. Brugger.

U., and Munder, P.G.
Cancer Res,, 39°4681 (1
979) Ko.

That is, alkyl ether compounds accumulate in large amounts in tumor tissues, whereas they are more rapidly degraded and inactivated in normal cells. Therefore, the present inventors believed that compounds with many ether bonds in the molecule would show selective effects on cancer cells, and as a result of extensive research, the glycerol derivative represented by formula I was found to be extremely effective. The present invention was completed after discovering that it has a useful antitumor effect. Also, - formula ■
The present invention was completed based on the discovery that the compound represented by has no platelet aggregation or blood pressure lowering effects and has low side effects.

Means for Solving the Problems In the above-mentioned formula (2), the higher alkyl group represented by R' is n-octyl, n-nonyl, n-decyl, n-
-undecyl, n-dodecyl, n-tetradecyl, n-
Examples include alkyl groups having 8 to 22 carbon atoms such as hexadecyl, n-octadecyl, and n-eicosyl. The higher alkyl group is cycloalkyl, allyl, halogen, ethynyl, l-propynyl, oxo.

It may have a substituent such as methoxy. 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 (C, -,) alkyl, lower (c 1-4) alkoxy, halogen, or the like. Examples of the halogen as a substituent for the higher alkyl group and the halogen as a substituent for the phenyl group include fluorine, bromine, and chlorine. When R1 is a substituted higher alkyl group, the substitution position may be any of the substitutable positions of the higher alkyl group, but the ω (omega) position is preferred. The substituted higher alkyl group includes 13-cyclopentyltridecyl, 12-cyclohexyldodecyl, 12-phenyldodecyl, octadecane-17-ynyl, l8.18.18-trifluorooctadecyl, 16,16,17 ,17,18゜18.18-hebutafluorooctadecyl, 12,12.13,13,14,
14,15,15,16,16゜17.17,18,1
8,19,19.19-heptadecafluorononadecyl,
1B-chlorooctadecyl.

Examples include groups such as 18.18-dichlorooctadecyl, 2-oxooctadecyl, and 2-methoxyoctadecyl. Examples of the higher alkyl group substituted with halogen include mono- to perhalogen higher alkyl groups, and among them, higher alkyl groups substituted with 3 to 7 halogens are preferred. Substituents other than halogen are usually preferably monosubstituted higher alkyl groups.

The lower alkyl group represented by R1 is methyl.

Ethyl, propyl, butyl, pentyl, isopropyl.

Examples include linear or branched alkyl groups having 1 to 5 carbon atoms such as butyl, isopentyl, and 5ec-butyl. You can also
Examples of the substituted lower alkyl group include 2-oxopropyl, 2-oxobutyl, and carboxymethyl.

Examples of the lower alkanoyl group represented by R2 include alkanoyl groups having 2 to 4 carbon atoms such as acetyl, propionyl, and butyryl. The lower alkanoyl group may be substituted, for example, with a lower alkanoyl group having 2 to 4 carbon atoms, and examples of the substituted lower alkanoyl group include acetoacetyl.

The lower alkylthiocarbamoyl group represented by R2 includes thiocarbamoyl substituted with a lower alkyl group having 1 to 4 carbon atoms, such as N-methylthiocarbamoyl, N-ethylthiocarbamoyl, N-propylthiocarbamoyl, and N-butylthiocarbamoyl. The basics are given.

m represents an integer of 1 to 4, preferably m=1 to 3.

n represents an integer of 2 to 12. Although the medicinal efficacy changes somewhat depending on the change in n, n=3 to IO is preferable.

The N-oxyto-tertiary amino group represented by R3 has the formula [wherein R4 and R5 each represent a lower alkyl group, or R4 and R5 together with the adjacent nitrogen atom form a cyclic amino group] ] Examples are groups represented by the following.

Examples of the lower alkyl group represented by R4 or R5 include alkyl groups having 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl, and pentyl, with methyl being preferred.

Cyclic amino groups include pyrrolidino 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.

propyl, butyl), hydroxyl group, carboxyl group.

It may have a substituent such as an ethoxycarbonyl group.

In the compound represented by formula (1), 2 of glycerin
Since the position carbon is an asymmetric center, there are two types of stereoisomers: R-coordination and S-coordination, but each of them, their racemates, and mixtures thereof are not included in the present invention. It is something that

The compound (1) of the present invention can be produced, for example, by the method shown below.

(i) When R'' is an optionally substituted lower alkyl group CHzOR' CHzO
R'I Cl0R2->CHOR” +C)+
2-X OHCH* X 0R(IX)
(X)CHZOR”C
HaOR' U formula, R represents benzenesulfonyl, lower alkylbenzenesulfonyl, or lower alkanesulfonyl, and other symbols have the same meanings as above] Compound (X) is prepared by combining compound (IX) and sulfonic acid halide in a suitable anhydrous solvent. (e.g. benzene, toluene.

dichloromethane, chloroform, pyridine, etc. or mixtures thereof), a suitable deoxidizing agent (e.g., tertiary amines such as triethylamine, pyridine, etc.), -20
It can be obtained by reacting at a temperature of 10°C to +50°C, preferably -10°C to +50°C. Examples of the sulfonic acid halide used include benzenesulfonyl halide (e.g., benzenesulfonyl chloride), lower (c
1-4) Alkylbenzenesulfonyl halide (e.g.
Examples include toluenesulfonyl chloride) and lower (C,...) alkanesulfonyl chloride (eg, methanesulfonyl chloride).

It can be obtained by reacting. The reaction is carried out in excess of amine or in a suitable solvent (eg water, methanol, ethanol, benzene, toluene).

(tetrahydrofuran, dimethylformamide, etc. or mixtures thereof), -20 to +150°C, preferably 0
It is carried out at temperatures between 0C and +800C. Furthermore, if necessary, the reaction can be carried out in a sealed tube at room temperature or under heating.

Compound (r) is prepared by combining compound (■) and a peroxidizing reagent in a suitable solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, acetic acid, acetic anhydride, ethanol,
(toluene, etc. or a mixture thereof).

m-chloroperbenzoic acid and peracetic acid as peroxidizing reagents.

Examples include perorganic acids such as permaleic acid and pertrifluoroacetic acid, or hydrogen peroxide. Reaction temperature is -50° to +50°
C1 Preferably carried out at -20° to +20°C. The reaction time can be determined by thin layer chromatography (silica gel: chloroform-methanol, 5:I) to determine the disappearance state of the raw material spot. Compound (1) from the reaction solution
Separation of.

Purification can be carried out using known techniques such as solvent extraction and silica gel column chromatography after operations such as solvent distillation and removal of residual peroxide.

In addition, the compound (■) which is a synthetic intermediate [X=Q(CHs
)n] can also be produced by the reaction shown below.

CH,OR'CH20R'C
1,01i'(V) (VI)
(■) [In the formula, the symbols have the same meanings as above, and Y represents a halogen] Compound (V [) can be obtained by reacting compound (V) with a dihaloalkane represented by the formula % formula % () Can be done. The reaction may be carried out without solvent or in a suitable solvent (e.g.
strong bases (e.g., sodium hydroxide,
under aqueous conditions, preferably in the presence of a phase transfer catalyst (e.g., cetyltrimethylammonium chloride, benzyltrimethylammonium chloride, etc.).
It is carried out at 0°C, preferably between +20°C and +100°C.

Further, the intermediate (■) can be obtained by reacting the compound (W) 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 in a suitable solvent (e.g. water,
Methanol, ethanol, benzene, toluene.

Tetrahydrofuran, dimethylformamide, etc. or mixtures thereof) at -20 to +150°C, preferably from 0 to +80°C. Also, if necessary, during sealing,
The reaction can also be carried out at room temperature or under heating.

In addition, the said raw material compound (IX) can be manufactured by the reaction shown below.

CH20R'CH,OR' C
1(,OR'(XI) (X[)
(Xllll)CH20R'CHOR"-'> (IX)CHI
0Tr (XIV) E In the formula, Tr represents tridel, and other symbols have the same meanings as above. The compound (XI), which is a raw material for synthesis, is synthesized in the presence of an alkali with the formula R'OH (R1 has the same meaning as above). It is easily obtained by reaction with the indicated alcohol and shrimp chlorohydrin. Compound (X[[) is the compound (X[) and formula % formula %]
Wa) or formula % formula %) U, where symbols have the same meanings as above] Diol (X
It can be obtained by reacting with V[lb). The reaction may be carried out in a suitable solvent (eg, hexane, benzene, toluene, tetrahydrofuran, dioxane).

dimethylformamide, dimethylsulfoxide, etc. or mixtures thereof) in the presence of a strong base (eg, sodium hydride) at a temperature of -20 to +150'C1, preferably from room temperature to the reflux temperature of the solvent.

The reaction of (X[)-(XIII) is a tritylation reaction of compound (■), using trityl chloride in an appropriate solvent (benzene, toluene, dichloromethane, chloroform, pyridine, etc.) and an appropriate deoxidizing agent ( For example, in the presence of tertiary amines such as triethylamine, pyridine, -
It can be carried out at a temperature of 20 to +150°C, preferably 0°C to +120°C.

The reaction (XI)-(XIV) is an alkylation reaction of compound (Xln). Alkylating agents used include alkyl halides [R'-Y (Y represents halogen)];
] p-Toluenesulfonic acid alkyl base, sodium hydride, caustic soda aqueous solution, etc.) in an appropriate solvent (benzene, toluene, etc.).

hexane, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, etc. or mixtures thereof), under aqueous conditions, preferably in the presence of a phase transfer catalyst (e.g. as above), at -20 to +150°C.
, preferably at 0°C to +100°C.

Compound (IX) is prepared by adding an acid (e.g., hydrochloric acid, trifluoroacetic acid, para-toluenesulfonic acid, etc.) to compound (XIV) in an appropriate water-containing solvent (methanol, ethanol, dioxane, etc. or a mixture thereof) under reflux while heating at IO'C. , or hydrogen chloride can be obtained in chloroform at -10 to +10°C, preferably around 0°C, and further in hydrous acetic acid at +30°C under heating under reflux.

Compound (IX) can also be produced by the reaction shown below.

[In the formula, each symbol has the same meaning as above] The reaction of (V)-(■) is similar to the reaction of (IX) → (X), and compound (IX) is added to compound (■) with diol (X
Vlla) or diol (XVIIb).

The reaction is carried out in a suitable solvent (eg dimethyl sulfoxide, dimethyl formamide, benzene, toluene).

hexane, dioxane, tetrahydrofuran, etc.).

In the presence of a strong base (e.g., sodium hydride, caustic soda, caustic potash, etc. or an aqueous solution thereof), under aqueous conditions, preferably in the presence of a phase transfer catalyst (e.g., cetyltrimethylammonium chloride, benzyltrimethylammonium chloride, etc.) It is carried out at -20 to +150°C, preferably at +200°C to +100°C.

(ii) When R' is hydrogen or optionally substituted lower alkanoyl The 2-position lower alkanoyl compound (1) can be produced by the reaction shown below.

(Margin below) (XI[) (XV)
(XW) C to R' [In the formula, each symbol has the same meaning as above. ) reaction is (X)-(■
) can be carried out in the same manner as the reaction.

Compound (■) can be obtained by subjecting compound (XVI) to an acylation reaction. Acylating agents that can be used include acid anhydrides, mixed acid anhydrides, acid halides, diketenes, and the like. The reaction was carried out in an appropriate solvent (benzene,
-20 to +150°C, preferably 0
It is carried out at a temperature of 100°C to +100°C. Compounds from the reaction solution (
Separation and purification of (2) can be carried out by the method described above.

The reaction of compound (■)-(I) can be produced in the same manner as the reaction for the 2-position lower alkyl compound described above. This can be achieved smoothly by adjusting the conditions to be slightly milder than in the case of alkyl compounds.

(Mountain) When R2 is lower alkylthiocarbamoyl, it can be produced by the same reaction route as for the 2-position acyl compound.

(XVI) -(■)→(1) Compound (■) can be obtained by subjecting compound (XVI) to a thiocarbamoylation reaction. Examples of the thiocarbamoylating agent used include isothiocyanates such as methylisothiocyanate. The reaction is carried out in an appropriate solvent (pyridine, benzene, toluene, ether,
dichloromethane, chloroform, etc., or mixtures thereof), θ to +150°C, preferably +50 to +120
Performed at °C.

Compounds obtained in each step above are separated by silica gel column chromatography, if necessary.

Can be purified. As an elution solvent, hexane-
Examples include ethyl acetate mixture and dichloromethane-ethyl acetate mixture.

The reaction from compound (■) to target compound (1) is as described in 2 above.
It can be carried out in the same manner as in the case of position-acyl compounds.

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

Work 4 - Compound (I) has virtually no platelet aggregating effect, hypotensive effect, or vascular permeability enhancing effect. Also, the compound (1
) has enhanced and sustained main effects (e.g. antitumor effects) and can be administered as a safe antitumor agent to tumor-bearing warm-blooded animals. The administration method, administration route, and dose can be appropriately selected depending on the subject and symptoms, but the dose for mammals is usually 0.1 to 150 mg as compound (I).
mg/kg (body weight), preferably 2 to 50 mg/kg
It weighs about kg.

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 further improved by preventing tissue (local) damage.

Compound (1) has excellent lipophilic properties and low toxicity. Therefore, it can be safely administered to mammals orally or parenterally as a pharmaceutical composition in an appropriate dosage form.

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, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.

Examples of non-aqueous solutions and suspensions include indoralipid, natural lecithin, 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, emulsifying agents, and dispersing agents; in the case of aqueous injections, in addition to these adjuvants, glucose, serum albumin, serum globulin, etc. It may contain adjuvants such as.

These are, for example, passed through a bacteria retention filter,
It is sterilized by adding a disinfectant or by irradiating it 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) is mixed with at least one inert carrier, excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, and the like. The compositions may contain, in conventional manner, additives other than inert carriers and excipients, such as lubricants such as magnesium stearate and disintegrants such as fibrin calcium gluconate.

EXAMPLES The present invention will be explained in more detail by referring to Reference Examples and Examples below, but the present invention is not limited thereto.

Reference Example 1 12.12,13,13,14,14.14-hebutafluorotetradecanol 10-undecen-1-ol 14,4 g (84,
Tetrahedron Let
ters, vol.

25, No. 3, 303-306 (1984) and Japanese Patent Publication No. 181093/1983, 20.9 g (73%) of the title compound was obtained.

IR (Nujol) cm - Hiroshi: 3380.
1: (50, 1230, 1210° 1200, 1165
．． 1015.105ON MR (90MHz, CDC
l25) δ: L, 20-2.40 (21H).

3.63 (2H) Reference Example 2 12.12,13,13,14,14.14-heptafluorotetradecyl bromide l obtained in Reference Example 1 2,12,13.13,14
.

14.14-hebutafluorotetradecanol 17,
Using 6 g (51.7 mmol), the published patent publication (
A) 18.6 g (89%) of the title compound was obtained by synthesis according to the method described in No. 60-181093.

IR(neat)cm-': 2930.1g60.
1465.1350°1220, 1195.1165.
tits, 945.910.725N M R (9
0MHz, CDCl25) δ: 1.17-2.40
(20H).

3.40 (2+1) Reference Example 3 16.16,17,17.18,18.18-Hebutafluorooctadecyl benzyl ether 1 obtained in Reference Example 2 2,12.13.13,14゜14.14 -hebutafluorotetradecyl bromide 14.6 g (60
published patent publication (A) 1981-181 using
When synthesized according to the method described in No. 093, the title compound 1
6.3g (84%) was obtained.

IR(neat) cm″″’: 2925.2855
．． 1350.1230°1220, 1170.1115
．． 730.720.69ON M R (90MHz, C
DCl23) δ: 1.20-2.40 (28H).

3.43 (2H), 4.47 (2H), 7.30 (
5H) Reference Example 4 16.16,17.17.18,18.18-heptafluorooctadecanol 1 6,16,17,17,18°18.18-heptafluorooctadecanol obtained in Reference Example 3 Using benzyl ether 16.3 g (33.5 mmol),
When synthesized according to the method described in Published Patent Publication (A) No. 181093/1980, 10.8 g (80%) of the title compound was obtained.
was gotten.

I R (Nujol)cm"-': 3430.340
0.1250.1230°1215, 1195.118
5.1160.1115.1105.1055゜105
0,945.725 N M R (90MH2, CDCl23) δ: 1.
17-2.40 (29H).

3.63 (2H) Example 1 Five 3-(12-cyclohexyldodecyloxy)-2-methoxypropanol 2, 9 g (8.15 mmol)
.

A mixture of 25 g of 1,4-dibromobutane, 2.0 g of 50% aqueous sodium hydroxide solution and 0.1 g of cetyltrimethylammonium chloride was stirred at 80° C. for 3 days, and then 50 hexane was added to the reaction mixture and washed with water.

After drying the hexane solution over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was chromatographed on a 100 g column of silica gel using a mixture of hexane and ethyl acetate (30:1).
It was eluted.

The desired fractions were concentrated under reduced pressure to obtain 2.6 g of the title compound as a colorless oil. (yield 65%) IR(neat)c
m″″’: 2920.2g50.1460.1440
゜1240, 111O N MR (90MHz, CDCf2s) δ: 1.0
0-1.40 (26H).

1.60-2.00 (11■), aJ5-3.60 (1
4) 1) Example 2 Ruamine 4-[3-(12-cyclohexyldodecyloxy)-
2-Methoxypropyloxycobutylbromide 1, 2
g (2.44 mmol) was dissolved in 7d of 20% dimethylamine toluene solution, stirred at room temperature for 2 days,
The reaction mixture was concentrated under reduced pressure. Dichloromethane and sodium chloride water were added to the residual color and mixed well, and the dichloromethane layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a 30 g column of silica gel and eluted with chloroform-methanol (6:1).

Both desired fractions were concentrated under reduced pressure to obtain 1.0 g of the title compound as a colorless oil. (Yield 90%) IR(neat)c
m-': 2945.2920.2g55.1465°NMR ('90MH2, CDCl23) δ: 1.1
0-1.40 (26H).

1.47-1.77 (IIH), 2.20-2.40
(8H), 3.36-3.55 (12H) Example 3 4-[3-(12-cyclohexyldodecyloxy)-
2-Methoxypropyloxycobutyldimethylamine 6
Dissolve 42 mg (1.41 mmol) in chloroform and stir under water cooling to dissolve m-chloroperbenzoic acid 2.
A solution of 68 mg (1.55 mmol) in chloroform was added dropwise over a period of 10 minutes. After stirring at room temperature for 3 hours, the reaction mixture was concentrated and the residue was purified using Amberlite 41.
The product was subjected to chromatography using a 0[OH] type 60 column and eluted with methanol. Both desired fractions were concentrated to dryness to obtain 665 mg of the title compound as a colorless solid. yield(
Typical) IR (neat) cm-': 3300.2
920.2850.1660°1465, 1445.1
115 N M R (90MH2, CDCl2. + CD30
D) δ: 1.20-2.10 (37H), 3.1
2 (6H), 3.25-3.67 (14H) Example 4 2-Methoxy-3-octadecyloxypronoquinol 4.5 g (12° 5 mmol) was reacted in the same manner as in Example 1 to obtain the title compound. The compound was obtained as a colorless oil. Yield 3.
25g (yield 52%) IR(neat)cm-': 292G, 2855
．． 1465.112ON MR (90MH2, CDC
l23) δ: 0.87 (3+1), 1.20~2
．． 10(36)1), 3.33-3.53(1410
Example 5 4-(2-methoxy-3-octadecyloxypropyloxy)butyl bromide 3,2 obtained in Example 4
g (6.49 mmol) was reacted in the same manner as in Example 2 to obtain the title compound as a colorless oil. Yield 2.8 g (yield 94%) IR(neat) cm-': 2925.2855.
1465.112ON M R (90MH2, CDCl
23) δ: 0.86 (3H), 1.24-1.7
3 (388), 2.20 (811), 3.33
~3.53 (12H) Example 6 4-(2-Methoxy-3-octadecyloxypropyloxy)butyldimethylamine 1 obtained in Oxide Example 5
, 0 g (2.18 mmol) was reacted in the same manner as in Example 3 to obtain the title compound as a colorless solid. Yield 0.9
8g (yield 95%) rR(neat)cm-': 3300.2925.
2850.1465°1120, 72O NMR (90MHz, CDCl23) δ: 0
, 87 (3H), 1.15-2.10 (368),
3.17 (611), 3.17-3.56 (14H)
Example 7 C) Propane, 1 obtained in Reference Example 4 6.16, 17, 17, 18
゜18.18-Heptafluorooctadecanol 2゜8
g (7 mmol), shrimp chlorohydrin 2.8 g (30
160 mg (0.5 mmol) of cetyltrimethylammonium chloride and 4 g (50 mmol) of 50% caustic soda were added to the solution and stirred at 60° C. for 3 hours.

After cooling, 2501n1 of hexane was added, insoluble matter was filtered off, and low boiling point matter was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Merck, Art, 773410
0g, elution solvent, hexane-ethyl acetate, 8:l~5:
Purification in step 1) yielded 2.3 g (70%) of the title compound.

IR(neat)cm-': 2925.2g55.
1465.1350°1220, 1195.1165.
1110.945.905.845.725N M R
(90MHz, CDCf2s) δ: 1.20-2.
40 (26H).

2.60 (18), 2. go(in), 3.03～
3.20C111), 3JO~4.80 (4H) Example 8 Siloxy) Probyloxybutyl trityl ether Obtained in Example 7! , 2-epoxy 3-(16, + 6.
17. + 2.3 g (5 mmol) of 7.18,18.18-heptafluorooctadesiloxy)propane and 1.
13.5 g (150 mmol) of 4-dihydroxybutane was dissolved in 100 d of dioxane and 160 mg (4 mmol) of 60% oily sodium hydride was added with vigorous stirring.

After stirring at room temperature for 30 minutes, stirring at 105°C for 15 hours, dioxane was distilled off under reduced pressure, the residue was thoroughly shaken with water and ether, the liquid was separated, and the ether layer was washed with water to remove Mg.
After drying at 5O, the ether was distilled off under reduced pressure.

Dissolve the residue in pyridine and add trityl chloride 2.
．． 2 g (8 mmol) was added and stirred at 50° C. for 6 hours. Furthermore, 0.2 mm of methanol was added, and the mixture was stirred at the same temperature for 13 hours, and the low boiling point components were distilled off under reduced pressure.

The residue was shaken with a mixed solvent of water and hexane to ether in a ratio of 2:1, and then the layers were separated, and the upper layer was washed with water and evaporated under reduced pressure.

The residue was purified by silica gel column chromatography (Merck & Co., Art, 7734.70 g, elution solvent: hexane-ethyl acetate, 4:1 to 3:1) to obtain 2.5 g (69%) of the title compound.

IR(neat)cm"-': 3430.3060
．． '! 925.2860°1490, 1465.14
50.1355.1220.1195.1170゜11
10, 1090.10?0.1030.745.70O
NMR(90MH2, CDCl23)δ: 1.
17-2.50 (32H).

2.97-3.20 (2H), 3.27-3.57 (
8H), 3.80~4.03(LH), 7.20~
7.53 (15H) Example 9 4-[2-hydroxy-3-(1
6,16,17,17,1B,18.18-hebutafluorooctadecyloxy)probyloxycobutyl trityl ether 2.5 g (3.4 mmol) and methyl p-toluenesulfonate 1.5 g (8 mmol) ) was dissolved in toluene quaternary, cetyltrimethylammonium chloride 96
mg (0.3 mmol) and 50% caustic soda 1.6
g (20 mmol) was added thereto and stirred at a bath temperature of 90°C for 17 hours.

100 parts of chilled hexane was added, insoluble matter was filtered off, and low boiling point matter was distilled off under reduced pressure. The residue was dissolved in a mixed solvent consisting of 15 d of dioxane, 15 d of tetrahydrofuran, and 10 d of methanol, added with concentrated hydrochloric acid, and stirred at a bath temperature of 80° C. for 1 hour.

30 parts of water was added and the organic solvent was distilled off under reduced pressure. Water and ether were added to the residue and the mixture was shaken and separated, and the upper layer was washed with water and distilled off under reduced pressure.

The residue was purified by silica gel column chromatography [Merck, Art, 7734.40 g (elution solvent, hexane-ethyl acetate, 4:1 to 2:1)] to obtain 1.6 g (84%) of the title compound. .

IR(neat)cI11″″’: 3460.29
25.286G, 1465°1350, 1220.1
195.1170.112ON MR (90MHz,
CDC12a) δ: 1.10-2.37 (33H)
.

3.33-4.8: ((14■) Example 10 4-[2-methoxy-3-(16,16,17°) 4-[2-methoxy-3-(16 ,+6
．． 17.17,18,18.18-hebutafluorooctadecyloxy)propyloxycobutanol I, 6
g (2.9 mmol) and triethylamine 500 mg (
5 mmol) was dissolved in 30 g of toluene, 520 mg (4.5 mmol) of methanesulfonyl chloride was added, and the mixture was left at room temperature for 0.5 hour. Water was added and the mixture was stirred for 0.5 hours to separate the layers. The upper layer was washed with aqueous sodium bicarbonate, and the toluene was distilled off under reduced pressure. Dissolve again in 15 volumes of toluene and add 5 ml of 20% (weight ratio) dimethylamine toluene solution to 1 oo
The tube was heated to a bath temperature of 50° C. for 60 hours in a stainless steel tube. Ether and water were added to the reaction solution, the mixture was shaken, and the layers were separated. The upper layer was distilled off under reduced pressure and subjected to silica gel column chromatography [Merck & Co., Art, 7734. 30g (elution solvent.

Purification with chloroform-methanol, 10:1 to 4:1) afforded 1.27 g (76%) of the title compound.

IR(neat)cm"-': 2920.2860
．． 2g10.2760°1465, 1355.1225
．． 1195.1150.112ONMR (90MHz,
CDC (2s) δ: 1.13-1.87 (30H).

1.90-2.40 (IOH), 3.30-L60 (
121+) Example 11 4-[2-methoxy-3-(16,16,17°17.
18,18.18-hebutafluorooctadesiloxy)
Probyloxycobutyldimethylamine N-oxide 4-[2-methoxy-3-(16
, 16,17,17,18,18,18-heptafluorooctadecyloxy)probyloxycobutyl The same procedure as in Example 3 was carried out using 1.3 g (2.2 mmol) of dimethylamine to give 1.0 g of the title compound. (75%).

I R (Nujol) cm″″’: 3330.135
5.1240.1225°1215, 117G, 11
15.905.725NMR (90MHz, CDC
Qz) δ: 1. ．． 13-2.40 (32H).

3.17-4.83 (20H) Example I2 3-(12-cyclohexyldodecyloxy)-2-methoxypropanol, 70 g (4,78 mmol)
, 657 mg (5.74 mmol) of mesyl chloride was added dropwise to a mixture of 580 mg (5.74 mmol) of triethylamine and 100 mg of dichloromethane under cooling with water. After stirring for 1 hour while cooling with water, the reaction mixture was washed with water, saturated aqueous sodium bicarbonate, and water in this order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was chromatographed on a column of silica gel (60 g) using hexane:ethyl acetate (
5:1) to give the title compound as a colorless solid. Yield 1.93g (97%).

I R(KBr)cm-': 2925,2g50,1
345,1170.1125°986,965.86O NMR (90MHz, CDCl+) δ: 1.27 (2
6H), 1.50-1.83 (7H), 3.05 (3
H), 3.38-3.70 (8H), 4.17-4.
50 (2H) Example! 3 Diethylene glycol 2.03g (19.2 mmol)
dissolved in dimethyl sulfoxide (DMSO),
0.576 g (14.4 mmol) of 60% sodium hydride was added and stirred at 75°C for 1 hour. This was returned to room temperature, and 1.93 g (4.62 mmol) of 3-02-cyclohexyldodecyloxy)-2-methoxypropyl methanesulfonate obtained in Example 12 was dissolved in 5 dD.
After adding the MSO solution, the mixture was stirred at 75°C for 1 hour. After the reaction, 20 d of water ice and 50 d of a mixture of hexane and ethyl acetate (1:1) were added to the reaction mixture, and after stirring well, the organic layer was separated. The aqueous layer was extracted with hexane-ethyl acetate (1:I).
The organic layers were combined, washed with water, and dried (MgS
O4) The solvent was then distilled off. The residue was soaked in silica gel (60
Chromatography on column g) and hexane-
Elution with ethyl acetate (1:1) gave the title compound as a colorless oil. Yield: 1.0 g (yield: 49%).

IR(neat)cm-': 3430.2920.
2850.1460.1445°NMR (90MHz,
CD CI, ) δ: 1.27 (768), 1.47
-1.75 (7H), 2.50 (1B), 3.3:1 (
-3,67(1+) Example 14 2-C2-[3-(12-Schiff a) obtained in Example 13
5.95 g (13.4 mmol) of hexyldodecyloxy)-2-methoxypropyloxycoethoxycoethanol was dissolved in dichloromethane (30° C.), and 1.76 g (17.4 mmol) of triethylamine was added thereto, followed by dilution of methanesulfonyl under water cooling. 1.84 g (16.1 mmol) of chloride was added dropwise over 30 minutes, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate.
The title compound was obtained as a colorless oil by distilling off dichloromethane. Yield fn7.0g (quantitative).

r R (neat) cm-': 2925, 2850, 1
465.1350,1170゜1110.1015,9
15,79O NMR (90MHZ, CD CI3) δ: 1
．． 26 (26H), 1.43-1, 75 (711)
, 3.04 (3H), 3.33-3.80 (1
6H), 4.35 (2H) Example 15 2-[2-C3-(12-cyclohexyldodecyloxy)-2-methoxopropyloxycoethoxycoethyl methanesulfonate 2 obtained in Example 14 .0g(
3.83 mmol) was dissolved in 10 d of 20% dimethylamine toluene solution and stirred overnight at room temperature and then at 30° C. for 4 hours, and then the reaction mixture was concentrated under reduced pressure. 30 d of dichloromethane and 10 d of saturated sodium bicarbonate solution were added to the residue, and the mixture was thoroughly shaken and the organic layer was separated. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off and the residue was purified with silica gel (
50 g) column and eluted with chloroform-methanol (6:1) to give the title compound as a colorless oil. Yield: 1.5 g (yield: 83%).

IR(neat)cm'''':2920,2g55
, 1465.112ON M R (90M HZ, C
D C13) δ: 0.80-1.35 (26+1).

1.45-1.80 (7H), 2.30 (6H), 2.
56 (2H), 3.33-3.67 (16H) Example I6 2-[2-[3-(12-cyclohexyldodecyloxy)-2-methoxypropyloxy]ethoxy obtained in Example 15 Conityldimethylamine 1.0g (2,1
2 mmol) was reacted in the same manner as in Example 3 to obtain 0.90 g of the title compound. Yield 87%IR(neat)cm
-' :2920.2850.1467, 112ON
M R (90MHz, CD CI3) δ: 0.9
0-1.37 (268).

145-1.75(7)1), 3.22(6H)'
, 3. L(-:(, 63(16B), 4.00(
2H) Example 17 2-methoxy-3-octadecyloxypropanol 5
．． 3 g (14.9 mmol) was reacted in the same manner as in Example 12 to obtain the title compound. Yield 6.50g (quantitative).

IR(KBr)am-': 2930,2855,1
465,1345,1330゜1170.1125,9
65,865 NMR (90MH2, CDC13) δ: 0.87 (3
H), 1.25 (30H), 1.53 (2H),
3.00 (3B), 3.33-3.67 (8H), 4
．． L(-4,50(2H) Example 18 6.50 g (14
, 9 mmol) was reacted in the same manner as in Example 13 to obtain the title compound as a colorless oil.

Yield 4゛, 28g (yield 64%).

I R(neat) cm″″’: 3425, 1110,
1065.72ON MR (90MHZ, CD
C13) δ, 0.87 (3H), 1.25 (301
1), 1.53 (21ri, 2.55 (LH), 3.3
3-3.80 (1811) Example 19 15 2-[ obtained in Example 18 in the same manner as in Example 14
The title compound was obtained as a colorless oil from 1.78 g (4.0 mmol) of 2-(2-methoxy-3-octadecyloxypropyl)ethoxy]ethanol. Collection ff12
．． IOg (quantitative).

r R(neat)cm'''': 2920, 2g50
,1465,1350,1175°11+0.920,
72O NMR (90M HZ, CD C13) δ: 0
．． 87 (3H), 1.27 (30H), 1.55 (
2H), 3.03(310, 3,33-3,80(
1611), 4.37 (2H) Example 20 2-[ obtained in Example 19 in the same manner as in Example 15
2-(2-methoxy-3-octadecyloxypropyl)ethoxy]ethyl methanesulfonate 2.10 g (
4.0 mmol) to give the title compound as a colorless oil. Yield: 11.6 g (yield: 85%).

IR(neat)cIll-': 2925,286
0,1465.112ON M R (90MHz,
CD CIs) δ: 0.87 (3H), 1.27 (3
011), 1.55 (2H), 2.23 (6H)
, 2.50(2Fl), 3.33-3.67 Example 21 N-oxide 2-[2Fl) obtained in Example 20 in the same manner as in Example 3
-(2-methoxy-3-octadecyloxypropyl)
The title compound was obtained as a colorless wax from 1.0 g (2.11 mmol) of ethoxyconityldimethylamine. Yield: 1.0 g (yield 97%).

IR(neat)cm'''': 3400,2925
．． 2850,1465,1110゜960.72O NMR (90MHz, CD Cla) δ: 0
．． 87 (3H), 1.27 (30H), 1.55 (
2H), 3.23(6H), 3.33-3.7
0(161), 4.05(2H) Example 22 1,2-epoxy-3-(16,+
6.17,17,18,18.18-heptafluorooctadecyloxy)propane (5.6 g (12.4 mmol)) was reacted in the same manner as in Example 8 to yield 6.6 g of the title compound.
(67%).

IR(neat)cm-': 34g0,3060,
2930, 2860, 1450°1225, 1200.
1170.1120,111 (1,109ON M R
(90MHz, CD C13) δ: 1. L7-2
．． 50 (29H).

3.17-4.03 (158), 7.17-7.60 (
15H) Example 23 Tadecyloxy)propyloxy]ethoxycoethanol 2-[2-[2-hydroxy-
3-(16,16,+7.17,18.1 B.

6.6 g (8.2 mmol) of 18-hebutafluorooctadecyloxy)probyloxycoethoxytrityl ether was reacted in the same manner as in Example 9 to obtain 3.85 g of the title compound.
g (82%) was obtained.

IR(neat)cm-': 3760,2925.
2g55,1465,1350゜1220.1190,
1165, 1115.1065NMR (1065N, C
DC13) δ: 1.20-2.50 (33H).

3.37-3.80 (18H) Example 24 2-[2-[2-methoxy-3- obtained in Example 23
3.85 g (6.7 mmol) of (16,16,17,17,18,18,18-heptafluorooctadecyloxy)probyloxy]ethoxy]ethanol were reacted in the same manner as in Example IO to obtain 3.6 g of the title compound. (90%
) was obtained.

IR(neat)cm-': 2920, 2860,
1465, 1350.1220°1195.1165.
1115 NMR (90MHz, CD CI3) δ: 1
．． 13-1. g3 (26H).

1.87-2.50 (28), 2.27 (68), 2.
50 (2H), 3.37-3.70 (16H) Example 25 Dimethyl-2-[2-methoxy- obtained in Example 24
3-(16, + 6.17.1 ?, 18.18°18
1.2 g (2 mmol) of -hebutafluorooctadecyloxy)propyloxy]ethoxyconitylamine was reacted in the same manner as in Example 3 to obtain 1.17 g (95%) of the title compound.
) was obtained.

I R (Nujol) cm-': 336G, 1255
,1240,1215,1190°1180.1165
, 1115.105ONMR (105ON, CD Cl
5) δ: 1.20-2.50 (28H).

3.27 (611), 3.33-3.70 (16+1)
, 3.97-4.10 (2H) Effects of the Invention The effects and effects of the compounds of the present invention will be explained below by showing test examples.

Test Example 1 4-[3-(12-cyclohexyldodecyloxy)-
Antitumor effect of 2-methoxypropyloxy]-butyldimethylamine N-oxide (Example 3) ICR mice (5 mice per group) were intraperitoneally implanted with 1×10 5 Sarcoma 180 cells per mouse. Then, 0.33 mg/mouse of the compound of Example 3 dissolved in physiological saline was added 1 hour and 1 day after transplantation.

Two days later, the drug was administered intraperitoneally three times in total. Table 1 shows the life extension rate (calculated only for those whose survival was less than 60 days) and the number of survivors 60 days after the start of the test compared to the control group in which no drug was administered.

Table 1 Test drug Life extension rate 60 days (T/C%)
Survival number/Test number Compound of Example 3 240 315 Test Example 2 Effect on platelets [Test method and effect] From male rabbits, 3.15% citric acid (ratio of 1 to 9 blood) as a blood coagulation inhibitor. Platelet-rich plasma (PRP: Pl
Atelet Rich Plasma) was obtained.

PRP was centrifuged at 300 Orpm for 15 minutes and platelet poor plasma (P P P
or Plasma) was obtained. Using PPP, PRP
The dilution was adjusted to a constant platelet concentration (400,000 cells/lμQ).

Using 250μQ of the PRP solution prepared in this way, add a test drug solution (e.g. 3xl) prepared in advance to this.
A certain amount of O-5M (concentration of O-5M) was added to adjust the drug concentration of the mixture to a predetermined concentration.

Platelet aggregation was measured using an aggregation needle (manufactured by Rika Denki). The results are shown in Table 2.

1x1α-8M, 3X10-'M Compound of Example 3 -0

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 hydrogen, or an optionally substituted lower alkyl group. group, an optionally substituted lower alkanoyl group or lower alkylthiocarbamoyl group, R^3 represents an N-oxide-tertiary amino group, and X represents the formula -(OCH_2CH_2)_m- (wherein, m is a divalent group represented by the formula -O(CH_2)_n- (in which n represents an integer of 2 to 12); .