JPH0256451A - Glycerin derivative - Google Patents

Abstract

NEW MATERIAL:A glycerin derivative shown by formula I [R<1> is (substituted) higher alkyl; R<2> is H, (substituted) lower alkyl, (substituted) lower alkyl, (substituted) alkanoyl or (substituted) nitrogen-containing 5-membered-7-membered heterocyclic group; R<3> is tertiary amine or quaternary ammonium; m and n are the same or different 3-18 integers wherein m+n is 6-24; J is O or group shown by formula II (r is 0-2)] and a salt thereof. EXAMPLE:N-[3-[3-[3-Octadecyloxy-2-(pyrimidinyl-2-oxy)propoxy]propoxy]p ropyl] thiazolium chloride. USE:Useful as an antitumor agent having high durability. PREPARATION:For example, a compound shown by formula III is reacted with a compound shown by formula IV and R<2> is introduced to a compound shown by formula V to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to glycerin derivatives useful as medicines. More specifically, the present invention provides compounds of general formula (1) useful as antitumor agents [wherein R' is an optionally substituted higher alkyl group, R' is a hydrogen atom, or R3 is a tertiary amino group or a quaternary ammonium group, rn and rl are the same or different, and m + n is 6 to 24. Indicates an integer between 3 and 18 within the range.

J is an oxygen atom or formula-3(0)r- (in the formula, "is O~
(indicates an integer of 2)] or a salt thereof.

3. Detailed description of the invention [wherein I<1 is optionally substituted higher alkyl J
, (, R2 is a hydrogen atom, or each optionally substituted lower alkyl group, lower alkameyl group, or nitrogen-containing 5-7 atom ring group, R3 is a tertiary amine group or a quaternary ammonium 8 , m and n are the same or different, and m+n is in the range of 6 to 24, 3 to 1
Indicates an integer of 8.

" is an oxygen atom or formula-3(0)r- (wherein r is O~
The present invention provides a compound represented by 1 representing a group represented by 1 (representing an integer of 2) and a salt thereof.

BACKGROUND OF THE INVENTION With recent advances in basic biochemical research, the differences between cancer cells and normal cells are gradually becoming clearer. It is believed that the abnormal proliferation and lack of contact inhibition of cancer cells are due to structural and functional changes in the cell membrane. Certain phospholipids, which are one of the constituent components of cell membranes and act as mimicking substances, are involved in the control of the activity of functional proteins present in membranes, and are important in various ways for cell function, metabolism, and life support. It has a great influence. From this biochemical background 11, among amphipathic glycerolipids,
Compounds with certain structural factors have been disclosed as having antitumor activity. For example, phospholipids represented by formula (II). [W, 1mi, l3erdel.

W, IiE Bauscrt, U, Fink, K.
Rosletter and P,G.

Munder, ^nticanccr Re5earc
h↓, 345 (1981)].

However, this compound is 101 small pseudoactivator (P
Because it is closely related to AI, it has various side effects such as bronchial stenosis, platelet aggregation, and decreased blood pressure. For this reason, clinical trials of the compound are currently subject to restrictions.

Recently, glycerolipids without phosphate groups (
In) [A = long chain alkyl, B - short or long chain alkyl or C2-5 °7'/l, [5 = -〇(Co
, ), -G, (1=I~12.G-ami7 groups, anruamiz group, dialkylami7 groups, quaternary ammonium group]
It has been disclosed that this compound suppresses platelet activating factor Tji(1) AF) antagonism and has potential as a therapeutic agent for PAF-related disorders (eg, anaphylaxis/Yonoku). [JP-A-60100544; JP-A-58-198445 flJ: T, Miyam
oto at al,, Kyot.

Conference of Prostagland
ins, Nov 26-28゜1984, AbsL
, p. 99], in actual use, there are demands for the persistence of action and the therapeutic index, and no equivalent specific disclosure has been made regarding the antitumor effect.

Problems to be Solved by the Invention In the case of drug therapy for cancer, there are many difficult problems such as existing anticancer drugs have poor selectivity compared to treatments for other diseases, are not effective against solid tumors, and have strong side effects or toxicity. has been done. Therefore, in the treatment of cancer, there is currently a particular desire for the development of more effective drugs based on new mechanisms of action, especially drugs that are highly selectively toxic to cancer cells. The inventors of the present invention have conducted extensive research to solve these problems, and have obtained the following solution.

Means for Solving the Problems In view of the above problems, the present inventors have developed a drug that has high selectivity for cancer cells and is useful as an anticancer agent among amphiphilic lipids having certain structural factors. I thought that it could exist.

Previous studies have reported that cancer cells generally have lower alkyl ether group-cleaving enzyme activity than normal cells. [R, L Wykle and F, 5nyder,
The Enzymes or Biological
Membranes, A., Martonosi.
Ed,, Vol.

2, Plenum Press, New York
, 1976, p87: IIl, Lin.

F, C, S, Ilo, and C, L, Il, Le
e, Cancer Rcs, 38. 946(+
978); M, Modell, R, And
rccscn, stomach, Pah I kc, U[3
rugger, and l', c, mundcr, c
ancer Res,, 39°4681 (197
9)].

Therefore, this type of alkyl etherified 6 compounds can be used for cancer cells,
In particular, if it accumulates in large amounts in focal tissues of solid cancers and has a highly selective antitumor effect, it is thought that it will exhibit a highly selective therapeutic effect.

Prior to the present invention, we focused on the ether type +A''9 form of glycerin, and as a result of intensive research on various derivatives,
The compound represented by the general formula (1) has high selectivity to various tumor cells and exhibits excellent antitumor activity;
In particular, for Sarcoma 5180 cells, compounds represented by the general formula (r) where m and n are 2 or less or the general formula (1
The present invention was completed by discovering that the antitumor effect is significantly enhanced compared to the compound represented by 11) in which B corresponds to R2, and that differentiation-inducing activity can also be expected.

That is, the present invention provides an antitumor agent containing the compound represented by the general formula (1) or a salt thereof.

In the general formula (1), the higher alkyl group represented by R1 is a linear group such as n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-icosyl, etc. and branched or branched alkyl groups having 8 to 20 carbon atoms. The higher alkyl group may have a substituent such as a phenyl group, naphthyl group, cycloalkyl group, hydroxy group, lower alkoxy group, or halogen atom. A phenyl group, a naphthyl group and a cycloalkyl group may be included in the higher alkyl group as a divalent group. Furthermore, methylene moieties other than the α (alpha) position may be substituted with an oxo group. Examples of the cycloalkyl group include 3- to 8-membered cycloalkyl groups such as cyclopentyl and cyclohexyl. The lower alkoxy group includes methoxy, ethoxy, propoxy, 1so-propoxy, n-butoxy, 1
Examples include alkyl groups having 1 to 4 carbon atoms such as so-butoxy, 5ac-butoxy, and tert-butoxy. Examples of the halogen atom as a substituent for the higher alkyl 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. .

Examples of the substituted higher alkyl group include 12-phenyldodecyl, I2-cyclopentyltridecyl, 10
-Cyclohequinrudecyl, 12-cyclohequinrudecyl, 2-hydroquineoctadecyl, 2-methoxyoctadecyl, 2-oxooctadecyl, 16,16.16-
) Rifluorohexadecyl, 18,18.18-trifluorooctadecyl, 14. I 4. I 5,15,16°16.16-hebutafluorohexadecyl, 16°16.
Examples include groups such as 17,17,18,18.18-heptafluorooctadecyl. The optionally substituted lower alkyl group represented by R1 includes methyl, ethyl,
Examples include alkyl groups having 1 to 6 carbon atoms such as furoyl, 1so-propyl, butyl, 5ec-butyl, tart-butyl, pentyl, and hexyl groups. The optionally substituted lower alkanoyl group represented by R'' includes formyl, acetyl, propionyl, n-butyryl, 1so
-butyryl, penta/yl, pivaloyl, valeryl, 1
Examples include alkanoyl groups having 1 to 6 carbon atoms such as so-valeryl. The optionally substituted nitrogen-containing 5- to 7-membered tυ ring group represented by R2 may be fused to a 2-membered ring, such as pyrrolyl, imitazolyl, pyrazolyl, oxasilyl, inoxasilyl, thiazolyl. , 1,2,3-oxadiazonol, triazolyl, tetrazolyl, thiadiazonol, piperidinyl, N-methylpiperazinyl, N-ethylpiperazinyl, morpholinyl, thiomorpholinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, azepinyl, diazepinyl, benzo Oxacylyl, benzothiazolyl, isoindolyl, indolyl, intridinyl, indazolyl, purinyl, quinolyl, isoquinolyl, quinolidinyl, phthalazinyl, naphthyridinyl, chimexalinyl,
Examples include bovine nasirinyl, dinolinyl, buteridinyl, and moieties or completely reduced groups corresponding to these groups.

The optionally substituted lower alkyl group, lower alkanoyl group, or nitrogen-containing 5- or 7-membered Pu ring group represented by R1 may have 1 to 3 substituents, and the substituents include: For example, halokene atoms (e.g., fluorine, bromine,
chlorine), lower (C1-C1) alkyl groups (e.g. methyl,
ethyl, propyl, butyl, pentyl, hexyl), lower (C7-C3) alkenyl groups (L vinyl, allyl,
l-methylvinyl, 2-methylvinyl), lower (03~
co) cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, /chlorohexyl), lower (C
6-C,) cycloalkenyl group (e.g., cyclopentenyl, cyclohexenyl), lower (07-C8) aralkyl group (e.g., benzyl, α-methylbenzyl, phenethyl)
, phenyl group, lower (C8-C6) alkyl group t jM
, lower (,C, ~C6) alkylsulfinyl group, phenylsulfinyl M, fukCC, ~C,)7/Lz-
1-lsulfonyl group, phenylsulfonyl group, mercapto group, sulfi7 group, sulfo group, phosphono group, sulfamoyl group, N-lower (C, ~C,)7/I/kylsulfamoyl group, N, N - di-lower (C, ~C6) alkylsulfamoyl group (e.g., N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N,N-
dipropylsulfamoyl, N,N-dibutylsulfamoyl), N,N- in which the alkyl moiety of the above N,N-dilower (C1-C8) alkylsulfamoyl group forms a ring
Disubstituted sulfamoyl group (e.g., ■-pyrrolidinylsulfamoyl, ■piperidinylsulfamoyl, l-piperazinylsulfamoyl, N-methylpiperazinylsulfamoyl, morpholinosulfamoyl), imino group, amidino group , ami7 group, N-lower (C, ~C,) alkylamino group, N,N-di-lower (C, ~C,) alkylamino group, 3- to G-membered cyclic ami7 group (e.g., i- azetidinyl, ■-pyrrolidinyl, 1-piperidinyl, l-piperazinyl, N-methylpiperazinyl, morpholino), lower (
C5-C8) alkanoyl group, lower (C1-C,) alkanoylamide group, benzamitono, (, benzoyl group, lower (C7-C,) alkanoyloxy group, benzoyloxyno, (, lower (C, - C,) alkoxycarbonyl group, lower (C2-C?) alkoxycarbonyl group, phenoxy group, phenylthiono, (, hydroxyl group, oxo group, thiooxoxy group, epoxy group, hydroquine-lower (01-C,
) alkyl group (e.g. hydroxyethyl), amino-lower (C, ~C,) alkyl group, carboxy group, carboxy-lower <c, ~C8) alkyl group, carbamoyl group, N
-lower (C1-C6) alkylcarbamoyl group, N, N
-(C,~C8)alkylcarbamoyl group (e.g., N,N-dimethylcarbamoyl, N,N-ethylcarbamoyl, N,N-dipropylcarbamoyl, N,N
-dibutylcarbamoyl), N,N-disubstituted carbamoyl in which the alkyl moiety of the N + N-dilower (C1-C,)alkylcarbamoyl group forms a ring! (Example, 1
Examples include substituents such as -azetidinylcarbamoyl, 1-pyrrolidinylcarbamoyl, 1-piperidinylcarbamoyl, 1-piperazinylcarbamoyl, N-methylpiperazinylcarbamoyl, morpholinocarbamoyl), sia/group, trifluoromethyl group, and ureido group. It will be done.

The tertiary amine 7 group represented by R3 has the formula [wherein R'
'' and R5 each represent a lower alkyl group which may have a substituent or a cyclic amino group formed by R4 and 15 together with the adjacent nitrogen atom] and a substituent. Examples include heterocyclic groups containing a good tertiary nitrogen atom.

The quaternary ammonium group represented by R3 is a quaternary ammonium group represented by the formula [wherein R', R6 and R'' are each a lower alkyl group which may have a substituent or R', R5 and R
Examples include a group represented by 6 indicating a cyclic ammonium group formed together with an adjacent nitrogen atom, and a heterocyclic group containing a quaternary nitrogen atom which may have a substituent.

The lower alkyl group represented by R', R' or R8 includes an alkyl moiety λ having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, butyl, pentyl, hexful), preferably a methyl group.

Cyclic amino J formed by R4 and R5 together with the adjacent nitrogen atom! It may be fused to a two-membered ring,
For example, pyrrolyl, pyrazolyl, imidazolyl, oxacylyl, thiazolyl, triazolyl, tetrazolyl,
Oxadiazolinyl, Thiadiazolinyl, Piperidino,
Dihydropyridyl, piperazinyl, l-[lower (C1~
C,) alkyl]piperazinyl, morpholino, thiomorpholino, indolyl, indolinyl, isoindolyl,
Examples include isoindolinyl groups and partial or completely reduced groups corresponding to these groups.

The cyclic ammonium group formed by R', Rll and R6 together with the adjacent nitrogen atom may be fused to a two-membered ring, such as l-pyridinio, 3-oxazole, 3-thiazolio, 1-imidazolio, l-pyridinio, l-pyrimidinio, l-pyridazinio, 4-intridinio, benzothiazolio, benzothiazolio,
1-quinolinio, 2-inquinolinio, 2-phthalazinio, l-naphthyridinio, 1-quinacillinio, 1- or 3-quinolinio, 1- or 2-quinolinio, l-
13-15- or 8-buteridinio, l [lower (C,
~C8) alkyl]-1-pyrrolinio, l[lower (C,
~C8) Alkyl]-1-pyrrolidinio, 1-[lower (
C,-C,)alkyl]-3-imidazolio, 1-[lower (C, ~C,)alkyl]-3-imidazolio, ■
-[lower (C, ~C,)alkyl]-2-virazolio,
1-[lower (C, -C,)alkyl]-1piperidinio, ■-[lower (C, -C6)alkyl]1-piperazinio, 4-[lower (C, -CO)alkyl]-4-morpholinio, 4-[lower (C1-Ca)alkyl]-4-thiomorpholinio, 1-[lower (C, ~C,)alkyl]l-indolinio, 1-[lower (C, ~C6)alkyl]-1-isoindolinio, etc. The basis of this can be mentioned.

R4, R5 or R8 in the tertiary amine 7 group and quaternary ammonium group represented by R3 may have 1 to 3 substituents at substitutable positions, and the substituents include: The substituents detailed as substituents for the optionally substituted lower alkyl group, lower alkanoyl group, or nitrogen-containing 5- to 7-membered nitrogen-containing cyclic group represented by R'' are suitable.

The 'fu ring group containing a tertiary nitrogen atom represented by R3 may be fused to a two-membered ring, for example, 1-[
Lower (C, ~Ca)alkyl copiveridine (2-3)-
yl, 1-1 lower (C, ~C,)alkyl"pyrroline-
(2-3)-yl, 1-[lower (C, -C,)alkyl]pyrrol-(2-3)-yl, 1-[lower (C, -C,
,)alkyl]imitazolin-(2-4)yl, 1-[
Lower (01-C6) alkyl coimidazole-(2-4
)-yl,]-[lower (01-c8)alkylcoindolyl-(3-5)-yl, l-[lower (C,~c,)alkyl]pyrazol-(3-5)-yl, oxazol-yl (2,4-5)-yl, thiazole-(2,4-5)
-yl, 1-1 lower (cl-c8) alkylcopiveridin-(2-4)-yl, pyridin-(2-4)-yl,
Pyrimidin-(2,4-6)yl, pyridazine-(3-
4)-yl, pyrazin(2-3)-yl, 1-[lower (
CI-Ca) 7l4l]piperazine-(2-3)
-yl, 4-[lower (C-CO)alkylcomorpholin-(2-3)-yl, 4-[lower r & (C, ~c8)alkyl]thiomorpholin-(2-3)-yl, hendioxazole-yl (2,4-7)-yl, benzothiazole-
(2,4-7)yl, 2-[lower (01-c6) alkyl]isoindolyl, l-[lower (C, -C8) alkylcoindolyl], 7-[lower (C, -c6) alkyl]
purinyl, inquinolinyl, quinolinyl, phthaladyl,
Examples include naphthyridinyl, chimexalinyl, quinazolinyl, dinolinyl, and buteridinyl groups.

The tow ring group containing a quaternary nitrogen atom represented by R3 may be fused to a two-membered ring (for example, 1,1-di[lower (C, ~CS) alkyl copiveridine group). −(2～
3)-yl, 1.1-di[lower (C,~C,)alkylcopiveridin-(2-3)-yl, ■.

3-di[lower (C, -C,)alkyl]imidazolinio(2-4)-yl, 1,3-di[lower (C, -C,)alkyl]imidazolinio(2-4)-yl, 3- [lower<c,~CO)alkyl]oxasilio(2,4
~5)-yl, 3-[lower (C, ~C,) alkyl]thiazolio-(2,4-5)-yl, 1-[lower (C, ~
C,)alkyl]pyridinio-(2-4)-yl, ■.

l-di[lower (C1-CO)alkylcopiperidinio(
2-4)-Inope 1,1-di[lower (C, -C,)alkyl]piperazinio-(2-3)-yl, l-[lower (C, ~C,)alkyl]virazinio (2-3 )-yl, 1-[lower (C3-Ca)alkyl]pyrimidinio-(2,4-6)-yl, l-[lower (C,-C,)alkyl]pyridacinio-(3-4)-yl, 4,4-di[1st class (C, ~C,)alkyl 17ruphorinio-(2~
3)-yl, 4,4-di[lower (C,~C,)alkylcothiomorpholinio-(2-3)-yl, 1-[lower (
C,~C,)alkyl]penzo-half-zolio-(2,4
~7)-yl, 1-[lower (C,-C,)alkyl]benzothiazolio-(2,4-7)-yl, 1-[low ff
1(C,~C6)alkylco~I-indolinio, I-
[Lower (C, ~C8) alkyl]-1~inindoly=
t, l-[(1(C,~C8)alkyl]quinolinio(
2-8)-yl, 2-[lower (C, ~C,) alkyl]
Isoquinolinio-(1,3-8)-yl, l, 1°4-
Tri[lower (C1-C8) alkyl]piperazinio (2
-3) Groups such as -yl are mentioned.

The heterocyclic group containing a tertiary nitrogen atom and a quaternary nitrogen atom represented by R' has R1
The optionally substituted lower alkyl group, lower alkanoyl group, or nitrogen-containing 5- or 7-membered chlorocyclic group shown in may have 1 to 3 substituents as detailed below.

When R3 is a tertiary amine group, the compound ([) is an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, boric acid, phosphoric acid, nitric acid, sulfuric acid) or an organic acid (e.g. , acetic acid, lactic acid,
It may also form pharmacologically acceptable salts with tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid).

When 1<3 is a quaternary ammonium group, a chemical compound (+
) may form a salt with an anion (W→), or may form an inner salt with an anion present in the molecule. 7! (
o- group), sulfide group (S-10), and carboxylade group (COO- group).When R3 is a quaternary ammonium group, the anion as W- is an inorganic acid (e.g., hydrochloric acid). , 1+3 ions of sulfuric acid, hydriodic acid, phosphoric acid, nitric acid, sulfuric acid), organic acids (e.g. acetic acid,
lactic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid)
Examples include pharmacologically acceptable anions such as the anion of .

In general formula (1), m and n are the same or different and represent an integer of 3 to 18 in which m+n is in the range of 6 to 24, but more preferably m and n are each 3 to 5.
It is.

J is an oxygen atom (-0-) or -5(0)r- (in the formula,
r represents an integer of O to 2), and J is more preferably an oxygen atom.

Furthermore, in the compound represented by formula (1), the carbon atom at position 2 of the glycerin skeleton is an asymmetric center, and its absolute configuration may be S, R, or SR (racemic). Furthermore, it may have an asymmetric center in addition to the glycerin skeleton, and in this case, it is possible for P(number of diastereoisomers to exist).

These diastereoisomers can be easily separated by conventional separation and purification means, if necessary. All diastereoisomers or mixtures thereof that can be separated in this way fall within the scope of the present invention.

The compound of the present invention can be produced, for example, by the following reaction steps.

In the above step, R1, R2, r<'', J, m and n have the same meanings as above, XSY and Z are each a removable group,
R7 and RII are optionally substituted phenyl groups,
It represents a tolyl group, a benzyl group, or a lower (C, to C,) alkyl group. R8 is an optionally substituted trityl group,
benzyl group, lower (C1-C8) alkyl group, lower (C
, -C11) alkyloxy lower (C, -C,) alkyl group, trisubstituted silyl group, tetrahydropyranyl group or tetrahydrofuranyl", (represents X, Y and Z
Examples of the releasable group represented by include halogen atom (chlorine, bromine, iodine atom), methanesulfonyloxy group, Hensensulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxoxy group, Examples include lower (C2-Co)alkanoyloxy groups. R7, R8 and R9 may be substituted; examples of such substituents include alkyl groups having from M1 to 4 carbons (eg, methyl, ethyl).

Propyl, isopropyl, butyl, isobutyl, sec
butyl, tert-butyl), alkoxy groups having about 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy).

1so-propoquine, n-butoxy, 1so-butoxy.

5aC-butoxy, Lert-butoxy group), halogen atom (e.g., fluorine, chlorine, bromine, iodine), nitro group,
Anono λ, trifluoromethyl group, di-lower (01-C
4) Alkylamino groups (e.g. dimethylamino, diethylamino/, dipropylamino, diisopropylami/, dibutylami 7 groups), alkylthio groups having about I to 4 carbon atoms (e.g. methylthio, ethylthio, propylthio, isopropylthio, n -butylthio, 5ec-butylthio,
tert-butylthio group), an alkylsulfinyl group having about 1 to 4 carbon atoms (e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl group), an alkylsulfonyl group having about 1 to 4 carbon atoms (L
Examples include methylsulfonylethylsulfonyl, propylsulfonyl, butylsulfonyl groups), etc. The 1/J-substituted silyl group represented by R' is, for example, substituted with three substituents selected from 8f consisting of a lower (C1-C8) alkyl group, a phenyl group, and a phenyl lower (01-C6) alkyl group. silyl groups, and these groups are further R? , RII and R11 may have 1 to 3 optionally substituted substituents.

The above steps will be explained in detail below.

First step: Glycine ether (■) is produced from alcohol (R'OH) according to a conventional method, and then HO-(CI,)
-0H is reacted to produce a compound (Rho).

Second process.

Compound (IV) is used in an amount of 08 to 1.5 equivalents, preferably 0.85 to 1.0 equivalents based on compound (III) and compound (1).
5 equivalent sulfonic acid-reactive derivative (R7S○.

X) in a suitable anhydrous solvent in the presence of a suitable basic catalyst or deoxidizing agent at -50° to +100°C, preferably -30° to +40°C for 0.5 to 48 hours, preferably 1
It can be produced by reacting for ~12 hours. Examples of anhydrous solvents used in the reaction include esters (e.g., ethyl acetate), ethers (e.g., dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), and halogenated hydrocarbons (e.g., dichloromethane, chloroform). ,Carbon tetrachloride)
, nitriles (e.g., acetonitrile), aliphatic hydrocarbons (e.g., pentane, hexane, heptane, octane), cycloaliphatic hydrocarbons (e.g., cyclopenkune,/chlorohexane), aromatic hydrocarbons (e.g., benzene, toluene) , xylene), nitromethane, pyridine, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, sulfolane or their suitable 1'7' 1flFj
A solvent is used.

Examples of basic catalysts or deoxidizing agents include tertiary amines (e.g., aliphatic tertiary amines such as triethylamine; pyridine, α-2β- or γ-picoline, 2,6-lutidine, 4-dimethyl /pyridine, 4/; aromatic tertiary amines such as 4-(1-pyrrolidinyl)pyridine, dimethylaniline, diethylaniline) are advantageously used.

Third king: Compound (V) has 1 to 50 equivalents, preferably 5 to 25 equivalents of HJ − with respect to compound (IV) and compound (IV).
(CfI,)-10H in the presence of a base in a suitable solvent at -10' to +100°C1, preferably at +1
0° to +50°C for 1 to 100 hours, preferably /I
It can be produced by reacting for ~24 hours. Examples of the base used in the reaction include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and barium hydroxide, sodium methoxide,
Metal alkoxides such as sodium methoxide and potassium tarj-butoxide, metal hydrides such as sodium hydride and potassium hydride, organometallic compounds such as phenyllithium and butyllithium, aliphatic tertiary amines such as triethylamine, pyridine, α -7β- or γ-
Examples include aromatic tertiary amines such as picoline, 2,6-lutidine, 4-dimethylami/pyridine, 4-(]-pyrrolidinyl)pinone, dimethylaniline, and diethylaniline. Examples of reaction solvents include water, alcohols (e.g. tert-butyl alcohol), ethers (
e.g., dimethyl ether, diethyl ether, tetrahydrofuran, /oxane, monoglyme, diglyme), halogenated hydrocarbons (e.g., 7chloromethane, chloroform,
carbon tetrachloride), nitriles (e.g. acetonitrile), aliphatic hydrocarbons (e.g. pentane, hexane, heptane, octane), cycloaliphatic hydrocarbons (e.g. cyclobencune,
cyclohexane), aromatic iA hydrogen hydride (e.g. benzene, toluene, xylene), nitromethane, pyridine,
Dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane or an appropriate mixed solvent thereof is used.

In addition, if necessary, 0, O
The reaction can also be advantageously progressed by using a phase transfer catalyst (eg, heptyl, IJ methyl ammonium chloride, etc.) in an amount of 1 to 0.2 equivalents, preferably 0.02 to 0.05 equivalents.

Fourth step.

Compound (Vl) is a compound obtained by protecting the primary hydroxyl group of compound (V). For example, benzyl, p-methoxy/hensyl, p-chlorobenzyl, p-nitrobenzyl, t-7' methyldimethyldinol, trityl, methoxymethyl, isopropylox7methyl, tetrahydropyranyl. , methyl, t-butyl, etc. The method for introducing the protective group is a method known to the public [j, 1ζw, McOm r [3, Protective Groups in Organic Chemistry (
Protective Groups in O
rganicChemistry), Planum
Press, London and NewYor
(1973)].

Regarding the third step, 1(J
Compound (V[) can also be produced by directly condensing -(C1-(,)-0R8 [wherein J and R8 have the same meanings as above] under the reaction conditions of the third step.

Regarding the first to fourth steps, the alcohol form HO(CI+,) was added to the compound (I[) according to a conventional method.
-J -(CH,) -OH or m
nl-10-(CI,)-J-(
cHt)-〇-R8 can also be condensed to form compound (V) or compound (Vl).

The raw material compound HO-(CI-1,)-J-(CI
-1,) n-OH or! 4O-(CH,)-J
-(CH,).

O-R8 is, for example, R''-0-(C1l,)-〇-3o, R' [in the formula,
R" is a hydrogen atom or a group represented by R8 or R9, and IIJ-(C11t)-ot+ or HJ-(CH2)-0-R" is condensed by the method of the third step, and the necessary If so, it can be easily produced by protecting it with R8 and, if necessary, deprotecting the protecting group (RIo).

The 5th king's compound (■) is prepared by combining compound (Vl) and R''Z in an amount of 1 to 5 equivalents, preferably 1.5 to 3 equivalents relative to compound (Vl), in the presence of a base. -1'O' to +80° in solvent
C1 Preferably, it can be produced by reacting at +10° to +40'C for 1 to 100 hours, preferably 4 to 24 hours. The base and solvent used are
Those used in the process can be applied mutatis mutandis. Also,
If necessary, 0.01-0.2 for compound (TV)
The reaction may be carried out using an equivalent, preferably 0.02 to 0.05 equivalent, of a phase transfer catalyst (eg, cetyltrimethylammonium chloride, etc.).

Sixth King's Process: The compound (■) is the compound (■) introduced in the fourth step.
It can be produced by deprotecting the Song group (R' group). Similar to the fourth step, the deprotection reaction of the protecting group is carried out by a method known per se [J. P. McOmie, Protective Groups in Organic Chemistry 1.
n Organic Chemistry), Plenu
m Press, London and N0IV
York (1973)].

Seventh step: Compound (IX) can be produced by reacting compound (■) with a sulfonic acid-reactive derivative (+29s O2X ) according to the method of the second step.

Eighth step - Compound (1) is prepared by itself or in a suitable solvent using an excess of secondary amine or tertiary amine/R4 R5 \R6 with respect to compounds (IX) and (IK). 20°~+
It can be produced by reacting at 150'C, preferably 00 to +100C. If necessary, it can also be produced by reacting the liquid in a sealed tube or under heating. Solvents used in the reaction include, for example, water, alcohols (M, methanol, ethanol, propatool,
1so-propertool, butyl alcohol, 5ec-butyl alcohol, tart-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol), ether M (e.g., dimethyl ether, diethyl ether J petetrahydrofuran, dioxane, monoglyme, diglyme), Halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), nitriles (e.g.
acetonide, lyle), aliphatic hydrocarbons (e.g., pentane,
hexane, heptane, octane), cycloaliphatic hydrocarbons (e.g., cyclobencune, cyclohexane), aromatic hydrocarbons (e.g., benzene, toluene, xylene), nitromethane, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane Or an appropriate mixed solvent thereof is used.

Regarding the fifth to eighth steps, the compound (1) of the present invention can also be produced, for example, by employing the following reaction steps.

(Left below) That is, compound (V) is converted to methanesulfone-1 in the same manner as in the second step, and this is treated with a secondary amine or tertiary amine in the same manner as in the eighth step. R1 was introduced in the same manner as in the fifth step, and the compound of the present invention (1
).

Regarding the first to fourth steps and the fifth to eighth steps, which reaction step is adopted can be appropriately selected depending on the physical properties of the intermediate and the final product.

In addition, 11 J −(CI,) used in the third step
Regarding n-〇I-[or HJ-(CH,)-〇R8 used in the combined process of the third and fourth steps, when J is -8(○)r-, r is 0 and At certain times, the reaction can proceed most advantageously. The compound (1) of the present invention in which r is O and the intermediates (V) to (IX) thus obtained can be subjected to an oxidation reaction commonly used in any step between the third step and the eighth step. By attaching
The compound of the present invention in which r is an integer of 1 or 2 (1
) and intermediates (V) to (IX).

This oxidation reaction is usually carried out in an amount of 0.50 to 1.50 equivalents, preferably 0.0 to 1.50 equivalents, based on the compound (1) of the present invention or intermediates (V) to (IX), when producing a compound in which r is 1. ．．
85 to 1.10 equivalents, and in the case of producing compounds where r is 2, 1.75 to 3.00 equivalents, preferably 1.8
Using 0 to 2.50 equivalents of oxidizing agent in a suitable solvent, -
50° to 100'C, preferably -20° to 50'C
．． It can be produced by reacting for 2 to 48 hours, preferably 0.5 to 12 hours. Oxidizing agents used in the reaction include, for example, oxygen, ozone, and halogens (
(e.g., chlorine, bromine, iodine), N-promosuccinimide, N-chlorosuccinimide, nitrogen oxide, nitrogen tetroxide, sulfuryl chloride, potassium permanganate, chromic anhydride, pyridinium chlorochromate, pyridinium dichromate , iodobenzene, hydrogen peroxide, 41-organic peroxide (
Examples, t-butylhypochloride, peracetic acid, perbenzoic acid,
p-chloroperbenzoic acid, etc.). Examples of reaction solvents include water, alcohols (e.g., methanol, ethanol, Floval, 1so-7" Lobanow/
Lz, ) (-alcohol, 5ec-butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxyethanol, 1-oxyethanol), esters (e.g., ethyl acetate), ethers (e.g., dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), halogenated hydrocarbons (e.g. dichloromethane, RIOOporm, carbon tetrachloride)
, nitriles (e.g., acetonitrile), aliphatic hydrocarbons (e.g., pentane, hexane, heptane, octane), cycloaliphatic hydrocarbons (e.g., /clopencune, nclohexane), aromatic iA hydrogen hydride (e.g., benzene, toluene) ,
xylene), nitromethane, pyridine, dimethylformamide, hexamethylphosphoramide, sulfolane, or an appropriate mixed solvent thereof. Furthermore, if necessary, compounds (I) or compounds (V) to (I
0.01 to 5.0 equivalents to X), preferably O1 to
25 equivalents of additives (e.g., quinoline, diazabicyclo-[
2,2,2]-octane, iodopotassium, tungstic acid, etc.), the reaction can proceed advantageously.

In addition, regarding the compound (1) of the present invention, the tertiary amine 7 group represented by R3 is a monocyclic group containing a tertiary nitrogen atom which may have a substituent, or the tertiary nitrogen atom represented by R3 is When the class ammonium group is a heterocyclic group containing a quaternary nitrogen atom which may have a substituent, for example, the following reaction steps may be employed.

That is, compound (II) and 1(O-(](2)-
J(CI+2)-R3 by the same method as in the first step, or compound (IV) and HJ(CH,)-R'
are condensed in the same manner as in the third step, and then in the fifth step
The compound (1) of the present invention can be produced by introducing R2 in the same manner as in the step.

The raw material compound +1O-(CH2)-J-(O112
)nR3 is, for example, R''-0(CI-It)-0-3OtR7 [wherein,
R7, RIO have the same meanings as above] and 1IJ-(CI
-[,)=R3 is condensed by the method of the third step, and if necessary, it is protected with Re, and if necessary, the protecting group (
It can be easily produced by deprotecting R10). In the compounds described in the above steps, J is -3(0)r-
When r is O, it can be easily converted into a compound where r is an integer of 1 or 2 as appropriate by the oxidation reaction described above.

In formula (1), a compound in which R3 is a quaternary ammonium group is a compound in which R3 is a tertiary amino group in formula (1), for example, a lower (C+ to C6) alkyl halide or a lower sulfonic acid. It can also be produced by reacting with (C, -C,) alkyl.

This reaction is usually carried out in the above-mentioned solvent at 0° to +100°C.

When R3 is a tertiary amine 7 group, a salt of compound (1) may be obtained in the step of producing compound (1) itself;
If necessary, a salt can also be produced by adding an inorganic or organic acid. When R3 is a quaternary ammonium group,
The target anion can also be exchanged using an anion exchange resin or the like.

Although a typical method for producing Compound (1) has been described below, the method for producing Compound ([) is not limited to this method only.

The active compound (1) has substantially no platelet aggregation effect, hypotensive effect, or vascular permeability acceleration effect. Also, the compound (
1) is the main effect (e.g., antitumor activity including differentiation-inducing effect)
1) enhancement and persistence are observed.

In other words, 1 piece of mouse meat, 5I80, mouse mammary cancer,
In addition to showing λ and fL survival effects in tumor-bearing mice inoculated with MM46 cells, it has also been shown to be effective against human promyelocytic leukemia, l1160 cells, human non-small cell lung cancer, which is said to be highly drug-resistant, and HUT2.
9, A349, etc., is significantly suppressed. Therefore, compound (1) and its salts can be administered to cancer-bearing warm-blooded animals as safe antitumor agents. administration method,
The administration route and dosage can be selected as appropriate depending on the subject and symptoms, but the dosage for 1-0 mammals is usually 0. The amount is about 1 to 150 mg/kg (body weight), preferably 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 70 ft/J. Also,
It is also possible to administer the drug intravenously over a long period of time in order to maintain the drug concentration in the tissues at the required level for a long period of time. If drugs are administered via the parenteral route in combination with serum albumin or various glupurins, the drug's efficacy will not be affected and the tissue (local)
Further improvements in safety, such as prevention of accidents, can be expected.

Compound (]) and its salts have excellent hydrophilic and lipophilic properties, and are safe for oral or parenteral administration to mammals, either as a powder or as a pharmaceutical composition with an appropriate agent q2. It can be administered to

The pharmaceutical composition used for administration comprises an effective amount of compound (1)
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. 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 ura, alcohols such as ethanol, and polysorbate 80. Such compositions may further contain Nli adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, and, in the case of aqueous injections, glucose, serum albumin, blood tN (plasma) globulin, and the like. These may be sterilized, for example, by filtration through a Bacterium Noah retention filter, by incorporation of a disinfectant, or by UV irradiation.They may also be used to produce a sterile solid composition; 11; 1 to 111 (can also be used closed or dissolved in a sterile injection solvent).

Tablets, capsules, etc. can also be manufactured 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, hydroxypropyl cellulose, crystalline cellulose, starch, etc. 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.

Effect of the invention The effects of the compounds of the present invention will be explained in detail using test examples.

Test Example 1 Cell proliferation inhibitory effect on HL-60 of the compound obtained in Example! ! (IC,,) Human white-faced disease cells HL-60 (2 x 105 cells/ml) were suspended in GIT medium (Wako Pure Chemical Industries, Ltd.) containing example compounds, and
0.2 ml of each formula was inoculated into a 6-well microwell plate. Static culture was performed for 68 hours at 37°C and 5% CO, and 1 μCi of ['H]thymidine (5Ci/mm
ol) was added, and the culture was continued for an additional 4 hours. In order to measure the uptake of thymidine into cells, the acid-insoluble fraction was collected on a glass filter, and its radioactivity was measured using a liquid scintillation counter. The concentration of drug required to reduce the radioactivity taken up into cells to 50% of the untreated control group was defined as the IC6° value of the compound. The results obtained (rc, .) are shown in Table 1.

Table 1 Compound of Example 2 2.50 Compound of Example 3 1.25 Compound of Example 6
2.50 Compound of Example 8 5.00 Compound of Example 9 1.25 Compound of Example 18
2.50 Compound 2 of Example 19
．． 50 Compound of Example 20 < 0.63 Compound of Example 21 5.00 Test Example 2 Antitumor activity of the compound of Example 6 against Sarcoma 180 cells.
×lO6 Sarcoma 180 cells were subcutaneously transplanted into the dorsal region. 8 days, 9 days, 10 days, 13 days, 14 days after transplantation,
15th, 16th, 17th, 201 days later.

The compound of Example 6 (0
, 3 mg/mouse) was orally administered. After 211 days, the tumor tissue was excised and the tumor weight was measured. Tumor growth inhibition rate (inhibition rate) compared to that of a control group without drug administration
tion ratio) are shown in Table 2.

Table 2 Test compound Administration ffl (mg/mouse) Growth inhibition rate (+-T/C%) Compound of Example 6, 0.
372 Test Example 3 Antitumor activity of the compound of Example 6 against breast cancer cells MM46 C31-1 mice (5 mice per group) were administered 1x per mouse.
To' mouse breast cancer cells MM46 were implanted intraperitoneally. After transplantation, the compound of Example 6 (0.20 mg/mouse) dissolved in physiological saline was intraperitoneally administered once a day for 4 days from the second white of the eye. Table 3 shows the survival prolongation rate and the survival comparison of 60 [I after the start of the study compared to the control 1if without drug administration.

Table 3 Test compound Survival extension rate (T/C%) Live (T-number/
Number of tests Compound-1-515 of Example 6 Control group 100 01
EXAMPLES Below, the present invention will be explained in more detail by referring to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 1. Production of 2-epoxy-3-octadecylpropylene/propane Shrimp chlorohydrin (41.1 g), stearyl alcohol (30 g) and cetyltrimethylammonium chloride (1.8 g) were dissolved in toluene (80 ml), Then, 50% aqueous sodium hydroxide solution (40 ml) was added and stirred at 60°C for 5 hours. Hexane (40
After removing insoluble matter, the filtrate was distilled off under reduced pressure. Hexane (500 ml) was added to the residue, left overnight, and the re-generated insoluble matter was filtered off, and the filtrate was distilled off under reduced pressure to obtain the title compound (22.35 g').

I R (Nujol): v 1250.1115.
905.855.725°715 am-' NMR (90MIIZ, CDCl5): δ0.
74-1.16 (311), 1.16-1.78 (3
211), 2.51-2.6 111), 2.68
-2.38 (111), 3゜01-3.26 (IH)
, 3.26-3.82 (4H) Reference Example 2 Production of 3-[(2-hydroxy-3-octadecyloxy)propoxy]propanol Trimethylene glycol (95.8 g) was mixed with dioxane (
600 ml), 60% oily thorium hydride (1.78 g) was added thereto, and the mixture was stirred at room temperature until the generation of hydrogen gas stopped. Then, the compound of Reference Example 1 (24,
3g) was added and reacted at +10°C for 4 hours. The solvent was distilled off, and the residue was partitioned between hexane-ether-water.

The organic layer was separated, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel-12 ram chromatography [carrier: 300 g, developing solvent: hexane:ethyl acetate:acetone-4:l:l→2:1:l
] The title compound Qt, zg) was obtained.

NMR (90MIIz, CDCl5): δ 0
．． 80-1. , 02 (311), 1.081, 74
(3411), 3.37-4.01 (11!1) Reference Example 3 Manufacture of 3-[3-[(2-hydroxy-3-octadecyloxy)propoxy]propoxy]propertool η Compound of Example 2 (++, 2g)/chloromethane (200m
1) and added triethylamine (2.2 ml). To this, methanesulfonyl chloride (
A dichloromethane solution (30 ml) of 4.0 ml) was added dropwise, and the mixture was left stirring for 1.5 hours. The reaction irM was washed with dilute hydrochloric acid, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography [carrier: 140 g, developing solvent: chloroform] to give 3-[3-[(2-hydroxy-3-
Octadesyloxy)propoxy]propyl methanesulfonate (9.3 g) was obtained. The total amount of this stuff is 1.3
-Dissolved in propanediol (22,4 g), added 60% oily sodium hydride (0,88 g) and heated at 80 °C for 4 hours.
The mixture was left stirring for an hour. Add 60% oily sodium hydride (0.58g) and heat at 80°C for 4 hours at 100°.
The reaction was carried out at C for 40 minutes. Add hexane-ether to the reaction solution.
Water was added to the mixture for partition, and the organic layer was separated, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.

The residue was subjected to silica gel chromatography [carrier:
250 g, developing solvent; hexane:ethyl acetate:acetone-5:I:l→2:l:1] to obtain the title compound (2.36g).

NMR (90MllZ, CDC13): δ
Q, 74-1.17 (all), 1.172.1
4 (3611), 2.72 (ilri), 2.98 (I
ll), 3.35-4.06 (+511) Reference Example 4 3-[3-[(2-hydroxy-3-octadecyloxy)propoxy]propoxy]bu! Manufacture of panol triphenyl methyl ether The compound (2.74 g) of Reference Example 3 was mixed with pyridine (25 ml).
), trityl chloride (2,6 g) was added, and the mixture was reacted at 80°C for 4 hours. Add methanol (
7 ml) was added and stirred at 80°C for 20 minutes to decompose excess reagent. Pyridine and methanol were distilled off, and the residue was partitioned between hexane-ether-water. The organic layer was separated, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography [carrier; 55 g
, Fji opening solvent; hexane:ethyl acetate-10:1→
4:1] to give the title compound (3.33 g).

l R (Neat): ν 2930. 2g60
．． 1460. 1443. 1110°756, 74
2.700 cm NMR (90MllZ, CDC13): δ Q
, 7l-IO2(3+1), 1,022.07(3
60), 2.48(Ill), 3.01-3.65
(+511), 3,653, 88 (Ill), 7.
03-7.52 (15+1) Reference Example 5 3-[3-[3-octadecyloxy-2-(pyrimidinyl-2-oxy)furoboxy]propoxy]prop/-
The compound of Example 4 (3.31 g) was dissolved in tetrahydrofuran (40 ml) and 60% oily hydrogenated thorium (
0.21 g) was added and stirred at room temperature for 10 minutes. to this,
Add 2-chloropyrimidine (2,t5g) and stir at 80°
After reacting at C for 4 hours, ethanol (5 ml) was added and the solvent was distilled off. The residue was partitioned between hexane-ether-water, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off to give crude 3-[3-[3-octadecyloxy-2(
pyrimidinyl-2-oxy) propoxy]
Proper tool triphenyl methyl ether was obtained. Next, add this to tetrahydrofuran (50ml)
- Dissolve in methanol (25 ml) mixture and add concentrated hydrochloric acid (l m
After adding l), the mixture was left stirring at room temperature for 3.5 hours. After neutralizing the reaction solution with an aqueous potassium carbonate solution, the organic solvent was distilled off,
To this was added hexane-ether (120ml). The organic layer was separated, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [carrier: ao g, development m'S: hexane: ethyl acetate: acetone = 7:1:l → 4 :11] to obtain the title compound (2.18 g).

IR (Neat): v 2920.2g50.
1575.1560.1460°1420, 1325.
1110.726 cm-'N M R (90 Mtlz
, CDC13): δ 0.73-1.08 (3+1
), 1.08-2.00 (36+1), 2.64 (
ill), 3.33-3.93 (14+1), s,
1s (tI+), 6.89 (1,11), 8.74
(210 Reference Example 6 3-[3-[3-octadecyloxy-2-(pyrimidinyl-2-oxy)propoxy]propoxy]propyl
Methane sulfonate! Preparation The compound of Reference Example 5 (2.16 g) was dissolved in dichloromethane (5 g).
Triethylamine (0 ml) was dissolved in triethylamine (0 ml) and stirred with water cooling.
72 ml) and methanesulfonyl chloride (0.4 ml)
added. After being left at room temperature for 3.5 hours, triethylamine (0.39 ml) and methanesulfonyl chloride (0.22 ml) were added again under water cooling, and the mixture was left stirring at room temperature for 30 minutes. The reaction solution was sequentially washed with dilute hydrochloric acid, saturated dehydrated water, and water, dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain the title compound (2.41 g).

I R (Neat): ν2925.2860. 1
575. 1563. 14621420, 1350.
1330. 1170.1110.9B5.945c
mNMR (90MIIZ, CDC13): 60
．． 73-1.03(311), 1.032, +6(
3611), 2.98 (311,s), 3.33-
3.93 (1211), 4.30 (2+1), 5.
45 (ill), 6.89 (II+), 8.74 (
2+1) Reference Example 7 Production of 5-[(2-Hydroxy-3-octadecyloquine/]pentyl alcohol The compound (4.17 g) of Reference Example 1 was treated in the same manner as Reference Example 2, and 1.5 Condensation with -bentanediol gave the title compound (4.57 g).

11? (Nujol): ν3500.3320.1
380.1340°1125 cm NMR (90MIIz, CDCl 3): 60
．． 87 (3+1), 1.13-1.77 (39+1)
, 2.53 ([11), 3J7-4.10 (til
l) Diagnosis - Example 8 5-[5-[(2-Hydroxy-3-octadecyloxy)proboxycopentoxy]pentyl alcohol Production of triphenyl methyl ether The compound (1.0 g) of Reference Example 7 was prepared as a reference example. Methanesulfonylation was performed in the same manner as in 3, followed by condensation with 1,5-bentanediol to obtain 5-[5-[(2-hydroxy-3-octadecyloxy)propoxy]pentoxy]pentyl alcohol. When the entire amount of this product was triphenylmethylated in the same manner as in Reference Example 4, the title compound (0,8
2g) was obtained.

NMR (90MIIz, CDCl5): δ0.
87 (3+1), 1.02-1.83 (4 old 1),
2.52 (II+), 2.80-3.73 (14
11), 3.88 (II+).

7,07-7,62(15+1) Reference Example 9 5-[5-[(2-methoxy-3-octadecyloxy)
Propoquine (pentoxy)pentyl alcohol The compound of Reference Example 8 (9.0 g) was dissolved in toluene (25 ml).
6g), 50% aqueous sodium hydroxide solution (13ml) and cetyltrimethylammonium chloride (0,3
8g) was added thereto, and the mixture was stirred and reacted at a bath temperature of 80°C for 24 hours. After the reaction was completed, toluene (1.0 ml) was added to the reaction solution, washed with water, and then the aqueous layer was diluted with hexane-ethyl acetate (1:l, 60ml).
ml). The organic layers were combined, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (50 ml) and tetrahydrofuran (50 ml).
(2) The mixture was dissolved in &, sulfuric acid (1.0ml) was added, and the mixture was left at room temperature for 65 hours.

l) Neutralized with rum aqueous solution, solvent distilled off, and the residue was subjected to licage gel column chromatography [carrier;
135 g, developing solvent: hexane: ethyl acetate: acetone = 4+l:O→5:1. :1] to give the title compound (4.17 g).

NMR(90MIIz, CDCl+): δ0.
86 (3H), 1.05-1.83 (440), 3
．． 22-3.75 (+811) Reference Example 10 5-[5-[(2-methoxy-3-octadecyloxy)
Production of propoxy]pentoxy]pentyl methanesulfonate Reference Example 9 compound (t17g) was subjected to a methanesulfonylation reaction in the same manner as in Reference Example 6 to produce the title compound (4.5
7g) was obtained.

NMR (90MIIz, CDCl 3):
60.87 (311), 1.0g1.98 (44
11), 2.9'1 (311), 3.27-3.7
2(16+1), 4.22(2+1) Reference Example 11 5-[5-[(2-carboxymethoxy-3-octadecyloxy)propoquine]pentoxy]pentyl alcohol Production of triphenylmethyl ether: Compound of Example 1 (3,80 g) was dissolved in tetrahydrofuran (50 ml), and 60% oily hydrogenated sodium chloride (+,00 g) was added.
was added and stirred at 70°C for 2 hours. Add iodoacetic acid (
2.79 g) was added thereto, and the mixture was further stirred at 70°C for 30 minutes. Water (50 ml) was added to the reaction solution, extracted with ethyl acetate (300 ml), and the ethyl acetate layer was separated, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [
Support: 200 g, developing solvent: hexane, ethyl acetate-10:l → 5:l and chloroform:meth/-l:
Purification with water-65:1.0:1.1 yielded the title compound (3
, 62g) was obtained.

1 1? (Neat): ν 2940. 2g
75. 1655. 1610. 1500°1450
, 1430. 1320. 1120.765.750
．． 710 cmN M R (90) Allz, CDC
13) 60.87 (311), 1.25-1
．． 70 (45+1), 3.04 (2+1), 3
．． 27-3.56 (+411), 4.06 (III
)7, 15-7.47 (1511) Reference Example 12 5-[5-[(2-methoxycarbonylmethoxy/-3-
Production of octadecyloxy)propoxy'pentoxy]pentyl alcohol and 5-[5-[(2-calphokydimethoxy3-octadecyloxy)propoxy]pentoxy]pentyl alcohol The compound (3.62 g) of Reference Example 11 was mixed with dioxane ( 15
0ml), methanol (70ml) and 2N hydrochloric acid (
72 ml) and stirred at 60°C for 1 hour. After neutralizing the reaction solution by adding baking soda (12.15 g), the volume was reduced to about 70 ml! Shrunk. The residue was subjected to silica gel column chromatography [carrier: 100 g, developing solvent,
Hexane:ethyl acetate - 4:l→3.1 and chloroform:methanol:water -65:10:l→65:15:
2] to produce 5-[5-[(2methoxylpoxy-3-octadecyloxy)propoxy]pentoxy]pentyl alcohol (A+, 43 g) and 5
-[5-[(2-carboxymethoxy-3-octadecyloxy)propoxy]pentoxy]pentyl alcohol (B, 0.915 g) was obtained.

Compound (A): 11<(Neat): v 3460.2930.2
870.1780.1465゜13g0.1205.1
115 cm-'NMR (90MIIZ, CDC
13): δ0.80-0.93(311), 1.2
5 (3211), 1.40-1.73 (1411),
3.33-3.80 (1511), 3.72 (31
1), 4.31 (2+1).

Compound (B): IR(Neat): v 3400.2930.2
870.1610.1465゜1430, 1115
cm-' NMR (90 MIlz, CDC13): 60
．． 80-0.93 (3+1), 1.25 (3211
), 1.401.71 (+411), 3.33
-3.73(1511), Cl0(2+1) Reference Example 13 5-[5-[(2-methoxylponylmethoxy/-3-
Octadesyloxy)propoxy]pentoxy]pentyl alcohol Methanesulfonate (7) Production reference example 1
Compound 2(A) (960 mg) was subjected to methanesulfonylation reaction in the same manner as in Reference Example 6 to give the title compound (890 mg).
mg) was obtained.

I R (NeaL): v 2930.2870.
1760.1470. 1355°1205, 11
75.1120.955 amN M R (90Mtl
z, CDC13): δ 0.87 (311), 1
．． 27 (3211).

1, 40-1.85 (1411), 2.98 (3+1
), 3.33-3.55 (12+1).

3.39 (311), 4.18 (2+1), 4.3
0 (211).

Reference Example 14 5-[5-[(3-octadecyloxy-2-(pyrimidinyl 2-oxy)propoxy]pentoxy]pentyl
Production of methanesulfonate In the same manner as in Reference Example 5, the compound of Reference Example 8 (7.6 g)
and 2-chloropyridine (2.9 g) to 5-[5-[
(3-Ophtadecyloxy-2-(pyrimidinyl-2-oxy)propoxy]pentoxy]pentyl alcohol was obtained. The entire amount of this alcohol was subjected to a methanesulfonylation reaction in the same manner as in Reference Example 6, and the title compound (4゜6
7 g) was obtained.

1 1<(Nujol): v 15g0. 1
570. 1430. 1415. 13801345
, +320. 1165.1120.955 ct
nNMR(90Mllz, CDCl3): δ
0.87 (3+1), 1.10-1.90 (471
1), 3.00 (3+1), 3.27-3.57 (
8+1), 3.70 (411).

4.23 (2+1), '5.47 (Ill), 6.9
0 (Ill), 8.53 (2+1).

Reference Example 15 Production of 7-[(2-hydroxy-3-octadecyloxy)propoquine]heptyl alcohol The compound of Reference Example 1 (8.24 g) was condensed with 1,7-heptanediol in the same manner as in Reference Example 2. The title compound (6.44 g) was then obtained.

I R (KBr): ν2920.2850.14g0
．． 1468.1127°1060, 1032.715
cm-'NMR(90MIlz, CDC1,)
: δ 0.86 (3+1), 1.08-1.80
(42+1), 3.34-3.78 (1011),
3.78-4.08 (Ill) Reference Example 16 Production of 7-[7-[(2-hydroxy-3-octadecyloxy)propoxy]hebutyloxy]-heptyl alcohol triphenyl methyl ether Compound of Reference Example 15 ( 6,44g) was methanesulfonylated in the same manner as in Reference Example 3, and then condensed with 1,7-hebutanediol to give 7-[7-[(2-hydroxy-3
Octadef 0xy) propoxy 1 heptyloxy J hebutyl alcohol was obtained. When the entire amount of this product was triphenylmethylated in the same manner as in Reference Example 4, the title compound (
3.94 g) was obtained.

IR(KBr): v 2920.2850.15
92. 1490. 14641442, lf[3
,1070,700cmNMR(90MllZ,
CDC13) 60.87 (3+1), 1.03-
1.81 (52+1), 3.03 (2+1), 3.
17-3.73 (+211), 3.73-1.03 (
Ill), 7.07-7, 58 (15+1) 5 Example 1
7 Production of 7-[7-[3-octadecyloxy-2-(pyridinyl-2oxy)propoxy]hebutyloxy]heptyl alcohol The compound of Reference Example 16 (3.86 g) was prepared in the same manner as in Reference Example 5, and 2 Treatment with -chloropyridine (1,09g) gave the title compound (2,09g).

+ R (Neat): v 2930.2860.
1576, 1560.1461゜1422, 1330
．． 1308. 1115. 1055.802cm-'
NMR (90MIIz, CDC1,): 60.
86 (3+1), 1.03-1.74 (5211)
, 3.23-3.80 (1411), 5.45 (il
l), 6.87 (110°8, 47 (21+) Reference Example 18 Production of 7-[7-[3-octadecyloxy-2-(pyridinyl-2-oxy)propoxy]hebutyloxy]hebutyl methanesulfonate When the compound of Reference Example 17 (2.05 g) was subjected to methanesulfonylation reaction in the same manner as in Reference Example 6, the title compound (t,
a9g) was obtained.

IR (Neat): v 2935.2g60.1
578. 1562. 14231355, 1320
．． 1175. 1115 cm-'N M R (90
MIIZ, CDC13): 60.87 (311)
, 1.09-0.98 (52+1), 1.09
-1.90 (4211), 2.98 (3+1),
3.25-3.72 (1211), 4.20 (2
+1), 5.31-5.60 (III), 6.
87 (Ill).

8.47 (2+1) Reference Example 19 Production of 5-(tetrahydropyranyloxy)pentyl mercaptan 5-(tetrahydropyranyloxy)pentan-l ol (4,Ig) was dissolved in dichloromethane (50 ml), and under water cooling, Methanesulfonyl chloride (3.74g)!・
Ethylamine (3.3 g) was added and stirred at room temperature for 1 hour. The reaction solution was washed with water and aqueous sodium bicarbonate, dried, and concentrated to obtain 5-(tetrahydropyranyloxy)pentyl methanesulfonate (5.4 g). This methanesulfone +- (5.37 g) was mixed with dimethyl sulfoxide (4
After adding potassium thioacetate (33.6 g), the mixture was stirred at room temperature for 1 hour. Cold water (10
0 ml) was added, extracted with ethyl acetate (100 ml), washed with water and then with aqueous sodium bicarbonate, dried and concentrated to give 5(tetrahydropyranyloxy)pentyl thioacetate-1-(
5g) was obtained. The entire amount (5 g) of this product was dissolved in tetrahydrofuran (30 ml), and hydrazine hydrate (2 ml) was dissolved in tetrahydrofuran (30 ml).
1) was added and stirred at room temperature for 1 hour. After concentrating the reaction solution and dissolving the residue in ethyl acetate (50 ml), washing with water and then saturated brine, and concentrating, the title compound (3.6 g) was obtained.
was gotten.

NMR (90MIIZ, CDCl5): δ 1
．． 25-2.00 (12+1), 2.16 (211)
, 3.20-4.00 (All), 4.55 (il
l) Reference Example 20 Production of 5-[5-(2-hydroxy-3-octadecyloxypropoxy)pentylthiocobentyl tetrahydropyranyl ether Reference η The compound of Example 7 (3.5 g) was dissolved in dichloromethane (70 g).
ml), and methanesulfonyl chloride (1°O2 g) and triethylamine (1.24 ml) were added under water cooling. After stirring for 1 hour under water cooling and further stirring for 1 hour at room temperature,
The mixture was washed with water and then with an aqueous sodium bicarbonate solution, dried, and concentrated to obtain the methanesulfonate compound of Reference Example 7 (4.42 g). The total amount of this product (4.1 g) and the compound of Reference Example 19 (
3.6 g) was dissolved in tetrahydrofuran (40 ml), and a 28% methanol solution of sodium methoxide (2.6 g) was dissolved in tetrahydrofuran (40 ml).
, 4 ml) and then stirred at room temperature for 20 hours. The reaction solution was concentrated, and the residue was dissolved in a mixture of hexane and /I'+ethyl acid, washed with water, dried, and then the solvent was distilled off. The residue was removed by silica gel column chromatography [carrier; 50 g
, developing solvent; hexane:ethyl acetate-10:lI5:I
] The title compound (3,: (6 g) was obtained.

I R (Krlr): 3460.2930.286
0. 1465. 13651355, 1260.
1120. 1080. 1035. 1020 cm
-'NMR(90MIlz, CDC13):
δ 0.87(3+1), 1.05-1.80(
50+1), 2.50 (4+1), 3.30-4.
05 (1311), 4.56 (Ill) Reference Example 21 Production of 5-[5-[3-octadecyloxy-2-(pyrimidinyl-2oxy)propoxy]pentylthio]pentanol Compound (3 , 3g) in tetrahydrofuran (30ml), and dissolved 2-chloropyrimine (0,9
2g) and 60% oily sodium hydride (0.32g) were added and stirred at room temperature for 4 hours. The reaction solution was concentrated, hexane was added, washed with water, dried, and concentrated. Residue (3°7
3 g) was dissolved in a mixture of tetrahydrofuran (30 ml) and methanol (9 ml), and normal hydrochloric acid (6 ml) was added thereto, followed by stirring at room temperature for 4 hours. After neutralizing the reaction solution by adding sodium bicarbonate, the L layer and the residue were dissolved in a mixture of hexane and ethyl acetate, washed with water, dried, and concentrated to dryness.

The residue was subjected to silica gel column chromatography [carrier;
50 g, developing solvent; hexane:ethyl acetate-4=l→
1:1] to give the title compound (2.2 g).

I R (KBr): ν3400.2930.2860
．． 157g, 1560°1430, 1420.
1330. 1115 cmN M R (90 Mll
z, CDC13): δ 0.87 (311),
1. l-1,8 (4411), 2.50 (41
1), 3.35-3. f! to(IOH), 5
．． 46(Ill), 6°89(Ill), 8.4
7(2+1) Reference Example 22 Production of 5-[5-[3-octadecyloxy-2-(pyrimidinyl-2-oxy)furboxy]pentylsulfonyl]pentanol The compound (2.2 g) of Reference Example 21 was dissolved in dichloromethane ( 2
0 ml), and chloroperbenzoic acid (1°61 g) was added little by little under water-cooling. After stirring for 2 hours at room temperature,
The precipitated insoluble matter was filtered off. After washing with 1 to 11 g of water, Kosei was dried, concentrated to dryness, and the residue was subjected to column chromatography on silica gel [carrier: 35 g □ developing solvent: hexane:
Purification with ethyl acetate (2:l→ethyl acetate) gave the title compound (1.59 g).

11<(Krlr): ν3380.2920.28
50.1678.14601420, 1325.125
5.1220.1120 cm-'N M R (90M
IIz, CDC1a): δ0.87 (311),
1. to-2,05 (44+1), 2.80-3
．． 05 (4+1), 3.35-3.60 (4+1)
, 3.67 (2+1), 3.69 (211),
5.44 (Ill), 6.90 (II[), δ, 4
9 (211) Reference Example 23 Production of 5-[5-[3-octadecyloxy-2-(pyrimidinyl-2-oxy)furboxy]pentylsulfonyl]pentyl methanesulfonate The compound (1,59 g) of Reference Example 22 was dissolved in dichloromethane. (
Methanesulfonyl chloride (15 ml) was dissolved under water cooling.
0.43 g) and triethylamine (0.52 ml) were added. The reaction mixture was stirred for 1 hour under water cooling, washed with water and then with aqueous sodium bicarbonate, dried, and concentrated to give the title compound (1.78 g) as a colorless solid.

I R (KBr): ν2920.2g50. 157
8. 1560. 1462°1420, 1340.
1265. 1160. 1120 cm-'NM
R(90MIIZ, CDCl5): δ0.87(
311), 1.05-2.05 (4411), 2.
80-3.10(4)1), 2.99(311),
3.35-3.60 (4+1), 3.60-3.76
(411), 4.23 (2+1), 5.46 (il
l), 6°92 (Ill), 8.51 (211) Example I N-[3-[3-[3-octadecyloxy-2-(pyrimidinyl-2-oxy)propoxy]propoxy]propyl]thiaturium Production of chloride Compound (o, go g) of Reference Example 6 was added with thiazole (1,
0 ml) was added thereto, and the mixture was left stirring at 80°C overnight. The reaction solution was partitioned between dichloromethane and saturated heavy water, and 11 layers were separated, washed with saturated brine, dried over anhydrous sulfuric acid, and the solvent was distilled off under reduced pressure. The residue was subjected to Silino J Kel column chromatography [carrier; 25 g.

The title compound (0.43 g) was obtained by purification with developing solvent: chloroform:methanol-13:5].

I R (KBr) Niji 3450.2940.15g
5.1570.1454゜1432, 1330. 1
120 amN MR (90MIIZ, CDC13
): δ 0.66-1.90 (3911), 3.
24-3.81 (12+1), 5.00 (211)
, 5.33-5.59(ill), 6.95(
Ill), 8.21-8.35 (11, 8.
45-8.59(311), 11.84-11 Example 2 N-5-cs-c(z-methoxy-3-octadecyloxy)propoxy]pentoxy]pentyl-N, N,
Preparation of N, -trimethylammonium chloride The compound of Example 10 (1.0 g) was dissolved in a small amount of tetrahydrofuran, and 30% aqueous trimethylamine solution (3.0 g) was dissolved in a small amount of tetrahydrofuran.
, 3 ml) and then let stand at room temperature for 1 minute.

Excess reagents and solvent were distilled off under reduced pressure, and the remaining 2 ft.
I), developing solvent: treated with methanol/water-4:11,
The effluent was condensed to dryness to give the title compound (0.65 g)
was gotten.

I R (KBr): ν 3430. 292
0. 2g55. 1633. 1462°1380,
1195. 1110 cmN M R (90 MIl
z, CDCl3-TFA): δ 0.11
6 (311), l, 26 (32H), 1.6
1 (+211), 3.12 (911), 3.4
0-3.79 (18H) Example 3 Production of +1-[5-[5-[(2-methoxy-3-octadecyloxy)propoquine]pentoxy]pentyl]pyridinium chloride Compound of Reference Example 10 (1,0 g ) to pyridine (3,0m
1) and left stirring at 60°C for 8 hours and then at 80°C overnight. Excess reagents and solvent were distilled off under reduced pressure, and then the residue-i was dissolved in dichloromethane and washed with water.

The organic layer was separated, the solvent was distilled off, and the residue was applied to an ion exchange resin column using Amberlite I RA-410 (CI-).
The effluent was collected and concentrated to dryness to obtain the title compound (0.56 g).

NMR(90MllZ, CDCl3-CD30D
): δ 0.87 (311), 1.021, 83
(4411), 3.20-3゜70 (1611),
4.67 (211), 7.97-8.23 (2+1
), 8.59 (IH), 9.02 (2+1) Example 4 1[5-[5-[(2-methoxy3-octadecyloxy)propoxy]pentoxy]bentylcobiridinio-
Production of 4-carboxylene-1. The compound (1.2 g) of Reference Example 10 was mixed with innicotinic acid x
Dissolve 2.0 g of f. at 70°C for 5 hours, 1
The reaction was stirred for 1 hour at 00'c. The reaction solution was subjected to 7 silica gel column chromatography [carrier: 120 g, developing solvent: chloroform; methanol - 25 l → 5:1].
n G2, ethyl l-[5-[5-[(2-
Methoxy-3-octadecyloxy)propoquine]pentoxy]pentyl J pyridinio-4-carboxylate was obtained. Dissolve this material in methanol (20ml) and add 10% aqueous sodium hydroxide solution (2.5n+l).
was added and stirred at room temperature for 20 minutes. Neutralize with 2N hydrochloric acid, evaporate the solvent, and dissolve the residue in dichloromethane (100ml).
Dissolve in water and wash with water. The organic layer was separated and the solvent was distilled off to obtain the title compound (0.66 g).

T R (Kllr): v 3430.2925.
2g55.1736.1635゜1570, +46
4. 1373.1120 cmNMR(90MI
Iz, CDC1, -CD, OD): δ 0.87 (
3+1), l, 031.77 (4411), 3.2
5-3.55 (1611), 4.07<211),
8.35-8.57 (2+1), 8.85-9.07
(211) Example 5 Production of N-[5-[5-[(2-methoxycarbonylmethoxy-3octadecyloxy)propoxy]pentoxycopentyl]thiazolium chloride The compound of Reference Example 13 was prepared in the same manner as in Example 1. (300m
g) and thiazole (1.0ml) to produce the title compound (1
82 mg) was obtained.

I R (KBr): v 3400.2930.2
860.1760.14701210, 1120c
mNMR(90MIIz, CDC1t): δ
0.87 (3+1), 1.28 (3211).

1, 38-1.73 (1411), 2.05 (2+
1), 3.31-3.56 (11+1) 3.73 (
311), 4.31 (2+1), 4.79 (2+1)
, 8.33-8.49 (211), 10.99 (
III).

Example II: Preparation of N-[5-[5-[3-ophtadecyloxy-2-(pyrimidinyl-2-oxy)furboxy]bentoquincopentyl]thiazolium chloride in the same manner as in Example 1, Reference Example 14 Compound (1,25
g) and thiazole (1.0 ml) to obtain the title compound (0
,70g> was obtained.

l R (Nujol): 3370. 1575.
1560. 1420. 1375°+325. 13
10. 1110 ctnN M R (90 MIIZ
, CDC13-CD30D): 60.87(
311), 1.171, 73 (45+1), l
, 87-2.00 (2+1), 3.27-3.5
7 (811) 3.73 (411), 4.73 (2+
1), 5.47 (III), 6.93 (III
), 8゜23 (group), 11.37 (III),
l'! , 50(2+1), 10.83(III) Example 7 14.5-[5-[3-octadecyloxy-2-(pyriminyl-2-oxy)furoboxy/]pentoki/]pentyl]pyridinio-4- Preparation of carboxylate In the same manner as in Example 4, the title compound (
0.84 g) was obtained.

l R (Nujol): v 3375.1640.
1615.1580.15651425, 1375.
+330.1310.1115 cmN M R (90
Mllz, CDCl, CD30D): δ
0.87 (3+1), 1.171.80 (45+1
), I, 83-2.20 (2+1), 3.37
-3.57 (810°3.70 (4+1), 4.7
0(2+1), 5.47(Ill), 8.43
-8.67 (4+1), 9.10 (2+1) Example 8 3-carbamoyl-1-[5-[5-[3-octadecyloxy 2-(pyrimidinyl-2-oxy)propoxy]
Production of pentoxy]pentyl]pyridinium chloride In the same manner as in Example 3, the compound of Reference Example 14 (800 m
The title compound (640 mg) was obtained from m) and nicotinic acid amide (844 mg).

l R (Nujol): ν3250.3060.1
710.1580.1565゜1425, 13g0.1
325.1115 cmNMR(90MIIZ,
CDCl3-CD30D): δ0.87 (3+1),
1.101, 77 (42+1), l, 93-2.
23 (2+1), 3.23-3.57 (8+1).

3.67 (2+1), 3.73 (2H), 4.83
(2+1), 5.47 (Ill), 6°93 (II
I), 8.17 (III), +! , 50 (2+1)
, 9.03(]III, 9.17(Ill),
10.27 (Group) Example 9 Production of 2-[5-[5-[3-octadecyloxy-2-(pyrimidinyl-2-oxy)furboxy]pentoxy]pentyl]inquinolinium chloride Same as Example 3 and the compound of Reference Example 14 (600 m
g) and inquinoline (1.0 ml) to prepare the title compound (
316 mg) was obtained.

I R (Nujol) + v 3400. 164
0. 1580. 1565. 1425°1330,
1310. 1115 cm-'N M R (90 M
IIZ, CDCl5): δ 0.87 (31
1), 1.10-1.67 (4211), 1.9
0 (411), 1.93-2.33 (2+1), 3
．． 23-3.53 (8II), 3.43 (2+1)
, 3.70 (411), 5.10 (2+1),
5.47 (Ill).

6.90 (III), 7.97 (Ill), 8
．． 13 (2+1), 8.30 (III), 8°47 (211), 8.67 (Ill), 8.8
3(ill), 11.40(III) Example 1O N-[3-[3-[3-octadecyloxy-2-(pyrimidinyl-2-oxy)propoxy]propoquincobropyl]N, N, N -1-limethylammonium
Production of chloride In the same manner as in Example 2, the title compound (410 mg) was obtained from the compound of Reference Example 6 (5301+1 g) and an aqueous trimethylamine solution.

I R (Nujol): v 3400.1575.
1565. 1420.1375°+320.1110
．． 1100 am-'NMR (90MHz, C
DCI--CD30D): 60.87 (3+1),
1.231.67 (32+1), 1.80 (2+
1), 1.90-2.23(2+1), 3.23(
9II), 3.37-3.77 (1411), 5.
47 (III), 6.97 (II), 8゜50 (2
1+) Example 11 Preparation of 1-[3-[3-[3-octadecyloxy-2-(pyrimidinyl-2-oxy)propoxy]propoxy]propyl]pyridinio-3-carboxylate Same as Example 4 , the compound of Reference Example 6 (530 mg) and ethyl toisonicotinate, and the title compound (215 mg)
was gotten.

I R (Nujol): v 33g0. 164
0. 1610. 1575.1565°1425,
1375. 1320. 1110 cm-'NM
R (200MllZ, CDC13): 60.8
8 (3H), 1.25 (30+1).

1.52 (2+1), 1.77 (21+), 2.
28 (211), 3.34-3.79 (12I+),
4.85 (2+1), 5.46 (Ill), 6.
93(ill), 7.96(1,11).

8.47 (2+1), 8.72 (ill), 9.0
6(ill), 9.54(Ill) Example 12 N-[7-[7-[3-octadecyloxy-2-(pyrimidinyl-2-oxy)propoxy]hebutyloxy]
Production of hebutyl]thiazolium chloride In the same manner as in Example 1, the compound of Reference Example 18 (800 m
g) and thiazole (3.0ml) to produce the title compound (5
10 mg) was obtained.

I R (Neat): ν2920. 2855. 1
575. I”560. 1462°1420, 1
328. 1105. 750 cmNMR(90
MIlz, CDCIa): δ 0.87 (3+1
), 1.00-1.73 (5211), 3.1
7-3.77 (12+1), 4.87 (2+1),
5.47 (Ill).

6.89(Ill), 8.28(Ill), 8
．． 37-8.53 (3+1), 11.69 (1 Example 13 [3-[3-[3-[3-octadecyloxy-2-(pyrimidinyl-2-oxy)propoquine]propoxy]propyl]l- Preparation of imitazolio]acetate In the same manner as in Example 4, the compound of Reference Example 6 (530 mg
) and iminozole. The title compound (414 mg) was obtained from ethyl -1-yl acetate.

I R (Nujol): v 3400.162
0. 1575. 1565°1420, 1375.1
310.1110 cmN M R (90 MIlz,
CDCl5-CD*OD): δ0.87 (311).

1, 20-1.63 (3211), 1.80 (21+
), 1.93-2.23 (21+).

3.30-3.73 (12+1), C27 (2+1)
, 4.73(2+1), 5.47(Ill), 6
．． 93(ill), 7.27(ill), 7.43
(III), 8.47 (2II), 9.07 (Il
l) Example 14 Production of 1-[5-[5-[2-(methoxycarbonylmethoxy)-3(octadecyloxy)propoxy]pentyloquine]pentyl]pyridinium methanesulfonate The compound (1,45 g) of Reference Example 13 was Dry pyridine (2
0 ml) and stirred at 80°C for 6 hours. The solvent was distilled off under reduced pressure, and the remaining 7 fU was subjected to silica gel column chromatography [carrier: 45 g, developing solvent: chloroform:
Methanol: The title compound (1.38g) was obtained.

+ R (KBr): v 3440, 2930.
2860. 1765, +630.

1490, 1470. 1390. 12+0. 1
195. 1120, 1060.

90 am N M R (90 Mllz, CI) C1. ) :δ
0. 87(311), 1. 13-1. 73 (4
2+1), 1.98(2+1), 2.73(3+1
), 3.30-3.55 (12+1).

3, 71 (311), 4.29 (2+1), 4.8
5 (2H), 8. (1g (211), 8.

45(III), 9. 23(2+1) Example 15 Production of 2-[5-[5-[2-(methoxycarbonylmethoxy)-3-(octadecyloxy)propoxy]pentyloxic]pentyl]isoquinolinium methanesulnidonate Same as Example 14 Then, the compound of Reference Example 13 (2.3
4 g) and 3-(3-hydroquinepropyl)bi11dine (1.

The title compound (1.77 g) was obtained from 85 g).

] R (Neat): v 3450, 2930
, 2860, 1755, 1640.

1400, 1200. 1110. 1040
．． 770 cm-'NMR (90MIIZ,
CDCI, ): δ0. 88 (3+1), 1.
25-4. 60 (4411), 2.80 (311)
, 3.25-3.77 (1311), 3.70 (3
11) 4, 30 (2+1), 4. 93 (2+1)
, 7. 68-8. 80 (7+1) Example 16 1-[5-[5-[2-(methoxysulfonylmethquine)-3(octadecyloxy)propoxy]pentyloxy]benthylco-4-dimethylaminopyridinyl t-
Preparation of chloride In the same manner as in Example 1, the compound of Reference Example 13 (700
mg) and 4-dimethylaminopyridine (542 mg)
The title compound (600 B) was obtained.

I R (Neat): v 3390, 2925
, 2860, 1760, 1650.

1570, 1465. 1205. 1170. 1
115. 835. 7505II-'NMR(9
0MIIZ, CDCl5): δ 0.87 (311
), 1.20-2. t.

(4411), 3.28 (6+1), a, 3o-3
,8o(taio, 4.30(2+1).

4.36 (2+1), 7.03 (2+1), 8
．． 50 (211) Example 17 1-[5-[5-[2-(methoxycarbonylmethoxy)-3-(octadefoxy)proboxycopentyloxycobentyl]-3-(3-hydroxypropyl)pyridinium chloride Production of the compound of Example 13 (2゜3) in the same manner as in Example 1
4g) and 3-(3-hydroxypropyl)pyridine (1
, 85 g) to obtain the title compound (1.77 g).

Volume <(Neat): ν33130.2930.285
5.1760.1470°1205, 1115 c
rn NMR(90MIlz, CDCl3-CD30D
): δ0.87(311), 1.1.51.70(
42+1), 1.80-2.20 (411), 3.
00 (2+1), 3.273.84 (18+1),
4.29 (211), 4.75 (2+1), 7.9
5(III), 8°31(III), 8.81(I
II), 9.20(III) Example 18 Preparation of 2-[5-[5-pyridiniopentyloxycobentyloxy]-1(octadecyloxymethyl)ethoxyacetate-1. Compound of Example 14 ( 1, (LOg) was added to a 1N aqueous sodium hydroxide solution (25ml) and stirred at room temperature for 1 hour.The reaction solution was adjusted to pH = 6.0 to 6.5 with 1N hydrochloric acid.The reaction solvent was removed under reduced pressure. The residue was extracted with chloroform A (50 ml). The extract was concentrated, and the residue was subjected to silica gel column chromatography [carrier: 30 ml].
g, developing solvent; chloroform: methanol water-65:
25:4] to give the title compound (0.71 g).

! R (Neat): v 3380.2920.
1600. 1485.1460°1405',
1310. 1110 cmN M R (90 Mllz
, CDC1z): δ 0.87 (3+1), 1
．． 27-1.61 (4211), 2.01 (2+1)
, 3.31-3.71 (12+1), 4.02 (2
+1).

4.88 (2+1), 8.07 (2+1), 8.4
0 (Ill), 9.84 (2+1) Example 19 Production of 2-[5-[5-inquinoliniopentyloxy]pentyloxy]-i(octadecyloxymethyl)ethoxyacetate-1. Same as Example 18 and the compound of Example 15 (420
mg) to obtain the title compound (96 mg).

I R (Neat): v 3400.2920.
2850.1590.1460°1400, 1310.
1105 cm-'NMR (90MIIZ, C
DCl5): δ0.86 (311), 1.25-1
．． 67 (42+1), 2.03 (21+), 3.3
0-3.61 (131114,06(21+).

4, 93 (2+1), 7.77-8.73 (711)
Example 20 Preparation of 2-[5-[5-(4-methylamineviridinio)pentyloxy]pentyloxy]-r-(octadecyloxymethyl)-methoxy/acetate In the same manner as in Example 18, Compound of Example 16 (600
mg) to obtain the title compound (430 mg).

I R (Neat): v 3380.2930.
2g55. 1650.1600°1565, 146
5. 1405.1170. 1110.835.72
0cm-'NMR (90MIIz, CDC13)
:δ0.87(311), 1.2(12,05(4
4+1), 3.20 (6+1), 3.33-3.7
0 (1311), 4.03 (2+1).

4.20 (2+1), 6.93 (2H), 8.17
(2H) Example 21 Production of 2-[5-[5-[3-(3-hydroxypropyl)pyridinio)bentyloxycopentyloxy]-1(octadecyloxymethyl)ethoxy acetate in the same manner as in Example 18. , the compound of Example 17 (500 mg
) The title compound (330 mg) was obtained.

I R (NeaL): 3360.2920.2g
50.1600.1460°1310 1105
cm NMR (90MIlz, CDC1a-CD30D
)'δ 0.87(3+1), 1.151.75(
4211), 1.80-2.18 (4+1),
2.97 (2+1), 3,303.75 (1511
), 4.02 (21+), 4.70 (2+1),
7.91 (Ill), 8°26 (Group), 8.79 (
Ill), 9.13 (Ill) Example 22 1-[5-[5-[3-octadecyloxy-2-(pyrimidinyl-2-oxy)furboxy]pentyloxy]
Production of pentyl]pyridinio-3-ylcarboxylate In the same manner as in Example 4, the compound of Reference Example 14 (942
The title compound (570 mg) was obtained from ethyl isonicotinate (1.0 g) and ethyl isonicotinate (1.0 g).

I R (Nujol): ν3430.1845.1
615.15g0.1565°1425, 1375.
1325. 1115 cm-'N M R (90 M
IIz, CDC1a-CDaOD)' δ 0.8
7 (3H), 1.201, 70 (4211),
1.90-2.23 (2H), 3.30-3.53
(8+1).

3.70 (411), 4.63 (2+1), 5
．． 47 (IH), 6.93 (III), 793
(III), 8.47 (2+1), 8.67 (
Ill), 8.97(1,11), 9.23(
Ill) Example 23 3-[1-[5-[5-[3-octadecyloxy-2-
(pyrimidinyl-2-oxy)propoxy]pentyloxy]pentyl]pyridinio]-3-ylpropione-
). In the same manner as in Example 4, the title compound (610 mg) was obtained from the compound of Reference Example 14 (942 mg) and ethyl 3-(3-pyridyl)propionate (360 mg).

1 [<<Nujol) 2 ν 33g0. 15
75. +560. 1420. 1375°132
5, 1310. 1110 cm-NMR (90
Mtlz, CDC1, -CD30D): δ0.87
(311), 1.171, 70 (42+1), 1
．． 80-2.13 (2+1), 2.43-2.73 (
2+1).

2.93-3.20 (2+1), 3.37-3.53
(8+1), 3.70 (411), 467 (2+1
), 5.47(ill), 6.93(III)
, 7.90 (group), 8.37 (2+1),
8.47 (IH), 8.67 (Ill), 9.
00(Ill) Example 24 6-[3-[5-[5-[3-octadecyloxy-2-
Preparation of (pyrimidinyl-2-oxy)furboxy]pentyloxy]pentyl]imidazoliol-1-yl]hexanony 1. In the same manner as in Example 4, the compound of Reference Example 14 (942m
g) and methyl 6-(imitazol-l-yl)hexanoate (392 mg) to produce the title compound (840 mg) or 1
1t was lost.

IR (Nujol): 3360. 1570.
1560. 1420. 1320°1110 cm
-' NMR (90MHz, CDCl 2-CD30D)
:δ 0.87(311), 1.172.07(
50+1), 2.27(2+1), 3°27-3.
57 (8+1), 3.70 (41+), 4.2
7 (411), 5.47 (ill), 6.93
(Ill), 7.40(Ill), 7.53(I
ll), 8.50 (2+1), 9.67 (III)
Example 25 Preparation of N~[5-[5-[3-octadecyloxy-2-(pyrimi/nyl-2-oxy)propoxy]pentylsulfonylcopentyl 1 thiazolium chloride Example 1
In the same manner as above, the title compound (0.38 g) was obtained from the compound of Reference Example 23 (071 g) and thiazole (3 ml).

IR (Film): v 3420. 2920
．． 2g50. 1620. 15g5゜1560,
1462. 1420. 1310. 127g,
1118 cn+-'N M R (200MIIz,
CDCIa): δ 0.87 (311), 1.
05-2.20 (44+1), 2.94-3.11
(2+1), 3.44-3.55 (411),
3.71 (4I+), 4.95 (211), 5
．． 47(ill), 6.95(ill), 8.
20 (ill).

8.50 (III), 8.55 (21+), 1
1.59(Ill) Example 26 6-[3-[5-[5-[3-octadecyloxy-2-
Production of (pyrimidinyl-2-ox7)propoxy]pentylsulfonyl]pentyl]imidazolium]hexanoate The compound of Reference Example 23 (1
The title compound (0.63 g) was obtained from 5-methoxycarbonylpentylimitazole (0.7 g) and 5-methoxycarbonylpentylimitazole (0.7 g).

+ R (KBr): v 3425.2920.2
850. 1565. 1558°+460. 142
0. 1310. 1285. 1115 cm-'N
M R (200MH2, CDC13): δ 0
．． 8g (311), 1.25 (3211).

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a higher alkyl group that may be substituted, R^2 is a hydrogen atom, or each is substituted] R^3 is a tertiary amino group or a quaternary ammonium group, m and n are the same or different, and m+n is 6 to 6. 3 to 1 within the range of 24
Indicates an integer of 8. J is an oxygen atom or the formula -S(O)_r- (wherein r is 0
(representing an integer of 2 to 2) or a salt thereof.