JP2824536B2 - Pyridinium derivatives - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a pyridinium derivative useful as a medicament.
You. More specifically, the invention relates to platelet activating factor (PAF)
Formulas useful as antagonists[Where,Represents an optionally substituted pyridinium ring, and R¹Is low
Represents a lower alkyl group or an aralkyl group;⁷, R^TenAnd R
¹¹Is hydrogen, lower alkyl group, aryl group or
Represents an aralkyl group; l represents 0 or 1;^FiveIs Fe
Represents a nylene group or an optionally substituted alkylene group
Then R¹²Is the expression(Where R¹³, R¹⁴, R^Fifteen, R¹⁶And R¹⁷Is hydrogen
Or a lower alkyl group;¹⁶And R¹⁷Are combined
Which may form a benzene ring),
n ′ represents an integer of 1 to 3, and X represents a formula —CH_TwoOCH_Two− Or expression(Where R⁶Is hydrogen, lower alkyl group or alkoxy group
And m represents an integer of 0 to 4).
And U is the formula(Where R^FourIs hydrogen, lower alkyl group, aryl group or
Represents an aralkyl group), Y and
Z is the formula-CO-, -S- and -SO_Two-(Where R is hydrogen, lower
Alkyl group. Represents an acyl group or an aryl group)
A divalent chain group consisting of 1 to 6 groups selected from
Where at least one is of the formulaIs a group represented by the formulaWhen there are two or more groups represented by
And R may be different from each other,
Y may be the formulaWhen a group represented by is represented by R^FourMay be combined with
No. Also, W Represents an anion.]
About.

(Problems to be Solved by the Prior Art and the Invention) PAF is a chemical mediator having a phospholipid structure and existing in a living body. PAF has been shown to be closely involved in allergy, anaphylaxis, inflammation, and the like in vivo, and is known to have a strong blood pressure lowering action and a platelet aggregation action. When PAF is administered to animals, the animals may exhibit shock symptoms and even die. The shock symptoms caused by PAF are very similar to those caused by endotoxin, and it has been shown that PAF is involved in endotoxin shock.

On the other hand, although various compounds having PAF antagonism are known, very few compounds are satisfactory in PAF antagonism in vivo. Also, PA in vivo
Even if the F-antagonism is satisfactory, there are many compounds that are restricted in the administration method.

(Means for Solving the Problems) The present invention provides a pyridinium derivative represented by the above formula (I).

In the formula (I), a group Represents an optionally substituted pyridinium ring. A group R ¹ is bonded to position 1 of the pyridinium ring, and a side chain is located at any of positions 2 to 6. Are combined. The pyridinium ring may be, for example, a halogeno group, a lower alkyl group,
1 to 4 (preferably 1 to 2) substituents such as a lower alkoxy group, a nitro group, a cyano group, a lower alkoxycarbonyl group, a carbamoyl group and a lower alkylcarbamoyl group.
) May be present, or an aroma may be bonded. The side chain is preferably bonded to positions 2 to 4 of the pyridinium ring, and the substituent is preferably bonded to one or two of positions 3 to 5 of the pyridinium ring.

^{R 1, R 4, R 6} , R 7, R 10, R 11, R 13, R 14, R 15, R 16, R
Examples of the lower alkyl group as a substituent on the ¹⁷ or pyridinium ring include linear or branched carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. Alkyl groups of about 1 to 6 are mentioned. The lower alkyl group may have an unsaturated bond. Examples of the unsaturated lower alkyl group include vinyl and allyl.
l) Lower alkenyl groups having about 2 to 6 carbon atoms, such as 2,2-butenyl and 3-butenyl.

Examples of the lower alkoxy group as a substituent on R ⁶ or a pyridinium ring include straight-chain or branched alkoxy groups having about 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy and the like. Can be

The lower alkoxy group as R ⁶ may have a substituent, and the substituent may be bonded to form a 5- to 7-membered heterocycle (eg, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, etc.). The hetero ring may be substituted with, for example, a lower alkyl group, an acyl group, an aryl group, an aralkyl group and the like.

Examples of the halogeno group as a substituent on the pyridinium ring include, for example, fluoro, bromo, chloro, iodo and the like.

Examples of the lower alkoxycarbonyl group as a substituent on the pyridinium ring include an alkoxycarbonyl group having about 1 to 6 carbon atoms in the alkoxy moiety such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like.

The lower alkylcarbamoyl group as a substituent on the pyridinium ring includes, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl and the like, in which the alkyl moiety has about 1 to 6 carbon atoms.
-Alkylcarbamoyl groups and N, N-dialkylcarbamoyl groups in which each alkyl moiety has about 1 to 6 carbon atoms, such as dimethylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl and methylethylcarbamoyl.

The aryl group as R ⁴ , R ⁷ , R ¹⁰ or R ¹¹ includes, for example, aromatic monocyclic, bicyclic or tricyclic carbons such as phenyl, 1-naphthyl, 2-naphthyl, phenanthryl and anthryl. Hydrogen residues such as thienyl,
Examples include aromatic monocyclic or bicyclic heterocycles such as furyl, benzothienyl and benzofuranyl. The aryl group may have a substituent such as a halogeno group, a lower alkyl group, a lower alkoxy group, a nitro group, a cyano group, an oxo group, a hydroxy group, an amino group, a lower alkoxycarbonyl group, a carbamoyl group or a lower alkylcarbamoyl group.
To 4 (preferably 1 or 2).
Examples of the halogeno group include fluoro, bromo, chloro, and iodo. The lower alkyl group has 1 to 1 carbon atoms.
About 6 alkyl groups are mentioned, and the lower alkyl group may have an unsaturated bond. Examples of the lower alkyl group having an unsaturated bond include lower alkenyl groups having about 2 to 6 carbon atoms. Specific examples of the alkyl group having about 1 to 6 carbon atoms and the lower alkenyl group having about 2 to 6 carbon atoms include the same groups as the lower alkyl groups as the substituents for the pyridinium ring. Examples of the lower alkoxy group include an alkoxy group having about 1 to 6 carbon atoms, examples of the lower alkoxycarbonyl group include an alkoxycarbonyl group having about 1 to 6 carbon atoms in the alkoxy moiety, and examples of the lower alkylcarbamoyl group include an alkyl group. N-alkylcarbamoyl group having about 1 to 6 carbon atoms and N, N- having about 1 to 6 carbon atoms in each alkyl moiety
And dialkylcarbamoyl groups. Specific examples of these groups include the same groups as the lower alkoxy, lower alkoxycarbonyl, and lower alkylcarbamoyl groups as the substituents on the pyridinium ring. Examples of the aryl group having an oxo group include benzoquinonyl, naphthoquinonyl, anthraquinonyl and the like.

As the aralkyl group as R ¹ , R ⁴ , R ⁷ , R ¹⁰ or R ^11, for example, the alkyl part such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl and the like has 1 to 1 carbon atoms.
A phenyl-lower alkyl group having about 6 carbon atoms, a naphthyl-alkyl group having (1-naphthyl) methyl, 2- (1-naphthyl) ethyl and 2- (2-naphthyl) ethyl having about 1 to 6 carbon atoms; And lower alkyl groups. The phenyl part of the phenyl-lower alkyl group and the naphthyl part of the naphthyl-lower alkyl group may be, for example, a halogeno group, a lower alkyl group, a lower alkoxy group, a nitro group, a cyano group,
1 to 4 (preferably 1 or 2) substituents such as an oxo group, a hydroxy group, an amino group, a lower alkoxycarbamoyl group, a carbamoyl group and a lower alkylcarbamoyl group.
). Examples of these substituents include the same groups as those described above for the aryl group.

As the phenylene group as R ⁵ , o-phenylene (1,
2-phenylene), m-phenylene (1,3-phenylene) and p-phenylene (1,4-phenylene).

Examples of the alkylene group as R ⁵ include methylene,
Examples thereof include an alkylene group having about 1 to 6 carbon atoms such as ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene. The alkylene group has a substituent such as a lower alkyl group having about 1 to 5 carbon atoms. Is also good.

As the divalent chain group represented by Y, for example, [Wherein, n represents 1 or 2, R ² and R ³ each represent hydrogen, a lower alkyl group, an acyl group or an aryl group, and R ² may combine with R ⁴ to form a ring] And a divalent functional group represented by

As the divalent chain group represented by Z, for example, [Wherein, n represents 1 or 2, R ⁸ and R ⁹ each represent hydrogen, a lower alkyl group, an acyl group or an aryl group].

Examples of the lower alkyl group as R, R ² , R ³ , R ⁸ or R ⁹ include straight-chain or branched groups such as methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. Alkyl group having about 1 to 6 carbon atoms. The lower alkyl group may have an unsaturated bond, and examples of the unsaturated lower alkyl group include lower alkenyl groups having about 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl and 3-butenyl. Can be

Examples of the acyl group as R, R ² , R ³ , R ⁸ or R ⁹ include lower alkanoyl having about 2 to 6 carbon atoms such as acetyl, propanoyl, butyryl, and pivaloyl, and aromatic carbonyl (eg, benzoyl). Can be

Examples of the aryl group as R, R ² , R ³ , R ⁸ or R ⁹ include aromatic monocyclic, bicyclic or tricyclic hydrocarbons such as phenyl, 1-naphthyl, 2-naphthyl, phenanthryl and anthryl Residues include, for example, aromatic monocyclic or bicyclic heterocycles such as thienyl, furyl, benzothienyl, benzofuranyl. The aryl group may have a substituent such as a halogeno group, a lower alkyl group, a lower alkoxy group, a nitro group, a cyano group, an oxo group, a hydroxy group, an amino group, a lower alkoxycarbonyl group, a carbamoyl group or a lower alkylcarbamoyl group. It may have four (preferably one or two). Examples of the halogeno group include fluoro, bromo, chloro, and iodo. Examples of the lower alkyl group include an alkyl group having about 1 to 6 carbon atoms, and the lower alkyl group may have an unsaturated bond. Examples of the lower alkyl group having an unsaturated bond include lower alkenyl groups having about 2 to 6 carbon atoms. Specific examples of the alkyl group having about 1 to 6 carbon atoms and the lower alkenyl group having about 2 to 6 carbon atoms include the same groups as the lower alkyl groups as the substituents for the pyridinium ring. The lower alkoxy group includes an alkoxy group having about 1 to 6 carbon atoms, the lower alkoxycarbonyl group includes an alkoxycarbonyl group having about 1 to 6 carbon atoms in the alkoxy moiety, and the lower alkylcarbamoyl group includes an alkyl group. Part of which has 1 to
An N-alkylcarbamoyl group having about 6 and an N, N-dialkylcarbamoyl group having about 1 to 6 carbon atoms in each alkyl portion are exemplified. Specific examples of these groups include the same groups as the lower alkoxy, lower alkoxycarbonyl, and lower alkylcarbamoyl groups as the substituents on the pyridinium ring.

U is the formula In the case of a group represented by, R ² and R ⁴ may combine to form a ring. In particular as [Wherein p and q each represent 2 or 3].

m is preferably 0 or 1, and n 'is preferably 1. When n 'is 2 or 3, R ¹¹ as a substituent may be the same or different, and R ¹¹ may combine with each other to form a double bond to form a double bond. A group represented by the alkylene group which may be substituted may indicate (e.g., -CH ₂ -CH = CH-, etc.).

Pyridinium ring fused with aromatic ring Examples thereof include a quinolinium group and an isoquinolinium group.

 W As an anion, for example, chloride
Ion, bromide ion, iodide ion, sulfate ion
Anions of inorganic acids such as on, nitrate and phosphate ions
, Acetate ion, tosylate ion, mesylate ion
Pharmacologically acceptable such as anions of organic acids
Anions are listed, and among them, nitrate ion
Is preferred.

Formula as R ¹² R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ^{17 in the} group represented by
May be the same or different, and among them, a group in which R ¹³ and R ¹⁴ are the same is preferable, and further, R ¹⁵ and R ¹⁶
And groups in which R ¹⁷ is the same.

 In a preferred embodiment among the above compounds, the formula[Where R¹Represents a lower alkyl group, R^FourIs substituted with a halogeno group
A phenyl group which may be^FiveIs an ethylene group or
The trimethylene group is replaced by R¹⁸Represents a halogeno group, and X represents a group represented by the formula-(C
H_Two)_m-(Where m represents 0 or 1), Is halo
Geno ion or nitrate ion, Y is, R¹³, R¹⁴, R^Fifteen, R¹⁶And R¹⁷Is hydrogen or
Which represents a lower alkyl group].
You.

The compound (I) may have an asymmetric carbon in the molecule, but when two kinds of stereoisomers of R-coordination and S-coordination exist, each of them or a mixture thereof is used in the present invention. Is included.

The pyridinium derivative of the present invention can be synthesized, for example, by the following method.

(A) formula [Where, Represents a pyridium ring which may be substituted, and other symbols have the same meanings as defined above, and a compound represented by the formula R ¹ -Q ¹ (III) wherein Q ¹ is a group which easily substitutes for a nitrogen atom (Eg, a halogeno group such as chloro, bromo, iodo, etc., a toluenesulfonyloxy group, a methanesulfonyloxy group, etc.).

And the same as the substituent for the pyridinium ring represented by.

(B) formula [Wherein A represents -NR ⁴ -or -O-, and other symbols are as defined above] and a compound represented by the formula Wherein, B is -CO- or -SO ₂ - indicates, the other symbols the same meanings as defined] subjecting a compound represented by the dehydration condensation reaction.

(C) formula [Where E ¹ is And the other symbols are as defined above. [Where Q ² is (Wherein Ph represents a phenyl group and G represents a halogeno group such as chloro), and the other symbols are as defined above. [In the formula (I), l is 1,
Y is (D) formula [Where Q ³ is (Wherein, G represents a halogeno group such as chloro).
And other symbols are as defined above. [Where E ² is And the other symbols are as defined above]. [In the formula (I), 1 is 1, Y is Equation (E) [Where E ³ is And the other symbols have the same meanings as defined above. [Where Q ⁴ is (Wherein, G represents a halogeno group such as chloro).
R ¹¹ , R ¹² and n ′ are as defined above]. [In the formula (I), Z is Formula (F) [Where Q ⁵ is (Wherein, G represents a halogeno group such as chloro).
And other symbols are as defined above. [Where E ⁴ is And R ¹¹ , R ¹² and n ′ are as defined above]. [In the formula (I), Z is (G) The compound represented by the formula (IV) has the formula [Wherein Q ⁶ represents a halogeno group (eg, chloro, bromo), and the other symbols are as defined above].

The reaction of compound (II) with compound (III) in method A is carried out in the presence or absence of a solvent at 0 ° to + 200 ° C. using 1 equivalent to a large excess of compound (III) relative to compound (II). be able to. Examples of the solvent include toluene, benzene, ether, dioxane, tetrahydrofuran and the like, and compound (III) itself can be used as the solvent. The reaction may be performed in a sealed tube under heating.

The dehydration condensation reaction of the compounds (IV) and (V) in the method B can be carried out, for example, by a usual amide and ester condensation forming reaction. That is, 1-ethoxycarbonyl-2ethoxy-1,2-dihydroquinoline, dicyclohexylcarbodiimide, 1-cyclohexyl-3
-(2-morpholinoethyl) carbodiimide meso-p
-Toluenesulfonate, N, N-carbonyldiimidazole, diphenylphosphoric amide, diethyl cyanophosphate, 1
Amide and ester forming reagents such as -ethyl-3- (3-diethylaminopropyl) carbodiimide hydrochloride are used alone or compound (V)
For example, phenols such as 2,4,5-trichlorophenol, pentachlorophenol, pentafluorophenol, 2-nitrophenol or 4-nitrophenol or N-hydroxysuccinimide, 1-hydroxybenztriazole, N-hydroxypiperidine, N N-hydroxy compound such as -hydroxy-5-norbornene-2,3-dicarbodiimide is condensed in the presence of a catalyst such as dicyclohexylcarbodiimide to be converted into an active ester form, and then reacted with compound (IV), or The reaction can be carried out by reacting the compound (V) with an acid chloride such as ethyl chlorocarbonate, isobutyl chlorocarbonate or benzyl chlorocarbonate to convert it to a mixed acid anhydride and then reacting with the compound (IV). In the present amide and ester bonding reaction, compound (V) can be used as it is or as compound (V).
In any case where the compound (IV) is reacted with the compound (IV) after conversion into an active ester or a mixed acid anhydride, an organic base such as a tertiary amine (eg, triethylamine, pyridine, dimethylpyridine, N-methylpiperidine) is preferred. Can be promoted. The reaction is carried out at −30 ° to + 50 ° C. in a solvent (eg, ether, toluene, benzene, chloroform, dichloromethane, dioxane,
(Tetrahydrofuran) or in the absence of a solvent.

The reaction of the compounds (VI) and (VII) in the method C can be carried out in the absence or presence of a solvent (eg, ether, toluene, benzene, chloroform, dichloromethane, dioxane, tetrahydrofuran, dimethylformamide) at -10 °
Performed at + 150 ° C. Tertiary amines (eg, triethylamine, pyridine, dimethylaminopyridine, N-methylpiperidine) may be added to accelerate the reaction.
When Q ² is —NCO, boron trifluoride ethyl ether (BF ₃ .Et ₂ O) may be added as a catalyst.

The reaction between the compounds (VIII) and (IX) in the method D, the reaction between the compounds (X) and (XI) in the method E, and the reaction between the compounds (XII) and (XIII) in the method F are carried out using the compound (V
The reaction is carried out under the same conditions as the reaction conditions of (I) and (VII).

The reaction of compound (IV) with compound (XIV) in Method G is carried out in the presence or absence of a solvent (eg, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, benzene, toluene, ethyl acetate, chloroform, dichloromethane). −20
Performed at ° to + 150 ° C. At this time, a base such as potassium carbonate, sodium hydroxide, sodium hydrogen carbonate, pyridine, triethylamine and the like can be coexisted in the reaction system for the purpose of accelerating the reaction rate.

Compound (II) is, for example, (i) compound (IV) [Wherein the symbols are as defined above], by subjecting the compound represented by the formula (ii) to a compound (IV) and a compound represented by the formula [Wherein each symbol is as defined above], by reacting the compound (iii) with a compound (VI) [Wherein each symbol is as defined above], by reacting the compound (iv) with a compound (VIII) Wherein each symbol is as defined above, by reacting the compound represented by (v) [Wherein each symbol is as defined above] and compound (XI), or (vi) [Wherein the symbols are as defined above], and the compound (XIII).

The reaction between compound (IV) and (XV) is performed by compound (IV) and (V)
The reaction is performed in the same manner as in the above reaction. Compounds (IV) and (XVI)
Is carried out in the same manner as in the reaction of compounds (IV) and (XIV). Reaction of compound (VI) with (XVII), compound (VII
The reaction between I) and (XVIII), the reaction between compounds (XIX) and (XI), and the reaction between compounds (XX) and (XIII) are performed in the same manner as the reaction between compounds (VI) and (VII).

Compound (VI) can be obtained, for example, by the method shown below.

[Wherein T ² is a protecting group (eg, a protecting group for a hydroxy group such as diphenylmethyl, trifluoroacetyl, 2-tetrahydropyranyl, trityl, benzyl, etc.) and a mercapto group; benzyloxycarbonyl, tert-butoxycarbonyl, trifluoro A protecting group for an amino group such as acetyl, trityl and benzyl), G represents a halogeno group such as chloro and bromo, and the other symbols have the same meanings as described above.] Reaction of compound (XXI) with (XI), compound ( The reaction between (XXIII) and (XIII) and the reaction between compounds (XXIV) and (XXV) are carried out under the same conditions as for the reaction between compounds (VI) and (VII) in the above-mentioned Method C.

Compound (IV) can be obtained, for example, by the method shown below.

[Wherein T ¹ is a protecting group (benzyloxycarbonyl, tert.
-Butoxycarbonyl, trifluoroacetyl, trityl, benzyl, etc.), and other symbols are as defined above.] Reaction of compounds (VI) and (XVII), reaction of compounds (VIII) and (XXIX) Reaction of compounds (XXX) and (XI), reaction of compounds (XXXII) and (XIII) and compound (XXXIII)
The reaction of (XXV) with the compound (VI) and (V
The reaction is carried out under the same conditions as in II).

Compounds (IX) and (XVIII) can be obtained, for example, by the following method.

The reaction between the compounds (XXXV) and (XVI) is carried out under the same conditions as the reaction conditions for the compounds (IV) and (XIV) in the method G, and the reaction between the compounds (XVIII) and (III) is the same as the method A Under the same conditions as in the reaction of compounds (II) and (III).

Compounds (X) and (XIX) can be obtained, for example, by the following method.

[Wherein T ³ is a protecting group (eg, a protecting group for a hydroxy group such as diphenylmethyl, trifluoroacetyl, 2-tetrahydropyranyl, trityl, benzyl, etc.) and a mercapto group; benzyloxycarbonyl, tert-butoxycarbonyl, trifluoro Acetyl, trityl, benzyl and the like), and other symbols are as defined above. The reaction between compound (XXXVII) and (XVII) is the same as that of compound (VI) and (VII) in the above-mentioned Method C. The reaction between compound (XXXVIII) and (III) is carried out under the same conditions as the reaction conditions between compound (II) and compound (III) in Method A described above. The reaction between compound (XL) and (XVI) is carried out under the same conditions as the reaction conditions between compound (IV) and (XIV) in the above-mentioned Method G, and the reaction between compound (XLI) and (III) The reaction is carried out under the same conditions as the reaction between the compounds (II) and (III).

Compounds (XII) and (XX) can be obtained, for example, by the following method.

Wherein Q ⁵ ′ is a protected amino group (eg, benzyloxycarbonylamino, tert-butoxycarbonylamino, trifluoroacetamino, tritylamino, benzylamino, phthalimide), a protected hydroxy group (eg, diphenyl Methyloxy, trifluoroacetoxy, 2-tetrahydropyranyloxy, trityloxy,
Benzyloxy), protected mercapto group (eg, diphenylmethylthio, trifluoroacetylthio, 2-tetrahydropyranylthio, tritylthio, benzylthio), protected carboxyl group (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.) Represents the lower (C _1-6 ) alkoxycarbonyl, benzyloxycarbonyl), and the other symbols are as defined above. The reaction between compound (XLIII) and (XVII) is the same as in compound (VI) and (VII The reaction of compound (XLIV) with (III) under the same conditions as the reaction conditions with compound (II) and (III) in the above-mentioned Method A, The reaction between (XLVI) and (XVI) is carried out under the same conditions as the reaction conditions between compound (IV) and (XIV) in Method G described above.

The reaction of Q ⁵ ′ → Q ⁵ is performed by the following method after removing the protecting group.

After removal of the protecting group, Q ⁵ ′ Or a compound (XLIV), (XLV) or (XLVII) which is -SH
Alternatively, (XLVIII) is reacted with carbonyl halide such as phosgene.

After removing the protecting group, the compound wherein Q ⁵ ′ is —OH (XLI
V), (XLV), (XLVII) or (XLVIII) are reacted with phenyl chlorocarbonate.

After removal of the protecting group, compounds (XLIV), (XLV), (XLVII) or (XLVII) wherein Q ⁵ ′ is —COOH or —SO ₃ H
I) is reacted with a phosphorus halide such as phosphorus trichloride or phosphorus pentachloride or a thionyl halide such as thionyl chloride.

(Iv) Q ⁵ = -NCO The compound wherein Q ⁵ 'is -NH ₂ after removing the protecting group (XLI
V), (XLV), (XLVII) or (XLVIII) is reacted with phosgene, and further heated to remove hydrochloric acid.

These reactions are all publicly known reactions and can be performed according to those conditions.

The reaction for removing the protecting group can be performed by a method known per se. That is, a benzyloxycarbonyl group, a benzyl group, and a diphenylmethyl group are subjected to a catalytic reduction reaction in a solvent (eg, alcohol, acetic acid, water, tetrahydrofuran, and a mixed solvent thereof) in the presence of a catalyst (palladium carbon, platinum oxide, etc.). (Reaction temperature, room temperature to + 100 ° C). If a mercapto group causes poisoning of the catalyst, it can be removed with metallic sodium in liquid ammonia.

In the case of a trityl group, 2-tetrahydropyranyl group or tert-butoxycarbonyl group, in a solvent (eg, water, alcohol, tetrahydrofuran, dioxane, etc.), an acid (eg,
Mineral acids such as hydrochloric acid, phosphoric acid, and sulfuric acid, and organic acids such as toluenesulfonic acid, methanesulfonic acid, and acetic acid)
It can be removed from 0 ° to + 150 ° C. The trifluoroacetyl group can be easily removed by treating with an alkali (eg, sodium hydroxide, aqueous sodium hydrogen carbonate).

The phthalimide group can be removed by reacting with hydrazine hydrate in a solvent (eg, methanol, ethanol).

Separation and purification of compound (I) from the reaction mixture are carried out according to ordinary separation and purification means (eg, extraction, concentration, filtration, recrystallization, column chromatography, thin-layer chromatography).

 If necessary, the desired W Conversion to
You can also.

Note that R ¹² is the formula When both R ¹³ and R ¹⁴ represent hydrogen (in the case of hydroquinone type), R ¹² is easily oxidized to form a group represented by the formula To the quinone type group represented by

Also R ¹² is the formula In those compounds (I) is a group represented by a known oxidizing agent, for example Furemi salt (Fremy's salt), by using a cerium (IV) nitrate ammonium, R ¹² has the formula Can be easily converted to a quinone type compound (I) which is a group represented by

(Action) Compound (I) exhibits an excellent PAF antagonistic action, and circulatory disorders caused by PAF such as thrombosis, stroke (eg, cerebral hemorrhage, cerebral thrombosis), myocardial infarction, angina, thrombophlebitis, nephritis (Eg, glomerulonephritis), diabetic nephropathy, shock (eg, severe infection or postoperative endotoxin shock, intravascular coagulation syndrome caused by endotoxin, anaphylactic shock, hemorrhagic shock); PAF
Gastrointestinal illness (eg, stomach ulcer); diseases associated with allergy and inflammation (eg, bronchial asthma, psoriasis); pneumonia; rejection associated with increased PAF production during organ transplantation; organs (eg, heart, Prevention of organ failure at the time of surgery (liver, kidney)
Useful as a therapeutic. It can also be used for the purpose of suppressing the conception of female mammals by suppressing cell division and / or implantation into the uterus. Furthermore, the compound (I) has a lipid peroxide production inhibitory action, and the elimination action of reactive oxygen species by the compound (I) can be applied to the above diseases. Since compound (I) has low toxicity,
It can be orally or parenterally administered to mammals (eg, human, rabbit, dog, cat, rat, mouse, guinea pig) as a powder as it is or as a pharmaceutical composition in a suitable dosage form. . The dose varies depending on the administration subject, target disease, symptoms, administration route, and the like. For example, when used for prevention or treatment of adult shock, compound (I) is usually administered in a dose of 0.001 to 1.0 mg as a single dose. /kg
It is convenient to administer about body weight, preferably about 0.01 to 0.1 mg / kg body weight, by intravenous injection about 1 to 5 times a day, preferably about 1 to 3 times a day. Compound (I)
Can be administered by infusion at a dose of about 0.01 to 0.1 mg / kg body weight / min. For about 1 hour, about 1 to 5 times a day, preferably about 1 to 3 times a day. In the case of other parenteral administration and oral administration, an equivalent amount can be administered. If the shock symptoms are particularly severe, the dose may be increased according to the symptoms.

When orally administered for the prevention or treatment of diseases such as thrombosis, asthma and nephritis in adults, compound (I)
It is convenient to administer usually about 0.1 to 30 mg / kg body weight, preferably about 1 to 10 mg / kg body weight as a single dose, about 1 to 5 times a day, preferably about 1 to 3 times a day. In the case of other parenteral administration, an equivalent amount can be administered.

The pharmaceutical composition used for administration contains an effective amount of compound (I) and a pharmacologically acceptable carrier or excipient. The composition is in a dosage form suitable for oral or parenteral administration. Provided.

Compositions for oral administration include, for example, solid or liquid dosage forms, specifically tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules), Syrups, emulsions, suspensions and the like can be mentioned. Such a composition is produced by a method known per se and contains a carrier or excipient usually used in the field of pharmaceuticals. For example, carriers and excipients for tablets include lactose, starch, sucrose, magnesium stearate and the like. Compositions for parenteral administration include, for example, injections, suppositories, ointments,
Examples include poultices, liniments, and the like, and examples of the injectables include intravenous, subcutaneous, intradermal, intramuscular, and infusion dosage forms. Such injections are prepared by a method known per se, for example, by dissolving, suspending or emulsifying Compound (I) in a sterile aqueous or oily liquid usually used for injections. Aqueous solutions for injection include physiological saline, isotonic solutions containing glucose and other adjuvants, and suitable solubilizing agents such as alcohols (eg, ethanol) and polyalcohols (eg, propylene glycol, polyethylene glycol). ), Nonionic surfactants [eg polysorbate 80, HCO-50 (po
lyoxyethylene (50mol) adduct of hydrogenated casto
r oil)]. Examples of the oily liquid include sesame oil and soybean oil, and benzyl benzoate, benzyl alcohol and the like may be used in combination as a solubilizing agent.
The prepared injection is usually filled in an appropriate ampule and provided as an injection. Suppositories to be used for rectal administration are prepared by a method known per se, for example, by mixing compound (I) with a usual suppository base and molding.

Each of the above-mentioned compositions may contain other active ingredients as long as an undesirable interaction is not caused by compounding with the compound (I). For example, to a mammal suffering from an infection, compound (I) can be administered together with an antibiotic to prevent endotoxin shock.

Effect of the Invention The pyridinium derivative (I) of the present invention exhibits excellent PAF antagonistic activity even in oral administration. Therefore, the pyridinium derivative (I) can be administered orally in addition to parenteral administration such as administration by injection.

Hereinafter, the effects of the present invention will be described in more detail with reference to experimental examples.

Example 1 Platelet Aggregation Inhibitory Effect [Test Method] Blood was directly collected from male rabbits by cardiac puncture using a syringe containing 3.15% citric acid (1 to 9 blood) as an anticoagulant. Next, platelet-rich plasma (PRP) was obtained by centrifugation at 800 rpm for 10 minutes at room temperature. The remaining blood was further centrifuged at 3000 rpm for 10 minutes to separate platelet poor plasma (PPP) as a supernatant. P by PPP
RP was diluted to adjust the platelet count to about 500,000 / μl. 250 μl of this PRP was stirred at 37 ° C. for 2 minutes, the test drug was added, and the mixture was further stirred for 2 minutes, and then a predetermined concentration of PAF was added. Platelet aggregation was measured with a platelet aggregometer (manufactured by Rika Denki). The aggregation-inhibiting activity of the test drug was determined from the inhibition rate against the maximum light transmittance (maximum aggregation rate) by PAF in the control PRP.

[Results] Table 1 shows the results.

Example 2 Inhibitory effect on PAF hypotension in rats [Test method] Male Sprague-Dawley rats weighing about 250 g were used.
A cannula was inserted and fixed in the unilateral hip artery for blood pressure measurement and in the unilateral hip vein for drug administration. Blood pressure was measured via a pressure transducer and recorded on a polygraph. First, PAF 1 μg / kg is administered intravenously (iv) to determine the degree of decrease in blood pressure, and then the test drug is administered intravenously or orally.
Intravenous administration of 1 μg / Kg of PAF at 5 μm, 1, 2, 4, 6, 8 hours after intravenous administration and 1, 2, 4, 6, 8 hours after oral administration to lower blood pressure I checked the degree.

[Results] The inhibitory effect on PAF hypotension was expressed (% suppressed) as the ratio of the PAF hypotensive (ΔmmHg) after drug administration to the PAF hypotensive (ΔmmHg) before administration of the test drug. The results are shown in Tables 2 and 3.

Experimental Example 3 Rat Reverse Passive Arthus Reaction [Test method] Male Sprague-Dawley rats (7
(Weekly, body weight: about 250 g) The back was shaved, and a physiological saline solution of the test drug was administered into the tail vein in an amount of 0.2 ml per 100 g of body weight. Immediately antigen antigen albumin 0.5% saline solution (1ml)
Was administered via the tail vein. Immediately thereafter, 0.1 ml of rabbit anti-egg albumin serum (containing 6 mg of protein antibody / ml) was intradermally administered to the left and right sides of the rat one point at a time.
After 3 hours, 1 ml of 1% Evans Blue saline solution
Was administered intravenously, the skin was peeled off 30 minutes later, the area of the blue spot (mm ² ) was measured, and the inhibition rate was determined in comparison with the group to which no drug was administered.

[Results] In this test, the compound produced in Production Example 2 showed an inhibitory effect by intravenous administration, and its ID ₅₀ value was 2.6 μg / kg.

Experimental Example 4 PAF Inhibitory Effect on Airway Stenosis Male and female Hartley guinea pigs weighing about 400 g were used. Urethane (1.5g / kg, intraperitoneal)
One cannula (four legs) is inserted into the trachea, and two of the other three legs are placed on a respirator (Harvard apparatus rodent res).
pirator). Bronchosp the remaining monopod (side branch)
It was linked to an asm transducer 7020 (Ugobasile). 5-7 ml of air per time, air supply frequency 70 times / min, load pressure on lung 10cm H ₂ O
And the amount of air that overflows via the transducer Recti
The data was recorded on a graph (Rectigraph-8S, Sanei Sokki). Gallamine triethodide (1mg
After treatment, histamine dihydrochloride (10 μg / kg) was administered intravenously, and the reactivity of the animals was examined. PAF (0.3μg / k
g) After intravenous administration, a maximal airway constriction reaction was observed 30 seconds later. Under these conditions, the inhibitory effect of the subject was examined.
For oral administration, subjects were suspended in a 5% gum arabic solution and administered 1 hour before PAF administration. For intravenous administration, subjects were dissolved in saline and administered 2 minutes before PAF administration.

[Results] Tables 4 and 5 show the results of the guinea pig airway stricture inhibitory effect of the test drug in intravenous administration and oral administration, respectively.

Experimental Example 5 Lipid Peroxide Production Inhibition The production of lipid peroxide using brain homogenate was performed according to the method of Stocks et al. [Clin. Sci. Mol. Med., 47 , 215-222 (1974)]. That is, Wistar rats (male, 1
(0-week-old) was decapitated, the brain tissue was taken out, and a four-fold amount of phosphate buffered saline (pH 7.5, 100 mM) was added and homogenized. The obtained homogenate was centrifuged (2,700 rpm, 10
The supernatant was diluted 3-fold with the same buffer (protein concentration, about 50 mg / ml). 1 ml thereof was transferred to a 10 ml test tube, and ethanol solutions (10 μl) of various concentrations of the test compound were added. After mixing, the mixture was incubated at 37 ° C. for 1 hour. The reaction was stopped by adding 35% perchloric acid (200 μl), and after centrifugation (3,000 rpm, 10 minutes), the lipid peroxide in the supernatant was
Hkawa et al. [Anal. Biochem, 95 , 351-358 (1979)]
Quantified by That is, thiobarbituric acid (0.67%, 0.5 ml) dissolved in 50% acetic acid was added to 0.5 ml of the supernatant, and 95%
Heated at ° C for 60 minutes. After cooling in ice water, the absorbance at 532 nm was measured with a spectrophotometer. From the absorbance at each concentration of the test substance, calculate the lipid peroxide production inhibition rate,
The results are shown in Table 6.

[result] Experimental Example 6 Active oxygen production inhibitory activity [Method] 16% Triton-X- in 0.2 ml of 0.5 M phosphate buffer (pH 7.8)
100 0.1 ml, 1 mM EDTA · 2Na 0.1 ml, 0.8 mM neotetrazolium chloride 0.3 ml, water 1.10 ml, compound 0.02 ml, xanthine oxidase (manufactured by Sigma, 125-fold diluted), and 2 mM hypoxanthine 0.08 ml were added in this order. Leave at 20 ° C for 20 minutes. Reaction stop solution (1 mM formate buffer, pH 3.5 100 ml, 10% Triton-
X-100 36ml, 37% formalin 50ml, water 400ml)
2.0 ml is added, and the absorbance of this solution at a wavelength of 540 nm is measured. A blank containing 0.1 ml of water instead of xanthine oxidase is used as a blank, a control containing 0.02 ml of water instead of a compound is used as a control, and a compound containing benzoquinone as a compound is used as a positive control.

The inhibition rate (%) at each compound concentration is calculated as follows.

Activity inhibition rate (%) = [1- {E ₅₄₀ (SA-SB) / E ₅₄₀ (C-CB)}] × 100 where E ₅₄₀ (SA): E ₅₄₀ with compound E ₅₄₀ (SB): Blank E ₅₄₀ E ₅₄₀ (C): control E ₅₄₀ E ₅₄₀ (CB): control blank E ₅₄₀ [Results] Table 7 shows the results.

Production Example 1 5-bromo-3- [N- [2-[[2-
[(1,4-dimethoxy-3,5,6-trimethylbenzene-2
-Yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium iodide (II) i) Synthesis of methyl 3-anilinopropionate (1) 2-anilinopropionic acid To a solution of 4.95 g (30.0 mmol) of methanol (10 ml) was added a 14 M solution of hydrogen chloride in methanol (30.0 ml), and the mixture was stirred at room temperature for 1 hour. The methanol was distilled off under reduced pressure, the residue was made alkaline with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off under reduced pressure to obtain 3,80 g (70.0%, pale brown powder) of the desired product.

^{IR (KBr) cm -1:.} 3400,3050,3030,1720,1600 NMR (CDCl 3, 90MHz) δ2.59 (2H, t, J = 7Hz), 3.42 (2H,
t, J = 7 Hz), 3.67 (3H, s), 6.47−6.87 (3H, m), 7.19 (2
H, t, J = 8Hz). ii) 3- [N- (5-bromonicotinoyl) anilino]
Methyl propionate (2) 10.2 g (57.2 mmol) of compound (1) synthesized with i)
To a solution of 17.5 ml (126 mmol) of trimethylamine and chloroform (120 ml) was added 16.2 g (73.5 mmol) of 5-bromonicotinic acid chloride under ice-cooling and stirring, followed by stirring at room temperature for 30 minutes. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate and dried,
The solvent was distilled off. The residue was washed with hexane,
8.2 g (87.7%, light brown powder) was obtained.

IR (KBr) cm ^-1 : 3040,1700,1660,1590. NMR (CDCl ₃ , 90 MHz) δ 2.67 (2H, t, J = 7 Hz), 3.60 (3H,
s), 4.20 (2H, t, J = 7 Hz), 6.90-7.57 (5H, m), 7.82 (1
H, t, J = 2Hz), 8.32 (1H, d, J = 2Hz), 8.52 (1H, t, J = 2H)
z). iii) Synthesis of 3- [N- (5-bromonicotinoyl) anilino] propionic acid (3) 18.0 g (49.6 mmol) of compound (2) synthesized in ii)
Was added to a methanol (200 ml) solution, and the mixture was stirred at room temperature for 1 hour. After neutralization with 1N hydrochloric acid, methanol was distilled off under reduced pressure. The mixture was acidified with 1N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water and dried, and then the solvent was distilled off under reduced pressure. The residue was washed with ether to obtain 15.5 g (90.0%, pale yellow powder) of the desired product.

^{IR (KBr) cm -1:.} 3220,3030,1730,1660,1580 NMR (CDCl 3, 90MHz) δ 2.74 (2H, t, J = 7Hz), 4.24 (2H,
t, J = 7Hz), 6.83-7.56 (5H, m), 7.88 (1H, t, J = 2Hz),
8.36 (1H, d, J = 2Hz), 8.54 (1H, t, J = 2Hz), 10.13 (1H,
m). iv) Synthesis of 5-bromo-3- [N- [2-[(2-hydroxy) ethyl] carbamoyl] ethyl-N-phenyl] carbamoylpyridine (4) iii) Compound (3) synthesized with 28.0 g (80.2) Mmol)
And 12.0 g (104 mmol) of N-hydroxysuccinimide were dissolved in 400 ml of methylene chloride, and 18.5 g (96.5 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added under ice-cooling. For 1 hour. Ethanolamine in the reaction solution
4.84 ml (80.2 mmol) was added, and the mixture was stirred for 2 hours. The deposited precipitate was removed by decantation, the supernatant was washed with water, dried over anhydrous potassium carbonate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography (silica gel; eluent: ethyl acetate / acetone = 2/1) to obtain 21.0 g (66.8%, yellow oil) of the desired compound (5).

IR (KBr) cm ^-1 : 3310, 3060, 2940, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 2.60 (2H, t, J = 7 Hz), 3.41 (2
H, q, J = 6Hz), 3.72 (2H, q, J = 6Hz), 4.25 (2H, t, J = 7H)
z), 6.22 (1H, brt, J = 6Hz), 7.00 ~ 7.40 (5H, m), 7.80
(1H, t, J = 2Hz), 8.30 (1H, d, J = 2Hz), 8.51 (1H, t, J =
2Hz). v) 5-bromo-3- [N- [2-[(2-phenoxycarbonyloxy) ethyl] carbamoyl] ethyl-N
Synthesis of (phenyl) carbamoylpyridine (5) iv) Compound (4) 21.0 g (53.5 mmol)
And pyridine (4,33 ml, 53.5 mmol) in chloroform
Dissolved in 300 ml and cooled with ice to phenylchlorocarbonate 13.
After adding 4 ml (107 mmol), the mixture was stirred at room temperature for 10 minutes. The reaction solution was washed with 5% sodium bicarbonate, and the organic layer was dried over anhydrous sodium sulfate.
The obtained crude product was purified by column chromatography (silica gel; eluent: ethyl acetate) to obtain the desired product (5)
20.0 g (72.9%, white powder) was obtained.

IR (KBr) cm ^-1 : 3340,3090,2930,1770,1670,1630,1590. NMR (200 MHz, CDCl ₃ ) δ 2.16 (2H, t, J = 7 Hz), 3.64 (2
H, q, J = 6Hz), 4.27 (2H, t, J = 7Hz), 4.35 (2H, t, J = 6H)
z), 6.48 (1H, brt, J = 6Hz), 7.00 ~ 7.46 (10H, m), 7.8
5 (1H, t, J = 2Hz), 8.32 (1H, d, J = 2Hz), 8.50 (1H, d, J
= 2Hz). vi) Synthesis of 1,4-dimethoxy-2,3,5-trimethylbenzene (6) 5.52 g of 60% sodium hydride (in oil) under a nitrogen stream.
(138 mmol) was washed twice with hexane, 35 ml of DMF was added, and 2,4,5-trimethylhydroquinone 1 was added with stirring.
A solution of 0.0 g (65.8 mmol) in 70 ml of DMF was added at a reaction temperature of 0 ml.
The solution was added dropwise at -10 ° C. After stirring for 30 minutes, 8.96 ml (144 mmol) of iodomethane was added, and the mixture was stirred for 1 hour.
Water was added and extracted with isopropyl ether. Dry (Na
_{After 2} CO ₃ ), the solvent was distilled off. Distill the residue (100-102 ° C
/ 4 mmHg) to give 9.46 g (79.9%, yellow oil) of the desired product.

IR (Neat) cm ^-1 : 2990, 2940, 1589. NMR (90 MHz, CDCl ₃ ) δ 2.10 (3H, s), 2.20 (3H, s), 2.2
7 (3H, s), 3.63 (3H, s), 3.77 (3H, s), 6.52 (1H, s). vii) Synthesis of 2,5-dimethoxy-3,4,6-trimethylbenzyl chloride (7) A mixture of 9.00 g (49.9 mmol) of the compound (6) synthesized in vi), 9 ml of formalin and 36 ml of concentrated hydrochloric acid was added at 70 ° C. 4
The mixture was heated and stirred for hours. After cooling, the mixture was extracted with isopropyl ether. After drying (Na ₂ CO ₃ ), the solvent was distilled off, and the residue was recrystallized from methanol to obtain 11.0 g (96.3%, colorless needles) of the desired product.

IR (KBr) cm ^-1 : 2990,2940. NMR (200 MHz, CDCl ₃ ) δ 2.19 (3H, s), 2.21 (3H, s), 2.
34 (3H, s), 3.66 (3H, s), 3.79 (3H, s), 4.74 (2H,
s). viii) Synthesis of N- (2,5-dimethoxy-3,4,6-trimethylbenzyl) phthalimide (8) 9.00 g (39.3 mmol) of compound (7) synthesized by vii)
Was added to a solution of 40 ml of DMF in 7.29 g (39.3 mmol) of potassium phthalimide, and the mixture was heated and stirred at 100 ° C. for 2 hours. After cooling,
Water was added and extracted with ethyl acetate. The organic layer was separated and washed with water. After drying (K ₂ CO ₃ ), the solvent was distilled off, and the residue was washed with isopropyl ether.
%, Light brown powder).

IR (KBr) cm ^-1 : 3190, 2945, 1770, 1720, 1600. NMR (200 MHz, CDCl ₃ ) δ 2.14 (3H, s), 2.17 (3H, s), 2.
38 (3H, s), 3.64 (3H, s), 3.73 (3H, s), 4.88 (2H, s),
7.10-7.94 (4H, m). ix) Synthesis of 2.5-dimethoxy-3,4,6-trimethylbenzylamine (9) 6.0 g (17.7 mmol) of compound (8) synthesized in iii)
Hydrazine (hydrate) 1.03ml in methanol 100ml solution of
(21.2 mmol) was added and the mixture was refluxed for 4 hours. After cooling, the solvent was distilled off, and the residue was washed with chloroform.
The washings were extracted with 1N hydrochloric acid, and the aqueous layer was made alkaline with concentrated aqueous ammonia. After extraction with ethyl acetate, the organic layer was dried (K ₂ CO ₃ ), and the solvent was distilled off to obtain 2.90 g (78.4%, pale brown powder) of the desired product.

IR (KBr) cm ^-1 : 3370, 3300, 3000, 2940, 1570. NMR (200 MHz, CDCl ₃ ) δ 2.19 (6H, s), 2.30 (3H, s), 3.
64 (3H, s), 3.71 (3H, s), 3.84 (2H, s). x) 5-bromo-3- [N-2-[[2-[(1,4-dimethoxy-3,5,6, -trimethylbenzene-2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl- Synthesis of N-phenyl] carbamoylpyridine (10) ix) Compound (9) 490 mg (2.34 mmol)
And 1.00 g (1.95 mmol) of the compound (5) synthesized in v) were heated and stirred at 120 ° C. for 2 hours.

After cooling, the residue was purified by column chromatography (silica gel; eluent: ethyl acetate) to give 1.16 g of the desired product
(95.0%, colorless oil).

^{IR (KBr) cm -1:.} 3410,3320,3050,2940,1720,1650,1600 NMR (200MHz, CDCl 3) δ 2.17 (3H, s), 2.20 (3H, s), 2.
28 (3H, s), 2.60 (2H, t, J = 7Hz), 3.47 (2H, q, J = 5H
z), 3.36 (3H, s), 3.67 (3H, s), 4.16 (2H, t, J = 5Hz),
4.21 (2H, t, J = 7Hz), 4.38 (2H, d, J = 6Hz), 5.29 (1H,
t, J = 5Hz), 6.35 (1H, m), 7.00-7.38 (5H, m), 7.83 (1
H, t, J = 2Hz), 8.30 (1H, d, J = 2Hz), 8.36 (1H, d, J = 2H)
z). xi) 5-bromo-3- [N- [2-[[2-[(1,4-
Dimethoxy-3,5,6, -trimethylbenzene-2-yl)
Methyl] carbamoyloxy] ethyl] carbamoyl]
Synthesis of ethyl-N-phenyl] carbamoyl-1-propylpyridinium iodide (11) Compound (10) synthesized by x) 546 mg (0.87 mmol)
15 ml of 1-iodopropane, and shield from light in a nitrogen stream
The mixture was heated and stirred for 36 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was subjected to column chromatography (silica gel;
The eluate was purified with chloroform / methanol = 6/1) to obtain 633 mg (91.2%, pale yellow powder) of the desired product.

NMR (90 MHz, CDCl ₃ ) δ 0.76 (3H, t, J = 7 Hz), 1.81 (2H,
q, J = 7Hz), 2.11 (3H, s), 2.14 (3H, s), 2.24 (3H, s),
2.66 (2H, m), 3.34 (2H, m), 3.60 (3H, s), 3.64 (3H,
s), 3.85-4.50 (6H, m), 4.74 (2H, brt), 5.38 (1H, b
r), 7.0-7.5 (6H, m), 8.38 (1H, br s), 9.34 (2H, br
s). Production Example 2 5-bromo-3- [N- [2-[[2-
[(1,4-dimethoxy-3,5,6, -trimethylbenzene-
2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-
Synthesis of propylpyridinium nitrate (12) 19.4 g (30.9) of compound (10) synthesized in Production Example 1-x)
(Millimol), 1-iodopropane (100 ml) was added thereto, and the mixture was heated and stirred for 7 hours while shielding light in a nitrogen stream. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was dissolved in 200 ml of 70% methanol / water, treated with IRA-410 (NO ₃ ⁻ ) [100 ml], and further subjected to column chromatography (silica gel; elution). Liquid: chloroform / acetonitrile / methanol / water = 6/10/1 /
Purified in 1), 21.1 g of the desired product (93.2%, pale yellow oil)
I got

NMR (200 MHz, CDCl ₃ ) δ 0.73 (3H, t, J = 7 Hz), 1.78 (2
H, q, J = 7Hz), 2.14 (3H, s), 2.18 (3H, s), 2.23 (3H,
s), 2.61 (2H, t, J = 5 Hz), 3, 35 (2H, q, J = 5 Hz), 3.63
(3H, s), 3.67 (3H, s), 4.03 (2H, t, J = 5Hz), 4.16 (2
H, t, J = 5Hz, 4.35 (2H, d, J = 5Hz), 4.55 (2H, t, J = 7H)
z), 5.62 (1H, m), 7.26 (5H, m), 7.59 (1H, m), 8.23 (1
H, brs), 9.11 (1H, brs), 9.28 (1H, brs). Production Example 3 5-bromo-3- [N- [2-[[2-
[(1,4-dimethoxy-3,5,6, -trimethylbenzene-
2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-
Synthesis of propylpyridinium chloride (13) 1.05 g (1.67) of compound (10) synthesized in Production Example 1-x)
(Mmol), and 1-iodopropane (10 ml) was added thereto. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was dissolved in 50 ml of 70% methanol / water, treated with IRA-410 (Cl ⁻ ) [50 ml], and further subjected to column chromatography (silica gel; eluent). : Chloroform / methanol = 8/1), and 980 mg (83.0
%, Yellow oil).

IR (KBr) cm ^-1 : 3370, 3050, 2940, 1720, 1660, 1590 NMR (200 MHz, CDCl ₃ ) δ 0.73 (3H, t, J = 7 Hz), 1.77 (2
H, m), 2.16 (3H, s), 2.19 (3H, s), 2.25 (3H, s), 2.73
(2H, t, J = 6Hz), 3.39 (2H, q, J = 6Hz), 3.64 (3H, s),
3.69 (3H, s), 4.05 (2H, t, J = 6Hz), 4.20 (2H, t, J = 6H
z), 4.33 (2H, d, J = 6Hz), 4.68 (2H, m), 5.62 (1H, m),
7.04-7.50 (5H, m), 8.06 (1H, m), 8.32 (1H, brs), 9.
10 (1H, br s), 9.83 (1H, br s). Production Example 4 5-bromo-3- [N- [2-[[2-
[(1,4-di (1-propoxy) -3,5,6, -trimethylbenzene-2-yl] methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium chloride ( Synthesis of 30) i) Synthesis of 1,4-di (1-propoxy) -2,3,5-trimethylbenzene (14) 5.52 g of 60% sodium hydride (in oil) under a nitrogen stream.
(138 mmol) was washed twice with hexane, 35 ml of DMF was added, and 10.0 g of trimethylhydroquinone (65.
(8 mmol) in 70 ml of DMF was added dropwise while maintaining the reaction temperature at 0-10 ° C. After stirring for 30 minutes, 8.96 ml (144 mmol) of 1-iodopropane was added, and the mixture was stirred for 1 hour. Water was added and extracted with isopropyl ether. Dry (Na ₂ C
After O ₃ ), the solvent was distilled off. The residue was subjected to column chromatography (silica gel; eluent: hexane-ethyl acetate =
Purification by 20/1) gave 12.8 mg (82.4%, brown oil) of the desired product.

IR (Neat) cm ^-1 : 2960, 2940, 1590. NMR (200 MHz, CDCl ₃ ) δ 1.04 (3H, t, J = 7 Hz), 1.07 (3
H, t, J = 7Hz), 1.80 (2H, sextet, J = 7Hz), 1.80 (2H, sex
tet, J = 7Hz), 2.12 (3H, s), 2.19 (3H, s), 2.25 (3H,
s), 3.63 (2H, t, J = 7 Hz), 3.86 (2H, t, J = 7 Hz), 6.52
(1H, s). ii) Synthesis of 2.5-di (1-propoxy) -3,4,6-trimethylbenzyl chloride (15) A mixture of 9.00 g (38.1 mmol) of the compound (14) synthesized in i), 9 ml of formalin and 36 ml of concentrated hydrochloric acid was prepared. 4 at 70 ° C
The mixture was heated and stirred for hours. After cooling, the mixture was extracted with isopropyl ether. After drying (Na ₂ CO ₃ ), the solvent was distilled off. The residue was recrystallized from methanol to obtain 8.50 g (78.4%, colorless powder) of the desired product.

IR (KBr) cm ^-1 : 2990,2940. NMR (200 MHz, CDCl ₃ ) δ 1.08 (3H, t, J = 7 Hz), 1.10 (3
H, t, J = 7Hz), 1.83 (2H, sextet, J = 7Hz), 1.87 (2H, sex
tet, J = 7Hz), 2.17 (3H, s), 2.19 (3H, s), 2.33 (3H,
s), 3.63 (2H, t, J = 7 Hz), 3.80 (2H, t, J = 7 Hz), 4.74
(2H, s). iii) Synthesis of N- [2,5-di (1-propoxy) -3,4,6-trimethylbenzyl] phthalimide (16) 4.00 g (17.5 mmol) of compound (15) synthesized in ii)
3.89 g (21.0 mmol) of potassium phthalimide was added to a DMF (20 ml) solution, and the mixture was heated and stirred at 100 ° C. for 1 hour. After cooling,
Water was added and extracted with ethyl acetate. The organic layer was separated and washed with water. After drying (K ₂ CO ₃ ), the solvent was distilled off, and the residue was washed with isopropyl ether.
%, Colorless powder).

IR (KBr) cm ^-1 : 1770,1720. NMR (200 MHz, CDCl ₃ ) δ 0.99 (3H, t, J = 7 Hz), 1.05 (3
H, t, J = 7Hz), 1.80 (2H, sextet, J = 7Hz), 1.84 (2H, sex
tet, J = 7Hz), 2.14 (3H, s), 2.16 (3H, s), 2.29 (3H,
s), 3.60 (2H, t, J = 7 Hz), 3.74 (2H, t, J = 7 Hz), 7.60-
7.90 (4H, m). iv) Synthesis of 2,5-di (1-propoxy) -3,4,6-trimethylbenzylamine (17) 2.00 g (5.89 mmol) of compound (16) synthesized in iii)
0.34 ml of hydrazine (hydrate) in 70 ml of methanol
(7.07 mmol) was added and the mixture was refluxed for 4 hours. After cooling, the solvent was distilled off, and the residue was washed with chloroform.
The washings were extracted with 1N hydrochloric acid and made alkaline with concentrated aqueous ammonia. Extract with chloroform and dry the organic layer (K ₂ CO
₃ ) After that, the solvent was distilled off to obtain 750 mg (48.0%, pale yellow powder) of the desired product.

IR (KBr) cm ^-1 : 3350,2930,1580. NMR (200 MHz, CDCl ₃ ) δ 1.07 (3H, t, J = 7 Hz), 1.08 (3
H, t, J = 7Hz), 1.83 (2H, sextet, J = 7Hz), 1.84 (2H, sex
tet, J = 7Hz), 2.16 (3H, s), 2.17 (3H, s), 2.28 (3H,
s), 3.62 (2H, t, J = 7Hz), 3.68 (2H, t, J = 7Hz), 3.63
(2H, s). v) 5-bromo-3- [N- [2-[[2-[[1,4-
Di (1-propoxy) -3,5,6, -trimethylbenzene-
Synthesis of 2-yl] methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoylpyridine (18) iv) Compound (17) 404 mg (1.52 mmol)
And 650 mg (1.2%) of compound (5) synthesized in Production Example 1-v).
(7 mmol) was heated and stirred at 120 ° C. for 1 hour. After cooling, the residue was purified by column chromatography (silica gel; eluent: hexane-ethyl acetate = 1/5) to give the desired product (672 mg, 77.5%, colorless oil).

IR (KBr) cm ^-1 : 3310,3070,1680,1640. NMR (200 MHz, CDCl ₃ ) δ 1.05 (3H, t, J = 7 Hz), 1.06 (3
H, t, J = 7Hz), 1.82 (4H, sextet, J = 7Hz), 2.16 (3H,
s), 2.18 (3H, s), 2.26 (3H, s), 2.60 (2H, t, J = 7Hz),
3.46 (2H, q, J = 5 Hz), 3.60 (2H, t, J = 7 Hz), 3.65 (2H,
t, J = 7Hz), 4.15 (2H, t, J = 5Hz), 4.21 (2H, t, J = 7H)
z), 4.37 (2H, d, J = 5Hz), 5.27 (1H, t, J = 5Hz), 6.35
(1H, m), 7.00-7.50 (5H, m), 7.84 (1H, t, J = 7Hz), 8.
30 (1H, d, J = 2Hz), 8.42 (1H, d, J = 2Hz). vi) 5-bromo-3- [N- [2-[[2-[[1,4-
Di (1-propoxy) -3,5,6, -trimethylbenzene-
2-yl] methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-
Synthesis of propylpyridinium chloride (19) v) Compound (18) synthesized in v) 640 mg (0.94 mmol)
To 10 ml of 1-iodopropane, and shield from light in a nitrogen stream.
The mixture was heated and stirred for 18 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was dissolved in 70% methanol / water (50 ml).
The mixture was treated with 10 (Cl ⁻ ) [50 ml], and further purified by column chromatography (silica gel; eluent: chloroform / methanol = 6/1) to obtain 536 mg (75.1%, yellow oil) of the desired product. .

IR (KBr) cm ^-1 : 3320,3060,1710.1660,1590. NMR (200 MHz, CDCl ₃ ) δ 0.74 (3H, t, J = 7 Hz), 1.05 (3
H, t, J = 7Hz), 1.07 (3H, t, J = 7Hz), 1.70-2.00 (6H,
m), 2.15 (3H, s), 2.18 (3H, s), 2.23 (3H, s), 2.73 (2
H, m), 3.39 (2H, m), 3.62 (2H, t, J = 7Hz), 3.66 (2H, t,
J = 7Hz), 4.05 (2H, m), 4.21 (2H, m), 4.34 (2H, d, J = 5
Hz), 4.63 (2H, m), 5.55 (1H, m), 7.20-7.50 (5H, m),
7.98 (1H, m), 8,27 (1H, t, J = 2Hz), 9.01 (1H, d, J = 2H
z), 9.79 (1H, d, J = 2 Hz). Production Example 5 5-bromo-3- [N- [2-[[2-
[[1,4-Di (2-propoxy) -3,5,6, -trimethylbenzene-2-yl] methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridium chloride Synthesis of (25) i) Synthesis of 1,4-di (2-propoxy) -2,3,5-trimethylbenzene (20) 60% sodium hydride (in oil) 5.52 under nitrogen stream
g (138 mmol) was washed twice with hexane, 35 ml of DMF was added, and while stirring, 10.0 g (6.
(5.8 mmol) in 70 ml of DMF at a reaction temperature of 0-10 ° C.
The solution was dropped. After stirring for 30 minutes, 8.96 ml (144 mmol) of 2-iodopropane was added, and the mixture was stirred for 1 hour.
Water was added and extracted with isopropyl ether. Dry (Na
_{After 2} CO ₃ ), the solvent was distilled off. The residue was purified by column chromatography (silica gel; eluent: hexane-ethyl acetate = 20/1) to obtain 3.50 g (22.5%, yellow oil) of the desired product.

IR (Neat) cm ^-1 : 2970,2920,1590. NMR (200 MHz, CDCl ₃ ) δ 1.27 (6H, d, J = 2 Hz), 1.31 (6
H, d, J = 6Hz), 2.10 (3H, s), 2.16 (3H, s), 2.23 (3H,
s), 4.03 (1H, quint., J = 6Hz), 4.38 (1H, quint., J = 6H)
z), 6.56 (1H, s). ii) Synthesis of 2.5-di (2-propoxy) -3,4,6-trimethylbenzyl chloride (21) A mixture of 2.80 g (11.8 mmol) of the compound (20) synthesized in i), 3 ml of formalin and 11 ml of concentrated hydrochloric acid was prepared. 4 at 70 ° C
The mixture was heated and stirred for hours. After cooling, the mixture was extracted with isopropyl ether. After drying (Na ₂ CO ₃ ), the solvent was distilled off.
g (quant., colorless powder) was obtained.

IR (KBr) cm ^-1 : 2970,2930. NMR (200 MHz, CDCl ₃ ) δ 1.28 (6H, d, J = 6 Hz), 1.32 (6
H, d, J = 6Hz), 2.15 (3H, s), 2.17 (3H, s), 2.33 (3H,
s), 4.04 (1H, quint., J = 6Hz), 4.26 (1H, quint., J = 6H)
z), 4.74 (2H, s). iii) Synthesis of N- [2.5-di (2-propoxy) -3,4,6-trimethylbenzyl] phthalimide (22) ii) 3.06 g (13.4 mmol) of compound (21) synthesized in ii)
2.97 g (16.1 mmol) of potassium phthalimide was added to a solution of the above in 15 ml of DMF, and the mixture was heated with stirring at 100 ° C. for 1 hour. After cooling,
Water was added and extracted with ethyl acetate. The organic layer was separated and washed with water. After drying (K ₂ CO ₃ ), the solvent was distilled off, and the residue was washed with ipropyl ether to give 3.25 g of the desired product (71.6 g).
%, Colorless powder).

IR (KBr) cm ^-1 : 1770, 1710, 1610. NMR (200 MHz, CDCl ₃ ) δ 1.25 (6H, d, J = 6 Hz), 1.30 (6
H, d, J = 6Hz), 2.10 (3H, s), 2.14 (3H, s), 2.30 (3H,
s), 4.00 (1H, quint., J = 6Hz), 4.12 (1H, quint., J = 6H)
z), 4.92 (2H, s), 7.60-7.80 (4H, m). iv) Synthesis of 2,5-di (2-propoxy) -3,4,6-trimethylbenzylamine (23) 2.50 g (7.37 mmol) of compound (22) synthesized in iii)
Hydrazine (hydrate) 0.43ml in 90ml methanol solution
(8.84 mmol) was added and the mixture was heated under reflux for 4 hours. After cooling, the solvent was distilled off, and the residue was washed with chloroform.
The washings were extracted with 1N hydrochloric acid, and the aqueous layer was made alkaline with concentrated aqueous ammonia. After extraction with chloroform, the organic layer was dried (K ₂ CO ₃ ), and the solvent was distilled off to obtain 1.05 g (53.7%, yellow oil) of the desired product.

IR (KBr) cm ^-1 : 3370,3310,2970,2930. NMR (200 MHz, CDCl ₃ ) δ 1.27 (6H, d, J = 6 Hz), 1.28 (6
H, d, J = 6Hz), 2.15 (6H, s), 2.27 (3H, s), 3.86 (2H,
s), 4.02 (1H, quint., J = 6Hz), 4.10 (1H, quint., J = 6H)
z). v) 5-bromo-3- [N- [2-[[2-[[1,4-
Di (2-propoxy) -3,5,6, -trimethylbenzene-
Synthesis of 2-yl] methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoylpyridine (24) iv) Compound (23) 709 mg (2.67 mmol)
And 1.14 g (2.2) of compound (5) synthesized in Production Example 1-v).
(2 mmol) was heated and stirred at 120 ° C. for 1 hour. After cooling, the residue was purified by column chromatography (silica gel; eluent: hexane-ethyl acetate = 1/5) to obtain 1.47 g (96.6%, colorless oil) of the desired product.

IR (KBr) cm ^-1 : 3270, 3200, 1720.1640, 1590. NMR (200 MHz, CDCl ₃ ) δ 1.26 (6H, d, J = 6 Hz), 1.27 (6
H, d, J = 6Hz), 2.14 (3H, s), 2.16 (3H, s), 2.25 (3H,
s), 2.10 (2H, t, J = 7 Hz), 3.47 (2H, q, J = 5 Hz), 4.10
(2H, quint., J = 6Hz), 4.15 (2H, t, J = 5Hz), 4.21 (2H,
t, J = 7Hz), 4.40 (2H, d, J = 6Hz), 5.24 (1H, m), 6.35
(1H, m), 7.07 (2H, dd, J = 2.8Hz), 7.15-7.40 (3H,
m), 7.83 (1H, t, J = 2Hz), 8.30 (1H, d, J = 2Hz), 8.42
(1H, d, J = 2Hz). vi) 5-bromo-3- [N- [2-[[2-[[1,4-
Di (2-propoxy) -3,5,6, -trimethylbenzene-
2-yl] methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-
Synthesis of propylpyridinium chloride (25) v) 1.40 g (2.05 mmol) of compound (24) synthesized by
Add 20 ml of 1-iodopropane to
The mixture was heated and stirred for 18 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was dissolved in 70% methanol / water (50 ml).
The residue was treated with 10 (Cl ⁻ ) [50 ml] and further purified by column chromatography (silica gel; eluent: chloroform / methanol = 6/1) to obtain 1.05 g (67.3%, yellow oil) of the desired product. Was.

IR (KBr) cm ^-1 : 3310,3050,1710.1660,1590. NMR (200 MHz, CDCl ₃ ) δ 0.72 (3H, t, J = 7 Hz), 1.26 (12
H, d, J = 6Hz), 1.65-2.00 (2H, m), 2.13 (3H, s), 2.16
(3H, s), 2.21 (3H, s), 2.74 (2H, m), 3.39 (2H, q, J = 5
Hz), 3.90-4.15 (4H, m), 4.20 (2H, t, J = 7Hz), 4.37
(2H, d, J = 6Hz), 4.63 (2H, m), 5.51 (1H, m), 7.20-7.
50 (5H, m), 8.01 (1H, m), 8.28 (1H, brs), 9.05 (1H, br
s), 9.77 (1H, d, J = 2 Hz). Production Example 6 5-bromo-3- [N- [2-[[2-
[[1,4-di (1-hexyloxy) -3,5,6, -trimethylbenzene-2-yl] methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium chloride ( Synthesis of 30) i) Synthesis of 1,4-di (1-hexyloxy) -2,3,5-trimethylbenzene (26) 60% sodium hydride (in oil) 5.52 under nitrogen stream
g (138 mmol) was washed twice with hexane, 35 ml of DMF was added, and while stirring, 10.0 g (6.
(5.8 mmol) in 70 ml of DMF at a reaction temperature of 0-10 ° C.
The solution was dropped. After stirring for 30 minutes, 8.96 ml (144 mmol) of 1-iodohexane was added, and the mixture was stirred for 1 hour.
Water was added and extracted with isopropyl ether. Dry (Na
_{After 2} CO ₃ ), the solvent was distilled off. The residue was purified by column chromatography (silica gel; eluent: hexane) to give 20.0 g of the desired product (94.8%, yellow oil).

IR (Neat) cm ^-1 : 2930, 2660, 1590. NMR (200 MHz, CDCl ₃ ) δ 0.90 (6H, m), 1.20-1.60 (12
H, m), 1.76 (4H, m), 2.11 (3H, s), 2.17 (3H, s), 2.23
(3H, s), 3.66 (2H, t, J = 7Hz), 3.88 (2H, t, J = 7Hz),
6.52 (1H, s). ii) Synthesis of N- [2,5-di (2-hexyloxy) -3,4,6-trimethylbenzyl] phthalimide (27) 16.0 g (49.9 mmol) of compound (26) synthesized in i), 16 ml of formalin, A mixture of 64 ml of concentrated hydrochloric acid is
The mixture was heated and stirred for a week. After cooling, the mixture was extracted with isopropyl ether. After drying (Na ₂ CO ₃ ), the solvent was distilled off to obtain 16.0 g of a chloromethyl compound (about 50%). 5.00 g of the above crude product D
1.51 g (8.13 mmol) of potassium phthalimide was added to a 30 ml solution of MF, and the mixture was heated and stirred at 100 ° C. for 1 hour. After cooling, water was added and extracted with ethyl acetate. The organic layer was separated and washed with water. After drying (K ₂ CO ₃ ), the solvent was distilled off, and the residue was purified by column chromatography (silica gel; eluent: hexane-ethyl acetate = 10/1) to obtain 2.20 g of the desired product (2
9.4%, pale yellow powder) 2.70g (54.0%) of raw material (26)
Collected.

IR (KBr) cm ^-1 : 1770, 1720, 1610. NMR (200 MHz, CDCl ₃ ) δ 0.88 (3H, t, J = 7 Hz), 0.90 (3
H, t, J = 7Hz), 1.34 (12H, m), 1.76 (quint., 4H, J = 7H)
z), 2.13 (3H, s), 2.15 (3H, s), 2.28 (3H, s), 3.62 (2
H, t, J = 7Hz), 3.77 (2H, t, J = 7Hz), 4.90 (1H, s), 7.60
−7.86 (4H, m). iii) Synthesis of 2.5-di (2-hexyloxy) -3,4,6-trimethylbenzylamine (28) ii) Compound (27) 2.00 g (4.17 mmol) synthesized in ii)
Hydrazine (hydrate) in methanol 140ml solution
(5.01 mmol) was added and the mixture was refluxed for 2 hours. After cooling, the solvent was distilled off, and the residue was washed with chloroform.
The washings are concentrated under reduced pressure, and the resulting residue is purified by column chromatography (silica gel; eluent: acid-methanol = 10/1) to give 1.03 g (70.7%, pale yellow oil) of the desired product. Obtained.

IR (Neat) cm ^-1 : 3370, 3310, 2930, 2660. NMR (200 MHz, CDCl ₃ ) δ 0.92 (6H, d, J = 7 Hz), 1.20-1.
67 (12H, m), 1.80 (4H, m), 2.16 (3H, s), 2.17 (3H,
s), 2.28 (3H, s), 3.65 (2H, t, J = 7 Hz), 3.71 (2H, t, J
= 7Hz), 3.81 (2H, s). iv) 5-bromo-3- [N- [2-[[2-[[1,4-
Synthesis of di (1-hexyloxy) -3,5,6, -trimethylbenzene-2-yl] methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoylpyridine (29) iii) Compound synthesized with iii) 28) 818 mg (2.34 mmol)
And 1.00 g (1.9 g) of the compound (5) synthesized in Production Example 1-v).
(5 mmol) was heated and stirred at 120 ° C. for 1 hour. After cooling, the residue was purified by column chromatography (silica gel; eluent: hexane-ethyl acetate = 1/2) to obtain 1.22 g (81.7%, colorless oil) of the desired product.

IR (Neat) cm ^-1 1: 3220,1720,1650,1590. NMR (200 MHz, CDCl ₃ ) δ 0.92 (6H, d, J = 7 Hz), 1.20-1.
60 (12H, m), 1.79 (4H, m), 2.16 (3H, s), 2.18 (3H,
s), 2.26 (3H, s), 2.60 (2H, t, J = 7 Hz), 3.46 (2H, q, J
= 5Hz), 3.63 (2H, t, J = 7Hz), 3.67 (2H, t, J = 7Hz), 4.
16 (2H, t, J = 5Hz), 4.22 (2H, t, J = 7Hz), 4.37 (2H, d, J
= 6Hz), 5.26 (1H, m), 6.37 (1H, m), 7.06 (2H, dd, J =
2,8 Hz), 7.15-7.40 (3H, m), 7.83 (1H, t, J = 2Hz), 8.3
0 (1H, d, J = 2Hz), 8.42 (1H, d, J = 2Hz). v) 5-bromo-3- [N- [2-[[2-[[1,4-
Di (1-hexyloxy) -3,5,6, -trimethylbenzene-2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1
Synthesis of -propylpyridinium chloride (30) iv) To 1.10 g (1.43 mmol) of the compound (29) synthesized in iv), 10 ml of 1-iodopropane was added, and the mixture was heated and stirred for 18 hours in a nitrogen stream while protecting from light. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was dissolved in 100 ml of 70% methanol / water.
The mixture was treated with RA-410 (Cl ⁻ ) [100 ml], and further subjected to column chromatography (silica gel; eluent: chloroform /
Purified with methanol = 10/1), 960 mg (76.1
%. A pale yellow oil was obtained.

IR (KBr) cm ^-1 : 3310, 3060, 1720, 1660, 1590. NMR (200 MHz, CDCl ₃ ) δ 0.73 (3H, t, J = 7 Hz), 0.91 (6
H, t, J = 7Hz), 1.20-1.60 (14H, m), 1.60-2.00 (4H,
m), 2.16 (3H, s), 2.17 (3H, s), 2.26 (3H, s), 2.74 (2
H, m), 3.38 (2H, m), 3.63 (2H, t, J = 7Hz), 3.66 (2H, t,
J = 7Hz), 4.05 (2H, m), 4.20 (2H, m), 4.33 (2H, d, J = 6
Hz), 4.10 (2H, m), 5.55 (1H, m), 7.00-7.50 (5H, m),
7.96 (1H, m), 8.25 (1H, brs), 8.95 (1H, brs), 9.78 (1
H, d, J = 2Hz). Production Example 7 5-bromo-3- [N- [2-[[2-
Synthesis of [[1,4-dimethoxy-3-methylnaphthalen-2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium chloride (34) i) 1,4- Synthesis of dimethoxy-3-methyl-2-phthalimidomethylnaphthalene (31) To a solution of 510 mg (2.03 mmol) of 2-chloromethyl-1,4-dimethoxy-3-methylnaphthalene in 20 ml of DMF was added 414 mg (2.23 mmol) of potassium phthalimide. , 100
The mixture was heated and stirred at 2 ° C. for 2 hours. After cooling, water was added and extracted with ethyl acetate. The organic layer was separated and washed with water. After drying (K ₂ CO ₃ ), the solvent was distilled off, and the residue was purified by column chromatography (silica gel; eluent: hexane-ethyl acetate = 4/1). Recrystallization afforded 547 mg (74.4%, colorless powder) of the desired product.

IR (KBr) cm ^-1 : 3460, 3060, 1770, 1590. NMR (200 MHz, CDCl ₃ ) δ 2.55 (3H, s), 3.87 (3H, s), 3.
99 (3H, s), 5.08 (2H, s), 7.38−7.56 (2H, m), 7.64−
7.88 (4H, m), 7.97−8.13 (2H, m). ii) Synthesis of 2-aminomethyl-1,4-dimethoxy-3-methylnaphthalene (32) 450 mg (1.25 mmol) of compound (31) synthesized in i)
Hydrazine (hydrate) 0.07ml in methanol 15ml solution
(1.50 mmol) was added and the mixture was heated under reflux for 4 hours. After cooling, the solvent was distilled off, and the residue was washed with chloroform.
The washings were concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel; eluent: methanol) to obtain 290 mg (quant., Yellow oil) of the desired product.

IR (Neat) cm ^-1 : 3370, 3260, 3062, 2940, 1590. NMR (200 MHz, CDCl ₃ ) δ 2.50 (3H, s), 3.88 (3H, s), 3.
96 (3H, s), 4.05 (2H, s), 7.40-7.56 (2H, m), 8.00-
8.13 (2H, m). iii) 5-bromo-3- [N- [2-[[2-[(1,4-
Synthesis of dimethoxy-3-methylnaphthalen-2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoylpyridine (33) 243 mg (1.05 mmol) of compound (32) synthesized by ii)
And 538 mg (1.0) of compound (5) synthesized in Production Example 1-v).
(5 mmol) was heated and stirred at 120 ° C. for 1 hour. After cooling, the residue was purified by column chromatography (silica gel; eluent: hexane-ethyl acetate = 1/10) to obtain 450 mg (66.0%, colorless oil) of the desired product.

IR (KBr) cm ^-1 : 3320, 3060, 2940, 1720, 1650, 1590 NMR (200 MHz, CDCl ₃ ) δ 2.55 (3H, s), 2.68 (2H, t, J = 7
Hz), 3.58 (2H, q, J = 5Hz), 3.96 (3H, s), 4.02 (3H,
s), 4.20-4.35 (4H, m), 4.68 (2H, d, J = 6Hz), 5.43 (1
H, t, J = 6Hz), 6.44 (1H, t, J = 6Hz), 7.14 (2H, dd, J = 2,
8Hz), 7.23-7.43 (3H, m), 7.50-7.70 (2H, m), 7.90
(1H, t, J = 2Hz), 8.80−8.24 (2H, m), 8.38 (1H, d, J = 2
Hz), 8.46 (1H, d, J = 2Hz). iv) 5-bromo-3- [N- [2-[[2-[(1,4-
Synthesis of dimethoxy-3-methylnaphthalen-2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium chloride (34) 400 mg (0.62) of compound (33) synthesized in iii) Mmol)
To the mixture was added 10 ml of 1-iodopropane, and the mixture was heated and stirred in a nitrogen stream for 18 hours while shielding light.
After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was dissolved in 50 ml of 70% methanol / water, treated with IRA-410 (Cl ⁻ ) [50 ml], and further subjected to column chromatography (silica gel; eluent). : Chloroform / methanol = 7/1) to give 330 mg (73.6%, yellow oil) of the desired product.

IR (KBr) cm ^-1 : 3360, 3060, 1710, 1660, 1590. NMR (200 MHz, CDCl ₃ ) δ 0.58 (3H, t, J = 7 Hz), 1.40-1.
90 (2H, m), 2.40 (3H, s), 2.73 (2H, m), 3.40 (2H, m),
3.88 (3H, s), 3.95 (3H, s), 4.06 (2H, m), 4.20 (2H,
m), 4.30 (2H, m), 4.56 (2H, d, J = 6Hz), 6.18 (1H, m),
7.00-7.60 (9H, m), 8.10 (2H, m), 8.95 (1H, brs), 9.8
8 (1H, brs). Production Example 8 5-bromo-3- [N- [2-[[1,4-dimethoxy-3,5,6-trimethylbenzene-2-yl) methoxycarbonyl] amino] ethyl-N-phenyl] carbamoyl-1 Synthesis of -propylpyridinium chloride (38) i) Synthesis of 2,5-dimethoxy-3,4,6-trimethylbenzyl alcohol (35) 7.54 g (33.0) of compound (7) synthesized in Production Example 1-vii)
Mmol) in 100 ml of dioxane, 100 ml of a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred at room temperature for 2 hours, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure, and the residue obtained was hexane / ethyl acetate =
Recrystallization from 1/10 gave 5.50 g (79.3%, colorless needles) of the desired product.

IR (KBr) cm ^-1 : 3370,3300,2990,2940. NMR (200 MHz, CDCl ₃ ) δ 2.18 (3H, s), 2.20 (3H, s), 2.
32 (3H, s), 3.66 (3H, s), 3.74 (3H, s), 4.74 (2H, d, J
= 6Hz). ii) 2,5-dimethoxy-3,4,6-trimethylbenzyl N-
Synthesis of (2-anilinoethyl) carbamide (36) 1.27 g (6.04 mmol) of compound (35) synthesized in i)
And pyridine 0.98 ml (12.08 mmol) of chloroform (2
5ml) 1.54ml of phenyl chlorocarbonate under ice-cooling and stirring
(12.08 mmol) was added and stirred for 30 minutes. The reaction solution was washed with 5% saturated aqueous sodium hydrogen carbonate and water, and dried (NaSO ₄ ). The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel; eluent: hexane-ethyl acetate = 40/1). 1.94 g of the obtained carbonate body
To the mixture was added 0.92 ml (7.05 mmol) of N-phenylethylenediamine, and the mixture was heated at 120 ° for 1 hour. After cooling, the crude product was purified by column chromatography (silica gel; eluent: hexane-ethyl acetate = 3/1) to obtain 1.54 g of the desired product
(68.5%, colorless powder) was obtained.

IR (KBr) cm ^-1 : 3330,3050,1690. NMR (200 MHz, CDCl ₃ ) δ 2.19 (3H, s), 2.21 (3H, s), 2.
27 (3H, s), 3.29 (2H, m), 3.44 (2H, m), 3.65 (3H, s),
3.66 (3H, s), 4.95 (1H, m), 5.22 (2H, s), 6.55-6.85
(3H, m), 7.17 (2H, t, J = 8Hz). iii) 5-bromo-3- [N- [2-[[1,4-dimethoxy-3,5,6-trimethylbenzene-2-yl) methoxycarbonyl] amino] ethyl-N-phenyl] carbamoylpyridine (37 1.52 g (4.08 mmol) of the compound (36) synthesized in ii)
1.26 g (5.72 mmol) of 5-bromonicotinic acid chloride was added to a 20 ml solution of chloroform and 1.37 ml (9.80 mmol) of triethylamine under ice-cooling and stirring, followed by stirring for 30 minutes. The reaction solution was washed with 1N aqueous sodium hydroxide solution and water,
Dried (KCO ₃ ). The residue obtained by evaporating the solvent under reduced pressure was subjected to column chromatography (silica gel; eluent:
Hexane-ethyl acetate = 1/1) was purified to give 1.65 g of the desired product
(72.7%, colorless powder) was obtained.

IR (KBr) cm ^-1 : 3310, 3060, 1680, 1660, 1600. NMR (200 MHz, CDCl ₃ ) δ 2.19 (3H, s), 2.21 (3H, s), 2.
25 (3H, s), 3.51 (2H, t, J = 6Hz), 3.66 (3H, s), 3.68
(3H, s), 4.11 (2H, t, J = 6Hz), 5.18 (3H, m), 7.00-7.
28 (5H, m), 7.82 (2H, t, J = 2Hz), 8.29 (2H, brs), 8.51
(2H, t, J = 2Hz). iv) 5-bromo-3- [N- [2-[(1,4-dimethoxy-3,5,6-trimethylbenzene-2-yl) methoxycarbonyl] amino] ethyl-N-phenyl] carbamoyl-1- Synthesis of propylpyridinium chloride (38) iii) Compound (37) 500 mg (0.90 mmol)
To 10 ml of 1-iodopropane, and shield from light in a nitrogen stream.
The mixture was heated and stirred for 18 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was dissolved in 70% methanol / water (100 ml).
The residue was treated with 410 (Cl ⁻ ) [50 ml] and further purified by column chromatography (silica gel; eluent: chloroform / methanol = 10/1) to obtain 420 mg (73.6%, yellow oil) of the desired product. .

IR (KBr) cm ^-1 : 3390, 3060, 1710, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 0.68 (3H, t, J = 7 Hz), 1.60-2.
00 (2H, m), 2.16 (3H, s), 2.20 (3H, s), 2.24 (3H, s),
3.37 (2H, q, J = 6Hz), 3.65 (3H, s), 3.67 (3H, s), 4.05
(2H, m), 4.71 (2H, t, J = 6Hz), 5.15 (3H, m), 6.90-7.
40 (5H, m), 8.35 (1H, brs), 9.42 (1H, brs), 8.60 (1
H, br s). Production Example 9 5-bromo-3- [N- [2- (2,5-dimethoxy-3,4,6-trimethyl-trans-cinnamyloxycarbonyl) amino] ethyl-N-phenyl] carbamoyl-1-propyl Pyridinium chloride (4
Synthesis of 4) i) Synthesis of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde (39) 1.00 g (5.55 mmol) of compound (6) synthesized in Production Example 1-vi) and dichloromethyl methyl ether 1.29 ml (14.3
Mmol) in 2 ml of dichloromethane under ice-cooling and stirring.
1.57 ml (14.3 mmol) of titanium tetrachloride in dichloromethane
A 5 ml solution was added and stirred for 2 hours. Ice-cold water was added to the reaction solution, and the organic layer was washed with water and dried (NaSO ₄ ), and then the solvent was distilled off to obtain 1.12 g (96.9%, colorless prism crystals) of the desired product.

IR (KBr) cm ^-1 : 1670,1580. NMR (200 MHz, CDCl ₃ ) δ 2.21 (3H, s), 2.27 (3H, s), 2.
50 (3H, s), 3.66 (3H, s), 3.70 (3H, s), 10.50 (1H,
s). ii) Synthesis of ethyl 2,5-dimethoxy-3,4,6-trimethyl-trans-cinnamate (40) 1.00 g (4.80 mmol) of compound (39) synthesized in i)
And 1.67 g (4.80 mmol) of ethoxycarbonylmethylidenetriphenylphosphorane in benzene (15 ml)
The mixture was heated and refluxed for 18 hours under a nitrogen stream. The residue obtained by evaporating the solvent is subjected to column chromatography (silica gel;
The eluate was purified by hexane / ethyl acetate = 20/1) to obtain 1.33 g of the desired product (quant., Pale yellow powder).

IR (KBr) cm ^-1 : 3350,1660,1600. NMR (200 MHz, CDCl ₃ ) δ 1.34 (3H, t, J = 7 Hz), 2.19 (3
H, s), 2.22 (3H, s), 2.33 (3H, s), 3.61 (3H, s), 3.65
(3H, s), 4.27 (2H, q, J = 7Hz), 6.55 (1H, d, J = 16Hz),
7.87 (1H, d, J = 16Hz). iii) Synthesis of 2,5-dimethoxy-3,4,6-trimethyl-trans-cinnamyl alcohol (41) A solution of 1.30 g (4.67 mmol) of the compound (40) synthesized in ii) in dichloromethane (50 ml) Diisobutylaluminum hydride (25wt%, toluene solution) with stirring at 78 °
6.11 ml (9.34 mmol) was added and stirred for 1 hour. After adding water-containing ether and stirring for 10 minutes, the mixture was stirred at room temperature for 20 minutes.
The organic layer was separated, dried (K ₂ CO ₃ ), and the solvent was distilled off. The resulting residue was purified by column chromatography (silica gel; eluent: hexane / ethyl acetate = 2/1). 1.10 g (quant., Pale yellow powder) were obtained.

NMR (200 MHz, CDCl ₃ ) δ 2.18 (3H, s), 2.20 (3H, s), 2.
27 (3H, s), 3.61 (3H, s), 3.65 (3H, s), 4.36 (2H, t, J
= 5Hz), 6.26 (1H, dt, J = 2.16Hz), 6.65 (1H, d, J = 16H)
z). iv) 2,5-dimethoxy-3,4,6-trimethyl-trans-
Synthesis of cinnamyl N- (2-anilinoethyl) carbamide (42) 1.10 g (4.65 mmol) of compound (41) synthesized in iii) and chloroform of 0.75 ml (9.31 mmol) of pyridine
In a 20 ml solution, under ice-cooling and stirring, 1.17 ml of phenyl chlorocarbonate
(9.31 mmol) was added and stirred for 30 minutes. Reaction solution 5
The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and water, and dried (NaSO ₄ ). The residue obtained by evaporating the solvent under reduced pressure was subjected to column chromatography (silica gel: eluent: hexane / ethyl acetate =
40/1). 0.58 ml (4.43 mmol) of N-phenylethylenediamine was added to 1.47 g of the obtained carbonate compound.
And heated at 120 ° for 1 hour. After cooling, the crude product was purified by column chromatography (silica gel; eluent; hexane / ethyl acetate = 3/1) to obtain 1.25 g of the desired product (67.4
%, Colorless powder).

IR (KBr) cm ^-1 : 1710, 1630. NMR (200 MHz, CDCl ₃ ) δ 2.17 (3H, s), 2.20 (3H, s), 2.
25 (3H, s), 3.30 (2H, t, J = 6Hz), 3.44 (2H, t, J = 6H
z), 3.58 (3H, s), 3.64 (3H, s), 4.77 (2H, d, J = 6Hz),
5.04 (1H, m), 6.17 (1H, dt, J = 6.17 Hz), 6.55-6.80 (4
H, m), 7.22 (2H, t, J = 8Hz). v) Synthesis of 5-bromo-3- [N- [2- (2.5-dimethoxy-3,4,6-trimethyl-trans-cinnamyloxycarbonyl) amino] ethyl-N-phenyl] carbamoylpyridine (43) iv 1.12 g (2.81 mmol) of compound (42) synthesized by
To a solution of 0.94 ml (6.75 mmol) of triethylamine and 15 ml of chloroform were added 866 mg (3.93 mmol) of 5-bromonicotinic acid chloride under ice cooling and stirring, followed by stirring for 30 minutes. The reaction solution was washed with 1N aqueous sodium hydroxide solution and water,
Dried (KCO ₃ ). The residue obtained by evaporating the solvent under reduced pressure was subjected to column chromatography (silica gel; eluent:
Hexane / ethyl acetate = 1/1) was purified, and 1.58 g of the desired product was obtained.
(96.5%, pale yellow oil).

IR (Neat) cm ^-1 : 3340, 3060, 1720, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 2.18 (3H, s), 2.21 (3H, s), 2.
25 (3H, s), 3.52 (2H, t, J = 6Hz), 3.58 (3H, s), 3.65
(3H, s), 4.11 (2H, t, J = 6Hz), 4.75 (2H, d, J = 6Hz),
5.33 (1H, m), 6.17 (1H, dt, J = 6.15Hz) 6.67 (1H, d, J =
15Hz), 7.00-7.40 (5H, m), 7.83 (1H, t, J = 2Hz), 8.31
(1H, d, J = 2Hz), 8.51 (1H, t, J = 2Hz). vi) 5-Bromo-3- [N- [2- (2,5-dimethoxy-3,4,6-trimethyl-trans-cinnamyloxycarbonyl) amino] ethyl-N-phenyl] carbamoyl-1-propylpyridinium Synthesis of chloride (44) 500 mg (0.86 mmol) of compound (43) synthesized in v)
To 10 ml of 1-iodopropane, and shield from light in a nitrogen stream.
The mixture was heated and stirred for 18 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was dissolved in 70 ml of methanol / water (00 ml).
The mixture was treated with 10 (Cl ⁻ ) [50 ml], and further purified by column chromatography (silica gel; eluent: chloroform / methanol = 10/1) to obtain 430 mg (75.5%, yellow oil) of the desired product. .

IR (KBr) cm ^-1 : 3380, 3040, 1710, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 0.68 (3H, t, J = 7 Hz), 1.70-2.
00 (2H, m), 2.17 (3H, s), 2.20 (3H, s), 2.24 (3H, s),
3.37 (2H, m), 3.57 (3H, s), 3.63 (3H, s), 4.05 (2H,
m), 4.23 (4H, m), 5.41 (1H, m), 6.15 (1H, m), 6.66 (1
H, d, J = 15Hz), 7.00-7.70 (5H, m), 8.37 (1H, brs),
9.32 (1H, br s), 9.77 (1H, br s). Production Example 10 5-bromo-3- [N- [2-[[3-
[(1,4-dimethoxy-3,5,6-trimethylbenzene-2
-Yl) methyl] carbamoyloxy] propyl] carbamoyl] ethyl] -N-phenyl] carbamoyl-1
Synthesis of -propylpyridinium iodide (47) i) Synthesis of 5-bromo-3- [N- [2-[(3-hydroxy) propyl] carbamoyl] ethyl] -N-phenyl] carbamoylpyridine (45) Production Example 1 2.00 g (5.73) of the compound (3) synthesized in -iii)
Mmol) and 857 mg of N-hydroxysuccinimide (7.4
1.32 g (6.88 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added to a solution of 5 mmol) in dichloromethane (30 ml) under ice-cooling and stirring, and the mixture was stirred at room temperature for 1 hour. Furthermore, 3-aminopropanol 0.44
ml (5.73 mmol) was added and stirred for 2 hours. The reaction solution is washed with water, dried (K ₂ CO ₃ ), and the solvent is distilled off. The resulting residue is subjected to column chromatography (silica gel; eluent:
Hexane / ethyl acetate = 2/1) to purify the product, 1.83 g
(75.7%, pale yellow oil) was obtained.

IR (Neat) cm ^-1 : 3310, 3060, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 1.70 (2H, quint., J = 6 Hz), 2.6
2 (2H, t, J = 7Hz), 3.42 (2H, q, J = 6Hz), 3.65 (2H, q, J
= 6Hz), 4.23 (2H, t, J = 7Hz), 6.45 (1H, m), 7.09 (1H,
dd, J = 2.8 Hz), 7.20-7.40 (3H, m), 7.80 (1H, t, J = 2H)
z), 8.31 (1H, d, J = 2 Hz), 8.52 (1H, d, J = 2 Hz). ii) 5-bromo-3- [N- [2-[[3- (1,4-dimethoxy-3,5,6-trimethylbenzene-2-yl) methyl] carbamoyloxy] propyl] carbamoyl]
Ethyl] -N-phenyl-carbamoylpyridine (46)
Synthesis of compound (45) 1.82 g (4.31 mmol) synthesized in i)
And pyridine 0.42 ml (5.17 mmol) in dichloromethane 20
0.65 ml of phenyl chlorocarbonate (5.
17 mmol) and stirred for 30 minutes. The reaction solution was washed with 5% saturated aqueous sodium hydrogen carbonate and water, and dried (NaSO ₄ ). 1.51 g (4.31 mmol) of the compound (9) synthesized in Production Example 1-ix) was added to a crude carbonate product obtained by evaporating the solvent under reduced pressure, and the mixture was heated at 120 ° for 1 hour. After cooling, the crude product was subjected to column chromatography (silica gel; eluent:
The residue was purified with ethyl acetate to give 2.35 g of the desired product (82.9%, pale yellow oil).

IR (Neat) cm ^-1 : 3310, 3060, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 1.78 (2H, quint., J = 6 Hz), 2.1
7 (3H, s), 2.19 (3H, s), 2.29 (3H, s), 2.59 (2H, t, J =
7Hz), 3.29 (2H, q, J = 6Hz), 3.64 (3H, s), 3.68 (3H,
s), 4.13 (2H, t, J = 6 Hz), 4.21 (2H, t, J = 7 Hz), 4.39
(2H, d, J = 6Hz), 5.19 (1H, m), 6.40 (1H, m), 7.07 (2
H, dd, J = 2.8 Hz, 7.20-7.40 (3H, m), 7.80 (1H, t, J = 2
Hz), 7.28 (1H, d, J = 2 Hz), 8.50 (1H, d, J = 2 Hz). iii) 5-bromo-3- [N- [2-[[3- (1,4-dimethoxy-3,5,6-trimethylbenzene-2-yl) methyl] carbamoyloxy] propyl] carbamoyl]
Ethyl] -N-phenyl-carbamoyl-1-propylpyridinium Synthesis of iodide (47) ii) Compound (46) synthesized in 450 mg (1.78 mmol)
To 10 ml of 1-iodopropane, and shield from light in a nitrogen stream.
The mixture was heated and stirred for 18 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was subjected to column chromatography (silica gel;
The eluate was purified with chloroform / methanol = 10/1) to obtain 534 mg (94.3%, yellow oil) of the desired product.

IR (KBr) cm ^-1 : 3330, 3040, 1710, 1660, 1590. NMR (90 MHz, CDCl ₃ ) δ 0.82 (3H, t, J = 7 Hz), 1.50-2.1
0 (4H, m), 2.13 (3H, s), 2.15 (3H, s), 2.25 (3H, s),
2.67 (2H, t, J = 6Hz), 3.20 (2H, q, J = 6Hz), 3.60 (3H,
s), 3.66 (3H, s), 4.05 (2H, t, J = 6 Hz), 4.18 (2H, t, J
= 6Hz), 4.34 (2H, d, J = 6Hz), 4.85 (2H, t, J = 7Hz), 5.
03 (1H, m), 7.15 (1H, m), 7.00-7.60 (5H, m), 8.39 (1
H, brs), 9.38 (2H, brs). Production Example 11 5-bromo-3- [N- [2-[[4-
[(1,4-dimethoxy-3,5,6-trimethylbenzene-2
-Yl) methyl] carbamoyloxy] butyl] carbamoyl] ethyl] -N-phenyl] carbamoyl-1-
Synthesis of propylpyridinium iodide (50) i) Synthesis of 5-bromo-3- [N- [2-[(4-hydroxy) butyl] carbamoyl] ethyl-N-phenyl-carbamoylpyridine (48) Production Example 1-iii 2.00 g (5.73) of the compound (3) synthesized by
Mmol) and 857 mg of N-hydroxysuccinimide (7.4
1.32 g (6.88 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added to a solution of 5 mmol) in dichloromethane (30 ml) under ice-cooling and stirring, followed by stirring at room temperature for 1 hour. Furthermore, 4-amino-1-butanol is used.
53 ml (5.73 mmol) was added and stirred for 2 hours. The reaction solution was washed with water, dried (K ₂ CO ₃ ), and the solvent was distilled off. The residue obtained was purified by column chromatography (silica gel; eluent: hexane / ethyl acetate = 2/1). Stuff
1.55 g (62.0%, colorless oil) were obtained.

IR (Neat) cm ^-1 : 3310, 3060, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 1.63 (4H, m), 2.60 (2H, t, J = 7)
Hz), 3.30 (2H, q, J = 6 Hz), 3.67 (2H, m), 4.22 (2H, t, J
= 7Hz), 6.32 (1H, m), 7.10 (2H, dd, J = 2.8Hz), 7.20-
7.40 (3H, m), 7.82 (1H, t, J = 2Hz), 8.30 (1H, d, J = 2H
z), 8.52 (1H, d, J = 2Hz). ii) 5-bromo-3- [N- [2-[[4-[(1,4-
Dimethoxy-3,5,6-trimethylbenzene-2-yl)
Methyl] carbamoyloxy] butyl] carbamoyl]
Synthesis of ethyl-N-phenyl-carbamoylpyridine (49) 1.08 g (2.48 mmol) of compound (48) synthesized in i)
And 0.24 ml (2,98 mmol) of pyridine in dichloromethane 15
0.37 ml of phenyl chlorocarbonate (2.
98 mmol) and stirred for 30 minutes. The reaction solution was washed with 5% saturated aqueous sodium hydrogen carbonate and water, and dried (NaSO ₄ ). To the crude carbonate product obtained by evaporating the solvent under reduced pressure, 867 mg (2,48 mmol) of the compound (9) synthesized in Production Example 1-ix) was added, and the mixture was heated at 120 ° for 1 hour. After cooling, the crude product was subjected to column chromatography (silica gel; eluent:
The residue was purified by ethyl acetate to give 1.41 g (84.8%, colorless oil) of the desired product.

IR (Neat) cm ^-1 : 3320, 3060, 1710, 11650, 1590. NMR (200 MHz, CDCl ₃ ) δ 4.60 (4H, m), 2.17 (3H, s), 2.
19 (3H, s), 2.28 (3H, s), 2.59 (2H, t, J = 7Hz), 3.27
(2H, q, J = 6Hz), 3.62 (3H, s), 3.67 (3H, s), 4.07 (2
H, t, J = 6Hz), 4.20 (2H, t, J = 7Hz), 4.38 (2H, d, J = 6H)
z), 5.34 (1H, m), 6.18 (1H, m), 7.07 (2H, dd, J = 2.8H
z) .7.15−7.35 (3H, m), 7.77 (1H, br s), 8.30 (2H, br
s). iii) 5-bromo-3- [N- [2-[[4-[(1,4-
Dimethoxy-3,5,6-trimethylbenzene-2-yl)
Methyl] carbamoyloxy] butyl] carbamoyl]
Synthesis of ethyl-N-phenyl] carbamoyl-1-propylpyridinium iodide (50) ii) Compound (49) 450 mg (0.67 mmol)
To 10 ml of 1-iodopropane, and shield from light in a nitrogen stream.
The mixture was heated and stirred for 18 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was subjected to column chromatography (silica gel;
The eluate was purified with chloroform / methanol = 10/1) to obtain 488 mg (86.5%, yellow oil) of the desired product.

IR (KBr) cm ^-1 : 3300, 3040, 1710, 1660, 1590. NMR (90 MHz, CDCl ₃ ) δ 0.78 (3H, t, J = 7 Hz), 1.30-2.0
5 (6H, m), 2.12 (3H, s), 2.14 (3H, s), 2.24 (3H, s),
2.66 (2H, t, J = 6Hz), 3.12 (2H, q, J = 6Hz), 3.60 (3H,
s), 3.63 (3H, s), 4.00 (2H, t, J = 6Hz), 4.17 (2H, t, J
= 6Hz), 4.35 (2H, d, J = 6Hz), 4.78 (2H, t, J = 7Hz), 5.
02 (1H, m), 7.03 (1H, m), 7.15-7.55 (5H, m), 8.34 (1
H, brs), 9.32 (1H, brs), 9.43 (1H, brs). Production Example 12 5-bromo-3- [N- [2-[[5-
[(1,4-dimethoxy-3,5,6-trimethylbenzene-2
-Yl) methyl] carbamoyloxy] pentyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-
Synthesis of propylpyridinium iodide (53) i) Synthesis of 5-bromo-3- [N- [2-[(5-hydroxy) pentyl] carbamoyl] ethyl] -N-phenyl] carbamoylpyridine (51) Production Example 1 2.00 g (5.73) of the compound (3) synthesized in iii)
857 mg (7.4 mmol) of N-hydroxysuccinimide.
1.32 g (6.88 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added to a solution of 5 mmol) in dichloromethane (30 ml) under ice-cooling and stirring, and the mixture was stirred at room temperature for 1 hour. Further, 0.62 ml (5.73 mmol) of 5-amino-1-pentanol was added, and the mixture was stirred for 2 hours. The reaction solution is washed with water, dried (K ₂ CO ₃ ), and the solvent is distilled off. The residue obtained is subjected to column chromatography (silica gel;
The eluate was purified by hexane / ethyl acetate = 4/1) to obtain 1.94 g of the desired product (75.2%, pale yellow oil).

IR (Neat) cm ^-1 : 3310, 3060, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 1.30-1.80 (6H, m), 2.60 (2H,
t, J = 7Hz), 3.27 (2H, q, J = 6Hz), 3,64 (2H, m), 4.22
(2H, t, J = 7Hz), 6.20 (1H, m), 7.08 (2H, dd, J = 2.8H)
z), 7.20-7.40 (3H, m), 7.81 (1H, t, J = 2Hz), 8.31 (1
H, d, J = 2Hz), 8.52 (1H, d, J = 2Hz). ii) 5-bromo-3- [N- [2-[[5-[(1,4-
Dimethoxy-3,5,6-trimethylbenzene-2-yl)
Methyl] carbamoyloxy] pentyl] carbamoyl] ethyl-N-phenyl] carbamoylpyridine (5
Synthesis of 2) 1.83 g (4.06 mmol) of compound (51) synthesized in i)
And 0.39 ml (4.88 mmol) of pyridine in dichloromethane 20
0.61 ml of phenyl chlorocarbonate (4.
88 mmol) and stirred for 30 minutes. The reaction solution was washed with 5% saturated aqueous sodium hydrogen carbonate and water, and dried (NaSO ₄ ). To a crude carbonate product obtained by evaporating the solvent under reduced pressure, 1.42 g (4.06 mmol) of the compound (9) synthesized in Production Example 1-ix) was added, and the mixture was stirred at 120 ° for 1 hour. After cooling, the crude product was subjected to column chromatography (silica gel; eluent:
Purification with ethyl acetate) gave 2.34 g (84.0%, colorless oil) of the desired product.

IR (Neat) cm ^-1 : 3320, 3060, 1710, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 1.20-1.80 (6H, m), 2.17 (3H,
s), 2.19 (3H, s), 2.29 (3H, s), 2.59 (2H, t, J = 7Hz),
3.23 (2H, q, J = 6Hz), 3.64 (3H, s), 3.68 (3H, s), 4.05
(2H, t, J = 6Hz), 4.21 (2H, t, J = 7Hz), 4.39 (2H, d, J =
6Hz), 5.10 (1H, m), 6.08 (1H, m), 7.06 (2H, dd, J = 2,8
Hz), 7.20-7.40 (3H, m), 7.78 (1H, t, J = 2Hz), 8.30
(1H, d, J = 2Hz), 8.45 (1H, d, J = 2Hz). iii) 5-bromo-3- [N- [2-[[5-[(1,4-
Dimethoxy-3,5,6-trimethylbenzene-2-yl)
Methyl] carbamoyloxy] pentyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium iodide (53) ii) Compound (52) 450 mg (0.66 mmol)
To 10 ml of 1-iodopropane, and shield from light in a nitrogen stream.
The mixture was heated and stirred for 18 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was subjected to column chromatography (silica gel;
The eluate was purified with chloroform / methanol = 10/1) to obtain 462 mg (82.3%, yellow oil) of the desired product.

IR (KBr) cm ^-1 : 3300, 3040, 1700, 1650, 1590 NMR (90 MHz, CDCl ₃ ) δ 0.82 (3H, t, J = 7 Hz), 1.20-2.0
5 (8H, m), 2.16 (6H, s), 2.26 (3H, s), 2.69 (2H, t, J =
6Hz), 3.12 (2H, q, J = 6Hz), 3.62 (3H, s), 3.67 (3H,
s), 4.01 (2H, t, J = 6 Hz), 4.19 (2H, t, J = 6 Hz), 4.35
(2H, d, J = 6Hz), 4.82 (2H, t, J = 7Hz), 5.02 (1H, m),
6.98 (1H, m), 7.20-7.55 (5H, m), 8.35 (1H, brs), 9.
32 (1H, br s), 9.47 (1H, br s). Production Example 13 5-bromo-3- [N- [2-[[6-
[(1,4-dimethoxy-3,5,6-trimethylbenzene-2
-Yl) methyl] carbamoyloxy] hexyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-
Synthesis of propylpyridinium iodide (56) i) Synthesis of 5-bromo-3- [N- [2-[(6- (hydroxy) hexyl] carbamoyl] ethyl-N-phenyl] carbamoylpyridine (54) Production Example 1- 2.00 g (5.73) of the compound (3) synthesized in iii)
Mmol) and 857 mg of N-hydroxysuccinimide (7.4
1.32 g (6.88 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added to a solution of 5 mmol) in dichloromethane (30 ml) under ice-cooling and stirring, followed by stirring at room temperature for 1 hour. Further, 692 mg (5.73 mmol) of 6-amino-1-hexanol was added and the mixture was stirred for 2 hours. The reaction solution was washed with water, dried (K ₂ CO ₃ ), and the solvent was distilled off. The residue obtained was purified by column chromatography (silica gel; eluent: hexane / ethyl acetate = 2/1). 2.13 g (80.1%, pale yellow oil) of the product were obtained.

IR (Neat) cm ^-1 : 3310, 3060, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 1.20-1.80 (8H, m), 2.61 (2H,
t, J = 7Hz), 3.26 (2H, q, J = 6Hz), 3.64 (2H, q, J = 6H
z), 4.22 (2H, t, J = 7Hz), 6.13 (1H, m), 7.08 (2H, dd, J
= 2,8Hz), 7.20-7.40 (3H, m), 7.81 (1H, t, J = 2Hz),
8.30 (1H, d, J = 2Hz), 8.52 (1H, d, J = 2Hz). ii) 5-bromo-3- [N- [2-[[6-[(1,4-
Dimethoxy-3,5,6-trimethylbenzene-2-yl)
Methyl] carbamoyloxy] hexyl] carbamoyl] ethyl-N-phenyl] carbamoylpyridine (5
Synthesis of 5) 2.02 g (4.35 mmol) of compound (54) synthesized in i)
And pyridine 0.42 ml (5.22 mmol) in dichloromethane (20 ml) under ice-cooling and stirring.
ml (5.22 mmol) was added and stirred for 30 minutes. The reaction solution was washed with 5% saturated aqueous sodium hydrogen carbonate and water, and dried (NaSO ₄ ). 1.51 g (4.3) of the compound (9) synthesized in Production Example 1-ix) was added to a crude product of a carbonate body obtained by evaporating the solvent under reduced pressure.
(1 mmol) and heated at 120 ° for 1 hour. After cooling, the crude product was purified by column chromatography (silica gel; eluent: ethyl acetate) to give 2.60 g of the desired product (85.4%,
(Colorless powder) was obtained.

IR (KBr) cm ^-1 : 3300,3060,1680,1640,1590. NMR (200 MHz, CDCl ₃ ) δ 1.20-1.80 (8H, m), 2.17 (3H,
s), 2.19 (3H, s), 2.30 (3H, s), 2.59 (2H, t, J = 7Hz),
3.23 (2H, q, J = 6Hz), 3.64 (3H, s), 3.69 (3H, s), 4.04
(2H, t, J = 6Hz), 4.22 (2H, t, J = 7Hz). 4.39 (2H, d, j =
6Hz), 5.08 (1H, m), 6.08 (1H, m), 7.07 (2H, dd, J = 2,8
Hz), 7.20-7.40 (3H, m), 7.78 (1H, t, J = 2Hz), 8.31
(1H, d, J = 2Hz), 8.44 (1H, d, J = 2Hz). iii) 5-bromo-3- [N- [2-[[6-[(1,4-
Dimethoxy-3,5,6-trimethylbenzene-2-yl)
Synthesis of methyl] carbamoyloxy] hexyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium iodide (56) 450 mg (0.64 mmol) of compound (55) synthesized by ii)
To 10 ml of 1-iodopropane, and shield from light in a nitrogen stream.
The mixture was heated and stirred for 18 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was subjected to column chromatography (silica gel;
The eluate was purified with chloroform / methanol = 10/1) to obtain 561 mg of the desired product (quant., Yellow oil).

^{IR (KBr) cm -1:.} 3310,3040,1700,1650,1590 NMR (90MHz, CDCl 3) δ 0.80 (3H, t, J = 7Hz), 1.10-2.1
0 (10H, m), 2.19 (6H, s), 2.27 (3H, s), 2.68 (2H, t, J
= 6Hz), 3.10 (2H, q, J = 6Hz), 3.61 (3H, s), 3.66 (3H,
s), 4.01 (3H, t, J = 6 Hz), 4.19 (2H, t, J = 6 Hz), 4.37
(2H, d, J = 6Hz), 4.80 (2H, t, J = 7Hz), 4.96 (1H, m),
6.90 (1H, m), 7.20-7.60 (5H, m), 8.35 (1H, brs), 9.
33 (1H, br s), 9.45 (1H, br s). Production Example 14 5-bromo-3- [N- [2-[[2-
Synthesis of [(3,5,6-trimethyl-1,4-benzoquinone-2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium iodide (58) i) 5 -Bromo-3- [N- [2-[[2-[(3,5,6
Synthesis of -trimethyl-1,4-benzoquinon-2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoylpyridine (57) 314 mg of compound (10) synthesized in Production Example 1-x) 0.5 mmol) of a 50% acetonitrile (8 ml) solution was added dropwise with a 50% acetonitrile (4 ml) solution of cerium (IV) ammonium nitrate 576 mg (1.05 mmol) under ice cooling and stirring, and the mixture was stirred at room temperature for 1 hour. After the reaction, 5% aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. After drying (NaSO ₄ ), the residue obtained by distilling off the solvent was purified by column chromatography (silica gel; eluent: ethyl acetate) to obtain 190 mg of the desired product
(63.6%, yellow powder) was obtained.

NMR (90 MHz, CDCl ₃ ) δ 1.99 (6H, s), 2.16 (3H, s), 2.5
9 (2H, t, J = 7Hz), 3.44 (2H, q, J = 6Hz), 3.90-4.32 (6
H, m), 5.57 (1H, m), 6.55 (1H, m), 6.97−7.45 (5H,
m), 7.78 (1H, m), 8.30 (1H, br s), 8.48 (1H, br s). ii) 5-bromo-3- [N- [2-[[2-[(3,5,6
-Trimethyl-1,4-benzoquinone-2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridium iodide (58) i) Compound (57) synthesized by i) (179 mg) 0.3 mmol) and 15 ml of 1-iodopropane, and protected from light in a nitrogen stream.
The mixture was heated and stirred for hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel; eluent: chloroform / methanol = 6/1).
205 mg (89.0%, yellow powder) of the desired product were obtained.

NMR (90 MHz, CDCl ₃ ) δ 0.79 (3H, t, J = 7 Hz), 1.78 (2H,
m), 1.97 (6H, s), 2.14 (3H, s), 2.70 (2H, m), 3.34 (2
H, m), 3.9-4.3 (6H, m), 4.80 (2H, m), 5.70 (1H, m),
7.1-7.5 (6H, m), 8.42 (1H, br s), 9.40 (2H, br s). Production Example 15 5-bromo-3- [N- [2-[[2- [2
Synthesis of-(3-methyl-1,4-naphthoquinone-2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium chloride (60) i) 5-bromo-3 -[N- [2-[[2-[[(3-
Methyl-1,4-naphthoquinone-2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-
Synthesis of phenyl] carbamoylpyridine (59) 600 mg (0.92) of compound (33) synthesized in Production Example 7-iii)
2.03 g (3.69 mmol) of cerium (IV) nitrate in a 50% acetonitrile (20 ml) solution
(Mmol) in 50% acetonitrile (10 ml) was added dropwise and stirred at room temperature for 1 hour. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying (NaSO ₄ ), the residue obtained by evaporating the solvent is subjected to column chromatography (silica gel; eluent: ethyl acetate methanol = 10/1).
To give 404 mg (70.9%, yellow oil) of the desired product.

IR (KBr) cm ^-1 : 3300, 3060, 2940, 1720, 1660, 1590. NMR (200 MHz, CDCl ₃ ) δ 2.38 (3H, s), 2.58 (2H, t, J = 7)
Hz), 3.48 (2H, q, J = 5 Hz), 4.16 (2H, t, J = 5 Hz), 4.20
(2H, t, J = 7Hz), 4.35 (2H, d, J = 6Hz), 5.64 (1H, m),
6.32 (1H, m), 7.05 (2H, dd, J = 2.8Hz), 7.20-7.40 (3
H, m), 7.65−7.80 (2H, m), 7.80 (1H, t, J = 2Hz), 8.00
−8.15 (2H, m), 8.27 (1H, d, J = 2Hz), 8.50 (1H, d, J = 2
Hz). ii) 5-bromo-3- [N- [2-[[2-[(3-methyl-1,4-naphthoquinone-2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl Synthesis of -1-propylpyridinium chloride (60) 390 mg (0.63 mmol) of compound (59) synthesized in i)
To the mixture was added 1-iodopropane (5 ml), and the mixture was heated and stirred for 6 hours in a nitrogen stream while protecting from light. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was dissolved in 140 ml of 70% methanol / water to obtain an IRA-
The residue was treated with 410 (Cl ⁻ ) [70 ml], and further purified by column chromatography (silica gel; eluent: chloroform / methanol = 4/1) to obtain 387 mg (88.1%, yellow oil) of the desired product. .

IR (KBr) cm ^-1 : 3360, 3250, 3060, 1710, 1660, 1590. NMR (200 MHz, CDCl ₃ ) δ 0.78 (3H, t, J = 6 Hz), 1.88 (2
H, m), 2.34 (3H, s), 2.74 (2H, m), 3.37 (2H, m), 4.04
(2H, m), 4.19 (2H, m), 4.33 (2H, d, J = 6Hz), 4.83 (2
H, m), 6.27 (1H, m), 7.15-7.50 (5H, m), 7.64-7.80
(2H, m), 7.95-8.20 (2H, m), 8.31 (1H, brs), 9.16
(1H, br s), 9.80 (1H, br s). Production Example 16 5-bromo-3- [N- [2-[(3,5,6-
Trimethyl-1,4-benzoquinon-2-yl) methyl]
Synthesis of carbamoyloxy] ethyl-N-phenyl] carbamoyl-1-propylpyridinium iodide (65) i) Synthesis of 5-bromo-3- [N- (2-hydroxyethyl) -N-phenyl] carbamoylpyridine (61) 2.058 g (15 mmol) of 2-anilinoethanol and 10.45 ml (75 mmol) of triethylamine were added to chloroform 1
Then, 4.24 g (16.5 mmol) of 5-bromonicotinic acid chloride hydrochloride was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with a 1N aqueous sodium hydroxide solution, the organic layer was dried over anhydrous potassium carbonate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography (silica gel; 100 g: eluent: hexane / ethyl acetate = 1/4) to obtain 3.427 g (71.1 g) of the desired product (61)
%, A colorless solid).

TLC (Silica Gel: AcOEt / acetone (5/1)): Rf = 0.33NMR
(90MHz, CDCl ₃ ) δ 3.16 (1H, br t), 3.86 (2H, br t),
4.11 (2H, t), 7.27 (5H, m), 7.86 (1H, m), 8.37 (1H,
d), 8.53 (1H, d) IR (KBr) cm ^-1 : 3440, 1640, 1590, 1400, 1295, 1080. ii) 5-Bromo-3- [N- (2-phenoxycarbonyloxyethyl) -N Synthesis of -phenyl] carbamoylpyridine (62) 707 mg (2.2 mmol) of alcohol (61) synthesized in i) and 348 mg (4.4 mmol) of pyridine were treated with methylene chloride.
Dissolve it in 10 ml and cool under ice-cooling phenyl chlorocarbonate 413 mg (2.64
(Mmol) was added and stirred at room temperature for 30 minutes. The reaction solution was washed with a 5% aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate.
1.229 g of a crude carbonate compound was obtained. The crude carbonate was recrystallized from n-hequine-ethyl acetate (5: 1) to obtain 888 mg (91.5%, colorless crystals) of the desired product.

NMR (90 MHz, CDCl ₃ ) δ: 4.28 (1H, t), 4.54 (2H, t), 7.0
0−7.53 (10H, m), 7.82 (1H, t), 8.31 (1H, d), 8.51 (1
H, d). iii) 5-bromo-3- [N- [2-[(1,4-dimethoxy-3,5,6-trimethylbenzene-2-yl) methyl]
Synthesis of carbamoyloxy] ethyl-N-phenyl] carbamoylpyridine (63) ii) Compound (62) 517 mg (1.171 mmol)
And 245 mg (1.171) of compound (9) synthesized in Production Example 1-ix).
(Mmol) was heated and stirred at 90 ° C for 2 hours. After cooling, the residue is subjected to column chromatography (silica gel;
Eluate: purified with hexane / ethyl acetate = 1 / 1.5)
652 mg (100%, white powder) of the desired product was obtained.

NMR (90 MHz, CDCl ₃ ) δ 2.20 (6H, s), 2.26 (3H, s), 3.63
(3H, s), 3.67 (3H, s), 3.97−4.50 (6H, m), 4.90 (1H,
br), 6.97-7.37 (5H, m), 7.80 (1H, t, J = 2Hz), 8.30
(1H, d, J = 2Hz), 8.50 (1H, d, J = 2Hz). iv) 5-bromo-3- [N- [2-[(3,5,6-trimethyl-1,4-benzoquinone-2-yl) methyl] carbamoyloxy] ethyl-N-phenyl] carbamoylpyridine (64) 556 mg (1.0 mmol) of the compound (63) synthesized in iii)
2.50 g (4.2 mmol) of cerium (IV) ammonium nitrate in a 50% acetonitrile (25 ml) solution under ice-cooling and stirring
Was added dropwise at room temperature to give a solution of 2.50% in acetonitrile (10 ml).
Stir for 5 hours. After the reaction, 5% aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. After drying (NaSO ₄ ), the residue obtained by evaporating the solvent was purified by column chromatography (silica gel; eluent: hexane-ethyl acetate = 1 / .5) to obtain 279 mg of the desired product (53.0%, yellow) Powder).

NMR (90 MHz, CDCl ₃ ) δ 2.02 (6H, s), 2.15 (3H, s), 4.0
2-4.47 (6H, m), 5.23 (1H, br), 6.97-7.43 (5H, m),
7.79 (1H, t, J = 2Hz), 8.28 (1H, br s), 8.50 (1H, br
s). v) 5-bromo-3- [N- [2-[(3,5,6-trimethyl-1,4-benzoquinone-2-yl) methyl] carbamoyloxy] ethyl-N-phenyl] carbamoyl-
Synthesis of 1-propylpyridinium iodide (65) iv) To 263 mg (0.50 mmol) of the compound (64) synthesized in iv), 20 ml of 1-iodopropane was added.
The mixture was heated and stirred for hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel; eluent: chloroform / methanol = 6/1).
295 mg (88.7%, yellow powder) of the desired product were obtained.

NMR (90 MHz, CDCl ₃ ) δ 0.77 (3H, t, J = 7 Hz), 1.79 (2H,
m), 2.00 (6H, s), 2.15 (3H, s), 4.15 (6H, m), 4.87 (2
(H, t, J = 7Hz), 5.75 (1H, m), 7.07-7.49 (5H, m), 8.35
(1H, m), 9.24 (1H, br s), 9.52 (1H, br s). Production Example 17 5-bromo-3- [N- [2-[(3,5,6-
Trimethyl-1,4-benzoquinone-2-yl) methyloxycarbonyl] amino] ethyl-N-phenyl] carbamoyl-1-propylpyridinium iodide (67)
I) 5-Bromo-3- [N- [2-[(3,5,6-trimethyl-1,4-benzoquinone-2-yl) methyloxycarbonyl] amino] ethyl-N-phenyl] carbamoylpyridine Synthesis of (66) 1.04 g (1.87) of compound (37) synthesized in Production Example 8-iii)
3.07 g (5.61 mmol) of cerium (IV) nitrate in a 50% acetonitrile (40 ml) solution under ice-cooling and stirring.
(Mmol) in 50% acetonitrile (20 ml) was added dropwise and stirred at room temperature for 1 hour. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying (NaSO ₄ ), the residue obtained by evaporating the solvent is subjected to column chromatography (silica gel; eluent: hexane-ethyl acetate = 1/1).
Then, 680 mg (69.1%, yellow oily substance) of the desired product was obtained.

R (KBr) cm ^-1 : 3390, 3060, 2940, 1720, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 2.04 (6H, s), 2.10 (3H, s), 3.
48 (2H, q, J = 6Hz), 4.09 (2H, t, J = 6Hz), 5.01 (2H,
s), 5.28 (1H, m), 6.90-7.50 (5H, m), 7.83 (1H, t, J =
2Hz), 8.29 (1H, d, J = 2Hz), 8.51 (1H, d, J = 2Hz). ii) 5-bromo-3- [N- [2-[(3,5,6-trimethyl-1,4-benzoquinone-2-yl) methyloxycarbonyl] amino] ethyl-N-phenyl] carbamoyl-1- Synthesis of propylpyridinium iodide (67) Compound (66) synthesized in i) 414 mg (0.79 mmol)
To 10 ml of 1-iodopropane, and shield from light in a nitrogen stream.
The mixture was heated and stirred for 18 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was subjected to column chromatography (silica gel;
The eluate was purified with chloroform / methanol = 7/1) to obtain 300 mg of the desired product (54.7%, yellow oil).

IR (KBr) cm ^-1 : 3390, 3230, 3060, 1710, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 0.74 (3H, t, J = 7 Hz), 1.60-2.
00 (2H, m), 2.02 (3H, s), 2.03 (3H, s), 2.14 (3H, s),
3.56 (2H, m), 4.04 (2H, m), 4.80 (2H, t, J = 6Hz), 6.10
(1H, m), 7.10-7.60 (5H, m), 6.41 (1H, brs), 9.33
(1H, br s), 9.40 (1H, br s). Production Example 18 5-bromo-3- [N- [2- [1-phenyl-1- (3,5,6-trimethyl-1,4-benzoquinone-2)
-Yl) methyloxycarbonyl] amino] ethyl-N
Synthesis of -phenyl] carbamoyl-1-propylpyridinium iodide (72) i) Synthesis of 1- (1,4-dimethoxy-3,5,6-trimethylbenzene-2-yl) -1-phenylmethanol (68) Magnesium 233 mg (9.60 mmol) in anhydrous ether 5
The solution was immersed in ml and heated with 5 mg of iodine. When the reaction starts, stop heating and add 1.51 benzene bromide to maintain reflux.
g (9.60 mmol) in anhydrous ether (20 ml) was added dropwise. After stirring for 30 minutes, a solution of 1.00 g (4.80 mmol) of the compound (40) synthesized in Production Example 9-i) in anhydrous ether (20 ml) was added dropwise under ice cooling. Ice water was added and the organic layer was separated. After drying (MgSO ₄ ), the residue obtained by evaporating the solvent is purified by column chromatography (silica gel; eluent: hexane / ethyl acetate = 10/1) to obtain the desired product
1.37 g (quant., Yellow oil) were obtained.

IR (Neat) cm ^-1 : 3460, 3080, 3060, 2940, 1600. NMR (200 MHz, CDCl ₃ ) δ 2.13 (3H, s), 2.21 (3H, s), 2.
29 (3H, s), 3.09 (3H, s), 3.68 (3H, s), 6.06 (2H, d, J
= 10Hz), 7.15-7.40 (5H, m). ii) Synthesis of 1- (1,4-dimethoxy-3,5,6-trimethylbenzene-2-yl) -1-phenylmethyl N- (2-anilinoethyl) carbamide (69) Compound synthesized with i) (68) ) 1.35 g (4.71 mmol)
And pyridine 1.14 ml (14.1 mmol) chloroform 50 ml
1.80 ml of phenyl chlorocarbonate (14.1
Mmol) and stirred for 30 parts. The reaction solution was washed with 5% saturated aqueous sodium hydrogen carbonate and water, and dried (NaSO ₄ ). The residue obtained by evaporating the solvent under reduced pressure is subjected to column chromatography (silica gel; eluent: hexane / ethyl acetate = 10/1).
And purified. To the obtained carbonate, 1.18 ml (9.00 mmol) of N-phenylethylenediamine was added, and 120
Heated for 1 hour. After cooling, the crude product was purified by column chromatography (silica gel; eluent: hexane / ethyl acetate = 4/1) to obtain 1.34 g (63.5%, pale yellow oil) of the desired product.

IR (Neat) cm ^-1 : 3390, 3050, 1710, 1600. NMR (200 MHz, CDCl ₃ ) δ 2.09 (3H, s), 2.22 (6H, s), 3.
31 (2H, t, J = 6Hz), 3.50 (2H, q, J = 6Hz), 3.61 (3H,
s), 3.66 (3H, s), 5.16 (1H, t, J = 6Hz), 6.61 (2H, d, J
= 8Hz), 6.72 (1H, t, J = 7Hz), 7.10-7.35 (7H, m), 7.5
2 (1H, s). iii) 5-bromo-3- [N- [2- [1-phenyl-
1- (1,4-dimethoxy-3,5,6-trimethylbenzene-
2-yl) methyloxycarbonyl] amino] ethyl]
Synthesis of [N-phenyl] carbamoylpyridine (70) ii) Compound (69) 700 mg (1.56 mmol)
480 mg (2.18 mmol) of 5-bromonicotinic acid chloride was added to a dichloromethane (20 ml) solution of the compound and 0.52 ml (3.74 mmol) of triethylamine under ice-cooling, and the mixture was stirred for 30 minutes. The reaction solution was washed with a 1N aqueous solution of sodium hydroxide and water, and dried (KCO ₃ ). The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel; eluent: hexane / ethyl acetate = 3/2) to obtain the desired product 8
52 mg (86.3%, colorless oil) were obtained.

IR (Neat) cm ^-1 : 3350, 3060, 1720, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 2.10 (3H, s), 2.21 (6H, s), 3.
54 (2H, q, J = 6 Hz), 3.60 (3H, s), 3.66 (3H, s), 4.13
(2H, t, J = 6Hz), 5.43 (1H, m), 7.00-7.40 (10H, m),
7.48 (1H, s), 7.80 (1H, br s), 8.27 (1H, br s), 8.50
(1H, d, J = 2Hz). iv) 5-bromo-3- [N- [2- [1-phenyl-1]
Synthesis of-(3,5,6-trimethyl-1,4-benzoquinone-2-yl) methyloxycarbonyl] amino] ethyl-N-phenyl] carbamoylpyridine (71) iii) 830 mg of compound (70) synthesized by (iii) 1.31 mmol)
2.50 g (3.93 mmol) of cerium (IV) ammonium nitrate in a 50% acetonitrile (30 ml) solution under ice-cooling and stirring
Of acetonitrile (15 ml) was added dropwise at room temperature.
Stirred for hours. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying (NaSO ₄ ), the residue obtained by evaporating the solvent is subjected to column chromatography (silica gel;
The eluate was purified with hexane-ethyl acetate = 3/2) to obtain 380 mg (48.1%, yellow oil) of the desired product.

IR (Neat) cm ^-1 : 3330, 3060, 1720, 1640, 1590. NMR (200 MHz, CDCl ₃ ) δ 2.01 (3H, s), 2.08 (3H, s), 2.
14 (3H, s), 3.54 (2H, m), 4.11 (2H, t, J = 6Hz), 5.52
(1H, m), 7.00-7.60 (11H, m), 7.78 (1H, brs), 8.27
(1H, br s), 8.51 (1H, br s). v) 5-bromo-3- [N- [2- [1-phenyl-1]
Synthesis of-(3,5,6-trimethyl-1,4-benzoquinone-2-yl) methyloxycarbonyl] amino] ethyl-N-phenyl] carbamoyl-1-propylpyridinium iodide (72) iv) (71) 350 mg (0.58 mmol)
To 10 ml of 1-iodopropane, and shield from light in a nitrogen stream.
The mixture was heated and stirred for 12 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was dissolved in 70% methanol / water (100 ml).
The residue was treated with 410 (Cl ⁻ ) [50 ml], and further purified by column chromatography (silica gel; eluent: chromatoform / methanol = 15/1) to obtain 100 mg of the desired product (22.3%, yellow oil). Was.

IR (Neat) cm ^-1 : 3250, 3060, 1720, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 0.70 (3H, t, J = 7 Hz), 1.76 (2
H, m), 2.00 (3H, s), 2.02 (3H, s) 2.08 (3H, s), 3,62
(2H, m), 4.12 (2H, m), 4.73 (2H, t, J = 7Hz), 6.58 (1
H, m), 7.50-7.60 (11H, m), 8.32 (1H, brs), 9.23 (1
H, brs), 9,38 (1H, brs). Production Example 19 5-bromo-3- [N- [2-[[3-
Synthesis of [(3,5,6-trimethyl-1,4-benzoquinone-2-yl) methyl] carbamoyloxy] propyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium iodide (74) i) 5 -Bromo-3- [N- [2-[[3-[(3,5,6
Synthesis of -trimethyl-1,4-benzoquinone-2-yl) methyl] carbamoyloxy] propyl] carbamoyl] ethyl-N-phenyl] carbamoylpyridine (73) 1.69 g of the compound (46) synthesized in Production Example 10-ii) (2.57
Mmol) in a 50% acetonitrile (50 ml) solution under ice-cooling and stirring, and 4.29 g (7.71 ammonium cerium (IV) nitrate).
(Mmol) in 25 ml of 50% acetonitrile was added dropwise and stirred at room temperature for 1 hour. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying (NaSO ₄ ), the residue obtained by evaporating the solvent was purified by column chromatography (silica gel; eluent: ethyl acetate), and 1.22 g of the desired product was obtained.
(75.6%, yellow oil) was obtained.

IR (Neat) cm ^-1 : 3320, 3060, 1720, 1640, 1590. NMR (200 MHz, CDCl ₃ ) δ 1.79 (2H, quint, J = 6 Hz), 2.01
(6H, s), 2.20 (3H, s), 2.61 (2H, t, J = 7Hz), 3.31 (2
H, q, J = 6 Hz), 4.10 (2H, t, J = 6 Hz), 4.20 (2H, d, J = 6H)
z), 4.21 (2H, t, J = 7Hz), 5.19 (1H, m), 6,40 (1H, m),
7.07 (2H, dd, J = 2.8Hz), 7.20-7.40 (3H, m), 7.80 (1
H, t, J = 2Hz), 7.28 (1H, d, J = 2Hz), 8.50 (1H, d, J = 2H)
z). ii) 5-bromo-3- [N- [2-[[3-[(3,5,6
-Trimethyl-1,4-benzoquinone-2-yl) methyl] carbamoyloxy] propyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium iodide (74) 1.12 g of compound (73) synthesized by i) 1.78 mmol)
To 10 ml of 1-iodopropane, and shield from light in a nitrogen stream.
The mixture was heated and stirred for 18 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was subjected to column chromatography (silica gel;
The eluate was purified by chromatography / methanol = 7/1) to obtain 1.28 g (89.9%, yellow oil) of the desired product.

IR (KBr) cm ^-1 : 3430, 3270, 3040, 1710, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 0.83 (3H, t, J = 7 Hz), 1.85 (4
H, m), 2.01 (6H, s), 2.18 (3H, s), 2,73 (2H, t, J = 7H
z), 3.21 (2H, t, J = 6Hz), 4.04 (2H, t, J = 6Hz), 4,18
(2H, d, J = 6Hz), 4.22 (2H, t, J = 7Hz), 4.78 (2H, t, J =
7Hz), 5.43 (1H, m), 7.01 (1H, m), 7.20-7.50 (5H,
m), 8.25 (1H, br s), 9.33 (1H, br s), 9.04 (1H, br)
s), 9.60 (1H, br s). Production Example 20 5-bromo-3- [N- [2-[[5-
Synthesis of [(3,5,6-trimethyl-1,4-benzoquinone-2-yl) methyl] carbamoyloxy] pentyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium iodide (76) i) 5 -Bromo-3- [N- [2-[[5-[(3,5,6
Synthesis of -trimethyl-1,4-benzoquinone-2-yl) methyl] carbamoyloxy] pentyl] carbamoyl] ethyl-N-phenyl] carbamoylpyridine (75) 1.91 g of the compound (52) synthesized in Production Example 12-ii) (2.79
Mmol) in a 50% acetonitrile (60 ml) solution under ice-cooling and stirring, and 4.66 g (8.37 g) ammonium cerium (IV) nitrate.
(Mmol) in 50% acetonitrile (30 ml) was added dropwise and stirred at room temperature for 1 hour. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying (NaSO ₄ ), the residue obtained by evaporating the solvent was purified by column chromatography (silica gel; eluent: ethyl acetate) to obtain 1.35 g of the desired product (73.9%, yellow oil). .

IR (Neat) cm ^-1 : 3320, 3060, 1720, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 1.20-1.80 (2H, m), 2.01 (6H,
s), 2,21 (3H, s), 2.60 (2H, t, J = 7Hz), 3.24 (2H, q, J
= 6Hz), 4.02 (2H, t, J = 6Hz), 4.20 (2H, d, J = 6Hz), 4.
22 (2H, t, J = 7Hz), 5.36 (1H, t, J = 6Hz), 6.09 (1H,
m), 7.09 (2H, dd, J = 2.8 Hz), 7.20-7.40 (3H, m), 7.80
(1H, t, J = 2Hz), 7.31 (1H, d, J = 2Hz), 8.52 (1H, d, J =
2Hz). ii) 5-bromo-3- [N- [2-[[5-[(3,5,6
Synthesis of -trimethyl-1,4-benzoquinone-2-yl) methyl] carbamoyloxy] pentyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium iodide (76) Compound (75) 1.05 synthesized with i) g (1.60 mmol)
Then, 10 ml of 1-iodopropane was added thereto, and the mixture was heated and stirred for 8 hours while shielding light in a nitrogen stream. After cooling, the reaction solution was concentrated under reduced pressure, and the obtained crude product was subjected to column chromatography (silica gel;
The eluate was purified with chloroform / methanol = 7/1) to obtain 1.24 g (93.8%, yellow oil) of the desired product.

IR (KBr) cm ^-1 : 3260, 3040, 1700, 1650, 1590. NMR (200 MHz, CDCl ₃ ) δ 0.84 (3H, t, J = 7 Hz), 1.20-1.
80 (6H, m), 1.92 (2H, m), 2.02 (6H, s), 2.20 (3H, s),
2.73 (2H, t, J = 7Hz), 3.14 (2H, q, J = 6Hz), 3.98 (2H,
t, J = 6Hz), 4.18 (2H, d, J = 6Hz), 4.24 (2H, t, J = 7H)
z), 4.77 (2H, t, J = 7Hz), 5.33 (1H, m), 6.92 (1H, m),
7.20−7.50 (5H, m), 8.19 (1H, br s), 9.31 (1H, br
s), 9.63 (1H, br s).

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/44 ACJ A61K 31/44 ACJ ACZ ACZ AED AED C07D 213/71 C07D 213/71 213/81 213/81 213/84 213 / 84 401/12 401/12 (56) Reference Patent 2756975 (JP, B2) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 213/00-213/84 C07D 401/00-401 / 12 A61K 31/00-31/44 CA (STN) REGISTRY (STN)

Claims (21)

(57) [Claims] (1) ExpressionA compound represented by the formula: [Where,Represents an optionally substituted pyridinium ring, and R¹Is low
A lower alkyl or aralkyl group;⁷, R^TenAnd R
¹¹Is hydrogen, lower alkyl group, aryl group or
Represents an aralkyl group; l represents 0 or 1;^FiveIs Fe
Represents a nylene group or an optionally substituted alkylene group
Then R¹²Is the expression[Where R¹³, R¹⁴, R^Fifteen, R¹⁶And R¹⁷Is hydrogen
Or a lower alkyl group, or R¹⁶And R¹⁷Joins
May form a benzene ring.]
And n ′ represents an integer of 1 to 3, and X represents a formula(Where R⁶Is hydrogen, lower alkyl group or lower alkoxy
A group represented by the formula: m represents an integer of 0 to 4)
And U is the formula(Where R^FourIs hydrogen, lower alkyl group, aryl group or
Represents an aralkyl group), Y and
Z is the formula(Wherein R is hydrogen, a lower alkyl group, an acyl group or
1 to 6 selected from groups represented by
A divalent chain group consisting of at least one of the formulaIs a group represented by the formulaWhen there are two or more groups represented by
And R may be different from each other,
Y may be the formulaWhen a group represented by is represented by R^FourMay be combined with
No. Also, W Indicates an anion] (2) Has 1 to 4 halogeno groups, lower alkyl groups, lower alkoxy groups, nitro groups, cyano groups, lower alkoxycarbonyl groups, carbamoyl groups or lower alkylcarbamoyl groups. (3) Binds to the side chain at positions 2-4. 4. The compound according to claim 1, wherein the aralkyl group represented by R ¹ , R ⁴ , R ⁷ , R ¹⁰ or R ¹¹ is phenyl-lower alkyl or naphthyl-lower alkyl. 5. An aryl group represented by R ⁴ , R ⁷ , R ¹⁰ or R ¹¹ is an aromatic monocyclic, bicyclic or tricyclic hydrocarbon residue or an aromatic monocyclic or bicyclic aromatic residue. The compound according to claim 1, which is a heterocycle. 6. Z is a formula Wherein R ⁸ and R ⁹ are each hydrogen, a lower alkyl group,
And n represents an acyl group or an aryl group, and n represents 1 or 2.]. 7. The compound according to claim 6, wherein the acyl group represented by R ⁸ or R ⁹ is lower alkanoyl or aromatic carbonyl. ^{8. The} aryl group represented by R ⁸ or R ⁹ is an aromatic monocyclic, bicyclic or tricyclic hydrocarbon residue or an aromatic monocyclic or bicyclic heterocycle. A compound as described. 9. Y is an expression Wherein R ² and R ³ are each hydrogen, a lower alkyl group,
R ² represents an acyl group or an aryl group, R ² may be bonded to R ⁴ to form a ring, and n represents 1 or 2.]. 10. The compound according to claim 9, wherein the acyl group represented by R ² or R ³ is lower alkanoyl or aromatic carbonyl. 11. The aryl group represented by R ² or R ³ is an aromatic monocyclic, bicyclic or tricyclic hydrocarbon residue or an aromatic monocyclic or bicyclic heterocycle. A compound as described. 12. R ² is bonded to R ^4, Is the expression The compound according to claim 9, which forms a group represented by the formula: wherein p and q each represent 2 or 3. 13. W Is a pharmacologically acceptable anion
The compound according to claim 1, which is 14. W Is Cl Or NO_Three Claim 1
A compound as described. 15. R ¹ is a lower alkyl group, R ⁵ is a phenylene group or an alkylene group, and U is a group represented by the formula The compound according to claim 1, which is a group represented by the formula: 16. The expressionThe compound according to claim 1, which is represented by the formula: [Where R¹Represents a lower alkyl group; R^FourIs a halogeno group
Represents an optionally substituted phenyl group, R^FiveIs ethylene
Group or trimethylene group, R¹⁸Represents a halogeno group
X is of the formula-(CH_Two)_m-(Wherein m represents 0 or 1)
A group represented by the formula: Is halogeno ion or nitrate
Represents an acid ion, and Y is a formulaR represents a group represented by¹³, R¹⁴, R^Fifteen, R¹⁶And R¹⁷
Each represents hydrogen or a lower alkyl group.] 17. A compound of the formula: 5-bromo-3- [N- [2-[[2-
[(1,4-dimethoxy-3,5,6-trimethylbenzene-2
-Yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium nitrate. 18. A method according to claim 18, wherein 5-bromo-3- [N- [2-[[2-
[(1,4-dimethoxy-3,5,6-trimethylbenzene-2
-Yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium chloride. 19. A method according to claim 19, wherein 5-bromo-3- [N- [2-[[2-
2. The compound according to claim 1, which is [(3,5,6-trimethyl-1,4-benzoquinone-2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium iodide. . 20. 5-bromo-3- [N- [2-[[-2
The compound according to claim 1, which is-[2- (3-methyl-1,4-naphthoquinone-2-yl) methyl] carbamoyloxy] ethyl] carbamoyl] ethyl-N-phenyl] carbamoyl-1-propylpyridinium chloride. 21. An anti-PAF containing the compound according to claim 1.
Agent.