JP2758584B2 - Glycerin derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel glycerin derivative having excellent action as a medicament and a pharmacologically acceptable salt thereof.

[0002]

BACKGROUND OF THE INVENTION Platelet Activating Factor (PAF)
(Hereinafter simply abbreviated as PAF) has been receiving a great deal of attention in recent years, and recently its association with various diseases is becoming apparent. That is, it is presumed to be involved in inflammation, DIC, endotoxin shock, asthma, gastrointestinal ulcer, nephritis, hepatitis and rejection at the time of organ transplantation.

[0003] Under such circumstances, a search for compounds having a PAF inhibitory action has been conducted. Among them, for example, JP-A-60-158172, JP-A-61-293954, and
There is a glycerin derivative as shown in Japanese Patent No. 60-243047. However, at present, no satisfactory anti-PAF agent has appeared.

[0004] In view of such circumstances, the present inventors have been searching for glycerin derivatives which have not only an excellent PAF inhibitory action but also an excellent sustainability of action and stability of a compound for many years. Have been.

[0005]

The present inventors have made intensive studies for many years with the above-mentioned objects, and as a result, have found that the following glycerin derivatives or pharmacologically acceptable salts thereof can achieve the objects. The present invention has been completed.

That is, the compound of the present invention has the following general formula (I)
Or a pharmaceutically acceptable salt thereof.

[0007]

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Where A is

[0009]

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(Wherein m represents an integer of 0 to 6, and R ² , R
³ , R ⁴ represents the same or different hydrogen atom or lower alkoxy group), a group represented by

[0011]

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Wherein p represents an integer of 0 to 6, and R ⁵ represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group or an arylalkyl group. , a group represented by formula (3) ^{_{-NH- (CH 2) q -R 6}} ( wherein, q is an integer of Less than six, R ⁶ denotes an aryl group or a heteroaryl group), ( 4) -NH- (CH ₂₎ in _r -OR ⁷ (wherein, r is represent an integer from 0 to 6, the group represented by R ⁷ means an alkyl group),

[0013]

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(Wherein s represents an integer of 0 to 20, and R ⁸ , R
⁹ is the same or different hydrogen atom, means a lower alkyl group) group,

[0015]

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[0016] (In the formula, t is an integer of 0~6, R ¹⁰
Represents a hydrogen atom or a lower alkoxycarbonyl group)

[0017]

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(In the formula, u represents an integer of 0 to 6, and R ¹¹ ,
R ¹² represents the same or different hydrogen atoms and lower alkyl groups, and R ¹¹ and R ¹² may together form a ring that may contain an oxygen atom. ) Group represented by (8) _{-NH- (CH 2) v -O- (} CH 2) w -O- (CH 2) in _x -H (wherein, v denotes an integer of 1 to 10 , W represents an integer of 1 to 10, x represents an integer of 1 to 10)

[0019]

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[0020] (wherein, y is an integer of Less than six, R ¹³
Represents a hydrogen atom or an alkyl group)
Or

[0021]

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(Wherein, z represents an integer of 0 to 6, a represents an integer of 3 to 4, and D represents an oxygen atom, a sulfur atom or a nitrogen atom). . B represents a lower alkyl group or an arylalkyl group. R ¹ represents an acyl group. n means the integer of 0-3.

[0023]

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That is, the glycerin derivative represented by the above general formula (I) has a characteristic that it has an excellent PAF inhibitory effect, a long-lasting effect, and the compound itself has high stability. doing.

Accordingly, an object of the present invention is to provide a novel glycerin derivative having excellent anti-PAF activity or a pharmacologically acceptable salt thereof, and a further object of the present invention is to provide a method for producing the same. Another object of the present invention is to provide a medicament containing the same.

A lower alkyl group as defined in the definition of R ⁸ , R ⁹ , R ¹¹ , R ¹² , B is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n- Propyl, n-
Butyl, isopropyl, isobutyl, n-heptyl, 1
-Ethylpropyl, isoamyl, n-hexyl and the like.

The alkyl group found in the definitions of R ⁵ , R ⁷ and R ¹³ is a linear or branched alkyl group having 1 to 30 carbon atoms. Specifically, the lower alkyl groups shown above, that is, linear or branched alkyl groups having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, n-heptyl , 1-ethylpropyl, isoamyl, n-hexyl and the like, as well as heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosanyl, heneicosanyl, docosanyl, tricosanil, Tetracosanyl, pentacosanyl, hexacosanil, heptacosanil, octacosanil, nonacosanil,
Although an alkyl group such as triacontanil can be used, an alkyl group having about 14 to 22 carbon atoms is preferable, and an alkyl group having about 16 to 20 carbon atoms is most preferable.

The term "lower alkoxy group" in the definition of R ² , R ³ and R ⁴ means a lower alkoxy group derived from the above lower alkyl group, that is, a lower alkoxy group having 1 to 6 carbon atoms. I do. The lower alkoxy of the “lower alkoxycarbonyl group” in the definition of R ¹⁰ means a lower alkoxy group having 1 to 6 carbon atoms as described above.

The "aryl group" in the definition of R ⁵ and R ⁶ means a substituted or unsubstituted phenyl group, naphthyl group, fluorenyl group and the like, and specifically, a lower alkyl group, halogen and the like. In addition to a phenyl group which may be substituted,

[0030]

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And the like. Further, the arylalkyl group found in the definitions of R ⁵ and B means an arylalkyl group derived from the above aryl group.

The number of methylene chains in the definition of A, ie, m, p,
q, r, t, u, y, and z mean an integer of 0 to 6, preferably about 1 to 3.

The acyl group in the definition of R ¹ includes a residue of an organic acid such as an aliphatic saturated carboxylic acid, an aliphatic unsaturated carboxylic acid, a carbocyclic carboxylic acid or a heterocyclic carboxylic acid. Specifically, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, lower alkanoyl groups such as pivaloyl, substituted or unsubstituted benzoyl, toluoyl, aroyl groups such as naphthoyl, furoyl, nicotinoyl,
Examples include a heteroaroyl group such as isonicotinoyl and a cyclohexylcarbonyl group. Of these, preferred are lower alkanoyl groups such as acetyl and propionyl, and substituted or unsubstituted benzoyl groups. Most preferred are, for example, acetyl group, o, m, p-methoxybenzoyl group and the like. be able to.

The definition of A is classified into (1) to (10), and among these, the compounds in the group defined in (2) and the compounds in the group defined in (9) are preferable. . Also in the definition of B, the case of a methyl group is the most preferable. Further, n means 0 or an integer of 1 to 3;
Is most preferred.

The compound of the present invention is a glycerin derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.
As these salts, any salts may be used. For example, in addition to the above-mentioned hydrochloride, hydrogen bromide, hydrogen iodide, sulfate, phosphate and the like of the glycerin derivative (I),
In the present invention, a quaternary salt in which the nitrogen atom of the pyridine ring in the definition of G is quaternized is most preferred. Any salt may be used as long as it is a quaternary salt. Among these quaternary salts, the quaternized group is represented by the formula

[0036]

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Wherein R ¹⁴ is a hydrogen atom or a lower alkyl group, and X is a pharmacologically acceptable anion.
Most preferred is a group represented by In the above definition, R ¹⁴ preferably has about 1 to 3 carbon atoms, and is most preferably an ethyl group.

[0038] X ^- is may be any anion but, to name representative ones, chlorine ion, bromine ion, iodine ion, sulfate ion, nitrate ion, phosphate ion, the anion of an acid such as acetate ion, hydroxide ion And so on. Most preferred anions are halogen ions such as chloride ions.

The compound of the present invention has an asymmetric carbon in the molecule and has various stereoisomers. In the present invention, each of them or a mixture thereof is included in the present invention. Needless to say.

Next, a typical production method of the present invention will be described.

[0041]

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(In the series of formulas, A, B, n, R ¹ , R ¹⁴ and X have the same meanings as described above.) (First Step) In this step, the compound represented by the general formula (II) is usually used. This is a step of obtaining a compound represented by the general formula (III) by acylation by a method.

The acylation is carried out by reacting a reactive derivative of a carboxylic acid represented by, for example, R ¹ OH (wherein R ¹ represents an acyl group), for example, an acid anhydride, an acid halide or the like with the general formula (II)
To give a compound represented by the general formula (III), which is one of the target substances. When an acetyl group is introduced, it is preferable to use acetic anhydride.

This reaction is preferably carried out in the presence of a base. Examples of the base include alkali metals such as potassium hydride and sodium hydride, alkali metals such as sodium metal, sodium alcoholate such as sodium methoxide, and hydroxides such as sodium hydroxide and potassium hydroxide. Examples include alkali, organic bases such as pyridine and triethylamine, and alkali carbonates such as potassium carbonate and sodium carbonate.

This reaction is carried out without solvent, or ethers such as tetrahydrofuran and diethyl ether, ketones such as acetone and methyl ethyl ketone, benzene,
The reaction is performed in a solvent selected from a benzene-based solvent such as toluene, acetonitrile, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide and the like. The reaction temperature is appropriately selected from -78 ° C to the boiling point of the solvent.

(Second Step) This reaction is a step of subjecting the compound represented by the general formula (III) obtained in the first step to quaternary salification by a conventional method to obtain the compound (IV) of the present invention. That is, the general formula
By reacting the compound represented by the formula (III) with a compound represented by the general formula R ¹⁴ -X (R ¹⁴ , X has the above-mentioned meaning), the compound of the present invention (IV) which is a target Get.
When converting into a hydrogen halide salt, it is reacted with R ¹⁴ -Hal.

This reaction is preferably carried out in a light-shielded atmosphere in nitrogen, without a solvent, or an alcohol such as methanol or ethanol, an ether such as tetrahydrofuran or diethyl ether, a ketone such as acetone or methyl ethyl ketone, benzene or toluene. The reaction is performed in a solvent selected from a benzene-based solvent such as acetonitrile, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The reaction temperature is appropriately selected from under ice-cooling to the boiling point of the solvent.

In this production method, the compound represented by the general formula (II) used as a starting material can be produced, for example, by the following several methods.

[0049]

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(Wherein, B, n has the above-mentioned meaning, Hal means a halogen atom, and A ′ means a residue obtained by removing A from the group represented by the formula —NH—). First step) A compound represented by the general formula (V) is converted to a compound represented by the general formula (VI)
This is a step of obtaining a compound represented by the general formula (VII) by reacting with an isocyanate represented by the formula in the presence of a base.

Examples of usable bases include pyridine, 4- (N, N-dimethylamino) pyridine, quinoline and the like. This reaction is without solvent, or tetrahydrofuran, ethers such as diethyl ether, benzene,
The reaction is performed in a solvent selected from benzene solvents such as toluene and xylene. The reaction temperature is appropriately selected from under ice-cooling to the boiling point of the solvent.

The isocyanate used at this time O = C = NA '
Is a compound such as 3,4,5-trimethoxyaniline
It can be obtained by reacting A′-NH ₂ with phosgene, oxalyl dichloride, trichloromethyl chloroformate and the like. This reaction is generally performed in an inert organic solvent such as benzene, toluene, and ethyl acetate. The reaction temperature is appropriately selected from under ice-cooling to the boiling point of the solvent.

(Second step) In this step, the compound represented by the general formula (VII) is reacted with phenyl halogenoformate in the presence of a base to obtain a compound (IX).

Examples of usable bases include pyridine and triethylamine. This reaction is carried out without a solvent or, for example, a chloroform-based solvent such as chloroform or methylene chloride, an ether such as tetrahydrofuran or diethyl ether, a ketone such as acetone or methyl ethyl ketone, a benzene-based solvent such as benzene or toluene, acetonitrile, or dimethylformamide. Dimethylsulfoxide, hexamethylphosphoric triamide and the like. The reaction temperature is appropriately selected from -78 ° C to the boiling point of the solvent.

(Third step) This is a step of reacting a compound represented by the general formula (IX) with an amine compound represented by the general formula (X) to obtain a compound represented by the general formula (XI). . When n = 1, compound (X) is 2- (aminomethyl) pyridine.

This reaction is carried out without a solvent, or a carbon-based solvent such as chloroform or methylene chloride; ethers such as tetrahydrofuran or diethyl ether; ketones such as acetone or methyl ethyl ketone;
The reaction is performed in a solvent selected from a benzene-based solvent such as toluene, acetonitrile, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide and the like. The reaction temperature is appropriately selected from under ice cooling to the boiling point of the solvent.

The compound represented by the general formula (XI) obtained by this step corresponds to the compound represented by the general formula (II).

[0058]

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[0059]

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(In the series of formulas, B, A ', n and Hal have the same meanings as described above.) (First step) Reaction of the compound represented by the general formula (V) with dihydropyran (XII) in the presence of an acid By the general formula (X
The compound represented by III) can be obtained.

Examples of the acid include p-toluenesulfonic acid, pyridinium p-toluenesulfonate and the like. This reaction is usually performed in a carbon chloride solvent such as dichloromethane or chloroform, ethers such as tetrahydrofuran or diethyl ether, a benzene solvent such as benzene or toluene, or a solvent such as hexane. The reaction temperature is appropriately selected from under ice cooling to the boiling point of the solvent.

(Second Step) The compound represented by the general formula (XIV) can be obtained by reacting the compound represented by the general formula (XIII) with phenyl halogenoformate in the presence of a base.

Examples of usable bases include, for example, pyridine, triethylamine and the like. This reaction is carried out without solvent, or for example, a chloroform-based solvent such as chloroform or dichloromethane, tetrahydrofuran, ethers such as diethyl ether, acetone, ketones such as methyl ethyl ketone, benzene, a benzene-based solvent such as toluene, acetonitrile, dimethylformamide, The reaction is performed in a solvent selected from dimethyl sulfoxide, hexamethylphosphoric triamide and the like. The reaction temperature is appropriately selected from -78 ° C to the boiling point of the solvent.

(Third Step) By reacting the compound represented by the general formula (XIV) with the amine compound represented by the general formula (X), the compound represented by the general formula (XV) can be obtained. it can.

This reaction may be carried out without solvent, or in a solvent such as carbon chloride such as chloroform and dichloromethane, ethers such as tetrahydrofuran and diethyl ether, ketones such as acetone and methyl ethyl ketone, benzene,
The reaction is performed in a solvent selected from a benzene-based solvent such as toluene, acetonitrile, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide and the like. The reaction temperature is appropriately selected from under ice-cooling to the boiling point of the solvent.

(Fourth Step) The compound represented by the general formula (XVI) can be obtained by reacting the compound represented by the general formula (XV) with water or an alcohol such as methanol or ethanol in the presence of an acid. it can.

Examples of the acid include p-toluenesulfonic acid, acetic acid, pyridinium p-toluenesulfonate, hydrochloric acid and the like. This reaction is carried out without solvent, or for example, alcohols such as methanol and ethanol, water,
Tetrahydrofuran, ethers such as diethyl ether, acetone, ketones such as methyl ethyl ketone,
Benzene, benzene solvents such as toluene, acetonitrile, dimethylformamide, dimethylsulfoxide,
This is performed in a solvent selected from hexamethylphosphoric triamide and the like. The reaction temperature is appropriately selected from under ice-cooling to the boiling point of the solvent.

(Fifth step) The isocyanate represented by the general formula O = C = NA '(VI) is reacted with the compound represented by the general formula (XVI) by a conventional method in the presence of a base to obtain a compound represented by the general formula:
The compound represented by (XI) can be obtained.

As the base, for example, pyridine, 4- (N, N
-Dimethylamino) pyridine, quinoline and the like. This reaction is carried out without solvent or in a solvent selected from ethers such as tetrahydrofuran and diethyl ether, and benzene-based solvents such as benzene and toluene. The reaction temperature is appropriately selected from under ice-cooling to the boiling point of the solvent.

[0070]

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(In the series of formulas, A ', n, B, and Hal have the same meanings as described above.) (First step) A glycerin derivative represented by the general formula (V) is prepared by a conventional method using phenyl halogenoformate (VIII). In which a compound represented by the general formula (XVII) is obtained.

This reaction is preferably carried out with triethylamine,
The reaction is performed in the presence of a base such as an amine such as pyridine, an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal such as metal sodium, or an alkali hydroxide such as sodium hydroxide or potassium hydroxide.

This reaction is carried out without solvent or with ethers such as tetrahydrofuran and dioxane, methylene chloride,
The reaction is performed in a halogen-based solvent such as chloroform, a benzene-based solvent such as benzene, toluene, or xylene, or a solvent such as dimethylformamide or dimethylsulfoxide.
The reaction temperature is appropriately selected from the temperature under ice cooling to the boiling point of the solvent.

(Second step) In the step of reacting the dicarbonate (XVII) obtained in the first step with an amine compound represented by the general formula (X) to obtain a compound represented by the general formula (XVIII) is there.

This reaction is carried out without solvent or in a halogen-based solvent such as chloroform or methylene chloride, an ether such as tetrahydrofuran, or a benzene-based solvent such as benzene or toluene. The reaction temperature is appropriately selected from the room temperature to the boiling point of the solvent.

(Third Step) The carbamoyl derivative (XVIII) obtained in the second step is reacted with an amine represented by the general formula H ₂ NA ′ (XIX) to give a compound represented by the general formula (XI) This is the step of obtaining.

This reaction is carried out without solvent or in a halogen-based solvent such as chloroform or methylene chloride, an ether such as tetrahydrofuran, or a benzene-based solvent such as benzene or toluene. The reaction temperature is appropriately selected from the room temperature to the boiling point of the solvent.

[0078]

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[0079]

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(In the series of formulas, R ¹⁴ , n, A ′, B, R ¹ and X have the above-mentioned meanings.) (First Step) In this step, a compound represented by the general formula (XVIII) is prepared. This is a step of obtaining a compound represented by the general formula (XX) by acylation by a conventional method.

In the acylation, a reactive derivative of a carboxylic acid represented by, for example, R ¹ OH (wherein R ¹ represents an acyl group), for example, an acid anhydride, an acid halide or the like is represented by the general formula (XVI
By reacting with the compound represented by II), a compound represented by the general formula (III), which is one of the target substances, is obtained. When an acetyl group is introduced, it is preferable to use acetic anhydride. This reaction is preferably performed in the presence of a base.

(Second step) A compound represented by the general formula (XX) is reacted with an amine represented by the general formula H ₂ N-A '(XIX) to give a compound represented by the general formula (XXI). This is the step of obtaining.

This reaction is carried out without a solvent or in a halogen-based solvent such as chloroform or methylene chloride, an ether such as tetrahydrofuran, or a benzene-based solvent such as benzene or toluene. The reaction temperature is appropriately selected from the room temperature to the boiling point of the solvent.

(Third Step) A quaternary salification step similar to the method described in the second step of Production Method 1.

Production Method 3 In the general formula (I), A is

[0086]

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(Wherein p and R ⁵ have the same meanings as described above) can also be produced by the following method.

[0088]

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[0089]

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(In a series of equations, R ¹⁴ , n, R ⁵ , p, B, R ¹ , Ha
l, X has the meaning described above) (First step) A compound represented by the general formula (XVIII) is reacted with sulfamoylphenylalkylamine (XXIII),
This is a step of obtaining a compound represented by the general formula (XXIV).

This reaction is carried out without solvent or in a halogen-based solvent such as chloroform or methylene chloride, an ether such as tetrahydrofuran, or a benzene-based solvent such as benzene or toluene. The reaction temperature is appropriately selected from the room temperature to the boiling point of the solvent.

(Second Step) The general formula (X) obtained in the first step
In this step, a compound represented by the general formula (XXVI) is obtained by reacting a compound represented by the general formula (XXV) with an alkyl halide represented by the general formula (XXV).

The reaction is preferably carried out with an alkali carbonate such as potassium carbonate, an alkali hydroxide such as sodium hydroxide or potassium hydroxide, an amine such as triethylamine or pyridine, or a hydrogenation such as sodium hydride or potassium hydride. The reaction is performed in the presence of a base such as an alkali metal.

This reaction is carried out without solvent or with ethers such as tetrahydrofuran and dioxane, methylene chloride,
The reaction is performed in a halogen-based solvent such as chloroform, a benzene-based solvent such as benzene or toluene, or a solvent such as dimethylformamide or dimethylsulfoxide. The reaction temperature is appropriately selected from the temperature under ice cooling to the boiling point of the solvent.

(Third Step) The general formula (X) obtained in the second step
XVI) is acylated by a conventional method to give a compound of the general formula
This is a step of obtaining a compound represented by (XXVII).

In the acylation, a reactive derivative of a carboxylic acid represented by, for example, R ¹ OH (wherein R ¹ represents an acyl group), for example, an acid anhydride or an acid halide is represented by the general formula (XXV
By reacting with the compound represented by I), a compound represented by the general formula (XXVII) is obtained. When an acetyl group is introduced, it is preferable to use acetic anhydride.

This reaction is preferably carried out using triethylamine,
The reaction is carried out in the presence of a base such as an amine such as pyridine, an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal such as metal sodium, or an alkali hydroxide such as sodium hydroxide or potassium hydroxide. This reaction is carried out without solvent or in an ether such as tetrahydrofuran, a halogen-based solvent such as methylene chloride or chloroform, a benzene-based solvent such as benzene or toluene, or a solvent such as dimethylformamide or dimethylsulfoxide. The reaction temperature is appropriately selected from the temperature under ice cooling to the boiling point of the solvent.

(Fourth Step) This reaction is a step of subjecting the compound represented by the general formula (XXVII) obtained in the third step to quaternary salification by a conventional method to obtain the present compound (XXVIII). That is,
A compound represented by the general formula (XXVII) is converted to a compound represented by the general formula R ¹⁴ -X (R ¹⁴ ,
X has the above-mentioned meaning) by reacting the compound of the present invention (XXV
III). R ¹⁴ -Hal (R ¹⁴
= H).

This reaction is preferably carried out in a light-shielded atmosphere in nitrogen, without a solvent or with an alcohol such as methanol or ethanol, an ether such as tetrahydrofuran or diethyl ether, a ketone such as acetone or methyl ethyl ketone, benzene or toluene. The reaction is performed in a solvent selected from a benzene-based solvent such as acetonitrile, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The reaction temperature is appropriately selected from under ice-cooling to the boiling point of the solvent.

Production Method 4 In the general formula (I), A is

[0101]

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(In the formula, y represents 0 to 6, R ¹³ represents a hydrogen atom or an alkyl group), and can also be produced by the following method.

[0103]

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[0104]

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(In a series of formulas, R ¹⁴ , n, R ¹ , y, R ¹³ , B, H
al has the above-mentioned meaning) (First step) A carbamoyl derivative (XVIII) is represented by the general formula (XXI)
This is a step of reacting with an amine represented by X) to obtain a compound represented by the general formula (XXX).

This reaction is carried out without solvent or in a halogen-based solvent such as chloroform or methylene chloride, an ether such as tetrahydrofuran, or a benzene-based solvent such as benzene or toluene. The reaction temperature is appropriately selected from the room temperature to the boiling point of the solvent.

(Second step) In this step, the compound represented by the general formula (XXXI) is subjected to a condensation reaction with phenyl halogenoformate (VIII) by a conventional method to obtain a compound represented by the general formula (XXXI).

This reaction is preferably carried out using triethylamine,
The reaction is performed in the presence of a base such as an amine such as pyridine, an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal such as metal sodium, or an alkali hydroxide such as sodium hydroxide or potassium hydroxide.

This reaction was carried out without solvent or with ethers such as tetrahydrofuran and dioxane, methylene chloride,
The reaction is performed in a halogen-based solvent such as chloroform, a benzene-based solvent such as benzene, toluene, or xylene, or a solvent such as dimethylformamide or dimethylsulfoxide.
The reaction temperature is appropriately selected from the temperature under ice cooling to the boiling point of the solvent.

(Third step) In this step, the carbamoyl derivative (XXXI) obtained in the second step is reacted with an amine represented by the general formula (XXXII) to obtain a compound represented by the general formula (XXXIII). .

This reaction is carried out without solvent or in a halogen-based solvent such as chloroform or methylene chloride, an ether such as tetrahydrofuran, or a benzene-based solvent such as benzene or toluene. The reaction temperature is appropriately selected from the room temperature to the boiling point of the solvent.

(Fourth Step) The general formula (X) obtained in the third step
XXIII) is a step of acylating a compound represented by the general formula to obtain a compound represented by the general formula (XXXIV).

In the acylation, a reactive derivative of a carboxylic acid represented by, for example, R ¹ OH (wherein R ¹ represents an acyl group), for example, an acid anhydride, an acid halide or the like is represented by the general formula (XXX)
By reacting with the compound represented by III), a compound represented by the general formula (XXXIV) is obtained. When an acetyl group is introduced, it is preferable to use acetic anhydride.

This reaction is preferably carried out with triethylamine,
The reaction is performed in the presence of a base such as an amine such as pyridine, an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal such as metal sodium, or an alkali hydroxide such as sodium hydroxide or potassium hydroxide. This reaction is carried out without a solvent or in an ether such as tetrahydrofuran, a halogen-based solvent such as methylene chloride or chloroform, a benzene-based solvent such as benzene or toluene, or a solvent such as dimethylformamide or dimethylsulfoxide. The reaction temperature is appropriately selected from the temperature under ice cooling to the boiling point of the solvent.

(Fifth Step) This reaction is a step of subjecting the compound represented by the general formula (XXXIV) obtained in the fourth step to quaternary salification by a conventional method to obtain the compound of the present invention (XXXV). That is, a compound represented by the general formula (XXXIV) is converted to a compound represented by the general formula R ¹⁴ -X (R ¹⁴ , X
Having the above-mentioned meaning) by reacting with the compound represented by
Get. R ¹⁴ -Hal (R ¹⁴ = H) when used as a hydrogen halide salt
And react with.

This reaction is preferably carried out in a light-shielded atmosphere in nitrogen, without solvent, or for example, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and diethyl ether, ketones such as acetone and methyl ethyl ketone, benzene and toluene. The reaction is performed in a solvent selected from a benzene-based solvent such as acetonitrile, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The reaction temperature is appropriately selected from under ice-cooling to the boiling point of the solvent.

In the above production method 4, the general formula
The compound represented by (XXXIII) can also be directly produced from the compound represented by formula (XXX) by the following method.

[0118]

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(Wherein R ¹³ , n, y, and B have the above-mentioned meanings) That is, the compound represented by the general formula (XXX) is converted to a compound represented by the general formula (XXXVI)
To give a compound represented by the general formula (XXXIII).

This reaction is preferably carried out in the presence of an amine such as triethylamine and pyridine. In addition, this reaction
The reaction is carried out without solvent, or in ethers such as tetrahydrofuran, halogen-based solvents such as methylene chloride and chloroform, and benzene-based solvents such as benzene and toluene. The reaction temperature is appropriately selected from the temperature under ice cooling to the boiling point of the solvent.

Next, experimental examples will be described below in order to explain the effects of the present invention in detail. Experimental Example 1 Effect on human platelet PAF-induced aggregation <Method> Blood was collected from the forearm vein of a healthy adult male who had not taken the drug for 2 weeks or more, and 1/9 volume of a 3.8% sodium citrate solution was added thereto. Platelet-rich plasma (PRP) was prepared by centrifugation. Measurement of platelet potency is Born
The measurement was carried out using a platelet aggregometer Hematracer II (registered trademark, Nikko Bioscience) according to the optical method. PAF was dissolved in Tyrode solution (Ca ⁺⁺ (+)) and the lowest concentration that caused maximum aggregation was used. The test compound was dissolved in physiological saline.

The aggregation inhibitory activity of the test compound was determined by the control PRP
The maximum light transmittance (maximum agglutination rate) due to PAF was determined from the inhibition rate. The IC ₅₀ was determined from the inhibition curve. Table 1 shows the results. The numbers in the column of the test compound are the compounds of the example numbers shown below. <Result>

[0123]

[Table 1]

[0124]Experimental example 2 PAF receptor binding assay using human platelets
(Receptor antagonist activity) <Method> Obtain platelets from a healthy male in accordance with a standard method.
Binding Buffer (Binding Buffer) (10mM phosphat
e-bufferes saline (pH 7.0), 0.1% (w / v) BSA, 0.9mM CaC
l_Two To 10)⁸Resuspend so that the volume becomes 460 μl.
Binding of test compound to polypropylene tube
Add 20 μl of the buffer solution and further 460 μl of the platelet solution.
Incubate at 37 ° C for 6 minutes after Vortex (incubation)
ate). Then^ThreeH-PAF binding buffer
-20 μl solution (final^ThreeH-PAF concentration of 0.6-1 nM)
Incubate for 6 minutes and wash with ice-cold wash solution (0.1% (W / V)
The reaction was stopped by adding 3 ml of Saline) containing BSA.
Suction-filter on a filter (WhatmanGF / C). Glass
After drying the filter, liquid scintillation counter
Measure the radioactivity at. Inhibition% is calculated according to the following formula.
And calculate the IC₅₀Was obtained by interpolation from the figure.

[0125]

(Equation 1)

Table 2 shows the total binding; dpm when the drug or PAF concentration was 0; non-specific binding; dpm when cold PAF 10 ^-5 M was added. <Result>

[0127]

[Table 2]

Experimental Example 3 Preventive effect on PAF lethal action <Method> Physiological saline or a test compound was intravenously injected into an ICR male mouse weighing about 30 g, and 15 minutes later, PAF 100 μm was injected.
g / kg was injected intravenously. One hour later, survival was judged and the survival rate was obtained. Table 3 shows the results. <Result>

[0129]

[Table 3]

Note:% in the column of survival rate indicates the survival rate. The denominator of the fraction indicates the number of mice, and the numerator indicates the number of dead mice.

[0131] cannulated carotid artery and jugular vein of F ₃₄₄ rat effects on experimental example 4 PAF induced hypotensive <method> Pento anesthesia (50mg / kg, ip), the blood pressure was measured from the artery, PAF from the vein Alternatively, 0.5 ml / kg of test compound
Was administered. The test compound was administered 3 minutes after the administration of 0.5 μg / kg of PAF, and its antagonistic action was evaluated. Table 4 shows the results. The recovery rate in Table 4 is the ratio of the increase in pressure by the test compound to the decrease in blood pressure. <Result>

[0132]

[Table 4]

Experimental Example 5 Measurement of Stability in Aqueous Solution A series of compounds are neutral to alkaline and unstable in an aqueous solution, mainly due to a hydrolysis reaction of N-acetyl or N-benzoyl. When the pH-degradation rate profiles of some compounds were examined, they all showed similar patterns.The decomposition rate constants at pH 7.4 and 37 ° C, which are relatively easy to decompose, were determined. went.

<Experimental Method> To 1 volume of an aqueous sample solution (1 mg / ml), 9 volumes of a buffer solution (0.5 M sodium phosphate, pH 7.4) was added and stored at 37 ° C. Sampling over time,
The residual ratio of the unchanged compound was measured by reversed-phase high performance liquid chromatography. Since most compounds are approximated by a first-order decomposition rate equation, decomposition rate constants were determined by the least squares method. Table 5 shows the results. <Result>

[0135]

[Table 5]

From the above experimental examples, it is clear that the compound of the present invention has an excellent PAF inhibitory action. Furthermore,
The compound of the present invention has been found to be excellent in the persistence of anti-PAF action and also in stability, and the value of the present invention is high.

Accordingly, the compounds of the present invention are effective for treating and preventing any disease caused by PAF. Representative diseases include thrombosis, stroke (cerebral hemorrhage, cerebral thrombosis), myocardial infarction, angina, human intravascular coagulation syndrome (DIC),
It is useful as a therapeutic / prophylactic agent for thrombophlebitis, glomerulonephritis, anaphylactic shock, hemorrhagic shock, allergic diseases and the like.

When the compound of the present invention is administered as an anti-PAF agent, it may be orally administered as powders, granules, capsules, syrups and the like, or as suppositories, injections, external preparations and drops. Although it may be administered parenterally, in the case of the present invention, it is usually preferred to administer it as an injection or infusion.

The dose varies remarkably depending on the type of disease, degree of symptoms, age, etc., but when administered as an infusion, it is about 0.01 to 10 mg / kg / hr, preferably 0.03 to 5 mg / kg.
Administer g / hr. When administered as an intravenous injection, it is usually about 0.001 to 50 mg / kg, preferably about 0.001 to 30 mg / kg, more preferably 0.001 to 5 mg / kg per day for an adult.
g, more preferably 0.003 to 3 mg / kg, once or several times a day.

Formulations for oral and parenteral administration are produced by a conventional method using a usual pharmaceutically acceptable carrier. When preparing injections, infusions, etc., add pH adjusters, buffers, stabilizers, solubilizers, etc. as necessary to the base drug, freeze-dry if necessary, and subcutaneously Intramuscular and intravenous injections and drip injections.

[0141]

EXAMPLES Next, typical examples of the present invention will be described, but it goes without saying that the present invention is not limited to them. In the chemical structural formulas in the examples,
Me means a methyl group, Et means an ethyl group, and Ph means a phenyl group.

Example 1 1-ethyl-2- [N-acetyl-N- {2-methoxy}
-3- (3,4,5-trimethoxy) phenylcarbamoylo
Xypropoxydicarbonyl] aminomethylpyridinium
Moyozide

[0143]

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(1) 2-O-methyl-1-O- (3,4,5-to
Synthesis of (Limethoxy) phenylcarbamoylglycerin

[0145]

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Toluene solution (600 ml) of 18.3 g of 3,4,5-trimethoxyaniline was added to 48 ml of trichloromethyl chloroformate.
Was added to a toluene solution (140 ml) and refluxed for 3 hours. After cooling, the solvent was distilled off, and the residue was distilled under reduced pressure (115 ° C./1 mmHg) to obtain 15.53 g of 3,4,5-trimethoxyphenyl isocyanate.

Of these, 4.1 g was taken and 2-methoxy-1,3
-The mixture was stirred at room temperature for 44 hours in a nitrogen atmosphere together with 2.1 g of propanediol and 21 ml of pyridine. The solvent was distilled off, dissolved in chloroform, washed with dilute hydrochloric acid, washed with water, washed with a saturated aqueous solution of sodium hydrogen carbonate, washed with water, and dried over magnesium sulfate. The residue obtained by removing the solvent was purified by silica gel column chromatography (elution solvent; ethyl acetate: n-hexane = 1: 1) to give 2.55 g of the desired product
I got

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 2.34 (m, 1
H), 3.36 to 3.94 (m, 3H), 3.50 (s, 3H), 3.80 (s, 3H), 3.84
(s, 6H), 4.32 (m, 2H), 6.66 (s, 2H), 6.80 (m, 1H) (2) 2-O-methyl-3-O- (2-pyridyl) methylca
Rubamoyl-1-O- (3,4,5-trimethoxy) phenyl
Synthesis of rucarbamoylglycerin

[0149]

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The 2-O-methyl-1-O- obtained in (1)
To a mixture of 1.70 g of (3,4,5-trimethoxy) phenylcarbomoylglycerin, 0.95 g of pyridine and 60 ml of methylene chloride was added dropwise 1.10 g of phenyl chloroformate under ice cooling, followed by stirring for 30 minutes. The reaction solution was washed twice with a 1% aqueous sodium hydrogen carbonate solution, washed with water and dried over magnesium sulfate. The oil obtained by evaporating the solvent was treated with 2- (aminomethyl) pyridine 2.
Dissolve in 38 g of chloroform solution (80 ml),
Stirred for hours. After cooling, the solvent was distilled off and the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate: n-ethyl acetate).
Hexane = 1: 1) to give 1.41 g of the desired product
I got

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 3.49 (s, 3
H), 3.52 to 3.92 (m, 1H), 3.80 (s, 3H), 3.85 (s, 6H), 4.2
6 (m, 4H), 4.50 (d, J = 5Hz, 2H), 5.76〜6.04 (m, 1H), 6.67
(s, 2H), 6.88 (br.S, 1H), 7.06-7.32 (m, 2H), 7.46-7.78
(m, 1H), 8.52 (m, 1H) (3) 3-O- ｛N-acetyl-N- (2-pyridyl) methyl
Rucarbamoyl-2-O-methyl-1-O- (3,4,5
-Trimethoxy) phenylcarbamoylglycerin
Success

[0152]

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The 2-O-methyl-3-O- obtained in (2)
(2-pyridyl) methylcarbamoyl-1-O- (3,4,5-
1.30 g of trimethoxy) phenylcarbamoylglycerin
A mixture of 30 g of acetic anhydride and 30 ml of pyridine was stirred at 110 ° C. for 15 hours in a nitrogen atmosphere. After cooling, the solvent was distilled off and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 1: 1) to obtain 0.87 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 2.62 (s, 3
H), 3.34 (s, 3H), 3.50 (m, 1H), 3.81 (s, 3H), 3.82 (s, 6
H), 3.90-4.18 (m, 2H), 4.29 (d, J = 5 Hz, 2H), 5.12 (s, 2H),
6.75 (s, 2H), 6.98 to 7.30 (m, 2H), 7.48 to 7.90 (m, 2H), 8.
36 to 8.54 (m, 1H) (4) 1-ethyl-2- [N-acetyl-N- ｛2-meth
Xy-3- (3,4,5-trimethoxy) phenylcarbamoy
Ruoxydipropoxycarbonyl] aminomethylpyridi
Synthesis of Nium Iodide

[0155]

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The 3-O- ｛N-acetyl- obtained in (3)
Dissolve 0.67 g of N- (2-pyridyl) methyl} carbamoyl-2-O-methyl-1-O- (3,4,5-trimethoxy) phenylcarbamoylglycerin in 25 ml of ethyl iodide,
The mixture was refluxed at 70 ° C. for 18 hours in a nitrogen atmosphere, protected from light. After cooling,
The precipitated solid was collected and reprecipitated twice with acetone-ether to obtain 0.2 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.65 (t, J = 8
Hz, 3H), 2.67 (s, 3H), 3.43 (s, 3H), 3.62 to 3.88 (m, 1H),
3.80 (s, 3H), 3.84 (s, 6H), 4.10 (m, 2H), 4.52 (m, 2H), 4.
96 (m, 2H), 5.45 (s, 2H), 6.89 (s, 2H), 7.72 to 7.97 (m, 3H),
8.28 to 8.52 (m, 1H), 9.07 to 9.22 (m, 1H) Example 2 1-ethyl-2- [N- {3- (2- fluorenamino )]
Carbonyloxy-2-methoxypropyloxyzcal
Bonyl-N- (2-methoxy) benzoyl] aminomethyl
Pyridinium chloride

[0158]

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(1) 2-O-methyl-3-O- ｛N- (2
-Pyridyl) methyl} carbamoyl-1-O- (tetra
Synthesis of hydro-2H-pyran-2-yl) glycerin

[0160]

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1-O- (tetrahydro-2H-pyran-2
-Yl) -2-O-methylglycerin in 250 ml of pyridine
And phenyl chloroformate was added dropwise with stirring under ice-cooling. Two hours later, the mixture was added to diluted hydrochloric acid and extracted with 300 ml of ether. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After adding 60 ml of 2-aminomethylpyridine to the residue and reacting at room temperature for 1 hour, the residue was purified by silica gel column chromatography (elution solvent; ethyl acetate: n-hexane = 1: 1) to obtain 46 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.30 to 2.00
(m, 6H), 3.26 ~ 3.94 (m, 5H), 3.40 (s, 3H), 4.04 ~ 4.26
(m, 2H), 4.40 (d, J = 6Hz, 2H), 4.55 (m, 1H), 5.96 (m, 1H),
6.96 to 7.40 (m, 2H), 7.55 (m, 1H), 8.42 (m, 1H) (2) 2-O-methyl-3-O- [N- (2-pyridyl)
Synthesis of [Methyl] carbamoylglycerin

[0163]

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The 2-O-methyl-3-O- obtained in (1)
{N- (2-pyridyl) methyl} carbamoyl-1-O-
(Tetrahydro-2H-pyran-2-yl) glycerin was dissolved in 200 ml of methanol, and p-toluenesulfonic acid 30 was dissolved.
g was added and reacted for 5 hours. The reaction solution was concentrated to 100 ml, added to 200 ml of a saturated aqueous solution of sodium hydrogen carbonate, and extracted three times with ethyl acetate. The organic layer was collected, concentrated under reduced pressure, and the aqueous layer was also concentrated under reduced pressure. Ethyl acetate was added to the residue, followed by filtration and concentrated under reduced pressure. The residue is combined and silica gel column chromatography (elution solvent; methanol: ethyl acetate = 5: 95)
Then, 27 g of the desired product was obtained.

[0165]¹H-NMR (90MHz, CDCl_Three) δ; 3.13 (br, 1
H) 3.28-3.80 (m, 3H), 3.42 (s, 3H), 4.20 (d, J = 5.4 Hz, 2
H), 4.43 (d, J = 5.6Hz, 2H), 6.16 (br, 1H), 7.00 ~ 7.30 (m, 2
H) 7.60 (m, 1H), 8.44 (m, 1H) (3)1-O- (2-fluoreneamino) carbonyl-2
-O-methyl-3-O- ｛N- (2-pyridyl) methyl
Synthesis of Rucarbamoylglycerin

[0166]

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5.7 g (31.2 mmol) of 2-aminofluorene was suspended in 100 ml of toluene, 12.5 g (62.9 mmol) of TCF (trichloromethyl chloroformate) was added, and the mixture was heated under reflux for 30 minutes.

The toluene and excess TCF were distilled off and the reaction product
After adding a solution of 5 g (20.8 mmol) of the alcohol obtained in (2) in tetrahydrofuran, 20 ml of pyridine was added.
After stirring at room temperature for 1 hour, the mixture was heated in an oil bath at 50 ° C. for 30 minutes.
After cooling, 200 ml of ice water and 100 ml of methylene chloride were added to the reaction solution, and the insolubles were removed by suction filtration. The organic layer is washed with water, concentrated, and purified by silica gel column chromatography (elution solvent: methylene chloride: acetone = 1: 1) to give the desired product
5.3 g were obtained.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 3.46 (s, 3
H), 3.64 (m, 1H), 3.83 (s, 2H), 4.00-4.36 (m, 4H), 4.46
(d, J = 5.5Hz, 2H), 6.98 (br.1H), 7.00-7.80 (m, 11H), 8.
46 (m, 1H) (4) 1-O- (2-fluoreneamino) -3-O- ｛N
-(2-methoxy) benzoyl-N- (2-pyridyl) me
Synthesis of tyl @ carbamoyl-2-O-methylglycerin

[0170]

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The 1-O- (2-fluoreneamino) carbonyl-2-O-methyl-3-O- ｛N- obtained in (3)
(2-Pyridyl) methyl @ carbamoylglycerin was added to 51 ml of pyridine, and 2-methoxybenzoic acid chloride was added dropwise with stirring at room temperature, and the mixture was reacted for 1.5 hours. The reaction solution was added to 50 ml of a saturated aqueous sodium hydrogen carbonate solution, and extracted three times with methylene chloride. The organic layer was collected, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 2: 1) to obtain 7 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.70 (br, 1
H), 3.07 (s, 3H), 3.10 (m, 1H), 3.85 (s, 3H), 3.88 (bs.2
H), 3.96 (m, 2H), 4.13 (m, 2H), 5.29 (s, 2H), 6.85 to 7.85
(m, 14H), 8.58 (m, 1H) (5) 1-ethyl-2- [N- ｛3- (2-fluorenamide
D) carbonyloxy-2-methoxypropyloxy
Carbonyl-N- (2-methoxy) benzoyl] amino
Synthesis of methylpyridinium chloride

[0173]

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The 1-O- (2-fluoreneamino) -3-O- {N- (2-methoxy) benzoyl-N- (2-pyridyl) methyl} carbamoyl-2-O obtained in (4)
-Methylglycerin was dissolved in 70 ml of ethyl iodide and heated under reflux for 24 hours. The reaction solution is returned to room temperature, concentrated to dryness, and the residue is ion-exchange resin (Amberlite IRA-410, Cl
^- type] (eluent: methanol: water = 7: 3) to give the treated crude chloride bodies 8.5g at. The crude chloride was purified by silica gel column chromatography (elution solvent; methanol: methylene chloride = 5: 95) to obtain 7.1 g of the desired product.

[0175]¹H-NMR (400MHz, CDCl_Three) δ; 1.58 (t, J
= 7Hz, 3H), 3.15 (s, 3H), 3.30 (bs, 2H), 3.31 (m, 1H), 3.8
9 (s, 3H), 3.91 (dd, J = 12Hz, 5Hz, 1H), 4.07 (m, 1H), 4.20
(m, 1H), 4.77 (q, J = 7Hz, 2H), 5.55 (bs, 2H), 7.07 (t, J = 7H
z, 1H), 7.13 (d, J = 8Hz, 1H), 7.26 (t, J = 7Hz, 1H), 7.35 (t, J
= 8Hz, 1H), 7.42 ~ 7.55 (m, 4H), 7.71 (bs, 1H), 7.79 (m, 2
H), 8.02 (d, J = 8Hz, 1H), 8.10 (t, J = 6Hz, 1H), 8.67 (t, J = 8H
z, 1H), 9.16 (d, J = 6Hz, 1H), 9.80 (bs, 1H) ・ MS FAB: 610 (M⁺)Example 3 1-ethyl-2- [N- (2-methoxy) benzoyl-
N- ｛2-methoxy-3- (2-tetrahydrofurani
G) Methyl carbamoyloxypropoxy carbonyl
Ru] aminomethylpyridinium chloride

[0176]

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(1) 1,3-O-diphenyloxy
Synthesis of carbonyl-2-O-methylglycerin

[0178]

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2-methoxy-1,3-propanediol 20
g was dissolved in 200 ml of pyridine, and 52.6 ml of phenyl chlorocarbonate was added dropwise over 30 minutes under ice cooling and stirring. Two hours later, the reaction solution was added to 1 liter of 4N-hydrochloric acid-water and extracted with ether.
The organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate, concentrated, and then subjected to silica gel column chromatography (elution solvent;
Purification with n-hexane: ethyl acetate = 1: 1) gave 52 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 3.52 (s, 3
H), 3.76 (m, 1H), 4.34 (m, 2H), 4.40 (m, 2H), 7.00 ~ 7.50
(m, 10H) (2) 2-O-methyl-1-O-phenoxycarbonyl-
3-O- {N- (2-pyridyl) methyl} carbamoyl
Glycerin synthesis

[0181]

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50 g of 1,3-O-diphenyloxycarbonyl-2-O-methylglycerin obtained in (1) was dissolved in 50 ml of chloroform, and 14.9 ml of 2- (aminomethyl) pyridine was added dropwise with stirring at room temperature. . After the reaction solution was heated under reflux for 7 hours, the solvent was concentrated, and the concentrate was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to obtain 29 g of the desired product. .

[0183]¹H-NMR (90MHz, CDCl_Three) δ; 3.53 (s, 3
H), 3.76 (m, 1H), 4.20 to 4.42 (m, 4H), 4.51 (d, J = 5 Hz, 2
H), 5.92 (br, 1H), 7.16 to 7.56 (m, 7H), 7.70 (m, 1H), 8.56
(m, 1H) (3)3-O- {N- (2-methoxy) benzoyl-N-
(2-pyridyl) methyl} carbamoyl-2-O-methyl
Synthesis of l-1-O-phenoxycarbonylglycerin

[0184]

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The 2-O-methyl-1-O- obtained in (2)
Phenoxycarbonyl-3-O- ｛N- (2-pyridyl)
16 g of methyl carbamoylglycerin in 160 ml of pyridine
And 2-methoxybenzoic acid chloride was added dropwise at room temperature. After stirring for 1 hour, a cold saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride. The organic layer was washed with water and concentrated, and the concentrate was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1) to obtain 21 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 3.24 (s, 3
H), 3.30 (m, 1H), 3.82 (s, 3H), 3.70-4.10 (m, 4H), 5.20
(s, 2H), 6.70 to 7.50 (m, 11H), 7.60 (m, 1H), 8.48 (m, 1H) (4) 3-O- ｛N- (2-methoxy) benzoyl-N- (2
-Pyridyl) methyl {carbamoyl-2-O-methyl-
1-O- (2-tetrahydrofuranyl) methylcarbamo
Synthesis of ilglycerin

[0187]

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1-g of 3-O- {N- (2-methoxy) benzoyl-N- (2-pyridyl) methyl} carbamoyl-2-O-methyl-1-O-phenoxycarbonylglycerin obtained in (3), Tetrahydrofurfurylamine 0.35
g and 30 ml of chloroform were refluxed for 12 hours. After cooling, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: n-hexane = 1: 1).
Purification in 1) gave 0.40 g of the desired product.

[0189]¹H-NMR (90MHz, CDCl_Three) δ; 1.70 to 2.08
(m, 4H), 2.84 to 4.22 (m, 10H), 3.17 (s, 3H), 3.82 (s, 3H),
4.84 to 5.28 (br, 1H), 5.18 (s, 2H), 6.76 to 7.72 (m, 7H),
8.48 (m, 1H) (5)1-ethyl-2- [N- (2-methoxy) benzoi
Ru-N- ｛2-methoxy-3- (2-tetrahydrofura
Nylmethyl carbamoyloxypropoxycarbonyl
[A] Synthesis of aminomethylpyridinium chloride

[0190]

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3-O- {N- (2-methoxy) benzoyl-N- (2-pyridyl) methyl} carbamoyl-2-O-methyl-1-O- (2-tetrahydrofuranyl obtained in (4) ) Methylcarbamoylglycerin (0.4 g) was dissolved in ethyl iodide (40 ml), and refluxed for 24 hours in a nitrogen atmosphere, protected from light. After cooling, the solvent was distilled off and the residue ion exchange resin [Amberlite IRA-410, Cl ^- type] (eluent: methanol: water = 7: 3) was treated with silica gel column chromatography (solvent; Purification with methanol: methylene chloride = 1: 9) gave 0.3 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.28 to 2.12
(m, 7H), 2.64-4.28 (m, 10H), 3.18 (s, 3H), 3.88 (s, 3H),
4.92 to 5.28 (m, 2H), 5.30 to 5.70 (m, 1H), 5.49 (s, 2H), 6.
76 ~ 7.08 (m, 2H), 7.25 ~ 7.55 (m, 2H), 7.80 ~ 8.20 (m, 2H),
8.30 to 8.56 (m, 1H), 9.88 (m, 1H) Example 4 1-ethyl-2- [N- (2-methoxy) benzoyl-
N- {2-methoxy-3- (3-octadecyloxy)
Propylcarbamoyloxy｝ propoxycarbonyl)
Aminomethylpyridinium chloride

[0193]

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(1) 2-O-methyl-1-O- (3-octane
Tadecyloxy) propylcarbamoyl-3-O- (2-
Synthesis of pyridyl) methylcarbamoylglycerin

[0195]

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The 2-O-methyl- obtained in Example 3 (2)
2.86 g of 1-O-phenoxycarbonyl-3-O- {N- (2-pyridyl) methyl} carbamoylglycerin, 3-
After dissolving 2.6 g of (octadecyloxy) propylamine in chloroform to make it uniform, the solvent was distilled off and the residue was evaporated to 100
Stirred at C overnight. After cooling, the residue was purified by silica gel chromatography (elution solvent: ethyl acetate: n-hexane = 1: 1) to obtain 1 g of the desired product.

[0197]¹H-NMR (90MHz, CDCl_Three) δ; 0.87 (m, 3
H), 1.00-1.86 (m, 34H), 3.00-3.74 (m, 6H), 3.39 (s, 3
H), 3.90-4.29 (m, 5H), 4.45 (d, J = 5Hz, 2H), 4.98-5.26
(br, 1H), 5.70-5.96 (br, 1H), 6.98-7.28 (m, 2H), 7.44
~ 7.70 (m, 1H), 8.34 ~ 8.52 (m, 1H) (2)3-O- {N- (2-methoxy) benzoyl-N-
(2-pyridyl) methyl} carbamoyl-2-O-methyl
Ru-1-O- (3-octadecyloxy) propylcal
Synthesis of Bamoylglycerin

[0198]

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The 2-O-methyl-1-O- obtained in (1)
(3-octadecyloxy) propylcarbamoyl-3
-O- (2-pyridyl) methylcarbamoylglycerin
1.0 g was dissolved in 20 ml of tetrahydrofuran, 0.2 g of potassium hydride was added at room temperature, and the mixture was stirred for 30 minutes. Under ice cooling, 0.29 g of 2-methoxybenzoic acid chloride was added, and the mixture was stirred for 1 hour. 0.2 g of acetic acid was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Then, ethyl acetate was added, and the mixture was washed twice with a saturated aqueous solution of sodium hydrogen carbonate, washed twice with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 1: 1) to obtain 0.25 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.88 (m, 3
H), 1.05 to 1.90 (m, 34H), 3.06 to 3.54 (m, 7H), 3.18 (s, 3
H), 3.70-3.90 (m, 2H), 3.81 (s, 3H), 3.92-4.22 (m, 2H),
5.00 to 5.26 (br, 1H), 5.19 (s, 2H), 6.74 to 7.73 (m, 7H),
8.48 (m, 1H) (3) 1-ethyl-2- [N- (2-methoxy) benzoyi
Ru-N- {2-methoxy-3- (3-octadecyloxy)
B) Propylcarbamoyloxypropoxycarboni
[A] Synthesis of aminomethylpyridinium chloride

[0201]

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The 3-O- [N- (2-methoxy) benzoyl-N- (2-pyridyl) methyl] carbamoyl-2-O-methyl-1-O- (3-octadecyloxy) obtained in (2) ) 0.25 g of propylcarbamoylglycerin was dissolved in 30 ml of ethyl iodide, and the mixture was refluxed for 48 hours in a nitrogen atmosphere, protected from light. After cooling, distilled off the residue of ion exchange resin and the solvent [Amberlite IRA-410, Cl ^- type] (eluent: methanol: water = 7: 3) then treated with silica gel column chromatography (solvent; methanol : Methylene chloride = 1: 9) and freeze-dried to give the desired product
0.20 g was obtained.

[0203]¹H-NMR (90MHz, CDCl_Three) δ; 0.89 (m, 3
H), 1.09 to 1.97 (m, 34H), 1.84 (m, 3H), 3.12 to 3.62 (m, 7
H), 3.27 (s, 3H), 3.73 to 3.89 (m, 2H), 3.97 (s, 3H), 4.03
~ 4.41 (m, 2H), 5.31 (m, 2H), 5.52 (m, 1H), 5.62 (s, 2H),
6.90 to 7.25 (m, 2H), 7.45 to 7.69 (m, 2H), 8.03 to 8.30 (m, 2
H), 8.41-8.62 (m, 1H), 10.29 (m, 1H)Example 5 1-ethyl-2- [N- {3- (10-N, N-dimethylca
Rupamylamino) decylcarbamoyloxy-2-meth
Xypropyloxy} carbonyl-N- (2-methoxy
B) Benzoyl] aminomethylpyridinium chloride

[0204]

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(1) 1-O- (10-N, N-dimethylcarba
(Mylamino) decylcarbamoyl-2-O-methyl-3
-O- {N- (2-pyridyl) methyl} carbamoylglyc
Synthesis of serine

[0206]

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The 2-O-methyl-1-O-phenoxycarbonyl-3-O- {N- (2-
1.5 g of pyridyl) methyl @ carbamoylglycerin was dissolved in 15 ml of chloroform, and 1.0 g of 1,10-diaminodecane was added, followed by stirring at 60 ° C. for 30 minutes. The reaction solution was returned to room temperature, and 2 ml of triethylamine and 1.2 ml of N, N-dimethylcarbamyl chloride were added and reacted for 30 minutes. The reaction solution was added to a saturated aqueous solution of sodium hydrogen carbonate and extracted three times with 20 ml of methylene chloride. The organic layer was collected, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methanol: ethyl acetate = 5: 95) to obtain 2.0 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.00 to 1.72
(m, 16H), 2.92 (s, 6H), 3.00 ~ 3.33 (m, 4H), 3.47 (s, 3H),
3.64 (m, 1H), 4.08 to 4.29 (m, 4H), 4.29 to 4.50 (m, 1H), 4.
32 (d, J = 8Hz, 2H), 4.92 (m, 1H), 6.98 (m, 1H), 7.10 ~ 7.39
(m, 2H), 7.70 (t, J = 8Hz, 1H), 8.57 (m, 1H) (2) 1-O- (N, N-dimethylcarbamylamino) dec
Rucarbamoyl-3-O- ｛N- (2-methoxy) benzo
Yl-N- (2-pyridyl) methyl} carbamoyl-2
Synthesis of -O-methylglycerin

[0209]

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1-O- (10-N, N-dimethylcarbamylamino) decylcarbamoyl-2-O- obtained in (1)
4.2 g of methyl-3-O- {N- (2-pyridyl) methyl} carbamoylglycerol was dissolved in 40 ml of pyridine, and 1.5 ml of 2-methoxybenzoic acid chloride was added thereto with stirring at room temperature, followed by a reaction for 30 minutes. The reaction solution was added to 40 ml of a saturated aqueous solution of sodium hydrogen carbonate and extracted three times with 40 ml of methylene chloride.
The organic layer was collected, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methanol: ethyl acetate = 5: 95) to obtain 4.2 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.04 to 1.60
(m, 16H), 2.80 (s, 6H), 2.90 ~ 3.05 (m, 5H), 3.12 (s, 3H),
3.62 to 3.80 (m, 2H), 3.75 (s, 3H), 3.87 to 4.03 (m, 2H), 4.
20 to 4.45 (br, 1H), 4.65 to 4.90 (br, 1H), 5.13 (s, 2H), 6.7
0 to 7.70 (m, 7H), 8.43 (m, 1H) (3) 1-ethyl-2- [N- Ｎ3- ( 10-N, N-dimethyl
Rucarbamylamino) decylcarbamoyloxy-2-
Methoxypropyloxy} carbonyl-N- (2-meth
Xy) benzoyl] aminomethylpyridinium chloride
Synthesis of

[0212]

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The 1-O- (N, N-dimethylcarbamylamino) decylcarbamoyl-3-O- ｛N obtained in (2)
1.2 g of-(2-methoxy) benzoyl-N- (2-pyridyl) methyl} carbamoyl-2-O-methylglycerol was dissolved in 20 ml of ethyl iodide and heated under reflux for 2 days. The reaction mixture was concentrated under reduced pressure was brought to room temperature, the residue ion exchange resin [Amberlite IRA-410, Cl ^- type] (eluent: methanol: water = 7: 3) was treated with to provide the crude chloride bodies 1.5g Was. This crude chloride is subjected to silica gel column chromatography (elution solvent: methanol: methylene chloride = 5: 9).
Purification in 5) gave 1.1 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ 1.04 to 1.60 (m, 16H), 1.77 (t, J = 7 Hz, 3H), 2.88 (s, 6H),
2.94 to 3.36 (m, 3H), 3.20 (s, 3H), 3.52 to 3.84 (m, 4H), 3.9
0 (s, 3H), 3.88 to 4.26 (m, 2H), 4.46 (m, 1H), 5.14 (q, J = 7H
z, 2H), 5.20 (m, 1H), 5.52 (br, 2H), 7.00 (m, 2H), 7.44 (m,
2H), 8.06 (m, 2H), 8.47 (m, 1H), 10.1 (m, 1H) Example 6 1-Ethyl-2- [N- {3- (4-ethoxycarbonyl)
L) cyclohexylmethylcarbamoyloxy-2-me
Toxoxydipropyloxycarbonyl-N- (2-methoxy
B) Benzoyl] aminomethylpyridinium iodide

[0215]

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(1) 1-O- (4-ethoxycarbonyl )
Clohexyl) methylcarbamoyl-3-O- ｛N- (2
-Methoxy) benzoyl-N- (2-pyridyl) methyl}
Synthesis of carbamoyl-2-O-methylglycerin

[0219]

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The 3-O- ｛N- (2) obtained in Example 3 (3)
-Methoxy) benzoyl-N- (2-pyridyl) methyl} carbamoyl-2-O-methyl-1-O-phenoxycarbonylglycerol (1.0 g) was dissolved in 30 ml of chloroform, and 4-aminomethylcyclohexanecarboxylic acid ethyl ester hydrochloride was dissolved. 0.5 g and triethylamine 0.4 g were added, and the mixture was refluxed for 2 hours. The reaction solution was washed with saturated saline, chloroform was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 7: 3) to obtain 1.1 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.64 to 2.24
(m, 10H), 1.25 (t, J = 8Hz, 3H), 3.01 (t, J = 6Hz, 2H), 3.04〜
3.28 (m, 1H), 3.22 (s, 3H), 3.72 to 4.50 (m, 2H), 3.86 (s, 3
H), 3.96-4.12 (m, 2H), 4.11 (q, J = 8Hz, 2H), 4.91 (m, 1H),
5.25 (s, 2H), 6.88 to 7.80 (m, 7H), 8.38 (d, J = 7 Hz, 1H) (2) 1-ethyl-2- [N- ｛3- (4-ethoxycal
Bonyl) cyclohexylmethylcarbamoyloxy-2
-Methoxydipropyloxycarbonyl-N- (2-meth
Toxy) benzoyl] aminomethylpyridinium iodi
Compound

[0220]

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1-O- (4-ethoxycarbonylcyclohexyl) methylcarbamoyl-3-O obtained in (1)
-{N- (2-methoxy) benzoyl-N- (2-pyridyl) methyl} carbamoyl-2-O-methylglycerin
1.1 g was dissolved in 20 ml of ethyl iodide and refluxed for 24 hours. The insoluble matter was separated by filtration and dissolved in acetone. Ether was added and reprecipitated to obtain 1.0 g of the desired product.

[0222]¹H-NMR (90 MHz, CDCl_Three) δ; 0.64 to 2.30
(m, 10H), 1.24 (t, J = 8Hz, 3H), 1.77 (t, J = 8Hz, 3H), 2.97
(t, J = 6Hz, 2H), 3.08 ~ 3.16 (m, 1H), 3.20 (s, 3H), 3.62 ~
4.24 (m, 4H), 3.90 (s, 3H), 4.08 (q, J = 8Hz, 2H), 4.80-5.2
0 (m, 3H), 5.54 (s, 2H), 6.78 ~ 7.12 (m, 2H), 7.08 ~ 7.36
(m, 2H), 7.90-8.20 (m, 2H), 8.56 (t, J = 8Hz, 1H), 9.24 (d,
(J = 7Hz, 1H)Example 7 1-ethyl-2- [N- (2-methoxy) benzoyl-
N- {2-methoxy-3- (2- (4-sulfamoyl)
Phenyl) ethylcarbamoyloxy) propyloxy
[Dicarbonyl] aminomethylpyridinium iodide

[0223]

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(1) 3-O- ｛N- (2-methoxy) benzo
Yl-N- (2-pyridyl) methyl} carbamoyl-2
-O-methyl-1-O- ｛2- (4-sulfamoyl) phenyl
Synthesis of phenylethyl carbamoylglycerin

[0225]

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The 3-O- ｛N- (2) obtained in Example 3 (3)
-Methoxy) benzoyl-N- (2-pyridyl) methyl} carbamoyl-2-O-methyl-1-O-phenoxycarbonylglycerin 1.0 g, 4- (2-aminoethyl)
0.5 g of benzenesulfonamide was mixed and stirred at 80 ° C. for 1 hour. The reaction mixture is brought to room temperature and silica gel column chromatography (elution solvent: chloroform: methanol = 9)
5: 5) to give 0.8 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ 2.84 (t, J = 7 Hz, 2H), 3.18 (s, 3H), 3.10 to 3.54 (m, 3H),
3.74 to 3.90 (m, 2H), 3.82 (s, 3H), 3.92 to 4.10 (m, 2H),
5.08 to 5.32 (m, 3H), 5.57 (br.s, 2H), 6.82 to 7.90 (m, 11
H), 8.54 (d, J = 7Hz, 1H) (2) 1-ethyl-2- [N- (2-methoxy) benzoy
Ru-N- {2-methoxy-3- (2- (4-sulfamoi)
Ruphenyl) ethylcarbamoyloxy) propyloxy
Dicarbonyl] aminomethylpyridinium iodide
Synthesis

[0228]

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The 3-O- {N- (2-methoxy) benzoyl-N- (2-pyridyl) methyl} carbamoyl-2-O-methyl-1-O- {2- (4 -Sulfamoyl) phenylethylcarbamoylglycerin 0.8g
Was dissolved in 10 ml of ethyl iodide and refluxed for 24 hours. The insoluble material was separated by filtration and dissolved in acetone. Ether was added and reprecipitated to obtain 0.7 g of the desired product.

¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.58 (t,
J = 8Hz, 3H), 2.60 ~ 2.88 (m, 2H), 3.04 ~ 3.40 (m, 3H), 3.3
3 (s, 3H), 3.56-3.76 (m, 2H), 3.88 (s, 3H), 3.96-4.16
(m, 2H), 4.79 (q, J = 8Hz, 2H), 5.56 (s, 2H), 6.96-7.84 (m, 2H)
11H), 7.96-7.24 (m, 2H), 8.70 (tJ = 8Hz, 1H), 9.18 (d, J = 7
Hz, 1H) Example 8 1-ethyl-2- [N- (2-methoxy) benzoyl-
N- {3- (3-morpholinocarbonylpropane-1-
Il) carbamoyloxy-2-methoxypropyloxy
[Dicarbonyl] aminomethylpyridinium chloride

[0231]

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(1)2-O-methyl-1-O- {3- (mo
Ruphorinocarbonyl) propyl} carbamoyl-3-O
-｛N- (2-methoxy) benzoyl-N- (2-pyridyl
B) Synthesis of methyl carbamoylglycerin

[0233]

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The 3-O- ｛N- (2) obtained in Example 3 (3)
-Methoxy) benzoyl-N- (2-pyridyl) methyl} carbamoyl-2-O-methyl-1-O-phenoxycarbonylglycerin (4.7 g) is dissolved in chloroform (50 ml), and N- (4-aminobutyryl) morpholine (2.4 g) is added. Then, the mixture is stirred and refluxed for 3 hours. After concentrating the solvent, the concentrate was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 95: 5) to obtain the desired product in 2.
9 g was obtained.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.80 (m, 2
H), 2.32 (t, J = 7Hz, 2H), 3.18 (s, 3H), 3.00-3.30 (m, 2
H), 3.30-3.70 (m, 9H), 3.70-4.10 (m, 4H), 3.80 (s, 3H),
5.12 (m, 1H), 5.20 (m, 2H), 6.75 to 7.04 (m, 2H), 7.04 to 7.
68 (m, 4H), 8.46 (m, 1H) (2) 1-ethyl-2- [N- (2-methoxy) benzoyi
Ru-N- {3- (3-morpholinocarbonylpropane-
1-yl) carbamoyloxy-2-methoxypropyl
Oxydicarbonyl] aminomethylpyridinium chloride
Compound

[0236]

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The 2-O-methyl-1-O- obtained in (1)
{3- (morpholinocarbonyl) propyl} carbamoyl-3-O- {N- (2-methoxy) benzoyl-N- (2
-Pyridyl) methyl @ carbamoylglycerin (0.9 g) was dissolved in ethyl iodide (10 ml), and the mixture was stirred and refluxed for 30 hours under a nitrogen stream. The reaction mixture was concentrated after cooling, the residue ion exchange resin [Amberlite IRA-410, Cl ^- type] (eluent: methanol: water = 7: 3) treatment at to: obtain a crude chloride 0.9 g.
The crude chloride was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 95: 5) to obtain 0.9 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.76 (J, J = 7
Hz, 3H), 1.82 (m, 2H), 3.38 (t, J = 7Hz, 2H), 3.20 (s, 3H),
3.00 to 3.30 (m, 2H), 3.30 to 3.70 (m, 11H), 3.80 to 4.30 (m,
4H), 5.20 (q, J = 7Hz, 2H), 5.52 (s, 2H), 5.80 (m, 1H), 6.80
~ 7.14 (m, 2H), 7.30 ~ 7.60 (m, 2H), 7.90 ~ 8.20 (m, 2H),
8.43 (m, 1H), 10.63 (m, 1H) Example 9 1-ethyl-2- [N-Ｎ3- (6,12-dioxahepta
Decyl) carbamoyloxy-2-methoxypropylo
Xy {carbonyl-N- (2-methoxy) benzoyl]
Aminomethylpyridinium iodide

[0239]

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(1) 5-pentyloxy-1-pentano
Synthesis of Le _{HO- (CH 2) 5 -O- (} CH 2) 4 -CH 3 1,5 - N pentanediol (10 g), N - dimethylformamide (150ml) sodium hydride solution (60%, 4.2 g)
Was added, 1-bromopentane (12 ml) was added, and the mixture was stirred at room temperature for 30 minutes. 3% hydrochloric acid was added to the reaction solution, and the mixture was extracted with ether. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 8: 2) to obtain the desired product (6 g).

¹ H-NMR (CDCl ₃ ) δ; 0.88 (t, J = 6 Hz, 3
H), 1.00-1.75 (m, 12H), 1.90 (s, 1H), 3.34 (t, J = 7Hz, 4
H), 3.58 (t, J = 6Hz, 2H) (2) 6,12- Synthesis of di oxa heptadecane nitrile _{CH 3 - (CH 2) 4} -O- (CH 2) 5 -O- (CH 2) _{To a} solution of 5-pentyloxy-1-pentanol (3 g) obtained in _4- CN (1) in N, N-dimethylformamide (50 ml),
After adding sodium hydride (60%, 0.75 g), 5-bromopentanenitrile (2 ml) was added, and the mixture was stirred at 60 ° C for 2 hours. 3% hydrochloric acid was added to the reaction solution, and the mixture was extracted with ether.
The organic layer is dried and concentrated, and the residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
9: 1) to give the desired product (1 g).

¹ H-NMR (CDCl ₃ ) δ; 0.88 (t, J = 7.2 Hz, 3
H), 1.10-2.10 (m, 16H), 2.36 (t, J = 7Hz, 2H), 3.36 (t, J = 7.
2Hz, 8H) (3) 6,12- Synthesis of di oxa heptadecyl amine CH ₃ - (CH ₂₎ obtained in _{4 -O- (CH 2) 5 -O-} (CH 2) 5 -NH 2 (2) To a solution of 6,12-dioxaheptadecanenitrile (1 g) in tetrahydrofuran (20 ml) was added lithium aluminum hydride (0.15 g), and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium sulfate solution was added to the reaction solution, and the mixture was filtered through celite. The filtrate was dried and concentrated, and the residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol = 9: 1) to obtain the desired product (0.3 g).

¹ H-NMR (CDCl ₃ ) δ; 0.88 (t, J = 7 Hz, 3
H), 1.10-1.80 (m, 18H), 2.68 (t, J = 7.2Hz, 2H), 2.92 (bs,
2H), 3.34 (t, J = 6Hz, 8H) (4) 1-O- (6,12-dioxaheptadecyl) carbamo
Ill-2-O-methyl-3-O- ｛N- (2-methoxy)
Benzoyl-N- (2-pyridylmethyl) carbamoy
Synthesis of luglycerin

[0244]

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The 3-O- ｛N- (2) obtained in Example 3 (3)
-Methoxy) benzoyl-N- (2-pyridyl) methyl} carbamoyl-2-O-methyl-1-O-phenoxycarbonylglycerol 0.53 g of chloroform (5 ml)
6,12-Dioxaheptadecylamine (0.28 g) obtained in (3) was added to the solution, and the mixture was refluxed for 4 hours. The reaction solution is concentrated and subjected to silica gel column chromatography (elution solvent;
Purified with benzene: acetone = 4: 1) to give the desired product (0.15g)
I got

[0246]¹H-NMR (CDCl_Three) δ; 0.85 (t, J = 6Hz, 3
H), 1.00-1.80 (m, 18H), 3.15 (s, 3H), 3.14 (m, 2H), 3.32
(t, J = 6Hz, 8H), 3.75 (s, 3H), 3.60-3.85 (m, 3H), 3.90-
4.05 (m, 2H), 4.60 to 5.00 (br, 1H), 5.16 (s, 2H), 6.70 to 7.
70 (m, 7H), 8.38 ~ 8.54 (d, J = 4Hz, 1H) (5)1-ethyl-2- [N- {3- (6,12-dioxa
(Ptadecyl) carbamoyloxy-2-methoxyprop
Ruoxydicarbonyl-N- (2-methoxy) benzoy
[A] Synthesis of aminomethylpyridinium iodide

[0247]

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1-O- (6,12-dioxaheptadecyl) carbamoyl-2-O-methyl-3-O obtained in (4)
-{N- (2-Methoxy) benzoyl-N- (2-pyridylmethyl)} carbamoylglycerin (0.15 g) was dissolved in ethyl iodide (10 ml), and the mixture was heated and refluxed for 48 hours in a nitrogen stream while protecting from light. The reaction solution was concentrated, and the residue was recrystallized from acetone-ether to obtain the desired product (0.1 g).

¹ H-NMR (CDCl ₃ ) δ; 0.86 (t, J = 6 Hz, 3
H), 1.10 ~ 2.00 (m, 18H), 1.75 (t, J = 7.2Hz, 3H), 3.18 (s,
3H), 2.95 to 3.50 (m, 2H), 3.35 (t, J = 5Hz, 8H), 3.65 to 3.80
(m, 3H), 3.88 (s, 3H), 4.00 to 4.20 (m, 2H), 4.80 to 5.20 (b
r, 1H), 5.05 (q, J = 7.2Hz, 2H), 5.50 (s, 2H), 6.86 (d, J = 8H
z, 1H), 7.05 (d, J = 7.2Hz, 1H), 7.30 ~ 7.52 (m, 2H), 7.90 ~
8.20 (m, 2H), 8.50 (t, J = 6 Hz, 1 H), 9.65 (d, J = 6 Hz, 1 H) MS: M / Z 688 (M ⁺ -I) Example 10 1-ethyl-2- [N- ｛3 (4-cyclohexylmethyl)
Rusulfamoyl) benzylcarbamoyloxy-2-
Methoxypropyloxy} carbonyl-N- (2-meth
Xy) benzoyl] aminomethylpyridinium chloride

[0250]

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(1) 2-O-methyl-3-O- (2-pyridy
) Methylcarbamoyl-1-O- (4-sulfamoi
L) Synthesis of benzylcarbamoylglycerin

[0252]

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The 2-O-methyl- obtained in Example 3 (2)
20.0 g of 1-O-phenoxycarbonyl-3-O- {N- (2-pyridyl) methyl} carbamoylglycerin and 4
19.0 g of-(aminomethyl) benzenesulfonamide hydrochloride hydrate was dissolved in 400 ml of tetrahydrofuran-water (3: 1), 17.0 g of triethylamine was added, and the mixture was refluxed for 12 hours. Tetrahydrofuran was distilled off under reduced pressure, water was added, and the mixture was extracted three times with 200 ml of ethyl acetate. The extract was washed with saturated saline, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol = 95: 5) to obtain 21.0 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 3.18 (s, 3
H), 3.40-3.72 (m, 1H), 4.00-4.48 (m, 8H), 5.48-6.00
(m, 4H), 6.96 to 7.60 (m, 6H), 7.71 (d, J = 9 Hz, 1H), 8.40 (d,
J = 8Hz, 1H) (2) 1-O- (4-cyclohexylmethylsulfamoy )
B) benzylcarbamoyl-3-O- ｛N- (2-methoxy
B) Benzoyl-N- (2-pyridyl) methyl} carbamo
Synthesis of yl-2-O-methylglycerin

[0255]

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The 2-O-methyl-3-O- obtained in (1)
2.0 g of (2-pyridyl) methylcarbamoyl-1-O- (4-sulfamoyl) benzylcarbamoylglycerin,
And cyclohexylmethyl bromide 0.8 g, anhydrous potassium carbonate
0.5 g was dissolved in 50 ml of N, N-dimethylformamide,
Stirred at 70 ° C. for 2 hours. Water is added to the reaction solution, and ethyl acetate 50
The mixture was extracted three times with ml, the extract was washed with saturated saline, and the solvent was distilled off under reduced pressure. The residue was dissolved in pyridine (50 ml), and 2-methoxybenzoic acid chloride (0.86 g) was added dropwise at room temperature.
Stirred at C for 2 hours. After the pyridine was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, and the organic layer was washed with a saturated saline solution.
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate: hexane = 3: 2).
And 1.5 g of the desired product was obtained.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.60 to 1.92
(m, 11H), 2.72 (t, J = 6Hz, 2H), 3.04 ~ 3.36 (m, 1H), 3.19
(s, 3H), 3.80 (s, 3H), 3.60 ~ 4.20 (m, 4H), 4.34 (d, J = 7Hz,
2H), 4.52 to 4.80 (m, 1H), 5.15 (s, 2H), 5.36 to 5.60 (m, 1
H), 6.70-7.64 (m, 10H), 7.70 (d, J = 8Hz, 1H), 8.41 (d, J = 7
Hz, 1H) (3) 1-ethyl-2- {N-3- (4-cyclohexyl)
Methylsulfamoyl) benzylcarbamoyloxy-
2-methoxypropyloxy} carbonyl-N- (2-
Methoxybenzoyl) aminomethylpyridinium chloride
Compound

[0258]

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The 1-O- (4-cyclohexylmethylsulfamoyl) benzylcarbamoyl-3 obtained in (2)
1.5 g of -O- {N- (2-methoxy) benzoyl-N- (2-pyridyl) methyl} carbamoyl-2-O-methylglycerin was dissolved in 10 ml of ethyl iodide and refluxed for 24 hours. Of ethyl iodide was distilled off under reduced pressure, the residue ion exchange resin [Amberlite IRA-410, Cl ^- type] (eluent: methanol: water = 7: 3) was treated with the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (elution solvent; methylene chloride: methanol = 9: 1) to obtain 1.0 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.60 to 1.92
(m, 14H), 2.68 (t, J = 6Hz, 2H), 3.00-3.40 (m, 1H), 3.20
(s, 3H), 3.89 (s, 3H), 3.60 to 4.52 (m, 6H), 5.08 (q, J = 8H
z, 2H), 4.80-5.20 (m, 1H), 5.56 (s, 2H), 6.20-6.48 (m, 1
H), 6.80-8.16 (m, 10H), 8.44 (t, J = 8Hz, 1H), 9.70 (d, J = 7
Hz, 1H) Example 11 1-ethyl-2- [N- (2-methoxy) benzoyl-
N- {2-methoxy-3- (4-octadecylsulfur)
Moyl) benzylcarbamoyloxypropyloxy｝
Carbonyl) aminomethylpyridinium chloride

[0261]

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(1) 2-O-methyl-1-O- (4-octa
Decylsulfamoyl) benzylcarbamoyl-3-O
-(2-pyridyl) methylcarbamoylglycerin
Success

[0263]

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The 2-O-methyl- obtained in Example 10 (1)
3-O- (2-pyridyl) methylcarbamoyl-1-O
Dissolve 14.0 g of-(4-sulfamoyl) benzylcarbamoylglycerin, 10.7 g of octadecyl bromide and 3.2 g of anhydrous potassium carbonate in 300 ml of N, N-dimethylformamide,
The mixture was stirred at 60 ° C to 70 ° C for 1.5 hours. The reaction solution was brought to room temperature, water was added, and the mixture was extracted three times with 200 ml of ethyl acetate. After the extract was washed with saturated saline, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent; ethyl acetate: n-hexane = 3: 2) to obtain the desired product.
9.1 g were obtained.

[0265]¹H-NMR (90 MHz, CDCl_Three) δ; 0.86 (t, J = 7
Hz, 3H), 1.00-1.60 (m, 32H), 2.68-3.00 (m, 2H), 3.40
(s, 3H), 3.40 to 3.68 (m, 1H), 4.00 to 4.48 (m, 8H), 5.00 to
5.24 (m, 1H), 5.64-5.84 (m, 1H), 5.84-6.12 (m, 1H), 8.0
0 ~ 8.60 (m, 6H), 8.68 (d, J = 8Hz, 1H), 9.40 (d, J = 7Hz, 1H) (2)3-O- {N- (2-methoxy) benzoyl-N-
(2-pyridyl) methyl} carbamoyl-2-O-methyl
Ru-1-O- (4-octadecylsulfamoyl) benzyl
Synthesis of rucarbamoylglycerin

[0266]

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The 2-O-methyl-1-O- obtained in (1)
9.1 g of (4-octadecylsulfamoyl) benzylcarbamoyl-3-O- (2-pyridyl) methylcarbamoylglycerol was dissolved in 100 ml of pyridine, and 2.2 g of 2-methoxybenzoyl chloride was added dropwise. After stirring at room temperature for 12 hours, pyridine was distilled off under reduced pressure, and the residue was dissolved in 200 ml of ethyl acetate. The organic layer was washed with saturated saline, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (elution solvent; ethyl acetate: hexane = 6: 4) to obtain 4.4 g of the desired product.

[0268]¹H-NMR (90 MHz, CDCl_Three) δ; 0.88 (t, J = 6
Hz, 3H), 1.00 to 1.60 (m, 32H), 2.90 (q, J = 8Hz, 2H), 3.06 to
3.32 (m, 1H), 3.20 (s, 3H), 3.82 (s, 3H), 3.75 to 4.20 (m, 4
H), 4.40 (d, J = 7Hz, 2H), 4.78 ~ 4.92 (m, 1H), 5.22 (s, 2H),
 5.56-5.72 (m, 1H), 6.84-7.76 (m, 10H), 7.80 (d, J = 8Hz,
1H), 8.53 (d, J = 7Hz, 1H) (3)1-ethyl-2 [N- (2-methoxy) benzoyl
-N- ｛2-methoxy-3- (4-octadecylsulfur
Amoyl) benzylcarbamoyloxypropyloxy
Dicarbonyl] aminomethylpyridinium chloride
Synthesis

[0269]

Embedded image

The 3-O- {N- (2-methoxy) benzoyl-N- (2-pyridyl) methyl} carbamoyl-2-O-methyl-1-O- (4-octadecylsulfate obtained in (2) Famoyl) benzylcarbamoylglycerin (1.9 g) was dissolved in ethyl iodide (50 ml) and refluxed for 24 hours. Ion exchange resins and the residue was evaporated under reduced pressure ethyl iodide [Amberlite IRA-410, Cl ^- type] (eluent: methanol: water = 7: 3) processing the solvent was distilled off under reduced pressure by. The residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 9: 1) to obtain 1.3 g of the desired product.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ; 0.85
(t, J = 7Hz, 3H), 1.10-1.38 (m, 32H), 1.57 (t, J = 7Hz, 3H),
2.67 (q, J = 7Hz, 2H), 3.09 (s, 3H), 3.10 ~ 3.20 (m, 1H), 3.
60 to 3.68 (m, 1H), 3.71 to 3.79 (m, 1H), 3.85 (s, 3H), 4.10
~ 4.20 (m, 1H), 3.95 ~ 4.02 (m, 1H), 4.20 ~ 4.25 (m, 2H),
4.75 (q, J = 7Hz, 2H), 5.53 (s, 2H), 7.01 ~ 7.21 (m, 2H), 7.3
8 ~ 7.53 (m, 5H) 7.73 (d, J = 9Hz, 2H), 7.82 (t, J = 6Hz, 1H),
7.99 (d, J = 8Hz, 1H), 8.07 (t, J = 7Hz, 1H), 8.64 (t, J = 7Hz, 1
H), 9.12 (d, J = 7 Hz, 1H) Example 12 1-ethyl-2- [N- (2-methoxy) benzoyl-
N- {2-methoxy-3- (3-octadecylcarbamo)
Yloxy) propylcarbamoyloxy @ propoxy
Carbonyl) aminomethylpyridinium chloride

[0272]

Embedded image

(1)1-O- (3-hydroxy) propyl
Carbamoyl-2-O-methyl-3-O- (2-pyridi
B) Synthesis of methylcarbamoylglycerin

[0274]

Embedded image

The 2-O-methyl- obtained in Example 3 (2)
10 g of 1-O-phenoxycarbonyl-3-O- {N- (2-pyridyl) methyl} carbamoylglycerin and 3.75 g of 3-amino-1-propanol were dissolved in 10 ml of chloroform, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 8 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.69 (m, 2
H), 2.68 to 3.76 (m, 6H), 3.43 (s, 3H), 3.94 to 4.32 (m, 4
H), 4.46 (d, J = 5Hz, 2H), 5.21 (b, 1H), 5.95 (b, 1H), 6.98
~ 7.36 (m, 2H), 7.48 ~ 7.74 (m, 1H), 8.48 (m, 1H) (2) 2-O-methyl-1-O- (3-octadecylcarba
Moyloxy) propylcarbamoyl-3-O- (2-
Synthesis of pyridyl) methylcarbamoylglycerin

[0277]

Embedded image

1-O- (3-hydroxy) propylcarbamoyl-2-O-methyl-3-O- obtained in (1)
To a methylene chloride solution (50 ml) of (2-pyridyl) methylcarbamoylglycerin (2.9 g) and pyridine (1.3 g) was added dropwise phenyl chloroformate (1.56 g) under ice-cooling, followed by stirring for 15 minutes. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, washed with water, and then dried over anhydrous magnesium sulfate. A mixture of the residue obtained by removing the solvent and 3 g of octadecylamine was stirred at 80 ° C. for 1 hour. After cooling, this was subjected to silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 1: 1).
Purification in 1) gave 3 g of the desired product.

[0279]¹H-NMR (90MHz, CDCl_Three) δ; 0.87 (m, 3
H), 0.98 to 1.87 (m, 34H), 2.86 to 3.71 (m, 5H), 3.43 (s, 3
H), 3.95-4.25 (m, 6H), 4.43 (d, J = 5 Hz, 2H), 4.76 (b, 1H),
 5.11 (b, 1H), 5.87 (b, 1H), 6.98-7.29 (m, 2H), 7.47-7.
72 (m, 1H), 8.47 (m, 1H) (3)3-O- {N- (2-methoxy) benzoyl-N-
(2-pyridyl) methyl} carbamoyl-2-O-methyl
1-O- (3-octadecylcarbamoyloxy) p
Ropyrcarbamoylglycerin

[0280]

Embedded image

The 2-O-methyl-1-O- obtained in (2)
3 g of (3-octadecylcarbamoyloxy) propylcarbamoyl-3-O- (2-pyridyl) methylcarbamoylglycerol was dissolved in 50 ml of pyridine, 1.3 g of 2-methoxybenzoic acid chloride was added at room temperature, and the mixture was stirred at 50 ° C for 2 hours. After cooling, the solvent was distilled off, the residue was dissolved in chloroform, washed with a saturated aqueous solution of sodium hydrogen carbonate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (elution solvent; ethyl acetate: n-hexane-1: 1) to give
3 g of the desired product was obtained.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.85 (m, 3
H), 1.04 to 1.92 (m, 34H), 2.88 to 3.86 (m, 7H), 3.16 (s, 3
H), 3.80 (s, 3H), 3.90-4.18 (m, 4H), 4.68 (b, 1H), 4.88
~ 5.30 (b, 1H), 5.16 (s, 2H), 6.68 ~ 7.68 (m, 7H), 8.44 (m,
1H) (4) 1-ethyl-2- [N- (2-methoxy) benzoy
Ru-N- ｛2-methoxy-3- (3-octadecylcal
Bamoyloxy) propylcarbamoyloxy @ propo
Xycarbonyl] aminomethylpyridinium chloride

[0283]

Embedded image

3-O- {N- (2-methoxy) benzoyl-N- (2-pyridyl) methyl} carbamoyl-2-O-methyl-1-O- (3-octadecylcarbamoyl obtained in (3) (Oxy) propylcarbamoylglycerin 3.
0 g was dissolved in 60 ml of ethyl iodide, and the mixture was refluxed for 48 hours in a nitrogen atmosphere while protecting from light. After cooling, the solvent was distilled off and the residue ion exchange resin [Amberlite IRA-410, Cl ^- type] (eluent: methanol: water = 7: 3) then treated with silica gel column chromatography (solvent; Purification with methanol: methylene chloride = 1: 9) yielded 2.8 g of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 0.88 (m, 3
H), 1.02-1.42 (m, 34H), 1.78 (t, J = 7Hz, 3H), 3.04-3.9
0 (m, 7H), 3.23 (s, 3H), 3.92 (s, 3H), 4.00 to 4.24 (m, 4H),
4.88 to 5.10 (b, 1H), 5.30 (m, 2H), 5.48 to 5.76 (b, 1H), 5.
59 (s, 2H), 6.92 to 7.20 (m, 2H), 7.40 to 7.65 (m, 2H), 8.01
8.28.26 (m, 2H), 8.36 to 8.64 (m, 1H), 10.20 to 10.40
(M, 1H)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/535 ABF A61K 31/535 ABF ABS ABS C07D 401/12 207 C07D 401/12 207 405/12 213 405/12 213 409 / 12 213 409/12 213 // (C07D 405/12 213: 40 307: 06) (72) Inventor Tetsuya Kawahara 2-23-5, Akumabo, Tsukuba, Ibaraki Pref. Maison Gakuen No. 304 (72) Inventor Nobuya Abe 1083-44, Meka-cho, Ushiku City, Ibaraki Prefecture (72) Inventor Shuhei Miyazawa 6-8-17 Shirayama Boreyama, Toride City, Ibaraki Prefecture (202) Mitsuaki Miyamoto 1-4-5 Nakatakatsu, Tsuchiura City, Ibaraki Prefecture (72) ) Inventor Hiroyuki Yoshimura 4-4-18 Ninomiya, Tsukuba, Ibaraki Prefecture Sunny Hill Terrace No. 301 (72) Inventor Kokichi Harada 2-11-2, Matsushiro, Tsukuba, Ibaraki Prefecture Greenha Im 3rd Building No.2 (72) Inventor Junsaku Nagaoka 1803-1 Kanada, Tsukuba City, Ibaraki Prefecture (72) Inventor Riki Kawada 2-16-23 Chuo, Tsuchiura-shi, Ibaraki Prefecture Kamejo Heights 25 (72) Inventor Tsutomu Yoshimura 2-7-18 Sengen, Tsukuba City, Ibaraki Prefecture Hosoda House No.4 Building (72) Inventor Hiromasa Suzuki 1-3-10 Daijuku, Toride City, Ibaraki Prefecture (72) Inventor Shigeru Shioda, 972-16 Ushikucho, Ushiku City, Ibaraki Prefecture ( 72) Inventor Yoshimasa Machida 500-81 Shimohirooka, Tsukuba-city, Ibaraki Pref. (72) Inventor Koichi Katayama 2- 30-3 Umezono, Tsukuba-shi, Ibaraki Pref. References JP-A-60-243047 (JP, A) JP-A-60-158172 (JP, A) JP-A-61-293954 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB Name) C07D 213/00-213/40 A61K 31/00-31/535 C07D 401/00-401/12 C07D 405/00-405/12 C07D 409/00-409/12 CA (STN) REGISTRY (STN)

Claims (22)

(57) [Claims] 1. A compound of the general formula (I) A In the formula, A is (In the formula, m represents an integer of 0 to 6, and R ² , R ³ , and R ⁴ represent the same or different hydrogen atoms or lower alkoxy groups.)
A group represented by the formula: (Wherein p represents an integer of 0 to 6, and R ⁵ represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group or an arylalkyl group). ) formula ^{_{-NH- (CH 2) q -R 6}} ( wherein, q is an integer of 0 to 6, a group R ⁶ is represented by means an aryl group or a heteroaryl group), (4) -NH- (CH ₂₎ (wherein, r is then an integer of Less than six, R ⁷ denotes an alkyl group) _r -OR ⁷ group shown by, embedded image (Wherein, s represents an integer of 0 to 20, and R ⁸ and R ⁹ represent the same or different hydrogen atoms and lower alkyl groups). (Wherein, t represents an integer of 0 to 6, and R ¹⁰ represents a hydrogen atom or a lower alkoxycarbonyl group). (Wherein, u represents an integer of 0 to 6, R ¹¹ and R ¹² represent the same or different hydrogen atoms and lower alkyl groups, and
¹¹ and R ¹² may together form a ring that may contain an oxygen atom. Groups represented by), (8) _{-NH- (CH 2) v -O- (} CH 2) w -
O- _{(CH 2)} x -H _(wherein, v denotes an integer of 1-10, w denotes an integer of 1-10, x is an integer of 1 to 10) represented by the group , (In the formula, y represents an integer of 0 to 6, and R ¹³ represents a hydrogen atom or an alkyl group), or a group represented by the following formula: (Wherein, z represents an integer of 0 to 6, a represents an integer of 3 to 4, and D represents an oxygen atom, a sulfur atom or a nitrogen atom). B represents a lower alkyl group or an arylalkyl group. R ¹ represents an acyl group. n means the integer of 0-3. Embedded image Or a pharmaceutically acceptable salt thereof. 2. The pharmaceutically acceptable salt according to claim 1, wherein the pharmaceutically acceptable salt is a quaternary salt quaternized at the nitrogen atom of the pyridine ring in the definition of G. 3. A pharmacologically acceptable salt having the general formula: Awhere A is (In the formula, m represents an integer of 0 to 6, and R ² , R ³ , and R ⁴ represent the same or different hydrogen atoms or lower alkoxy groups.)
A group represented by the formula: (Wherein p represents an integer of 0 to 6, and R ⁵ represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group or an arylalkyl group). ) formula ^{_{-NH- (CH 2) q -R 6}} ( wherein, q is an integer of 0 to 6, a group R ⁶ is represented by means an aryl group or a heteroaryl group), (4) ^{_{-NH- (CH 2) r -OR 7}} ( wherein, r is then an integer of Less than six, R ⁷ denotes an alkyl group), a group represented by embedded image (Wherein, s represents an integer of 0 to 20, and R ⁸ and R ⁹ represent the same or different hydrogen atoms and lower alkyl groups). (Wherein, t represents an integer of 0 to 6, and R ¹⁰ represents a hydrogen atom or a lower alkoxycarbonyl group). (Wherein, u represents an integer of 0 to 6, R ¹¹ and R ¹² represent the same or different hydrogen atoms and lower alkyl groups, and
¹¹ and R ¹² may together form a ring that may contain an oxygen atom. ) Group represented by (8) _{-NH- (CH 2) v -O- (} CH 2) w -O- (CH 2) in _x -H (wherein, v denotes an integer of 1 to 10 , W represents an integer of 1 to 10, x represents an integer of 1 to 10), a group represented by the following formula: (In the formula, y represents an integer of 0 to 6, and R ¹³ represents a hydrogen atom or an alkyl group), or a group represented by the following formula: (Wherein, z represents an integer of 0 to 6, a represents an integer of 3 to 4, and D represents an oxygen atom, a sulfur atom or a nitrogen atom). B represents a lower alkyl group or an arylalkyl group. R ¹ represents an acyl group. n means the integer of 0-3. Embedded image (Wherein, R ¹⁴ represents a hydrogen atom or a lower alkyl group,
X represents a pharmacologically acceptable anion). A quaternary salt represented by｝
The pharmacologically acceptable salt as described. 4. The pharmacologically acceptable salt according to claim 3, wherein X is a halogen. 5. The pharmacologically acceptable salt according to claim 4, wherein X is chlorine. 6. A is a compound of the formula (Wherein, p represents an integer of 0 to 6, and R ⁵ represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group or an arylalkyl group). Item 6. The glycerin derivative according to any one of Items 1 to 5, or a pharmacologically acceptable salt thereof. 7. The glycerin derivative or the pharmaceutically acceptable salt thereof according to claim 6, wherein p is 1 and R ⁵ is an alkyl group having 14 to 22 carbon atoms. 8. A is a compound of the formula Wherein p ′ represents an integer of 1, R ^{5 ′} represents an alkyl group having 14 to 22 carbon atoms, B is a methyl group, R ¹ is o-, The glycerin derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the glycerin derivative is an m- or p-methoxybenzoyl group, and n is 1. 9. A is a compound of the formula (Wherein, y represents an integer of 0 to 6, and R ¹³ represents a hydrogen atom or an alkyl group).
The glycerin derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5. 10. A is a compound of the formula (Wherein, y represents an integer of 0 to 6, R ¹³ represents a hydrogen atom or an alkyl group), B is a methyl group, and R ¹ is o-, m- or The glycerin derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the glycerin derivative is a p-methoxybenzoyl group and n is 1. 11. The formula: The glycerin derivative or a pharmacologically acceptable salt thereof according to claim 1, which is represented by the formula: 12. The formula The glycerin derivative or a pharmacologically acceptable salt thereof according to claim 1, which is represented by the formula: 13. The formula: (Wherein, R ¹⁴ represents a hydrogen atom or a lower alkyl group,
X represents a pharmacologically acceptable anion). The pharmacologically acceptable salt according to claim 1, wherein 14. The formula: (Wherein, R ¹⁴ represents a hydrogen atom or a lower alkyl group,
X represents a pharmacologically acceptable anion). The pharmacologically acceptable salt according to claim 1, wherein 15. The method according to claim 13, wherein X is halogen.
4. The pharmacologically acceptable salt according to 4. 16. The pharmaceutically acceptable salt according to claim 13, wherein R ¹⁴ is an ethyl group and X is chlorine. 17. A compound of the general formula A In the formula, A is (In the formula, m represents an integer of 0 to 6, and R ² , R ³ , and R ⁴ represent the same or different hydrogen atoms or lower alkoxy groups.)
A group represented by the formula: (Wherein p represents an integer of 0 to 6, and R ⁵ represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group or an arylalkyl group). ) formula ^{_{-NH- (CH 2) q -R 6}} ( wherein, q is an integer of 0 to 6, a group R ⁶ is represented by means an aryl group or a heteroaryl group), (4) -NH- (CH ₂₎ (wherein, r is then an integer of Less than six, R ⁷ denotes an alkyl group) _r -OR ⁷ group shown by, embedded image (Wherein, s represents an integer of 0 to 20, and R ⁸ and R ⁹ represent the same or different hydrogen atoms and lower alkyl groups). (Wherein, t represents an integer of 0 to 6, and R ¹⁰ represents a hydrogen atom or a lower alkoxycarbonyl group). (Wherein, u represents an integer of 0 to 6, R ¹¹ and R ¹² represent the same or different hydrogen atoms and lower alkyl groups, and
¹¹ and R ¹² may together form a ring that may contain an oxygen atom. ) Group represented by (8) _{-NH- (CH 2) v -O- (} CH 2) w -O- (CH 2) in _x -H (wherein, v denotes an integer of 1 to 10 , W represents an integer of 1 to 10, x represents an integer of 1 to 10), a group represented by the following formula: (Wherein, y represents an integer of 0 to 6, and R ¹³ represents a hydrogen atom or an alkyl group), or a group represented by the following formula: (Wherein, z represents an integer of 0 to 6, a represents an integer of 3 to 4, and D represents an oxygen atom, a sulfur atom or a nitrogen atom). B represents a lower alkyl group or an arylalkyl group. R ¹ represents an acyl group. n means the integer of 0-3. Embedded image An anti-PAF agent comprising a glycerin derivative represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient. 18. A compound of the general formula A In the formula, A is (In the formula, m represents an integer of 0 to 6, and R ² , R ³ , and R ⁴ represent the same or different hydrogen atoms or lower alkoxy groups.)
A group represented by the formula: (Wherein p represents an integer of 0 to 6, and R ⁵ represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group or an arylalkyl group). ) formula ^{_{-NH- (CH 2) q -R 6}} ( wherein, q is an integer of 0 to 6, a group R ⁶ is represented by means an aryl group or a heteroaryl group), (4) A group represented by —NH— (CH ₂ ) _r —OR ⁷ (wherein, r represents an integer of 0 to 6 and R ⁷ represents an alkyl group); (Wherein, s represents an integer of 0 to 20, and R ⁸ and R ⁹ represent the same or different hydrogen atoms and lower alkyl groups). (Wherein, t represents an integer of 0 to 6, and R ¹⁰ represents a hydrogen atom or a lower alkoxycarbonyl group). (Wherein, u represents an integer of 0 to 6, R ¹¹ and R ¹² represent the same or different hydrogen atoms and lower alkyl groups, and
¹¹ and R ¹² may together form a ring that may contain an oxygen atom. ) Group represented by (8) _{-NH- (CH 2) v -O- (} CH 2) w -O- (CH 2) in _x -H (wherein, v denotes an integer of 1 to 10 , W represents an integer of 1 to 10, x represents an integer of 1 to 10), a group represented by the following formula: (In the formula, y represents an integer of 0 to 6, and R ¹³ represents a hydrogen atom or an alkyl group). (Wherein, z represents an integer of 0 to 6, a represents an integer of 3 to 4, and D represents an oxygen atom, a sulfur atom or a nitrogen atom). B represents a lower alkyl group or an arylalkyl group. R ¹ represents an acyl group. n means the integer of 0-3. Embedded image A therapeutic or prophylactic agent for a disease in which an anti-PAF agent is effective, comprising a glycerin derivative represented by the formula or a pharmaceutically acceptable salt thereof as an active ingredient. 19. A pharmaceutically acceptable salt wherein the pyridine ring in the definition of G has the formula (Wherein, R ¹⁴ represents a hydrogen atom or a lower alkyl group,
X represents a pharmacologically acceptable anion), and is a quaternary salt represented by the formula (1):
Prophylactic agent. 20. The disease according to claim 18 or 1, wherein the disease is DIC.
9. The therapeutic / prophylactic agent according to 9. 21. The therapeutic or prophylactic agent according to claim 18, wherein the disease is shock. 22. The method according to claim 1, wherein the disease is an allergic disease.
20. The therapeutic or prophylactic agent according to 8 or 19.