Glycerol derivatives.

The present invention is concerned to new glycerol derivatives. More particularly, this invention is concerned to new glycerol derivatives having antagonistic effect on platelet activating factor (abbreviated as PAF hereafter), hypotensive effect like PAF, inhibitory effect on phospholipase and further, inhibitory effect on growth of tumour cell or induction of differentiation, and, furthermore, this invention is concerned to the process for their preparation and pharmaceutical composition comprising them as active ingredients.

Recently, the study on the release reaction of active amine dependent on leukocyte from platelet, has been energetically carried out. As a result, a substance strongly inducing platelet aggregation was discovered and it was named as PAF [cf. J. Immunol., 106, 1244 (1971), J. Exp. Med., 136, 1356 (1972) and Nature, 249, 581 (1974)]. Thereafter, it was confirmed that PAF exists in various animals including human beings. In 1979, its chemical structure was identified [cf. J. Biol. Chem., 254, 9355 (1979) and C. R. Acad. Sci., Serie D (Paris), 289, 1017 (1979)] and has turned out to be a mixture of two alkylphospholipids of the following general formula wherein n is 15 and 17 [cf. J. Biol. Chem., 255, 5514 (1980)]: <chemistry id="chem0001" num="0001"><img file="EP0109255A2_D0001.tif" /></chemistry>(wherein n represents 15 or 17).

It was found that PAF has not only strong secretory effect on platelet aggregation known at that time, but also powerful hypotensive effect and bronchodilating effect. PAF is considered to be one of platelet aggregating factors in human beings, and further, one of substances inducing allergy and inflammation. Accordingly, there is a great possibility that compounds having antagonistic effect on PAF (inhibitory effect on PAF) may become a platelet aggregation inhibitor, anti-asthmatic agent, anti-allergic agent or anti-inflammatory agent. Furthermore, PAF is considered to become a hypotensive agent without inhibitory effect on platelet aggregation by selecting hypotensive effect out of various effect.

Widespread investigations have been carried out in order to discover compounds possessing antagonistic effect on PAF or hypotensive effect like PAF, we have already proposed glycerol derivatives of the general formula: <chemistry id="chem0002" num="0002"><img file="EP0109255A2_D0002.tif" /></chemistry> [wherein A' represents an oxygen atom or a sulfur atom, B' represents an oxygen atom or a sulfur atom, D' represents an oxygen atom or a carbonyloxy group (i.e. <chemistry id="chem0003" num="0003"><img file="EP0109255A2_D0003.tif" /></chemistry>, in which the carbonyl group should be attached to a group R and the oxa group should be attached to the carbon atom at the third position of the glycerol skeleton), R^1' represents an alkyl group of 6 to 22 carbon atoms, or an alkyl group of 2 to 5 carbon atoms being substituted by a phenyl group, R^2' represents, when B' is an oxygen atom, a hydrogen atom, or a group of the general formula: <chemistry id="chem0004" num="0004"><img file="EP0109255A2_D0004.tif" /></chemistry>-COR^6' or -CONHR^7' -COR^6' or -CONHR^7', in which R^5' represents a hydrogen atom, a halogen atom, an alkyl group of 1 to 4 carbon atoms or an alkoxy group of 1 to 4 carbon atoms, R represents an alkyl group of 1 to 6 carbon atoms or a phenyl group and R^7' represents an alkyl group of 1 to 6 carbon atoms or a phenyl group, and R^2' represents, when B' is a sulfur atom, a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, or a group of the general formula: <chemistry id="chem0005" num="0005"><img file="EP0109255A2_D0005.tif" /></chemistry>or -CS-OR^8', in which R^8' represents an alkyl group of 1 to 6 carbon atoms or a phenyl group and R^5' is as hereinbefore defined, R^3' represents an alkylene group of 1 to 12 carbon atoms and R4 represents an amino group, or a group of the general formula: -NHCOR^9', -NHR^10', -N(R^10')₂, <img file="EP0109255A2_D0006.tif" />(R^10')₃·<img file="EP0109255A2_D0007.tif" />, in which R 9 represents an alkyl group of 1 to 6 carbon atoms or a phenyl group, R^10' represents an alkyl group of 1 to 8 carbon atoms, with the proviso that, when R^4' represents a group of the formula -N(R^10')₂ or <img file="EP0109255A2_D0008.tif" />(R^10')₃·<img file="EP0109255A2_D0009.tif" />, two or more of R^10' may be same or different to each other, and Y represents an anion of an acid], and non-toxic acid addition salts thereof (see the United States Patent Application No. 494481 and European Patent Application No. 83104345.5).

It has now been found that by replacing the group of the formula: -B'-R^2' ±n compounds of the above general formula by an amino group or derivatives thereof, the pharmacological effects of new glycerol derivatives (hereinafter described as compounds of the general formula I) are, in some aspects of their effects, improved or modified, having completed this invention.

Furthermore, it has been found that the compounds of the present invention of the general formula I have inhibitory effect on phospholipase A₂ and phospholipase C. Phospholipase A₂ and phospholipase C dependent on calcium in a living body are concerned in the mechanism for the release of arachidonic acid from phospholipids. It is known that arachidonic acid is released by physiological stimulus and then becomes incorporated into the metabolic routes of prostaglandins and is finally metabolized to thromboxane A₂ having a strong effect on platelet aggregation, to other prostaglandins or to various leukotrienes being a significant bronchostrictor in an asthmatic paroxysm. Accordingly, it is considered that compounds having an inhibitory effect on phospholipase A₂ and phospholipase C, which are concerned in the mechanism for the release of arachidonic acid, can become a platelet aggregation inhibitor, anti-asthmatic agent, anti-allergic agent or anti-inflammatory agent, based on the inhibition of phospholipase A₂ and phospholipase C, having a different mechanism from PAF antagonist and further, being different from conventional anti-inflammatory agents represented by aspirin based on the inhibition of cyclooxygenase.

Furthermore, the compounds of the present invention of the general formula I show inhibitory effect on growth of tumour cell and induction of differentiation and, therefore, are may be useful as anti-tumour agents.

Accordingly, the present invention provides new glycerol derivatives of the general formula: <chemistry id="chem0006" num="0006"><img file="EP0109255A2_D0010.tif" /></chemistry>[wherein A represents an oxygen atom or a carbonyloxy group (i.e. -0-CO-, in which the carbonyl group should be attached to a group R and the oxa group should be attached to the carbon atom at the third position of the glycerol skeleton), R¹ represents an alkyl group of 6 to 22 carbon atoms, or an alkyl group of 2 to 5 carbon atoms being substituted by a phenyl group, R² represents an azido group (-N₃ group), an amino group (-NH₂ group) or a group of the general formula: -NHCOR⁵, -NHCOOR⁵ or -NHCONHR⁵, in which R⁵ represents an alkyl group of 1 to 10 carbon atoms or a phenyl group, with the proviso that, when A represents a carbonyloxy group, R ² does not represent an amino group, R³ represents an alkylene group of 1 to 12 carbon atoms and R⁴ represents an amino group, or a group of the general formula: -NHCOR , -NHR⁷, -N(R⁷)₂ or <img file="EP0109255A2_D0011.tif" />(R⁷)₃·<img file="EP0109255A2_D0012.tif" />, in which R⁶ represents an alkyl group of 1 to 6 carbon atoms or a phenyl group, R represents an alkyl group of 1 to 8 carbon atoms, with the proviso that, when R⁴ represents a group of the formula: -N(R⁷)₂ or <img file="EP0109255A2_D0013.tif" />(R⁷)₃·<img file="EP0109255A2_D0014.tif" />, two or more of R⁷ may be same or different to each other, and <img file="EP0109255A2_D0015.tif" />represents an anion of an acid], and non-toxic acid addition salts thereof.

Throughout the specification including claims, the term "alkyl" or "alkylene" means a straight- or branched-chain alkyl or alkylene group.

As is obvious to those skilled in the art, the compounds of the general formula I have at least one asymmetric center, i.e. the carbon atom at the second position of the . glycerol skeleton. When the alkyl or alkylene moiety of various substituents represented by R¹, R², R³ and R⁴ represents a branched-chain, there is a possibility that other asymmetric centers are occurred. The existence of an asymmetric center forms isomers as is well known. However the compounds of the general formula I in the present invention are concerned with all isomers or mixtures thereof.

Examples of the alkyl group represented by R are hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl and docosyl group and isomers thereof. Any group is preferred and hexadecyl group is most preferred.

Examples of the alkyl group substituted by a phenyl group, represented by R¹ are ethyl, propyl, butyl and pentyl group and isomers thereof replaced an optional hydrogen atom by a phenyl group.

Examples of the alkyl group represented by R in various groups represented by R are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl group and isomers thereof and any group is preferred and most preferable group is an alkyl group of 1 to 5 carbon atoms, i.e. a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl or 2-methylbutyl group. A phenyl group as R⁵ is also preferred.

Preferable R² group is an azido group, an amino group or a group of the general formula: -NHCOR⁵ , -NHCOOR⁵ or -NHCONHR⁵ group, in which R is as hereinbefore defined.

Examples of the alkylene group represented by R³ are methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octametylene, nonamethylene, decamethylene, undecamethylene and dodecamethylene group and isomers thereof, and any group is preferred.

Examples of the alkyl group represented by R in the general formula: -NHCOR⁶ in R⁴ are methyl, ethyl, propyl, butyl, pentyl and bexyl group and isomers thereof and any group is preferred. A phenyl group as R is also preferred.

Examples of the alkyl group represented by R⁷ in the general formulae: -NHR⁷, -N(R⁷)₂ and <img file="EP0109255A2_D0016.tif" />(R⁷)₃·<img file="EP0109255A2_D0017.tif" /> in R⁴ are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl and isomers thereof and any group is preferred. ⊖

The anion of an acid represented by Y means the anion of a pharmaceutically-acceptable non-toxic inorganic or organic acid, and examples of them are the anion of an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, or the anion of an organic acid such as acetic acid, lactic acid, tartaric acid, benzoic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid. Any anion is preferred and more preferable anion is a halogen ion, i.e. chlorine, bromine and iodine ions, or an anion of methanesulfonic acid or p-toluenesulfonic acid.

Preferable R⁴ group is an amino group or a group of the general formula: -NHR⁷ , -N(R⁷)₂ or <img file="EP0109255A2_D0018.tif" />(R⁷)₃·<img file="EP0109255A2_D0019.tif" /> (in which the various symbols are as hereinbefore defined) and most preferable R⁴ is a group of the general formula: -N(R⁷)₂ or <img file="EP0109255A2_D0020.tif" />(R⁷)₃·<img file="EP0109255A2_D0021.tif" /> (in which the various symbols are as hereinbefore defined).

According to a feature of the present invention, glycerol derivatives of the general formula I, wherein A represents an oxygen atom and the other symbols are as hereinbefore defined, i.e. compounds of the general formula: <chemistry id="chem0007" num="0007"><img file="EP0109255A2_D0022.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) may be prepared by the following methods: <ul id="ul0001" list-style="none"><li>(i) glycerol derivatives of the general formula IA, wherein R² represents an azido group and R⁴ represents a group of the general formula: -NHCOR⁶, -N(R⁷)₂ or <img file="EP0109255A2_D0023.tif" />(R⁷)₃·<img file="EP0109255A2_D0024.tif" />, in which the various symbols are as hereinbefore defined, i.e. compounds of the general formula: <chemistry id="chem0008" num="0008"><img file="EP0109255A2_D0025.tif" /></chemistry><ul id="ul0002" list-style="none"><li>(wherein R^4a represents a group of the general formula: -NHCOR⁶ , -N(R⁷)₂ or <img file="EP0109255A2_D0026.tif" />(R⁷)₃·Y, in which the various symbols are as hereinbefore defined and the other symbols are as hereinbefore defined) may be prepared by reaction of a compound of the general formula: <chemistry id="chem0009" num="0009"><img file="EP0109255A2_D0027.tif" /></chemistry></li><li>(wherein T represents an alkylsulfonyl group, having 1 to 4 carbon atoms in the alkyl group, or a substituted or unsubstituted arylsulfonyl group, preferably a mesyl group or a tosyl group and the other symbols are as hereinbefore defined) with sodium azide.</li></ul></li></ul>

The above reaction is well known and may be carried out by using sodium azide in an inert organic solvent such as hexamethylphosphoramide (abbreviated as HMPA hereafter), N,N-dimethylformamide (abbreviated as DMF hereafter), dimethyl sulfoxide (abbreviated as DMSO hereafter) at a temperature from ambient to 80°C. The method for the conversion of an alkyl- or arylsulfonyloxy group into an azido group is abbreviated as method A hereafter.

(ii) Glycerol derivatives of the general formula IA, wherein R represents an amino group and R ⁴ represents a group represented by R^4a, i.e. compounds of the general formula: <chemistry id="chem0010" num="0010"><img file="EP0109255A2_D0028.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) may be prepared by reduction of an azido group of a compound of the general formula IA-11 into an amino group.

The reduction is well known and may be carried out, for example, under an atmosphere of hydrogen in the presence of a hydrogenation catalyst such as palladium on carbon, palladium black or platinum dioxide in an inert organic solvent, e.g. a lower alkanol such as methanol or ethanol, or ethyl acetate or acetic acid, or a mixture of two or more of them at a temperature from ambient to the reflux temperature of the reaction mixture, or may be carried out, when R^4a is a group of the general formula: -N(R⁷)₂, by using lithium aluminium hydride in an appropriate inert organic solvent, e.g. tetrahydrofuran (abbreviated as THF hereafter) or diethyl ether at a temperature from ambient to the reflux temperature of the reaction mixture. The method for the conversion of an azido group into an amino group is abbreviated as method B hereafter.

(iii) Glycerol derivatives of the general formula IA, wherein R² represents a group of the general formula: -NHCOR⁵, in which R⁵is as hereinbefore defined, and R⁴ represents a group represented by R^4a, i.e. compounds of the general formula: <chemistry id="chem0011" num="0011"><img file="EP0109255A2_D0029.tif" /></chemistry><ul id="ul0003" list-style="none"><li>(wherein the various symbols are as hereinbefore defined) may be prepared by reaction of an amine of the general formula IA-12 with an acyl halide of the general formula: <chemistry id="chem0012" num="0012"><img file="EP0109255A2_D0030.tif" /></chemistry></li><li>(wherein X¹ represents a halogen atom and R⁵ is as hereinbefore defined) or with an acid anhydride of the general formula: <chemistry id="chem0013" num="0013"><img file="EP0109255A2_D0031.tif" /></chemistry></li><li>(wherein R⁵ is as hereinbefore defined).</li></ul>

(iv) Glycerol derivatives of the general formula IA, wherein R²represents a group of the general formula: -NHCOOR⁵, in which R⁵ is as hereinbefore defined, and R⁴ represents a group represented by R^4a, i.e. compounds of the general formula: <chemistry id="chem0014" num="0014"><img file="EP0109255A2_D0032.tif" /></chemistry><ul id="ul0004" list-style="none"><li>(wherein the various symbols are as hereinbefore defined) may be prepared by reaction of an amine of the general formula IA-12 with an ester of haloformic acid of the general formula: <chemistry id="chem0015" num="0015"><img file="EP0109255A2_D0033.tif" /></chemistry></li><li>(wherein X² represents a halogen atom and R⁵ is as hereinbefore defined).</li></ul>

(v) Glycerol derivatives of the general formula IA, wherein R²represents a group of the general formula -NHCONHR⁵, in which R⁵is as hereinbefore defined, and R⁴ represents a group represented by R^4a, i.e. compounds of the general formula: <chemistry id="chem0016" num="0016"><img file="EP0109255A2_D0034.tif" /></chemistry><ul id="ul0005" list-style="none"><li>(wherein the various symbols are as hereinbefore defined) may be prepared by reaction of an amine of the general formula IA-12 with an isocyanate of the general formula: <chemistry id="chem0017" num="0017"><img file="EP0109255A2_D0035.tif" /></chemistry></li><li>(wherein R⁵ is as hereinbefore defined).</li></ul>

The above reactions between an amine of the general formula IA-12 and a compound of the general formula III or IV, between an amine of the general formula IA-12 and a compound of the general formula V_o and between an amine of the general formula IA-12 and a compound of the general formula VI are well known and may be carried out in an inert organic solvent, e.g. ethyl acetate, benzene, hexane, diethyl ether, THF, chloroform, methylene chloride or carbon tetrachloride, or a mixture of two or more of them, or in the absence of a solvent, in the presence of tertiary amine such as pyridine or triethylamine at a temperature from 0°C to 50°C. The methods for the conversion of an amino group into groups of the general formulae: -NHCOR5, -NHCOOR⁵ and -NHCONHR⁵ are abbreviated hereafter as method C, D and E, respectively.

(vi) Glycerol derivatives of the general formula IA, wherein R⁴represents an amino group or a group of the general formula: -NHR , in which R is as hereinbefore defined, i.e. compounds of the general formula: <chemistry id="chem0018" num="0018"><img file="EP0109255A2_D0036.tif" /></chemistry><ul id="ul0006" list-style="none"><li>(wherein R⁸ represents a hydrogen atom or an alkyl group of 1 to 8 carbon atoms and the other symbols are as hereinbefore defined) may be prepared by elimination of tert-butoxycarbonyl group (i.e. boc group) of a compound of the general formula: <chemistry id="chem0019" num="0019"><img file="EP0109255A2_D0037.tif" /></chemistry></li><li>(wherein boc represents tert-butoxycarbonyl group and the other symbols are as hereinbefore defined).</li></ul>

The elimination of a boc group is well known, and may be carried out by using hydrochloric acid in an inert organic solvent such as ethyl acetate, methylene chloride, chloroform, carbon tetrachloride, a lower alkanol at a temperature from ambient to 50°C, or by using trifluoroacetic acid at room temperature.

Compounds of the general formula VII may be prepared by subjecting a compound of the general formula: <chemistry id="chem0020" num="0020"><img file="EP0109255A2_D0038.tif" /></chemistry> (wherein the various symbols are as hereinbefore defined) to the series of method A, B, C, D and E.

Compounds of the general formulae IIA.and IIB may be prepared by reaction of compounds of the general formulae: <chemistry id="chem0021" num="0021"><img file="EP0109255A2_D0039.tif" /></chemistry>and <chemistry id="chem0022" num="0022"><img file="EP0109255A2_D0040.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined), respectively, with a corresponding alkylsulfonyl chloride such as mesyl chloride or with a corresponding arylsulfonyl chloride such as tosyl chloride at a temperature from -30°C to 50°C (i) in the presence of a tertiary amine such as pyridine or triethylamine, in an inert organic solvent such as methylene chloride or (ii) in pyridine.

Compounds of the general formulae VIIIA and VIIIB may be prepared by reductive elimination of the benzyl group attached to the 2nd position of compounds of the general formulae: <chemistry id="chem0023" num="0023"><img file="EP0109255A2_D0041.tif" /></chemistry>and <chemistry id="chem0024" num="0024"><img file="EP0109255A2_D0042.tif" /></chemistry>(wherein 0 represents a phenyl group and the other symbols are as hereinbefore defined), respectively, under an atmosphere of hydrogen in the presence of a hydrogenation catalyst such as palladium on carbon, palladium black or platinum dioxide in an inert organic solvent, e.g. a lower alkanol such as methanol or ethanol, or ethyl acetate or acetic acid, or a mixture of two or more of them at a temperature from ambient to the reflux temperature of the reaction mixture.

Compounds of the general formulae IXA and IXB may be prepared by method described in our United States Patent Application No. 494481 and European Patent Application No. 83104545.5 and by the series of reactions depicted schematically below in Scheme A, wherein R⁹ represents a halogen atom or a group of the formula: -OT, in which T is as hereinbefore defined, THP represents a tetrahydropyran-2-yl group, Y¹ represents an anion of an acid other than an anion represented by <img file="EP0109255A2_D0043.tif" />R 9 (R⁹ is as hereinbefore defined), X represents a halogen atom and the other symbols are as hereinbefore defined. Scheme A <chemistry id="chem0025" num="0025"><img file="EP0109255A2_D0044.tif" /></chemistry> Scheme A (continued) <chemistry id="chem0026" num="0026"><img file="EP0109255A2_D0045.tif" /></chemistry>

In Scheme A, each step can be effected using methods known per se. For example, step (1) may be carried out by reacting with a benzyl halide such as benzyl chloride in the presence of sodium hydride in an inert organic solvent such as THF or DMF, or a mixture of two or more of them at a temperature from 0°C to 40°C, preferably at ambient.

Step (2) may be carried out by using a mixture of THF, acetic acid and water, a mixture of p-toluenesulfonic acid and anhydrous methanol, or a mixture of diluted hydrochloric acid and THF, at room temperature or with heating.

Step (3) may be conducted by using 2,3-dihydropyran in methylene chloride in the presence of p-toluenesulfonic acid.

Step (4) may be carried out by reacting a compound of the general formula XII or XIII with a compound of the general formula: <chemistry id="chem0027" num="0027"><img file="EP0109255A2_D0046.tif" /></chemistry>(wherein R represents a halogen atom or an alkylsulfonyloxy group, having 1 to 4 carbon atoms in the alkyl group, or a substituted or unsubstituted arylsulfonyloxy group, preferably a mesyloxy group or a tosyloxy group and R is as hereinbefore defined) in the presence of an alkali metal hydride such as sodium hydride in an inert organic solvent such as DMF or THF at a temperature from ambient to 100°C.

Step (5) may be carried out by methods hereinbefore described for step (2).

Step (6) may be carried out by reacting a compound o the general formula XV with a compound of the general formula: <chemistry id="chem0028" num="0028"><img file="EP0109255A2_D0047.tif" /></chemistry>(the various symbols are as hereinbefore defined) in the presence of an alkali metal hydride such as sodium hydride in an inert organic solvent such as DMF, THF or toluene at a temperature f₁ ambient to 100°C,

Step (7) may be carried out by methods hereinbefore described for step (6) by using a compound of the general formula: <chemistry id="chem0029" num="0029"><img file="EP0109255A2_D0048.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) inst_E of a compound of the general formula XXV.

Step (8) may be carried out by methods hereinbefore described for step (6) by using a compound of the general formula: <chemistry id="chem0030" num="0030"><img file="EP0109255A2_D0049.tif" /></chemistry> (wherein the various symbols are as hereinbefore defined) instead of a compound of the general formula XXV.

Step (9) may be carried out by methods hereinbefore described for step (6) by using a compound of the general formula: <chemistry id="chem0031" num="0031"><img file="EP0109255A2_D0050.tif" /></chemistry>(wherein the symbols are as hereinbefore defined) instead of a compound of the general formula XXV.

Step (10) may be carried out by methods hereinbefore described for the conversion of compounds of the general formula VIIIA to those of the general formula IIA.

Step (11) may be carried out by methods hereinbefore described for step (6) by using a compound of the general formula: <chemistry id="chem0032" num="0032"><img file="EP0109255A2_D0051.tif" /></chemistry>(wherein R is as hereinbefore defined) instead of a compound of the general formula XXV.

Step (12) and (13) may be carried out by reacting a compound of the general formula XXI with compounds of the general formulae: <chemistry id="chem0033" num="0033"><img file="EP0109255A2_D0052.tif" /></chemistry>(wherein R⁷is as hereinbefore defined), respectively, in an inert organic solvent such as a lower alkanol, e.g. methanol, ethanol, isopropyl alcohol, or DMF or a mixture of two or more of than at a temperature from ambient to a reflux temperature of the reaction mixture.

Step (14) may be carried out by using methods for salt-exchange hereinafter described.

Compounds of the general formula IXA-1 wherein R represents a halogen atom may also be prepared by reaction of a compound of the general formula IXA-3 with an alkyl halide such as methyl iodide in a lower alkanol such as methanol or ethanol at a temperature from ambient to the reflux temperature of the reaction mixture.

Step (15) may be carried out by using phthalimide in an inert organic solvent such as DMF at a temperature from 50°C to a reflux temperature of the reaction mixture.

Step (16) may be carried out by using hydrazine in a lower alkanol such as ethanol.

Step (17) may be carried out by methods hereinbefore described for the conversion of compounds of the general formula VII to those of the general formula IA-2.

Step (18) may be carried out by using a corresponding acyl chloride, e.g. benzoyl chloride or a corresponding acid anhydride, e.g. acetic anhydride in the presence of a tertiary amine such as pyridine or triethylamine in an inert organic solvent such as methylene chloride or in the absence of a solvei at a temperature below 50°C.

According to a further feature of the present invention, glycerol derivatives of the general formula IA, wherein the various symbols are as hereinbefore defined may als be prepared by the following another methods: <ul id="ul0007" list-style="none"><li>(i) glycerol derivatives of the general formula IA, where R⁴ represents a group of the general formula: <img file="EP0109255A2_D0053.tif" />(R⁷)₃·<img file="EP0109255A2_D0054.tif" />, in which the various symbols are as hereinbefore defined, i.e. compounds of the general formula: <chemistry id="chem0034" num="0034"><img file="EP0109255A2_D0055.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) may b_l prepared from a compound of the general formula: <chemistry id="chem0035" num="0035"><img file="EP0109255A2_D0056.tif" /></chemistry> (wherein the various symbols are as hereinbefore defined) by methods hereinbefore described for step (12) and, if desired, step (14) in Scheme A.</li><li>(ii) Glycerol derivatives of the general formula IA, wherein R4 represents a group of the general formula: -N(R⁷)₂, in which R⁷ is as hereinbefore defined, i.e. compounds of the general formula: <chemistry id="chem0036" num="0036"><img file="EP0109255A2_D0057.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) may be prepared from a compound of the general formula XXXII by methods hereinbefore described for step (13) in Scheme A.</li><li>(iii) Glycerol derivatives of the general formula IA, wherein R⁴ represents a group of the general formula: -NHR⁷, in which R⁷ is as hereinbefore defined, i.e. compounds of the general formula: <chemistry id="chem0037" num="0037"><img file="EP0109255A2_D0058.tif" /></chemistry> (wherein the various symbols are as hereinbefore defined) may be prepared from a compound of the general formula XXXII by methods hereinbefore described for step (12) by using a compound of the general formula: <chemistry id="chem0038" num="0038"><img file="EP0109255A2_D0059.tif" /></chemistry>(wherein R⁷ is as hereinbefore defined) instead of a compound of the general formula XXX.</li><li>(iv) Glycerol derivatives of the general formula IA, wherein R² represents an azido group, an amino group or a group of the general formula: -NHCONHR⁵, in which R⁵ is as hereinbefore defined, and R⁴ represents an amino group, i.e. compounds of the general formula: <chemistry id="chem0039" num="0039"><img file="EP0109255A2_D0060.tif" /></chemistry>(wherein R^2a represents an azido group, an amino group or a group of the general formula: -NHCONHR⁵, in which R⁵ is as hereinbefore defined, and the other symbols are as hereinbefore defined) may be prepared from a compound of the general formula XXXII, wherein R² represents a group represented by R^2a i.e. a compound of the general formula: <chemistry id="chem0040" num="0040"><img file="EP0109255A2_D0061.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) by methods hereinbefore described for step (15) and (16) in Scheme A, successively.</li><li>(v) Glycerol derivatives of the general formula IA, wherein R²represents a group of the general formula: -NHCOR⁵ or -NHCOOR⁵, in which R⁵ is as hereinbefore defined, and R⁴ represents an amino group, i.e. compounds of the general formula: <chemistry id="chem0041" num="0041"><img file="EP0109255A2_D0062.tif" /></chemistry>(wherein R^2b represents a group of the general formula: -NHCOR⁵ or -NHCOOR ⁵, in which R⁵ is as hereinbefore defined, and the other symbols are as hereinbefore defined) may be prepared from a compound of the general formula XXXII, wherein R² represents a group represented by R^2b, and R⁹ represents a group of the formula: -OT, in which T is as hereinbefore defined, i.e. a compound of the general formula: <chemistry id="chem0042" num="0042"><img file="EP0109255A2_D0063.tif" /></chemistry></li><li>(wherein the various symbols are as hereinbefore defined) by methods hereinbefore described as method A and B, successively.</li><li>(vi) Glycerol derivatives of the general formula IA, wherein R² represents a group other than an amino group and R⁴ represents a group of the general formula: -NHCOR⁶, in which R⁶ is as hereinbefore defined, i.e. compounds of the general formula: <chemistry id="chem0043" num="0043"><img file="EP0109255A2_D0064.tif" /></chemistry></li><li>(wherein R^2c represents an azido group or a group of the general formula: ^{-NHCOR5, -NHCOOR5} or ^-NHCONHRS, in which R⁵ is as hereinbefore defined, and the other symbols are as hereinbefore defined) may be prepared from a compound of the general formula IA-34, wherein R^2a represents an azido group or-a group of the general formula: -NHCONHR⁵, or from a compound of the general formula IA-35, i.e. a compound of the general formula: <chemistry id="chem0044" num="0044"><img file="EP0109255A2_D0065.tif" /></chemistry></li><li>(wherein the various symbols are as hereinbefore defined) by methods hereinbefore described for step (18) in Scheme A.</li><li>(vii) Glycerol derivatives of the general formula IA, wherein R² represents an amino group and R4 represents a group of the general formula: -NHCOR , in which R is as hereinbefore defined, i.e. compounds of the general formula: <chemistry id="chem0045" num="0045"><img file="EP0109255A2_D0066.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) may be prepared by protection of an amino group of a compound of the general formula XXXII, wherein R² represents an amino group, i.e. a compound of the general formula: <chemistry id="chem0046" num="0046"><img file="EP0109255A2_D0067.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) by a boc group by reacting with di-tert-butyldicarbonate in an aqueous solution of sodium hydroxide at room temperature, or in methylene chloride in the presence of a tertiary amine such as triethylamine at room temperature or below, and subjecting the resulting compound of the general formula: <chemistry id="chem0047" num="0047"><img file="EP0109255A2_D0068.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) to the series of methods (15), (16) and (18) in Scheme A, and then eliminating a boc group of the obtained compound of the general formula: <chemistry id="chem0048" num="0048"><img file="EP0109255A2_D0069.tif" /></chemistry></li><li>(wherein the various symbols are as hereinbefore defined) by methods hereinbefore described for the conversion of compounds of the. general formula VII to those of the general formula IA-2 to obtain compounds of the general formula IA-38.</li></ul>

Compounds of the general formula XXXII may be prepared by the series of reactions depicted schematically below in Scheme B and C, wherein R^2d represents an amino group or a group of the general formula: -NHCOR⁵, -NHCOOR⁵ or -NHCONHR⁵, in which R⁵ is as hereinbefore defined, and the other symbols are as hereinbefore defined. <chemistry id="chem0049" num="0049"><img file="EP0109255A2_D0070.tif" /></chemistry>

Scheme C

<chemistry id="chem0050" num="0050"><img file="EP0109255A2_D0071.tif" /></chemistry>

In Scheme B and C, each step can be effected using methods hereinbefore described.

Step (19) may be carried out by methods hereinbefore described for the conversion of compounds of the general formula IXA to those of the general formula VIIIA.

Step (20) may be carried out by methods hereinbefore described for the conversion of compounds of the general formula VIIIA to those of the general formula IIA.

Step (21) may be carried out by methods hereinbefore described as method A, B, C, D and E.

Step (22) may be carried out by methods hereinbefore described for step (5) in Scheme A.

Step (23) may be carried out by methods hereinbefore described as method A.

Step (24) may be carried out by methods hereinbefore described for the step (2) in Scheme A.

Step (25) and (26) may be carried out by methods hereinbefore described for step (3) and (4) in Scheme A, respectively.

Step (27) and (28) may be carried out by methods hereinbefore described for step (6) and (8) in Scheme A, respectively.

Step (29) may be carried out by methods hereinbefore described as method B, C, D and E.

According to another feature of the present invention, glycerol derivatives of the general formula I, wherein A represents a carbonyloxy group, R² represents a group other than an amino group and the other symbols are as hereinbefore defined, i.e. compounds of the general formula: <chemistry id="chem0051" num="0051"><img file="EP0109255A2_D0072.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) may be prepared by the following methods: <ul id="ul0008" list-style="none"><li>(i) glycerol derivatives of the general formula IB, wherein R⁴ represents a group of the general formula: <img file="EP0109255A2_D0073.tif" />(R⁷)₃·<img file="EP0109255A2_D0074.tif" />, in which the various symbols are as hereinbefore defined, i.e. compounds of the general formula: <chemistry id="chem0052" num="0052"><img file="EP0109255A2_D0075.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) may be prepared from a compound of the general formula: <chemistry id="chem0053" num="0053"><img file="EP0109255A2_D0076.tif" /></chemistry></li><li>(wherein the various symbols are as hereinbefore defined) by methods hereinbefore described for the step (12) and, if desired, step (14) in Scheme A.</li></ul>

Compounds of the general formula XLVIII, wherein R⁹ represents a halogen atom, i.e. compounds of the general formula: <chemistry id="chem0054" num="0054"><img file="EP0109255A2_D0077.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) may be prepared by esterification of a compound of the general formula: <chemistry id="chem0055" num="0055"><img file="EP0109255A2_D0078.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) with an acid of the general formula: <chemistry id="chem0056" num="0056"><img file="EP0109255A2_D0079.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) or a reactive derivative thereof. The esterification may be carried out in an inert organic solvent such as ethyl acetate, benzene, diethyl ether, chloroform, methylene chloride, THF or a mixture of two or more of them at a temperature from -10°C to 50°C (preferably at a temperature from ambient to 0°C). Examples of the reactive derivatives of an acid of the general formula L are an acid halide such as acyl chloride or acyl bromide, a mixed acid anhydride with pivaloyl chloride, isobutyryl chloride or isobutyl chloroformate, or an active ester with dicyclohexylcarbodiimide. Preferably, the reactive derivatives of an acid of the general formula L may be prepared in the presence of a base such as pyridine or triethylamine in a suitable inert organic solvent at 0°C.

Compounds of the general formula XLVIII, wherein R⁹ represents an alkylsulfonyl group or an arylsulfonyl group, i.e. compounds of the general formula: <chemistry id="chem0057" num="0057"><img file="EP0109255A2_D0080.tif" /></chemistry><ul id="ul0009" list-style="none"><li>(wherein the various symbols are as hereinbefore defined) may be prepared by esterification of a compound of the general formula XLIX with an acid of the general formula: <chemistry id="chem0058" num="0058"><img file="EP0109255A2_D0081.tif" /></chemistry></li><li>(wherein the various symbols are as hereinbefore defined) or a reactive derivative thereof by methods hereinbefore described for esterification, and then subjecting the resulting compound of the general formula: <chemistry id="chem0059" num="0059"><img file="EP0109255A2_D0082.tif" /></chemistry> (wherein the various symbols are as hereinbefore defined) to methods hereinbefore described for step (5) and (10) in Scheme A to obtain a compound of the general formula XLVIIIB.</li><li>(ii) Glycerol derivatives of the general formula IB, wherein R⁴ represents a group of the general formula: -N(R⁷)₂, in which R is as hereinbefore defined, i.e. compounds of the general formula: <chemistry id="chem0060" num="0060"><img file="EP0109255A2_D0083.tif" /></chemistry> (wherein the various symbols are as hereinbefore defined) may be prepared by esterification of a compound of the general formula XLIX with an acid of the general formula: <chemistry id="chem0061" num="0061"><img file="EP0109255A2_D0084.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) or a reactive derivative thereof by methods hereinbefore described for esterification,</li><li>(iii) Glycerol derivatives of the general formula IB, wherein R⁴ represents an amino group or a group of the general formula: -NHR⁷, in which R is as hereinbefore defined, i.e. compounds of the general formula: <chemistry id="chem0062" num="0062"><img file="EP0109255A2_D0085.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) may be prepared by esterification of a compound of the general formula XLIX with an acid of the general formula: <chemistry id="chem0063" num="0063"><img file="EP0109255A2_D0086.tif" /></chemistry> (wherein the various symbols are as hereinbefore defined) or a reactive derivative thereof by methods hereinbefore described for esterification, and then eliminating a boc group of the resulting compound of the general formula: <chemistry id="chem0064" num="0064"><img file="EP0109255A2_D0087.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) by methods hereinbefore described for the conversion of compounds of the general formula VII to those of the general formula IA-2.</li><li>(iv) Glycerol derivatives of the general formula IB, wherein R⁴ represents a group of the general formula: -NHCOR⁶ , in which R⁶ is as hereinbefore defined, i.e. compounds of the general formula: <chemistry id="chem0065" num="0065"><img file="EP0109255A2_D0088.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) may be prepared by acylation of a compound of the general formula IB-3, wherein R⁸ represents a hydrogen atom, i.e. a compound of the general formula: <chemistry id="chem0066" num="0066"><img file="EP0109255A2_D0089.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) by method hereinbefore described for step (18) in Scheme A.</li></ul>

Compounds of the general formula XLIX may be prepared by the series of reactions depicted schematically below in Scheme D, wherein the various symbols are as hereinbefore defined. <chemistry id="chem0067" num="0067"><img file="EP0109255A2_D0090.tif" /></chemistry>

In Scheme D, each step can be effected using methods hereinbefore described.

Step (30) can be carried out by methods hereinbefore described for step (3) in Scheme A.

Step (31), (32), (33) and (34) may be carried out by methods hereinbefore described as method B, C, D and E, respectively.

Step (35) may be carried out by methods hereinbefore described for step (5) in Scheme A.

Compounds of the general formulae III to VI, XXIV to XXXI, XXXIII, L, LI, LIII and LIV are well known per se or may be prepared by methods known per se.

Glycerol 1,3-benzylidene ether of the formula X, employed as the starting material is a known compound described in J. Amer. Chem. Soc., 50, 2235 (1928).

Glycerol derivatives of the general formula I, wherein R²represents a group other than an amino group and R⁴ represents a group of general formula: <img file="EP0109255A2_D0091.tif" />(R⁷)₃·<img file="EP0109255A2_D0092.tif" />, in which Y represents a halogen atom, i.e. compounds of the general formula: <chemistry id="chem0068" num="0068"><img file="EP0109255A2_D0093.tif" /></chemistry> (wherein the various symbols are as hereinbefore defined) may also be prepared by reaction of a compound of the general formula: <chemistry id="chem0069" num="0069"><img file="EP0109255A2_D0094.tif" /></chemistry>(wherein the various symbols are as hereinbefore defined) with an alkyl halide such as methyl iodide in a lower alkanol such as methanol or ethanol at a temperature from ambient to the reflux temperature of the reaction mixture.

Glycerol derivatives of the general formula I, wherein R⁴ represents a group of the general formula: <img file="EP0109255A2_D0095.tif" />(R⁷)₃·Y⊖, in which Y represents a group other than a halogen atom and other than a OT group, i.e. compounds of the general formula I, wherein R⁴ represents a group of the general formula: <img file="EP0109255A2_D0096.tif" />(R⁷)₃·<img file="EP0109255A2_D0097.tif" /> , in the various symbols are as hereinbefore defined may be easily prepared from a glycerol derivative of the general formula I, wherein R⁴ represents a group of the general formula: <img file="EP0109255A2_D0098.tif" />(R⁷)₃<img file="EP0109255A2_D0099.tif" /> , in which the various symbols are as hereinbefore defined, by salt-exchange, for example, by neutralizing of a compound of the general formula I, wherein R⁴ represents a group of the general formula: <img file="EP0109255A2_D0100.tif" />(R⁷)₃·<img file="EP0109255A2_D0101.tif" /> with an aqueous solution of sodium hydroxide, and then reacting with a desirable inorganic or organic acid, or by ion-exchange resin.

Glycerol derivatives of the general formula I, wherein R represents an amino group or R ⁴ represents an amino group or a group of the general formula: -NHR⁷ or -N(R⁷)₂ may be converted into acid addition salts thereof. Preferably, acid addition salts are non-toxic salts and are water-soluble. Suitable acid addition salts are, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphorate, nitrate, or organic acid salts such as acetate, lactate, tartrate, benzoate citrate, methanesulphonate, ethanesulphonate, benzenesulphonate, toluenesulphonate or isethionate. Acid addition salts may be prepared by methods known per se, for example, reacting of stoichiometric quantities of a compound of the general formula I, wherein R² represents an amino group or R⁴ represents an amino group or a group of the general formula: -NHR⁷ or -N(R⁷)₂ and a desirable acid in a suitable solvent.

Glycerol derivatives of the general formula I and acid addition salts thereof have antagonistic effect on PAF, hypotensive effect like PAF, inhibitory effect on phospholipase and further, inhibitory effect on growth of tumour cell or induction of differentiation, and are, therefore, useful as a platelet aggregation inhibitor, anti-asthmatic agent, anti-allergic agent, anti-inflammatory agent, hypotensive agent and anti-tumour agent for mammals including human beings, especially human beings. These effect were confirmed by standard laboratory test and, for example, antagonistic effect on PAF was confirmed by the following screening system.

Inhibitory effect on PAF-induced platelet aggregation

A mixture of 9 parts of blood obtained from male guinea-pig, and one part of 3.8% trisodium citrate was centrifuged for 10 minutes at 120 x g at room temperature to obtain platelet rich plasma (PRP). Using obtained PRP, PAF (lOnM)-induced aggregation was determined by the method of Born [cf. J. Physiol., 162, 67 (1962)].

The evaluation is conducted using the concentration of compounds of the present invention required to produce a 50% inhibition of the effect, i.e. IC₅₀. The results are shown in the following table. <tables id="tabl0001" num="0001"><img file="EP0109255A2_D0102.tif" /></tables>

On the other hand, it was confirmed that the acute toxicity of all extent of the compounds of the present invention was more. than 30 mg/kg by intravenous administration. Therefore, glycerol derivatives of the present invention may be considered to be sufficiently safe and suitable for medical use. For example, the mortality (dead/used) in glycerol derivatives of the present invention, i.e. compounds prepared in Example 8, 8(j) and 8(r) was 2/10, 0/10 and 0/10, respectively, when each glycerol compound was intravenously administered to tail vein in ten mice at the dose of 30 mg/kg.

For the purpose hereinbefore described, glycerol derivatives of the general formula I, or non-toxic acid addition salt thereof may normally be administered systemically or partially usually by oral or parenteral (e.g. intravenous, subcutaneous or intramuscular) administration. The dose to be administered is determined depending upon, for example, age, body weight, symptoms, the desired therapeutic effect, the route of administration, and the duration of the treatment.

In the human adult, the doses per person are generally between 1 mg and 1 g, preferably between 20 and 200 mg by oral administration, and between 100 ug and 100 mg, preferably between 1 and 10 mg by parenteral administration and can be administered up to several times per day.

As mentioned above, the doses to be used depend on various conditions. Therefore, there may be cases in which doses greater than the ranges specified above, or lower than the ranges specified above, may be used.

The present invention includes within its scope pharmaceutical compositions which comprise at least one glycerol derivatives of the general formula I, or non-toxic acid addition salt thereof, together with a pharmaceutical carrier or coating.

Solid compositions according to the present invention for oral administration include compressed tablets, pills; dispersible powders and granules. In such solid compositions, one or more of the active compound(s) is, or are, admixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or magnesium metasilicate aluminate. The compositions may also comprise, as is normal practice, additional substances other than inert diluents e.g. lubricating agents such as magnesium stearate, and, disintegrating agents such as cellulose calcium gluconate. The tablets or pills may, if desired, be made into enteric film-coated or gastric film-coated tablets or pills, such as sugar-coated, gelatin-coated, hydroxypropylcellulose-coated or hydroxypropylmethylcellulose phthalate-coated tablets or pills; two or more layers may be used.

The compositions for oral administration also include capsules of absorbable material such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients.

Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as distilled water or ethanol. Besides inert diluents such compositions may also comprise adjuvants such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents.

Other compositions for oral administration include spray compositions which may be prepared by known methods and which comprise at least one compound of the present invention.

Preparations according to the present invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of aqueous solvents or suspending media are distilled water for injection and physiological salt solution. Examples of non-aqueous solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (registered Trade Mark). These compositions may also include ajuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilized, for example, by filtration through a bacteria- retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

Other compositions include, for parenteral administration, liquids for external use, and endermic liniments such as ointments; suppositories for rectal administration; and pessaries for vaginal administration. Such compositions are prepared by known methods.

The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage for the therapeutic effect desired shall be obtained. Obviously several unit dosage forms may be administered at about the same time. In general, the preparations should normally contain at least 0.025% by weight of active substance when required for administration by injection; for oral administration the preparations will normally contain at least 0.1% by weight of active substance.

Preferred glycerol derivatives of the present invention are as follows: <ul id="ul0010" list-style="none"><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-azido-3-0-[4-(N,N,N-trimethyl- ammonio)butyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-azido-3-0-[5-(N,N,N-trimethyl- ammonio)pentyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-azido-3-0-[6-(N,N,N-trimethyl- ammonio)hexyl]glycerolehalide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-azido-3-0-[7-(N,N,N-trimethyl- ammonio)heptyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-azido-3-0-[8-(N,N,N-trimethyl- ammonio)octyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-amino-3-0-[4-(N,N,N-trimethyl- ammonio)butyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-amino-3-0-[5-(N,N,N-trimethyl- ammonio)pentyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-amino-3-0-[6-(N,N,N-trimethyl- ammonio)hexyl]glycerolehalide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-amino-3-0-[7-(N,N,N-trimethyl- ammonio)heptyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-amino-3-0-[8-(N,N,N-trimethyl- ammonio)octyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-benzoylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-benzoylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-benzoylamino-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-benzoylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-benzoylamino-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-acetylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-acetylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-acetylamino-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-acetylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-acetylamino-3-0-[8-{N,N,N-trimethylammonio)octyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-propionylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-propionylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-propionylamino-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-propionylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-propionylamino-3-0-[8-(N,N,N-trimethylammonio)octyl]glyceral·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-butyrylamino-3-0-[4-{N,N,N-trimethyiammonio)hutyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-butyrylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerolohalide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-butyrylamino-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-butyrylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-butyrylamino-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-valerylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-valerylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-valerylamino-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-valerylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerolohalide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-valerylamino-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-hexanoylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol·halide or its mesylate;</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-hexanoylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-hexanoylamino-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-hexanoylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-hexanoylamino-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-phenoxycarbonylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-phenoxycarbonylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-phenoxycarbonylamina-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-phenoxycarbonylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol·halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-phenoxycarbonylamino-3-0-[8-(N,N,N-trimethylammonio}octyl]glycerol·halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-methoxycarbonylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol·halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-methoxycarbonylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-methoxycarbonylamino-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerolehalide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-methoxycarbonylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-methoxycarbonylamino-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-ethoxycarbonylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-ethoxycarbonylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-ethoxycarbonylamino-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol·halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-ethoxycarbonylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyi-2-dehydroxy-2-ethoxycarbonylamino-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol·halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-propoxycarbonylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-propoxycarbonylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-propoxycarbonylamino-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-propoxycarbonylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-propoxycarbonylamino-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-butoxycarbonylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-butoxycarbonylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol halide or its mesylate, (2RS)-1-0-hexadecyl-2.-dehydroxy-2-butoxycarbonylamino-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-butoxycarbonylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-butoxycarbonylamino-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-pentyloxycarbonylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol·halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-pentyloxycarbonylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol·halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-pentyloxycarbonylamino-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol·halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-pentyloxycarbonylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-pentyloxycarbonylami.no-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-phenylureido)-3-0-[4-(N,N,N-trimethylammonio)butyl]glyeerol·halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-(N'-phenylureido)-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol·halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-(N'-phenylureido)-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol.halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-phenylureido)-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-phenylureido)-3-0-[8- {N,N,N-trimethylammonio)octyl]glpcerol·halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-(N'-methylureido)-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol·halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-(N'-methylureido)-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerolehalide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-methylureido)-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol·halide or its mesylate, (2RS)-l-0-hexadecyl-2-dehydroxy-2-(N'-methylureido)-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-methylureido)-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-ethylureido)-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-ethylureido)-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerolohalide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-ethylureido)-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-ethylureido)-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerolehalide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-ethylureido)-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-propylureido)-3-O-(4-(N,N,N-trimethylammonio)butyl]glycerolehalide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-propylureido)-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-propylureido)-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol·halide or its mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-propylureido)-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-(N'-propylureido)-3-0-[8-(N,N,N-trimethylammonio)octy1]glycerol-halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-butylureido)-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-(N'-butylureido)-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-(N'-butylureido)-3-0-[6-(N,N,N-trimethylammonio)hexyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-(N'-butylureido)-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-butylureido)-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-(N'-pentylureido)-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol·halide or its mesylate,</li><li>(2RS)-1-O-hexadecyl-2-dehydroxy-2-(N'-pentylureido)-3-0-[5-(N,N,N-trimethylammonio)pentyllglycerol-halide or its mesylate,</li><li>(2RS)-1-O-hexadecyl-2-dehydroxy-2-(N'-pentylureido)-3-0-[6-(N,N,N-trimethylammonio)hexyllglycerolehalide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-(N'-pentylureido)-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol·halide or its mesylate,</li><li>(2RS)-l-0-hexadecyl-2-dehydroxy-2-(N'-pentylureido)-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol·halide or its mesylate, and the corresponding 3-0-acyl analogues.</li></ul>

The following Reference Examples and Examples illustrate, but not limit, the preparation of compound of the present invention. In the Reference Examples and Examples, 'TLC', 'NMR', 'IR' and 'MS' represent 'Thin layer chromatography', 'Nuclear magnetic reasonance spectrum', 'Infrared absorption spectrum' and 'Mass spectrum', respectively. The solvents in parentheses specified in chromatographic separations show the developing solvents used : ratios are by volume. Except when specified otherwise, infrared absorption spectra were recorded by the liquid film method and nuclear magnetic resonance spectra were recorded in deutero- chloroform (CDC1₃) solution.

Various abbreviated words in Reference Example and Examples donate the following words: <ul id="ul0011" list-style="none"><li>THP : tetrahydropyran-2-yl group</li><li>Ø : phenyl group</li><li>Ms : mesyl group</li><li>Ts : tosyl group</li><li>AcOEt : ethyl acetate</li><li>DMF : dimethylformamide</li><li>CH₂Cl₂: methylene chloride</li><li>MeOH : methanol</li><li>AcOH : acetic acid</li><li>THF : tetrahydrofuran</li><li>HMPA : hexamethylphosphoramide</li><li>CHCl₃: chloroform</li><li>NaCl : sodium chloride</li><li>NaHCO₃: sodium bicarbonate</li><li>NaOH : sodium hydroxide</li><li>sat. : saturated</li><li>aq. : aqueous</li></ul>

Reference Example 1

<chemistry id="chem0070" num="0070"><img file="EP0109255A2_D0103.tif" /></chemistry>

A mixture of 161 g of 1,3-0-benzylideneglycerol [the compound is described in J. Amer. Chem. Soc., 50, 2235 (1928)], 50 g of sodium hydride (content: 64.1%) and 800 ml of dry DMF was stirred for one hour at 60°C. After cooling with ice-bath, 227 g of benzyl bromide was added thereto, and the mixture was stirred for 10 minutes at room temperature and further for 2 hours at 60°C. To the reaction mixture was added water and then the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue thus obtained, and the solution was washed with water and a sat. aq. solution of NaCl, successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of AcOEt and n-hexane) to give 218 g of the title compound having the following physical data: <ul id="ul0012" list-style="none"><li>TLC (AcOEt:n-hexane=1:2): Rf=0.47;</li><li>NMR: 8=7.53-7.07 (10H, m), 5.47 (lH, s), 4.63 (2H, s), 4.20 (4H, dt), 3.33 (lH, m).</li></ul>

Reference Example 2

<chemistry id="chem0071" num="0071"><img file="EP0109255A2_D0104.tif" /></chemistry>

A mixture of 218 g of the benzylidene compound (prepared in Reference Example 1), 2 liters of MeOH and 2 g of p-toluenesulfonic acid was stirred overnight at room temperature. After adding triethylamine thereto, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: AcOEt) to give 138 g of the title compound having the following physical data: <ul id="ul0013" list-style="none"><li>TLC (CHC1₃:acetone=10:l): Rf=0.12;</li><li>NMR: δ=8.22 (5H, s), 4.53 (2H, s), 3.63 (5H, m), 2.86 (2H, m); MS: m/e=182 (M⁺), 107.</li></ul>

Reference Example 3

<chemistry id="chem0072" num="0072"><img file="EP0109255A2_D0105.tif" /></chemistry>

A mixture of 49 g of the dihydroxy compound (prepared in Reference Example 2), 22.6 g of 2,3-dihydropyran, 200 mg of p-toluenesulfonic acid and 300 ml of CH₂C1₂ was stirred for 30 minutes at room temperature. The reaction mixture was neutralized with a sat. aq. solution of NaHCO₃ and the solution was extracted with AcOEt. The extract was washed with water and a sat. aq. solution of NaCl, successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of AcOEt and cyclohexane) to give 37.4 g of the title compound having the following physical data: TLC (CHC1₃:acetone=10:l): Rf=0.39;

NMR: δ=7.28 (5H, s), 4.8-4.4 (3H, m), 4.0-3.3 (7H, m), 2.54-2.25 (1H, m), 1.92-1.2 (6H, m);

IR: v=3450, 2930, 2860, 1440, 1350 cm^-1.

Reference Example 4

<chemistry id="chem0073" num="0073"><img file="EP0109255A2_D0106.tif" /></chemistry>

Under an atmosphere of argon, to a suspension of 10.4 g of sodium hydride (content: 64.1%) in 500 ml of dry DMF was added a solution of 37 g of the hydroxy compound (prepared in Reference Example 3) in 150 ml of dry DMF. The mixture was stirred for one hour at 60°C. After cooling to 40°C, thereto was added a suspension of 84.8 g of hexadecyl bromide in 150 ml of dry DMF and the mixture obtained was stirred for 10 minutes at room temperature and further, for 3 hours at 60°C - 80°C. After adding 50 ml of water thereto, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of CH₂C1₂ and n-hexane, and CH₂Cl₂ only, successively) to give 57 g of the title compound having the following physical data: <ul id="ul0014" list-style="none"><li>TLC (AcOEt:cyclohexane=l:5): Rf=0.63;</li><li>NMR: δ=7.16 (5H, s), 4.6 (2H, s), 4.63-4.36 (lH, m), 4.0-3.16 (9H, m), 1.8-0.7 (35H, m);</li><li>IR: v=2920, 2840, 1460, 1110 cm^-1.</li></ul>

By the same procedure as described in Reference Example 4, the compound having the following physical data was prepared. <chemistry id="chem0074" num="0074"><img file="EP0109255A2_D0107.tif" /></chemistry>Starting Material: the hydroxy compound prepared in Reference Example 3 and hexyl bromide; <ul id="ul0015" list-style="none"><li>TLC (AcOEt:n-hexane=1:5): Rf=0.49;</li><li>NMR: 6=7.4-7.0 (5H, m), 4.61 (2H, s), 4.7-4.4 (lH, m), 4.0-3.1 (9H, m), 2.0-0.6 (17H, m);</li><li>IR: v=2930, 2860, 1120 cm^-1.</li></ul>

Reference Example 5

<chemistry id="chem0075" num="0075"><img file="EP0109255A2_D0108.tif" /></chemistry>

A mixture of 57 g of the 3-0-(tetrahydropyran-2-yl)-glycerol compound (prepared in Reference Example 4), 150 ml of CH₂Cl₂, 300 ml of MeOH and 500 mg of p-toluenesulfonic acid was stirred for 4 hours at room temperature. To the reaction mixture was added 100 ml of a sat. aq. solution of NaNCO₃ and concentrated under reduced pressure to distill off MeOH. To the residue was added 2 liters of AcOEt and the solution was washed with water and a sat. aq. solution of NaCl, successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of CH₂Cl₂ and AcOEt) to give 34.8 g of the title compound having the following physical data: TLC (AcOEt:cyclohexane=1:5): Rf=0.24; <ul id="ul0016" list-style="none"><li>NMR: 6=7.2 (5H, s), 4.6 (2H, s), 3.8-3.2 (7H, m), 2.3-2.0 (lH, m), 1.7-0.7 (31H, m);</li><li>IR: v=₃₄₅₀, 2920, 2840, 1460, 111⁰ cm^-1.</li></ul>

By the same procedure as described in Reference Example 5, the compound having the following physical data was prepared. <chemistry id="chem0076" num="0076"><img file="EP0109255A2_D0109.tif" /></chemistry>Starting Material: the 3-0-(tetrahydropyran-2-yl)glycerol

compound prepared in Reference Example 4(a); TLC (AcOEt:n-hexane=1:5): Rf=0.18; <ul id="ul0017" list-style="none"><li>NMR: δ=7.3-7.0 (5H, m), 4.56 (2H, s), 3.7-3.1 (7H, m), 2.43 (lH, s), 1.8-0.6 (11H, m);</li><li>IR: v=3450, 2940, 2860, 1110 cm^-1.</li><li>MS: m/e=266 (M⁺), 175.</li></ul>

Reference Example 6

<chemistry id="chem0077" num="0077"><img file="EP0109255A2_D0110.tif" /></chemistry>

Under an atmosphere of argon, to a suspension of 1.1 g of sodium hydride (content: 64.1%) in 50 ml of dry DMF was added a solution of 10 g of the 3-hydroxy compound (prepared in Reference Example 5) in 50 ml of dry DMF and the mixture was stirred for 30 minutes at 70°C. A solution of 7.7 g of 4-(p-toluenesulfonyloxy)butyl chloride in 50 ml of dry DMF was added thereto at room temperature, and the mixture obtained was stirred for 15 minutes at 70°C. To the reaction mixture was added 10 ml of water and adjusted to pH 4 by adding 1N hydrochloric acid and then concentrated under reduced pressure. To the residue was added 500 ml of AcOEt and the solution was washed with water and a sat. aq. solution of NaCl, successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of AcOEt and n-hexane) to give 5.8 g of the title compound having the following physical data: <ul id="ul0018" list-style="none"><li>TLC (AcOEt:hexane=1:4): Rf=0.69;</li><li>NMR: δ=7.18 (5H, s), 4.62 (2H, s), 3.8-3.13 (11H, m), 2.13-0.63 (37H, m);</li><li>IR: V=2920, 2850, 1460, 1450, 1115, 735, 695 cm^-1;</li><li>MS: m/e=496 (M⁺), 434, 405, 390, 214.</li></ul>

By the same procedure as described in Reference Example 6, the compounds having the following physical data in Table 1 were prepared. <tables id="tabl0002" num="0002"><img file="EP0109255A2_D0111.tif" /></tables> Reference Example 7 <chemistry id="chem0078" num="0078"><img file="EP0109255A2_D0112.tif" /></chemistry>

By the same procedure as described in Reference Example 5, the title compound having the following physical data was prepared from the tetrahydropyran-2-yloxy compound prepared in Reference Example 6 (b). <ul id="ul0019" list-style="none"><li>TLC (AcOEt:n-hexane:l:5): Rf=0.15;</li><li>IR: v=3450, 2940, 2870, 1460, 1120 cm^-1;</li><li>MS: m/e=520 (M⁺), 429, 414.</li></ul>

Reference Example 8

<chemistry id="chem0079" num="0079"><img file="EP0109255A2_D0113.tif" /></chemistry>

A mixture of 2.9 g of the hydroxy compound (prepared in Reference Example 7), 3 ml of triethylamine, 20 ml of CH₂C1₂ and 0.55 ml of mesyl chloride was stirred for 30 minutes under cooling with ice-bath. After adding water thereto, the reaction mixture was extracted with AcOEt, and the extract was washed with water and a sat. aq. solution of NaCl, successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3.4 g of the title compound as crude product, having the following physical data: <ul id="ul0020" list-style="none"><li>TLC (GHGl₃:acetone=10:1): Rf=0.81;</li><li>NMR: 6=7.2 (5H, s), 4.63 (2H, s), 4.13 (2H, t), 3.8-3.2 (9H, m), 2.9 (3H, s), 2.0-0.7 (41H, m);</li><li>MS: m/e=598 (M⁺).</li></ul>

Reference Example 9

<chemistry id="chem0080" num="0080"><img file="EP0109255A2_D0114.tif" /></chemistry>

A mixture of 5.5 g of the chlorobutylglycerol compound (prepared in Reference Example 6), 45 ml of a 40% aqueous solution of dimethylamine and 130 ml of DMF was stirred for 6.5 hours at 60°C. The reaction mixture was concentrated under reduced pressure and to the residue thus obtained was added 300 ml of AcOEt. The resulting solution was washed with 1N aq. solution of NaOH and a sat. aq. solution of NaCl, successively, dried over potassium carbonate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of CHC13, MeOH and triethylamine) to give 5.1 g of the title compound having the following physical data: <ul id="ul0021" list-style="none"><li>TLC (AcOEt:AcOH:water=3:1:1): Rf=0.67;</li><li>NMR: δ=7.22 (5H, s), 4.63 (2H, s), 3.87-3.20 (9H, m), 2.50-2.0 (2H, m and 6H, s), 1.83-0.67 (35H, m);</li><li>IR: υ=3070, 3045, 2940, 2860, 1470, 1455, 1380, 1120, 740, 700 cm^-1;</li><li>MS: m/e=506, 505, 414, 398, 280.</li></ul>

By the same procedure as described in Reference Example 9, the compound having the following physical data in Table 2, were prepared. <tables id="tabl0003" num="0003"><img file="EP0109255A2_D0115.tif" /></tables> Reference Example 10 <chemistry id="chem0081" num="0081"><img file="EP0109255A2_D0116.tif" /></chemistry>

Under an atmosphere of hydrogen, a mixture of 5.1 g of the 2-0-benzylglycerol compound (prepared in Reference Example 9), 500 mg of palladium on carbon (content: 10%), 50 ml of EtOH and 0.7 ml of a concentrated hydrochloric acid was stirred for 3 hours at room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. To the residue thus obtained was added 300 ml of AcOEt and the solution was washed with 1N aq. solution of NaOH, dried over potassium carbonate and concentrated under reduced pressure to give 4.1 g of the title compound having the following physical data: TLC (AcOEt:AcOH:water=3:1:1): Rf=0.61; <ul id="ul0022" list-style="none"><li>NMR: 6=4.08-3.63 (lH, m), 3.63-3.15 (8H, m), 2.93 (lH, s), 2.45-2.08 (8H, m), 2.18 (6H, s), 1.92-0.67 (35H, m);</li><li>IR: v=3420, 2925, 2855, 1465, 1375, 1265, 1115, 755 cm^-1.</li></ul>

By the same procedure as described in Reference Example 10, the compounds having the following physical data in Table 3 were prepared. <tables id="tabl0004" num="0004"><img file="EP0109255A2_D0117.tif" /></tables> Reference Example 11 <chemistry id="chem0082" num="0082"><img file="EP0109255A2_D0118.tif" /></chemistry>

To a mixture of 3.4 g of the 2-hydroxy compound (prepared in Reference Example 10), 4 ml of triethylamine and 50 ml of CH₂Cl₂ was added 0.76 ml of mesyl chloride at 0°C and the mixture was stirred for one hour at the same temperature. After adding 300 ml of diethyl ether thereto, the reaction mixture was washed with 1N aq. solution of NaOH and a sat. aq. solution of NaCl, successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3.86 g of the title compound having the following physical data: TLC (AcOEt:AcOH:water=3:1:1): Rf=0.61; <ul id="ul0023" list-style="none"><li>NMR: δ=4.93-4.53 (lH, m), 3.80-3.16 (8H, m), 3.0 (3H, s), 2.16</li><li>(6H, s), 2.46-2.0 (2H, m), 1.83-0.66 (35H, m); IR: v=2920, 2840, 1450, 1350, 1170, 1110 cm^-1.</li></ul>

By the same procedure as described in Reference Example 11, the compounds having the following physical data in Table 4 were prepared. <tables id="tabl0005" num="0005"><img file="EP0109255A2_D0119.tif" /></tables>

Example 1

<chemistry id="chem0083" num="0083"><img file="EP0109255A2_D0120.tif" /></chemistry>

A mixture of 3.86 g of the 2-0-mesylglycerol compound (prepared in Reference Example 11), 1.5 g of sodium azide and 50 ml of HMPA was stirred overnight at 50°C. After adding 300 ml of diethyl ether thereto, the reaction mixture was washed with 1N aq. solution of NaOH, water and a sat. aq. solution of NaCl, successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of CH₂Cl₂, MeOH and triethylamine) to give 2.92 g of the title compound having the following physical data: <ul id="ul0024" list-style="none"><li>TLC (CHCl₃:AcOH:EtOH:water=20:4:3:1): Rf=0.76;</li><li>NMR: 6=3.74-3.38 (9H, m), 2.22 (6H, s), 2.36-2.20 (2H, m), 1.70-1.48 (6H, m), 1.25 (26H, m), 0.88 (3H, m);</li><li>IR: ν=2920, 2840, 2110, 2090, 1460, 1260, 1110 cm^-1;</li><li>MS: m/e=440 (M⁺), 398.</li></ul>

By the.same procedure as described in Example 1, the compounds having the following physical data in Table 5 were prepared. <tables id="tabl0006" num="0006"><img file="EP0109255A2_D0121.tif" /></tables>

Example 2

<chemistry id="chem0084" num="0084"><img file="EP0109255A2_D0122.tif" /></chemistry>

A mixture of 180 mg of the dimethylaminoglycerol compound (prepared in Example 1), 0.3 ml of methyl iodide and 5 ml of MeOH was stirred for one hour at room temperature, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of CHC1₃ and MeOH, and a mixture of CHC1₃, MeOH and water, successively) to give 224 mg of the title compound having the following physical data: <ul id="ul0025" list-style="none"><li>Melting Point: 50 - 52°C;</li><li>TLC (AcOEt:AcOH:water=3:1:1): Rf=0.49;</li><li>NMR: 6=3.42 (9H, s), 3.8-3.4 (11H, m), 2.04-1.5 (6H, m), 1.25 (26H, m), 0.88 (3H, m);</li><li>IR (KBr method): ν=3450, 2910, 2850, 2100, 1460, 1270, 1110 cm^-1; MS: m/e=398, 310.</li></ul>

By the same procedure as described in Example 2, the compound having the following physical data was prepared. <chemistry id="chem0085" num="0085"><img file="EP0109255A2_D0123.tif" /></chemistry><ul id="ul0026" list-style="none"><li>Starting Material: the dimethylaminoglycerol compound prepared in Example l(a), with the proviso that potassium bicarbonate was used in the reaction;</li><li>Melting Point: 47 - 51°C;</li><li>TLC (CH₂Cl₂:AcOH:EtOH:water=8:4:2:1): Rf=0.46;</li><li>NMR: δ=3.8-3.3 (11H, m and 9H, s), 2.1-1.0 (34H, m), 1.0-0.7 (3H, m)</li><li>IR (KBr method): v=3600-3100, 2910, 2840, 2120, 2080, 1460, 1270, 1110 cm^-1.</li></ul>

Example 3

<chemistry id="chem0086" num="0086"><img file="EP0109255A2_D0124.tif" /></chemistry>

Under an atmosphere of hydrogen, a mixture of 194 mg of the 2-azidoglycerol compound (prepared in Example 2), 100 mg of palladium on carbon (content: 10%) and 12 ml of MeOH was stirred for 2 hours at room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of CHC1₃, MeOH and water) to give 100.3 mg of the title compound having the following physical data: <ul id="ul0027" list-style="none"><li>TLC (AcOEt:AcOH:water=3:l:l): Rf=0.15;</li><li>NMR: 6=3.86-3.56 (8H, m), 3.45 (9H, s), 3.56-3.38 (3H, m), 2.2-2.0 (2H, m), 1.86-1.68 (2H, m), 1.68-1.50 (2H, m), 1.26 (26H, m), 0.88 (3H, m);</li><li>IR: v=3450, 2920, 2840, 1460, 1110 cm^-1;</li><li>MS: m/e=414, 399, 370.</li></ul>

By the same procedure as described in Example 3, the compounds having the following physical data in Table 6 were prepared. <tables id="tabl0007" num="0007"><img file="EP0109255A2_D0125.tif" /></tables>

Example 4

<chemistry id="chem0087" num="0087"><img file="EP0109255A2_D0126.tif" /></chemistry>

A mixture of 173 mg of the 2-azidoglycerol compound [prepared in Example l(b)], 100 mg of lithium aluminium hydride and 10 ml of diethyl ethyl was refluxed for one hour. To the reaction mixture was added a 10% aq. solution of NaOH until the mixture turned to white and then was added an adequate amount of magnesium sulfate and the mixture was filtered. The filtrate was concentrated under reduced pressure to give 153 mg of the title compound having the following physical data: <ul id="ul0028" list-style="none"><li>TLC (AcOEt:AcOH:water=3:1:1): Rf=0.38;</li><li>NMR: δ=3.8-3.2 (9H, m), 2.2 (6H, s), 2.4-2.0 (2H, m), 2.0-0.7 (25H, m);</li><li>IR: v=3400, 2950, 2860, 1460, 1110 cm^-1;</li><li>MS: m/e=331, 286.</li></ul>

By the same procedure as described in Example 4, the compounds having the following physical data were prepared. <chemistry id="chem0088" num="0088"><img file="EP0109255A2_D0127.tif" /></chemistry> Starting Material: the 2-azidoglycerol compound prepared in Example l(c);

<ul id="ul0029" list-style="none"><li>TLC (AcOEt:AcOH:water=3:l:l): Rf=0.42;</li><li>NMR: δ=3.6-3.0 (9H, m), 2.4-2.0 (2H, m), 2.1 (6H, s), 1.9-0.6 (43H, m);</li><li>IR: ν=2940, 2860, 1460, 1120 cm^-1. <chemistry id="chem0089" num="0089"><img file="EP0109255A2_D0128.tif" /></chemistry></li><li>Starting Material: the 2-azidoglycerol compound prepared in Example l(d);</li><li>TLC (AcOEt:AcOH:water=3:1:1): Rf=0.56;</li><li>MS: m/e=484 (M⁺), 470, 456, 412.</li></ul>

Example

<chemistry id="chem0090" num="0090"><img file="EP0109255A2_D0129.tif" /></chemistry>

To a mixture of 106.5 mg of the 2-aminoglycerol compound [prepared in Example 3(b)], 0.1 ml of triethylamine and 5 ml of CH₂Cl₂ was added 35.9 µl of benzoyl chloride at 0°C and the mixture was stirred for one hour at room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of CHC1₃, MeOH and triethylamine) to give 42.5 mg of the title compound having the following physical data: <ul id="ul0030" list-style="none"><li>TLC (AcOEt:AcOH:water=3:1:1): Rf=0.64;</li><li>NMR: 6=7.82-7.71 (2H, m), 7.54-7.35 (3H, m), 7.60-6.48 (lH, m), 4.45-4.32 (1H, m), 3.70-3.38 (8H, m), 2.20 (3H, s), 2.35-2.18 (2H, m), 1.69-1.44 (6H, m), 1.25 (26H, m), 0.87 (3H, m);</li><li>IR: ν=3300, 2920, 2850, 1640, 1460, 1110 cm^-1;</li><li>MS: m/e=518 (M⁺), 503, 474, 402, 388.</li></ul>

By the same procedure as described in Example 5, the compounds having the following physical data in Table 7 were prepared. <tables id="tabl0008" num="0008"><img file="EP0109255A2_D0130.tif" /></tables><tables id="tabl0009" num="0009"><img file="EP0109255A2_D0131.tif" /></tables>

Example 6

<chemistry id="chem0091" num="0091"><img file="EP0109255A2_D0132.tif" /></chemistry>To a mixture of 90.9 mg of the 2-aminoglycerol compound [prepared in Example 3(b)], 0.1 ml of triethylamine and 5 ml of CH₂Cl₂ was added 50 µl of phenyl chloroformate at 0°C. The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of CHC1₃, MeOH and triethylamine) to give 35.8 mg of the title compound having the following physical data: <ul id="ul0031" list-style="none"><li>TLC (AcOEt:AcOS:water=3:1:1): Rf=0.55;</li><li>NMR: δ=7.4-6.9 (5H, m), 5.56-5.2 (lH, m), 4.1-3.1 (9H, m), 2.2 (6H, s), 2.5-2.0 (2H, m), 2.0-0.7 (35H, m);</li><li>IR: v=1740 cm^-1;</li><li>MS: m/e=534 (M⁺), 440, 398.</li></ul>

By the same procedure as described in Example 6, the compounds having the following physical data in Table 8 were prepared. <tables id="tabl0010" num="0010"><img file="EP0109255A2_D0133.tif" /></tables><tables id="tabl0011" num="0011"><img file="EP0109255A2_D0134.tif" /></tables>

Example 7

<chemistry id="chem0092" num="0092"><img file="EP0109255A2_D0135.tif" /></chemistry>A mixture of 99.3 mg of the 2-aminoglycerol compound [prepared in Example 3(b)], 0.1 ml of phenyl isocyanate, 0.1 ml of triethylamine and 5 ml of CHC1₃ was stirred for one hour at room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of CHC1₃, MeOH and triethylamine) to give 91.2 mg of the title compound having the following physical data: Melting Point: 35 - 38°C; <ul id="ul0032" list-style="none"><li>TLC (AcOEt:AcOH:water=3:1:1): Rf=0.69;</li><li>NMR: δ=7.44-7.18 (5H, m), 7.06-6.94 (lH, m), 5.36-5.27 (lH, m), 4.10-3.96 (lH, m), 3.64-3.35 (8H, m), 2.22 (6H, s), 2.36-2.18 (2H, m), 1.64-1.45 (6H, m), 1.24 (26H, m), 0.86 (3H, m);</li><li>IR (KBr method): ν=3340, 2920, 2850, 1650, 1600, 1545, 1500, 1120 cm^-1; MS: m/e=533 (M⁺), 518, 489, 441, 413.</li></ul>

By the same procedure as described in Example 7, the compounds having the following physical data in Table 9 were prepared. <tables id="tabl0012" num="0012"><img file="EP0109255A2_D0136.tif" /></tables>

Example 8

<chemistry id="chem0093" num="0093"><img file="EP0109255A2_D0137.tif" /></chemistry>

A mixture of 101 mg of the dimethylaminoglycerol compound (prepared in Example 5), 0.2 ml of methyl iodide, 5 ml of MeOH and 20 mg of potassium bicarbonate was stirred for one hour at room temperature and then the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of CHC1₃ and MeOH, and a mixture of CHCl₃, MeOH and water, successively) to give 75.3 mg of the title compound having the following physical data: <ul id="ul0033" list-style="none"><li>Melting Point: 86 - 90°C;</li><li>TLC (AcOEt:AcOH:water=3:1:1): Rf=0.63;</li><li>NMR: δ=7.90-7.78 (2H, m), 7.60-7.38 (3H, m), 6.90-6.79 (lH, m), 4.56-4.44 (lH, m), 3.80-3.36 (10H, m), 3.25 (9H, s), 2.0-1.46 (6H, m), 1.25 (26H, m), 0.87 (3H, m);</li><li>IR (KBr method): v=3400, 3300, 2920, 2840, 1635, 1535, 1470, 1110 cm^-1;</li><li>MS: m/e=518, 503, 474, 402.</li></ul>

By the same procedure as described in Example 8, the compounds having the following physical data in Table 10 were prepared. <tables id="tabl0013" num="0013"><img file="EP0109255A2_D0138.tif" /></tables><tables id="tabl0014" num="0014"><img file="EP0109255A2_D0139.tif" /></tables><tables id="tabl0015" num="0015"><img file="EP0109255A2_D0140.tif" /></tables><tables id="tabl0016" num="0016"><img file="EP0109255A2_D0141.tif" /></tables><tables id="tabl0017" num="0017"><img file="EP0109255A2_D0142.tif" /></tables>

Reference Example 12 <chemistry id="chem0094" num="0094"><img file="EP0109255A2_D0143.tif" /></chemistry>

By the same procedure as described in Reference Example 8, the title compound having the following physical data was prepared.

Starting Material: the 3-hydroxy compound prepared in Reference

Example 5;

<ul id="ul0034" list-style="none"><li>TLC (CHC1₃:acetone=10:1): Rf=0.86;</li><li>NMR: δ=7.2 (5H, s), 4.6 (2H, s), 4.4-4.1 (2H, m), 3.9-3.2 (5H, m), 2.93 (3H, s), 1.8-0.6 (31H, m);</li><li>IR: ν=2930, 2850, 1470, 1360, 1120 cm^-1;</li><li>MS: m/e=484 (M⁺), 393.</li></ul>

Reference Example 13

<chemistry id="chem0095" num="0095"><img file="EP0109255A2_D0144.tif" /></chemistry>

Under an atmosphere of nitrogen, to a suspension of 2.5 g of sodium hydride (content: 64.1%) in 200 ml of dry DMF was added 4 g of 1,4-butanediol and the mixture was stirred for 10 minutes at room temperature. To the mixture was added a solution of 14.5 g of the mesylate compound (prepared in Reference Example 12) in 100 ml of dry DMF and the mixture was stirred for 2 hours at 70°C. To the reaction mixture was added 4 ml of water and the mixture was concentrated under reduced pressure. To the residue thus obtained was added 500 ml of AcOEt, and the solution was washed with water and a sat. aq. solution of NaCl, successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of AcOEt and n-hexane) to give 8.4 g of the title compound having the following physical data: <ul id="ul0035" list-style="none"><li>TLC (CHCl₃:acetone=10:1): Rf=0.43;</li><li>NMR:δ=7.2 (5H, bs), 4.6 (2H, s), 3.9-3.2 (11H, m), 2.75 (lH, bs), 2.0-0.8 (35H, m);</li><li>IR: V=3400, 2930, 2850, 1460, 1110 cm^-1;</li><li>MS: m/e=478 (M⁺), 406, 372, 297, 282.</li></ul>

Reference Example 14

<chemistry id="chem0096" num="0096"><img file="EP0109255A2_D0145.tif" /></chemistry>

By the same procedure as described in Reference Example 3, the title compound having the following physical data was prepared.

Starting Material: the hydroxy compound prepared in Reference

Example 13;

<ul id="ul0036" list-style="none"><li>TLC (AcOEt:n-hexane=l:5): Rf=0.32;</li><li>NMR: 6=7.23 (5H, bs), 4.66 (2H, s), 4.66-4.43 (1H, m), 3.9-3.1 (13H, m), 1.8-0.7 (41H, m);</li><li>IR: v=2930, 2850, 1450, 1120 cm^-1; MS: m/e=562 (M⁺), 478, 461.</li></ul>

Reference Example 15

<chemistry id="chem0097" num="0097"><img file="EP0109255A2_D0146.tif" /></chemistry>Under an atmosphere of hydrogen, a mixture of 8.6 g of the 2-0-benzylglycerol compound (prepared in Reference Example 14), 6 g of palladium on carbon (content: 10%) and 100 ml of EtOH was stirred for 2 days at 50°C. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 7.8 g of the title compound as crude product, having the following physical data: <ul id="ul0037" list-style="none"><li>TLC (CHCl₃:acetone=10:1): Rf=0.38;</li><li>NMR: δ=4.70-4.45 (lH, m), 4.2-3.1 (13H, m), 2.0-0.7 (41H, m).</li></ul>

Reference Example 16

<chemistry id="chem0098" num="0098"><img file="EP0109255A2_D0147.tif" /></chemistry>

By the same procedure as described in Reference Example 11, the title compound having the following physical data was prepared.

Starting Material: the 2-hydroxy compound prepared in Reference

Example 15;

<ul id="ul0038" list-style="none"><li>TLC (CHCl₃:acetone=10:1): Rf=0.71;</li><li>NMR: 6= 4.93-4.4 (2H, m), 3.95-3.1 (12H, m), 3.05 (3H, s), 2.0-0.7 (31H, m).</li></ul>

Reference Example 17

<chemistry id="chem0099" num="0099"><img file="EP0109255A2_D0148.tif" /></chemistry>

By the same procedure as described in Example 1, the title compound having the following physical data was prepared. Starting Material: the 2-0-mesylglycerol compound prepared in

Reference Example 16;

<ul id="ul0039" list-style="none"><li>TLC (AcOEt:n-hexane=1:5): Rf=0.49;</li><li>NMR: δ=4.66-4.36 (lH, m), 4.0-3.1 (13H, m), 2.0-0.7 (41H, m);</li><li>IR: ν=2940, 2850, 2150, 2090, 1460, 1120 cm^-1;</li><li>MS: m/e=469, 412, 396.</li></ul>

Reference Example 18

<chemistry id="chem0100" num="0100"><img file="EP0109255A2_D0149.tif" /></chemistry>By the same procedure as described in Example 3, the title compound having the following physical data was prepared. Starting Material: the 2-azidoglycerol compound prepared in

Reference Example 17;

<ul id="ul0040" list-style="none"><li>TLC (CHCl₃:MeOH=10:1): Rf=0.53;</li><li>NMR: δ= 4.63-4.4 (lH, m), 4.0-3.0 (13H, m), 2.0-0.7 (41H, m);</li><li>IR: v=2930, 2850, 1460, 1120 cm^-1.</li></ul>

Reference Example 19

<chemistry id="chem0101" num="0101"><img file="EP0109255A2_D0150.tif" /></chemistry>By the same procedure as described in Example 6, the title compound having the following physical data was prepared. Starting Material: the 2-aminoglycerol compound prepared in Reference Example 18 and isobutyl chloroformate; <ul id="ul0041" list-style="none"><li>TLC (AcOEt:n-hexane=1:5): Rf=0.31;</li><li>NMR: δ=5.15-4.8 (lH, m), 4.7-4.43 (lH, m), 4.1-3.1 (15H, m), 2.0-0.7 (42H, m and 6H, d);</li><li>IR: v=2920, 2850, 1720, 1500, 1460, 1110 cm^-1.</li></ul>

Reference Example 20

<chemistry id="chem0102" num="0102"><img file="EP0109255A2_D0151.tif" /></chemistry>

By the same procedure as described in Reference Example 5, the title compound having the following physical data was prepared.

Starting Material: the 3-0-(tetrahydropyran-2-yl)glycerol compound prepared in Reference Example 19;

TLC (CHCl₃:MeOH=10:1): Rf=0.66;

NMR: δ=5.15-4.8 (lH, m), 4.0-3.1 (11H, m), 2.2-0.7 (38H, m), 0.9 (6H, d).

Reference Example 21

<chemistry id="chem0103" num="0103"><img file="EP0109255A2_D0152.tif" /></chemistry>

By. the same procedure as described in Reference Example 8, the title compound having the following physical data was prepared.

Starting Material: the hydroxy compound prepared in Reference

Example 20;

<ul id="ul0042" list-style="none"><li>TLC (AcOEt:n-hexane=1:2): Rf=0.33;</li><li>NMR: δ=5.15-4.8 (lH, m), 4.2 (2H, t), 4.0-3.2 (11H, m), 3.0 (3H, s), 2.1-0.7 (36H, m), 0.93 (6H, d);</li><li>IR: v=2930, 2860, 1720, 1510, 1470, 1360, 1180, 1120 cm^-1.</li></ul>

Example 9

<chemistry id="chem0104" num="0104"><img file="EP0109255A2_D0153.tif" /></chemistry>

A mixture of 113 mg of the mesylate compound (prepared in Reference Example 21), 0.1 ml of triethylamine and 3 ml of DMF was stirred overnight at 70°C and then the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of CHC1₃ and MeOH, and a mixture of CHCl₃, MeOH and water, successively) to give 51 mg of the title compound having the following physical data: <ul id="ul0043" list-style="none"><li>Melting Point: 30 - 31°C;</li><li>TLC (AcOEt:AcOH:water=3:1:1): Rf=0.65;</li><li>NMR: 6=5.28-5.17 (lH, m), 3.96-3.72 (3H, m), 3.65-3.28 (16H, m), 2.76 (3H, s), 2.10-1.46 (7H, m), 1.36 (9H, t), 1.25 (26H, m), 0.92 (6H, d), 0.88 (3H, m);</li><li>IR: v=3450, 2930, 2860, 1700, 1460, 1190, 1120 cm^-1;</li><li>MS: m/e=542, 527, 513, 469.</li></ul>

Reference Example 22

<chemistry id="chem0105" num="0105"><img file="EP0109255A2_D0154.tif" /></chemistry>

By the same procedure as described in Reference Example 11, the title compound as white crystal having the following physical data was prepared.

<ul id="ul0044" list-style="none"><li>Starting Material: 1,3-0-benzylideneglycerol [the compound is described in J. Amer. Chem. Soc., 50, 2235 (1928)];</li><li>TLC (AcOEt:n-hexane=1:1): Rf=0.39;</li><li>NMR: δ=7.50-7.10 (5H, m), 5.40 (lH, s), 4.62-4.42 (lH, m), 4.30-4.10 (4H, m), 3.00 (3H, s);</li><li>IR (KBr method): v=13₃₀, 1170, 940 cm^-1.</li></ul>

Reference Example 23

<chemistry id="chem0106" num="0106"><img file="EP0109255A2_D0155.tif" /></chemistry>

By the same procedure as described in Example 1, the title compound having the following physical data was prepared.

Starting Material: the mesylate compound prepared in Reference

Example 22;

<ul id="ul0045" list-style="none"><li>TLC (benzene): Rf=0.51;</li><li>NMR: 6=7.40-7.10 (5H, m), 5.30 (lH, s), 4.40-4.00 (2H, m), 3.80-3.50 (3H, m);</li><li>IR: ν=2100, 1280, 1100, 970, 750, 700 cm^-1.</li></ul>

Reference Example 24

<chemistry id="chem0107" num="0107"><img file="EP0109255A2_D0156.tif" /></chemistry>

By the same procedure as described in Reference Example 2, the title compound having the following physical data was prepared.

Starting Material: the benzylidene compound prepared in Reference Example 23; <ul id="ul0046" list-style="none"><li>TLC (diethyl ether): Rf=0.41;</li><li>IR: ν=3350, 2150, 1270, 1050 cm^-1.</li></ul>

Reference Example 25

<chemistry id="chem0108" num="0108"><img file="EP0109255A2_D0157.tif" /></chemistry>

By the same procedure as described in Reference Example 3, the title compound having the following physical data was prepared. Starting Material: the dihydroxy compound prepared in Reference

Example 24;

<ul id="ul0047" list-style="none"><li>TLC (AcOEt:n-hexane=l:5): Rf=0.10;</li><li>NMR: δ=4.60-4.45 (lH, m), 4.00-3.30 (7H, m), 2.40-2.10 (lH, m);</li><li>IR: v=3450, 2250, 1125, 1070, 1030 cm^-1.</li></ul>

Reference Example 26

<chemistry id="chem0109" num="0109"><img file="EP0109255A2_D0158.tif" /></chemistry>

By the same procedure as described in Reference Example 4, the title compound having the following physical data was prepared.

Starting Material: the hydroxy compound prepared in Reference

Example 25;

<ul id="ul0048" list-style="none"><li>TLC (AcOEt:n-hexane=1:10): Rf=0.29;</li><li>NMR: δ=4.70-4.60 (lH, m), 3.94-3.68 (3H, m), 3.60-3.40 (6H, m), 1.80-1.45 (8H, m), 1.26 (29H, s), 0.88 (3H, bt);</li><li>IR: ν=2225, 2200, 1470, 1270, 1120, 1040 cm^-1;</li><li>MS: m/e=425 (M⁺), 397, 367.</li></ul>

Reference Example 27

<chemistry id="chem0110" num="0110"><img file="EP0109255A2_D0159.tif" /></chemistry>By the same procedure as described in Reference Example 5, the title compound having the following physical data was prepared. <ul id="ul0049" list-style="none"><li>Starting Material: the tetrahydropyran-2-yloxy compound prepared in Reference Example 26;</li><li>TLC (AcOEt:n-hexane=1:5): Rf=0.24;</li><li>NMR: δ=3.9-3.2 (7H, m), 2.3-1.9 (lH, m), 1.9-0.7 (31H, m);</li><li>IR (CHC1₃ solution): ν=3500, 2940, 2860, 2140, 2120, 1460, 1120 cm^-1;</li><li>MS: m/e=282, 255, 225.</li></ul>

Reference Example 28

<chemistry id="chem0111" num="0111"><img file="EP0109255A2_D0160.tif" /></chemistry>

By the same procedure as described in Reference Example 6, the title compound having the following physical data was prepared. <ul id="ul0050" list-style="none"><li>Starting Material: the 3-hydroxy compound prepared in Reference Example 27 and 1,5-dibromopentane;</li><li>TLC (AcOEt:n-hexane=1:5): Rf=0.64;</li><li>MS: m/e=461, 446, 382.</li></ul>

By the same procedure as described in Reference Example 28, the compounds having the following physical data in Table 11, were prepared. <tables id="tabl0018" num="0018"><img file="EP0109255A2_D0161.tif" /></tables> Reference Example 29 <chemistry id="chem0112" num="0112"><img file="EP0109255A2_D0162.tif" /></chemistry>

Under an atmosphere of hydrogen, a mixture of 2.16 g of the 2-azidoglycerol compound (prepared in Reference Example 26), 1.1 g of palladium on carbon (content: 10%) and 30 ml of EtOH was stirred for 4 hours at room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in 36 ml of CH₂Cl₂ and thereto was added 3.6 ml of triethylamine. To the solution was added dropwise 1.036 g of isobutyl chloroformate with stirring under cooling with ice-bath. The reaction mixture was concentrated under reduced pressure at a low temperature and the residue thus obtained was extracted with AcOEt. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of AcOEt and n-hexane) to give 1.78 g of the title compound having the following physical data: <ul id="ul0051" list-style="none"><li>TLC (AcOEt:n-hexane=1:5): Rf=0.33;</li><li>NMR: 6=4.65-4.50 (lH, m), 3.35 (2H, d), 4.00-3.20 (9H, m), 0.98 (6H, d);</li><li>IR: ν=3350, 1730, 1505, 1470, 1120, 1070, 1040 cm^-1;</li><li>MS: m/e=499 (M⁺), 469, 427, 415.</li></ul>

By the same procedure as described in Reference Example 29, the compounds having the following physical data in Table 12, were prepared. <tables id="tabl0019" num="0019"><img file="EP0109255A2_D0163.tif" /></tables><tables id="tabl0020" num="0020"><img file="EP0109255A2_D0164.tif" /></tables> Reference Example 30 <chemistry id="chem0113" num="0113"><img file="EP0109255A2_D0165.tif" /></chemistry>

By the same procedure as described in Reference Example 5, the title compound having the following physical data was prepared. <ul id="ul0052" list-style="none"><li>Starting Material: the tetrahydropyran-2-yloxy compound prepared in Reference Example 29;</li><li>TLC (AcOEt:n-hexane=1:5): Rf=0.09;</li><li>NMR: δ=5.50-5.10 (lH, m), 3.35 (2H, d), 3.35-3.25 (7H, m), 3.10-2.80 (1H, m), 0.98 (6H, d);</li><li>IR (KBr method): ν=3575, 3330, 1680, 1540, 1280, 1100 cm-¹; MS: m/e=415 (M⁺), 384, 328.</li></ul>

Reference Example 31

<chemistry id="chem0114" num="0114"><img file="EP0109255A2_D0166.tif" /></chemistry>

To a mixture of 120 mg of 4-bromobutanoic acid, 98 mg of isobutyl chloroformate and 5 ml of CH₂Cl₂was added dropwise 0.25 ml of triethylamine under cooling with ice-bath. To the mixture was added a solution of 150 mg of the 3-hydroxy compound (prepared in Reference Example 30) in 2 ml of CH₂C1₂ at room temperature and the mixture was stirred for 12 hours at room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of AcOEt and n-hexane) to give 82 mg of the title compound having the following physical data: <ul id="ul0053" list-style="none"><li>TLC (AcOEt:n-hexane=1:5): Rf=0.39;</li><li>NMR: 6=4.90 (lH, bd), 4.20-3.90 (3H, m), 3.77 (2H, d), 3.50-3.20 (6H, m), 0.88 (6H, d);</li><li>IR: v-3350, 1730, 1610, 1470 cm^-1;</li><li>MS: m/e=565, 563 (M⁺), 550, 548.</li></ul>

By the same procedure as described in Reference Example 31, the compounds having the following physical data in Table 13, were prepared. <tables id="tabl0021" num="0021"><img file="EP0109255A2_D0167.tif" /></tables> Reference Example 32 <chemistry id="chem0115" num="0115"><img file="EP0109255A2_D0168.tif" /></chemistry>

A mixture of 313 mg of the tetrahydropyran-2-yloxy compound [prepared in Reference Example 31(c)] and 5 ml of a mixed solvent of AcOH, water and THF (3:1:1) was stirred for one hour at 60°C. The reaction mixture was poured into an aq. solution of NaHCO₃ and neutralized with AcOH and then extracted with AcOEt. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of AcOEt and n-hexane) to give 252 mg of the title compound having the following physical data: <ul id="ul0054" list-style="none"><li>TLC (AcOEt:n-hexane=l:3): Rf=0.26;</li><li>NMR: δ=5.10-4.70 (lH, m), 4.20-3.90 (3H, m), 3.80 (2H, d), 3.70-3.20 (6H, m), 2.30 (2H, t), 0.90 (6H, d);</li><li>IR: v-3500, 3350, 1730, 1710, 1620, 1470, 1250, 1080 cm^-1;</li><li>MS: m/e=543 (M⁺), 528, 525, 513.</li></ul>

By the same procedure as described in Reference Example 32, the compound having the following physical data was prepared. <chemistry id="chem0116" num="0116"><img file="EP0109255A2_D0169.tif" /></chemistry>

Starting Material: the tetrahydropyran-2-yloxy compound prepared in Reference Example 31 (d);

<ul id="ul0055" list-style="none"><li>TLC (AcOEt:n-hexane=1:1): Rf=0.50;</li><li>NMR: δ=5.20-4.80 (lH, m), 4.30-4.00 (3H, m), 3.80 (2H, d), 3.70-3.20 (6H, m), 2.30 (2H, t), 0.95 (6H, d);</li><li>IR: v=3450, 3325, 1730, 1710, 1620, 1460, 1240, 1070 cm^-1</li><li>MS: m/e=557 (M⁺), 542, 539, 527.</li></ul>

Reference Example 33

<chemistry id="chem0117" num="0117"><img file="EP0109255A2_D0170.tif" /></chemistry>

By the same procedure as described in Reference Example 8, the title compound having the following physical data was prepared.

Starting Material: the hydroxy compound prepared in Reference Example 32;

<ul id="ul0056" list-style="none"><li>TLC (AcOEt:benzene=1:3): Rf=0.52;</li><li>NMR: δ=5.15-4.85 (1H, m), 4.35-4.00 (5H, m), 3.85 (2H, d), 3.60-3.30 (4H, m), 2.35 (2H, t), 0.98 (6H, d);</li><li>IR: v=3375, 1725, 1520, 1470, 1360, 1180 cm^-1;</li><li>MS: m/e=621 (M⁺), 564.</li></ul>

By the same procedure as described in Reference Example 33, the compound having the following physical data was prepared. <chemistry id="chem0118" num="0118"><img file="EP0109255A2_D0171.tif" /></chemistry>

Starting Material: the hydroxy compound prepared in Reference Example 32 (a);

<ul id="ul0057" list-style="none"><li>TLC (AcOEt:benzene=1:2): Rf=0.57;</li><li>NMR: δ=5.20-4.80 (1H, m), 4.40-4.00 (5H, m), 3.90 (2H, d), 3.65-3.30 (4H, m), 3.05 (3H, s), 2.40 (2H, bt), 0.98 (6H, d);</li><li>IR: v=3350, 1730, 1620, 1465, 1250, 1175 cm^-1;</li><li>MS: m/e=636, 562, 556.</li></ul>

Example 10

<chemistry id="chem0119" num="0119"><img file="EP0109255A2_D0172.tif" /></chemistry>

A mixture of 74 mg of the bromo compound [prepared in Reference Example 29 (a)], 3 ml of a 30% aqueous solution of trimethylamine and 9 ml of DMF was stirred for 4 hours at 50°C and then the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a mixture of CHC1₃ and MeOH, and a mixture of CHC1₃, MeOH and water, successively) to give 41 mg of the title compound having the following physical data: <ul id="ul0058" list-style="none"><li>TLC (AcOEt:AcOH:water=3:1:1): Rf=0.45;</li><li>NMR (CDCl₃+ CD₃OD solution): δ=5.55-5.2 (1H, m), 3.98-3.77 (3H, m), 3.58-3.35 (10H, m), 3.21 (9H, s), 2.00-1.39 (9H, m), 1.26 (26H, m), 0.93 (6H, d), 0.88 (3H, m);</li><li>IR: ν=3400, 2920, 2850, 1700, 1460, 1120 cm^-1;</li><li>MS: m/e=528, 514, 455, 453.</li></ul>

By the same procedure as described in Example 10, the compounds having the following physical data in Table 14, were prepared. <tables id="tabl0022" num="0022"><img file="EP0109255A2_D0173.tif" /></tables><tables id="tabl0023" num="0023"><img file="EP0109255A2_D0174.tif" /></tables><tables id="tabl0024" num="0024"><img file="EP0109255A2_D0175.tif" /></tables>

Example 11

5 g of (2RS)-l-0-hexadecyl-2-dehydroxy-2-butoxycarbonylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol iodide, 200 mg of cellulose calcium gluconate (disintegrator), 100 mg of magnesium stearate (lubricant) and 9.7 g of crystalline cellulose were mixed and punched out in a usual manner to obtain tablets each containing 50 mg of the active ingredient.