JPH05148222A - Naphthoic acid derivative - Google Patents

Abstract

PURPOSE:To provide the subject new compound having 5-lipoxygenaseinhibitory activity, thus useful as an antiallergic agent. CONSTITUTION:The objective compound of formula I (R1-R3 are each H, halogen, OH, lower alkoxy, aralkyloxy, etc.; R4 is H or lower alkyl; R5 is phenyl or aromatic heterocycle; X is CH2, N(R7), cyclic alkylamine, etc.,; Y is S(O)p, (CH2)n, O, etc.; Z is alkylene or single bond; R7 is H or lower alkyl; (q) is 0 or 1; (l) is 0-4; (m) is 0-8; (n) is 0 or 1; (p) is 0-2), e.g. N-[5-(2-thienylmethulthio) pentyl]-3,5-dicetoxy-2-naphthamide. The compound of the formula I is obtained by amidation of a carboxylic acid compound of formula II with an amine compound of formula III in the presence of a condensation agent (e.g. N,N'- dicyclohexylcarbodiimide) in an inert solvent (e.g. dichloronmethane) at 0-150 deg.C.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has the general formula

[0002]

[Chemical 2]

(In the formula, R ₁ , R ₂ and R ₃ are hydrogen atom, halogen atom, hydroxyl group, lower alkyl group, lower alkoxy group, lower alkanoyloxy group, hydroxyalkyl group, lower alkoxyalkyl group, lower alkanoyloxy group. Alkyl group or arylalkyloxy group, R ₄
Is a hydrogen atom or a lower alkyl group, R ₅ is a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group, and X is a group represented by —CH (R ₆ ) —. , cyclic alkylene group, a divalent nitrogen-containing heterocyclic group, a cyclic alkyl amino group or -N (R ₇₎ - or -NH
-R ₈ - with a group represented, wherein R ₆ and R ₇ is a hydrogen atom or a lower alkyl group, or R ₈ represents a cyclic alkylene group, or R ₆ or R ₇ together with R ₄ To form an alkylene group having 1 to 3 carbon atoms,
Y _{is, -S (O) p -,} - (CH 2) n -, - O-, or a single bond, Z is a substituted or unsubstituted alkylene group, or represents a single bond, Q is 0 1, _L is 0
4, m is 0 to 8, n is 0 or 1, and P is 0 to
It is 2. ) Relates to a naphthoic acid derivative.

The naphthoic acid derivative represented by the general formula (I) has a 5-lipoxygenase inhibitory action,
It is useful as a medicine, especially as an antiallergic agent.

[0005]

BACKGROUND OF THE INVENTION Diseases caused by allergic reactions include bronchial asthma, rhinitis, seasonal conjunctivitis, urticaria and the like.
It is known that these diseases involve chemical mediators such as histamine, leukotrienes, prostaglandins, thromboxane (TX), and platelet activating factor (PAF), and these various chemical mediators. Various anti-allergic agents that act individually on the above have been developed.

However, these anti-allergic agents are not always satisfactory in treating and curing allergic symptoms resulting from complicated involvement of chemical mediators. Therefore, various studies have been conducted to find compounds that simultaneously inhibit a plurality of chemical mediators, and some amide compounds have been proposed (Japanese Patent Publication No. 63-55508).
No. 63-55510).

[0007]

These amide compounds have an action of suppressing the production of leukotrienes by the inhibitory action of 5-lipoxygenase and a histamine antagonizing action. However, these amide compounds inhibit the production of these leukotrienes and antagonize histamine. Even the above-mentioned proposed amide compound having an action cannot be said to have a sufficient effect for treating and treating a disease caused by a complicated allergic reaction, and acts on a plurality of chemical mediators. The emergence of more effective antiallergic agents is strongly desired.

[0008]

Means for Solving the Problems The present inventors have conducted various studies in order to solve the above-mentioned problems and have a 5-lipoxygenase inhibitory action, as well as a TXA ₂ synthase inhibitory action (TXA ₂ antagonistic action) and histamine. The naphthoic acid derivative represented by the above general formula (I) having a novel naphthalene ring having both an antagonistic effect and a membrane stabilizing effect on histamine-releasing mast cells has been found, and the present invention has been completed.

In the present specification, the term "lower" is used to indicate that the group or compound to which the term is attached has 6 or less carbon atoms.

The "halogen atom" includes four kinds of fluorine, chlorine, bromine and iodine atoms.

The "alkyl group" may be linear or branched, and therefore "lower alkyl group".
Are, for example, methyl, ethyl, propyl, iso
-Propyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, hexyl groups and the like can be mentioned.

The "lower alkoxy group" is a lower alkyloxy group having a lower alkyl moiety as defined above, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, an iso-propoxy group, a butoxy group, a tert-butoxy group, a pentoxy group, and a hexyloxy group. Be done.

The "lower alkanoyloxy group" is a (lower alkyl) -C in which the lower alkyl moiety has the above meaning.
It is an O—O— group, and specifically includes, for example, an acetoxy, propionyloxy, butyryloxy group and the like.

The "hydroxy lower alkyl group" is a lower alkyl group substituted with a hydroxyl group, and examples thereof include a hydroxymethyl group, a 2-hydroxyethyl group, a 2- or 3-hydroxypropyl group, and a 4-hydroxybutyl group.

The "lower alkoxyalkyl group" is a lower alkoxy-substituted lower alkyl group having a lower alkoxy moiety and a lower alkyl moiety having the above-mentioned meanings, for example, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, Methoxypropyl, propoxymethyl, methoxybutyl groups and the like can be mentioned.

"Lower alkanoyloxyalkyl group"
Is a lower alkanoyloxy-substituted lower alkyl group in which the lower alkanoyloxy moiety and the lower alkyl moiety have the above-mentioned meanings, and includes, for example, acetoxymethyl, acetoxyethyl, propoxymethyl, and propoxyethyl groups.

The "aralkyloxy group" means a lower alkoxy group substituted with an aromatic hydrocarbon group, and the aromatic hydrocarbon group includes not only carbocyclic types such as phenyl and naphthyl groups but also pyridyl group. , Imidazolyl, pyrazinyl, furyl, thienyl, pyrrolyl, oxazolyl, and other heterocyclic types.

Here, specific examples of the aralkyloxy group include, for example, benzyloxy group, phenethyloxy group, phenylpropyloxy group, phenylbutyloxy group, phenylpentyloxy group, phenylhexyloxy group,
2-pyridylmethyloxy group, 3-pyridylmethyloxy group, 4-pyridylmethyloxy group, 1-imidazolylmethyloxy group, 2-pyrazinylmethyloxy group, 2-
Furylmethyloxy group, 3-furylmethyloxy group, 2
Examples thereof include a -thienylmethyloxy group, a 3-thienylmethyloxy group, a 1-pyrrolylmethyloxy group and a 2-oxazolylmethyloxy group.

The "aromatic hydrocarbon group" in the expression "substituted or unsubstituted aromatic hydrocarbon group" may be either monocyclic or polycyclic type, such as phenyl or naphthyl group. Is included. Further, the “aromatic heterocyclic group” in the expression “substituted or unsubstituted aromatic heterocyclic group” means at least one, preferably 1 to 4 selected from nitrogen, oxygen and sulfur atoms in the ring. A heterocyclic group having aromatic unsaturation containing 4 heteroatoms, preferably a 5- or 6-membered heterocyclic group, and examples thereof include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridyl and pyrazinyl groups. Included.

Possible substituents on the above aromatic hydrocarbon group and aromatic heterocyclic group are a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxy-lower alkyl group, a lower alkanoyl group. , Lower alkoxycarbonyl group, trifluoromethyl group, carboxyl group, lower alkoxycarbonyl group, hydroxyl group, nitro group, cyano group, amino group, phenyl group,
Examples thereof include an imidazolyl group, an imidazolylmethyl group and an alkylenedioxy group, and the aromatic hydrocarbon group and aromatic heterocyclic group may be substituted with 1 to 5 of these substituents.

Here, "substituted aromatic hydrocarbon group"
And specific examples of the “substituted aromatic heterocyclic group” include 2-chlorothienyl, 3-chlorothienyl, 3-bromothienyl, 3-fluoropyridyl, 3,4-dichloropyridyl, 2-methoxythienyl, 2-methoxyfuryl, 3,4-methoxypyridyl, 2-hydroxythienyl, 3-hydroxyfuryl, 3,4-dihydroxypyridyl, 2-aminothienyl, 3-aminothienyl, 3-
Amino-4-hydroxypyridyl, 2-acetoxythienyl, 3-acetoxyfuryl, 2-imidazolylmethylthienyl, 3-imidazolylmethylthienyl, 3-imidazolylmethylpyridyl, 2-imidazolylpyridyl,
3-imidazolyl furyl, 4-imidazolyl pyridyl,
3-trifluoromethylfuryl, 3,4-ditrifluoromethylpyridyl and the like can be mentioned.

The "cyclic alkylene group" is a cyclic alkylene group having 3 to 8 carbon atoms, preferably 5 to 7 carbon atoms, and examples thereof include cyclopropylene, cyclobutylene, cyclopentylene,
Cyclohexylene, cycloheptylene, cyclooctylene groups and the like are included.

The "divalent nitrogen-containing heterocyclic group" is a saturated heterocyclic group containing at least 1, preferably 1 to 2 nitrogen atoms in the ring, which is a 4- to 8-membered ring, Especially 6-7
A member ring is suitable.

Examples of such a divalent nitrogen-containing heterocyclic group include piperazine-1,4-diyl group and piperidine-
1,4-diyl group, perhydroazepine-1,4-diyl group, homopiperazine-1,4-diyl group, imidazolidine-1,3-diyl group and the like can be mentioned.

The "alkylene group" may be linear or branched and is, for example, methylene, ethylene, 1,3-propylene, 1,2-propylene, 1,4.
-Butylene, 1,2-butylene, pentamethylene, hexamethylene, heptamethylene, octamethylene groups and the like are included.

In the above general formula (I), R ₁ , R ₂ and R ₃ may be substituted at any position of the naphthalene ring, but generally speaking, R ₁ and / or R ₂ is 5 It is preferred that it is in the-and / or 7-position, and that R
₃ is preferably in the 2-position.

_One of R ₁ and R ₂ is a hydrogen atom and the other is a hydroxyl group, a lower alkoxy group (especially methoxy group), a lower alkanoyloxy group (especially acetyloxy group) or a pyridyl-substituted lower alkoxy. It is preferable to represent a group (particularly a pyridylmethyloxy or a pyridylethyloxy group), and R ₃ is a hydroxyl group,
It is preferable to represent a lower alkoxy group (especially methoxy group) or a lower alkanoyloxy group (especially acetyloxy group).

In the above general formula (I), X represents a group --CH (R ₆ )-or --N (R ₇ )-and R ₆
Or when R ₇ together with R ₄ represents an alkylene group having 1 to 3 carbon atoms, preferably 1 to 2 carbon atoms

[0029]

[Chemical 3]

Examples of the parts include the following.

For example, piperazine-1,4-diyl group, piperidine-1,4-diyl group, perhydroazepine-
1,4-diyl group, homopiperazine-1,4-diyl group, imidazolidine-1,3-diyl group and the like. A piperazine-1,4-diyl group and a piperidine-1,4-diyl group are preferred.

Further, in the "substituted or unsubstituted alkylene group" which can be represented by Z in the above general formula (I), the alkylene group generally has 1 carbon atom.
~ 4, the alkylene group is mono-substituted with a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group which is the same as or different from R ₅ and is defined for R ₅ . Can have been.

On the other hand, the substituted or unsubstituted aromatic hydrocarbon group represented by R ₅ or the substituted or unsubstituted aromatic heterocyclic group is preferably a phenyl group, a naphthyl group, a mono- or di- group. Halophenyl group,
Lower alkylphenyl group, lower alkoxyphenyl group,
Lower alkylthiophenyl group, nitrophenyl group, cyanophenyl group, lower alkoxycarbonylphenyl group,
Lower alkanoylphenyl group, biphenylyl group, mono-
Alternatively, a ditrifluoromethylphenyl group, a methylenedioxyphenyl group, a thienyl group, a halothienyl group, a furyl group, a pyridyl group and the like can be mentioned.

As Z, especially --CH _2- , --CH ₂ C
_{H 2 -, - CH (R} 9) - or preferably represent a single bond, wherein R ₉ represents a phenyl group, a halophenyl group or a pyridyl group.

In the general formula (I), X is preferably --CH _2- , --N (CH ₃ )-, piperazine-1,4-diyl group, piperidine-1,4-diyl group. , Homopiperazine-1,4-diyl group and the like. Further, R ₄ is usually preferably a hydrogen atom, and q is preferably 0.

Y represents --S (O) _p -,-(CH ₂ ) _n-, or --O--, wherein --S (O) _p --is p
Means a sulfide group when p is 0, a sulfyl group when p is 1 and a sulfonyl group when p is 2;
(CH _{2) n} - is, n is a single bond when 0, and when n is 1 means a methylene group. Therefore, preferable examples of Y include a sulfinyl group (-S-), a methylene group, -O- and a single bond, and particularly -S-,
-O- and a single bond are preferred.

Further, m is preferably in the range of 0-4.

The above-mentioned general formula (I) provided by the present invention
Representative examples of the compound (1) are as follows, except for those listed in Examples below.

N- [2- [4- (benzhydryloxy) piperidino] ethyl] -6,7-dihydroxy-2
-Naphthamide, N- [2- [4- (benzhydryloxy) piperidino] ethyl] -3- (6,7-dihydroxynaphtholyl)-(E) -2-propenamide, N-
[2- [4- (Benzhydryloxy) piperidino] ethyl] -3- (5,8-dihydroxynaphtholyl)-
(E) -2-propenamide, N- [2- [4- (benzhydryloxy) piperidino] ethyl] -5,8-dihydroxy-2-naphthamide, N- [2- [4- (benzhydryl) (Oxy) piperidino] ethyl] -3- (3,3
7-dihydroxynaphtholyl)-(E) -2-propenamide, N- [2- [4- (benzhydryloxy) piperidino] ethyl] -3- (3,5-dihydroxynaphtholyl)-(E) -2-propenamide, N- [2-
[4- (benzhydryloxy) piperidino] ethyl]
-6-Hydroxy-7-pyridylmethoxy-2-naphthamide, N- [2- [4- (benzhydryloxy) piperidino] ethyl] -6-hydroxy-7- [2- (pyridyl) ethoxy] -2- Naftamide, N- [2- [4-
(Benzhydryloxy) piperidino] ethyl] -6-
Hydroxy-7- [3- (pyridyl) propyloxy]
-2-naphthamide, N- [2- [4- (benzohydryloxy) piperidino] ethyl] -6-hydroxy-7-
[2- (1-Imidazolyldiyl) ethoxy] -2-naphthamide, N- [2- [4- (benzhydryloxy) piperidino] ethyl] -3- (6-hydroxy-7-pyridylmethoxynaphthoyl)- (E) -2-propenamide, N- [2- [4- (benzhydryloxy) piperidino] ethyl] -3- (6-hydroxy-7- (1-imidazolyl) ethoxy] naphthoyl]-(E) -2-propenamide, N- [2- [4- (benzhydryloxy) piperidino] ethyl] -8-hydroxy-5-pyridylmethoxy-2-naphthamide, N- [2- [4- (benzhydryl) Oxy) piperidino] ethyl] -8-hydroxy-5- [2- (pyridyl) ethoxy] -2-naphthamide, N- [2- [4- (benzhydryloxy) piperidino] ethyl -8-hydroxy-5- [3- (pyridyl) propyloxy] -2-naphthamide, N- [2-
[4- (benzhydryloxy) piperidino] ethyl]
-8-Hydroxy-5- [2- (1-imidazolyl) ethoxy] -2-naphthamide, N- [2- [4- (Benzhydryloxy) piperidino] ethyl] -3- (8-hydroxy-5- Pyridylmethoxynaphthoyl)-(E)
-2-propenamide, N- [2- [4- (benzhydryloxy) piperidino] ethyl] -3- [8-hydroxy-5- [2- (1-imidazolyl) naphthoyl]-
2-propenamide, N- [2- [4- (benzhydryloxy) piperidino] ethyl] -3- [3-hydroxy-7-pyridylmethoxynaphthoyl]-(E) -2-
Propenamide, N- [2- [4- (benzhydryloxy) piperidino] ethyl] -3- [3-hydroxy-
7- [2- (pyridyl) ethoxynaphthoyl]-(E)
-2-propenamide, N- [2- [4- (benzhydryloxy) piperidino] ethyl] -3- [3-hydroxy-7- [3- (pyridyl) propyloxynaphthoyl]-(E)- 2-propenamide, N- [2- [4-
(Benzhydryloxy) piperidino] ethyl] -3-
[3-Hydroxy-7- [2- (1imidazolyl) ethoxy] naphthoyl]-(E) -2-propenamide, N
-[2- [4- (benzhydryloxy) piperidino]
Ethyl] -3-hydroxy-5- [2- (pyridyl) ethoxy] -2-naphthamide, N- [2- [4- (benzhydryloxy) piperidino] ethyl] -3-hydroxy-5- [3- (Pyridyl) propyloxy] -2-naphthamide, N- [2- [4- (benzhydryloxy)
Piperidino] ethyl] -3-hydroxy-5- [2-
(1-Imidazolyl) ethoxy] -2-natamid, N
-[2- [4- (benzhydryloxy) piperidino]
Ethyl] -3- (3-hydroxy-5-pyridylmethoxynaphthoyl]-(E) -2-propenamide, N-
[2- [4- (Benzhydryloxy) piperidino] ethyl] -3- [3-hydroxy-5- [2- (1-imidazolyl) ethoxy] naphthoyl]-(E) -2-propenamide, N- [2- [methyl- [2-[(4-chlorophenyl) -phenylmethoxy] ethyl] aminoethyl] -3-hydroxy-5-pyridylmethoxy-2-naphthamide, N- [2- [methyl- [2- [ (4-Chlorophenyl)-(2-pyridyl) methoxy] ethyl] aminoethyl] -3-hydroxy-5-pyridylmethoxy-
2-naphthamide, N- [2- [methyl- [2-[(2-
Pyridyl) -phenylmethoxy] ethyl] aminoethyl] -3-hydroxy-5-pyridylmethoxy-2-naphthamide, N- [2- [methyl- [3-[(4-chlorophenyl)-(2-pyridyl) methoxy]] Propyl] aminoethyl] -3-hydroxy-5-pyridylmethoxy-2-naphthamide, N- [3- [4- (benzhydryloxy) piperidino] propyl] -3-hydroxy-5
-Pyridylmethoxy-2-naphthamide, N- [2- [4
-[(2-Pyridyl) -phenylmethoxy] piperidino] ethyl] -3-hydroxy-5-pyridylmethoxy-2-naphthamide, N- [2- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] ] Piperazino] ethyl] -3-hydroxy-5-pyridylmethoxy-2-
Naphthamide, N- [2- [4- (benzhydryloxy) piperidino] ethyl] -3-hydroxy-5-pyridylmethoxy-2-naphthamide, N- [2- [4-
[(2-Pyridyl) -phenylmethoxy] homopiperidino] ethyl] -3-hydroxy-5-pyridylmethoxy-2-naphthamide, N- [2- [4- (benzhydryloxy) cyclohexylamino] ethyl] -3- Hydroxy-5-pyridylmethoxy-2-naphthamide, N-
[2- [4- (Benzhydrylamino) cyclohexylamino] ethyl] -3-hydroxy-5-pyridylmethoxy-2-naphthamide, N- [2- [4- (benzhydrylamino) piperidino] ethyl]- 3-hydroxy-5-pyridylmethoxy-2-naphthamide, the compound of the general formula (I) of the present invention can be represented by, for example, the general formula

[0040]

[Chemical 4]

In the formula, R ₁ , R ₂ , R ₃ and Q are as defined above, and a carboxylic acid represented by

[0042]

[Chemical 5]

Where R ₄ , R ₅ , X, Y, Z, _L and m
Is as defined above, and can be produced by reacting with an amine compound represented by

The reaction between the carboxylic acid of the formula (II) and the amine compound of the formula (III) is an amidation reaction.
Usually, it can be performed in the presence of a condensing agent. As a condensing agent, it is widely used in the field of peptide chemistry. For example, N, N'-dicyclohexylcarbodiimide (DC
C), carbodiimide reagents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) can be used.

The amount of the amine compound of the formula (III) used with respect to the carboxylic acid of the formula (II) is not strictly limited, but in general, it is generally the formula (III) per mol of the carboxylic acid of the formula (II). 1.0 to 2.0 mol, especially 1.
A range of 0 to 1.1 moles is convenient.

The reaction is usually preferably carried out in an inert solvent, and examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride: diethyl ether, tetrahydrofuran (THF), dimethoxyethane (DME), dioxane. And the like: amides of dimethylformamide (DMF) and the like can be used alone or in combination.

The reaction can generally be carried out at temperatures in the range of about 0 ° C to about 150 ° C, but especially 10 to 100 ° C.
Is preferable in that the reaction proceeds efficiently.

In the above reaction, N, N-dimethylaminopyridine or the like can be used as a catalyst.

In the amidation reaction described above, the carboxylic acid of the formula (II) is converted into a reactive derivative thereof, for example, an active ester derivative, an acid halide, a mixed acid anhydride, etc., instead of using a condensing agent. It can also be carried out by reacting with the amine compound of the above formula (III) in an inert solvent as described above.

The active ester derivative of carboxylic acid of the formula (II) can be produced by a conventional method, for example, the compound of the formula (II)
Carboxylic acid and acid chloride such as N-hydroxysuccinimide, N-hydroxyphthalimide, 2-nitrophenol, 4-nitrophenol, and 2,4-dinitrophenol in the presence of a carbodiimide reagent in an inert solvent. It can be produced by a method of condensation with.

Examples of the carboxylic acid halide of the formula (II) include carboxylic acid chloride and carboxylic acid bromide. The acid chloride can be produced by a conventional method, for example, by reacting a carboxylic acid of the formula (II) with a halogenating agent such as thionyl chloride, thionyl bromide or phosphorus pentachloride in an inert solvent in the presence of a base. You can

The reaction of the reactive derivative of the carboxylic acid of the formula (II) with the amine compound of the formula (III) is usually carried out at a temperature in the range of about -20 to about 50 ° C, preferably 0-20 ° C. 1.0 to 2.0 moles, especially 1.0, of amine compound of formula (III) per mole of reactive derivative of carboxylic acid of formula (II)
~ 1.1 moles can be used.

The compound of formula (I) produced by the amidation reaction described above can be prepared by a method known per se, for example, the mixed acid anhydride derivative of carboxylic acid of formula (II) can be prepared by a conventional method. can do. For example, it can be produced by reacting the carboxylic acid of the formula (II) with an acid chloride such as ethyl chlorocarbonate, phenyl chlorocarbonate, acetyl chloride, pivaloyl chloride in an inert solvent in the presence of a base.

It can be separated and purified by a method such as column chromatography and recrystallization distillation.

Furthermore, the resulting R ₁ , R ₂ and / or R
_{When 3} is a lower alkanoyloxy group, the compound of formula (I) is hydrolyzed to give the corresponding R ₁ , R
It can be converted into compounds of formula (I) where ₂ and / or R ₃ are hydroxyl groups. This hydrolysis reaction can be carried out according to a conventional method using a base such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate or the like in an inert solvent.

The compound having an amino group among the naphthoic acid derivatives (I) produced above can be converted into a corresponding acid addition salt by a reaction with a pharmaceutically acceptable acid according to a conventional method. ..

The carboxylic acid of the formula (II) used as a starting material in the above-mentioned reaction is known per se, or is produced by the method described in Reference Examples 1 to 3 below or a method similar thereto. be able to.

Specific examples of the carboxylic acid of the formula (II) include:
For example, 3-hydroxy-2-naphthoic acid, 3,5-dihydroxy-2-naphthoic acid, 3,7-dihydroxy-2
-Naphthoic acid, 3-acetoxy-2-naphthoic acid, 3,
5-diacetoxy-2-naphthoic acid, 3,7-diacetoxy-2-naphthoic acid, 5-acetoxy-3-hydroxynaphthoic acid salt, 3-hydroxy-5-methoxynaphthoic acid, 3-hydroxy-5- (2-pyridyl) Examples thereof include methyl) naphthoic acid and 3,5-dimethoxy-2-naphthoic acid.

On the other hand, the amine compound of the formula (III) can be produced, for example, by the method described in the following reaction formulas A and B.

[0060]

[Chemical 6]

[0061]

[Chemical 7]

In the above formulas, R ₅ , X, Y, Z, _L , m and p are as defined above, and Hal represents a halogen atom.

For details of the reactions shown in the above reaction formulas A and B, refer to the description of Reference Examples 4 to 8 below.

Further in the amine compound of formula (III):
A compound in which X represents a methylene group can be produced from a thiol compound according to the method disclosed in JP-A-63-297373.

Typical examples of the amine compound of the formula (III) are, for example, 2- (3-furfurylmethylthio) ethanamine, 2- (3-furfurylmethylsulfinyl) ethanamine, 2- (3-furfurylmethylsulfonyl). ) Ethanamine, 2- (2-furfurylmethylthio) ethanamine, 2- (2-furfurylmethylsulfinyl) ethanamine, 2- (2-furfurylmethylsulfonyl)
Ethanamine, 2- (2-thienylmethylthio) ethanamine, 2- (benzhydrylthio) ethanamine, 2
-(4-chlorophenylmethylthio) ethanamine, 2
-(2-pyridylmethylthio) ethanamine, 2- (benzhydrylsulfonyl) ethanamine, 2- (2-pyridyl-phenylmethylthio) ethanamine, 2- {4
-(1-Imidazolylmethyl) phenylmethylthio} ethanamine, 5- (2-thienylmethylthio) pentanamine, 2-{(4-methoxyphenyl-2-thienyl) methylthio} ethanamine, 2-{(4- (1-imidazolyl) ) Phenylmethylthio} ethanamine, 3-
(2-thienylmethylthio) propanamine, 3- {2
-(2-thienyl) ethylthio} propanamine, 2-
{2- (2-thienyl) ethylthio} ethanamine, 4
-{3- (2-thienyl) propylthio} butanamine, 4- (2-thienylmethylthio) butanamine, 8
-(2-thienylmethylthio) octaneamine, 4-
{2- (2-thienyl) ethylthio} butanamine, 2
-(2-pyridylthio) ethanamine, 2- (2-pyrimidylthio) ethanamine, 2- (1-imidazole-
2-ylthio) ethanamine, 1- (2-aminoethyl) -4- {2- (2-thienyl) ethylthio} piperidine, 1- (2-aminoethyl) -4-diphenylmethylthiopiperidine, N- (2-amino Ethyl) -N'-
{2- (2-thienylmethylthio) ethyl} piperazine, 2- [N-methyl-N '-{2- (2-thienylmethylthio) ethyl} amino] ethanamine, N- (2-
Aminoethyl) -N '-{2- (diphenylmethylthio) ethyl} piperazine, 4- (2-aminoethyl)-
1- {2- (diphenylmethylthio) ethyl} piperidine, 1- (2-aminoethyl) -4- {2- (diphenylmethylthio) ethyl} homopiperazine, N- (2-aminoethyl) -N '-{2 -{4- (1-imidazolylmethyl) phenylmethylthio} ethyl} piperazine, 4
-(2-Aminoethyl) -1- {2- {4- (1-imidazolylmethyl) phenylmethylthio} ethyl} piperidine, 1- (2-aminoethyl) -4- {2- {4-
(1-Imidazolylmethyl) phenylmethylthio} ethyl} homopiperazine, N- {2- (diphenylmethylthio) ethyl} piperazine, 4- {2- (diphenylmethylthio) ethyl} piperidine, N- {2- (diphenylmethylthio) ethyl } Homopiperidine, N- {2- {4
-(1-imidazolylmethyl) phenylmethylthio} ethyl} piperazine, 4- {2- {4- (1-imidazolylmethyl) phenylmethylthio} ethyl} piperidine,
N- {2- {4- (1-imidazolylmethyl) phenylmethylthio} ethyl} homopiperidine, N- (2-aminoethyl) -N ′-{2- {6- (1-imidazolylmethyl) pyridine-2- Il-methylthio} ethyl} piperazine, 4- (2-aminoethyl) -1- {2- {6-
(1-Imidazolylmethyl) pyridin-2-yl-methylthio} ethyl} piperidine, 1- (2-aminoethyl) -4- {2- {6- (1-imidazolylmethyl) pyridin-2-yl-methylthio} ethyl } Homopiperazine, N- (2-aminoethyl) -N '-{2- (2-pyridyl-phenylmethylthio) ethyl} piperazine, 4
-(2-aminoethyl) -1- {2- (2-pyridyl-
Phenylmethylthio) ethyl} piperidine, 1- (2-
Aminoethyl) -4- {2- (2-pyridyl-phenylmethylthio) ethyl} homopiperidine, N- {2- (2
-Pyridyl-phenylmethylthio) ethyl} piperazine, 4- {2- (2-pyridyl-phenylmethylthio)
Ethyl} piperidine, N- {2- (2-pyridyl-phenylmethylthio) ethyl} homopiperidine, N- (2-
Aminoethyl) -N '-{2- {4- (1-imidazolyl) phenylmethylthio} ethyl} piperazine, 4-
(2-Aminoethyl) -1- {2- {4- (1-imidazolyl) phenylmethylthio} ethyl} piperidine, 1
-(2-Aminoethyl) -4- {2- {4- (1-imidazolyl) phenylmethylthio} ethyl} homopiperazine, N- (2-aminoethyl) -N '-{2- (3-pyridylphenylmethylthio) ) Ethyl} piperazine, 4-
(2-Aminoethyl) -1- {2- (3-pyridylphenylmethylthio) ethyl} piperidine, 1- (2-aminoethyl) -4- {2- (3-pyridylphenylmethylthio) ethyl} homopiperazine, N -(2-Aminoethyl) -N '-{2- {4- (4-chlorophenyl) phenylmethylthio} ethyl} piperazine, 4- (2-aminoethyl) -1- {2- {4- (4-chlorophenyl) )
Phenylmethylthio) ethyl} piperidine, 1- (2-
Aminoethyl) -4- {2- {4- (4-chlorophenyl) phenylmethylthio} ethyl} homopiperazine, N
-(2-aminoethyl) -N '-{2- {di- (4-chlorophenyl) methylthio} ethyl} piperazine, 4-
(2-Aminoethyl) -1- {2- {di- (4-chlorophenyl) methylthio} ethyl} piperidine, 4- (2
-Aminoethyl) -1- {2- {di- (4-chlorophenyl) methylthio} ethyl} homopiperazine, 2- (4
-Benzhydryl-1-piperazinyl) ethanamine,
2- {4- (2-pyridyl-phenylmethyl) piperazino} ethanamine, 2- {4- (3-pyridyl-phenylmethyl) piperazino} ethanamine, 2- {4- (4
-Pyridyl-phenylmethyl) piperazino} ethanamine, 2- {4- (benzhydryloxy) piperazino}
Examples thereof include ethaneamine.

[0066]

The naphthoic acid derivative of the above formula (I) provided by the present invention not only inhibits 5-lipoxygenase but also inhibits TXA ₂ synthase (TXA ₂ antagonism),
It has a histamine antagonistic action and a membrane stabilizing action on histamine-releasing mast cells, and is expected to be used as an antiallergic agent. Such advantageous pharmacological effects of the compounds of the invention can be demonstrated by the following tests.

Test Example 1: 5-Inhibition of lipoxygenase activity
Action RBL-1 cells (rat basophil leuk
emia-1 cell) with 1 mM EDTA, 0.1
% Gelatin, adjusted to 5 × 10 ⁷ cells / ml with 50 mM phosphate buffer (PBS, pH 7.0) containing 14 μM indomethamin, sonicated, and then centrifuged at 10,000 × G for 20 minutes. Kiyoshi was used as the enzyme solution. Enzyme solution 460 μl
10 μl of the test drug solution was added to the mixture, and the mixture was reacted at 37 ° C. for 5 minutes, and then 7.4 KBq ¹⁴ C-arachidonic acid and 10
A 0 mM calcium chloride aqueous solution was added, and the mixture was reacted at 37 ° C. for 10 minutes. After cooling with ice, the pH was adjusted to 3 with 1N hydrochloric acid to stop the reaction, and the mixture was extracted with 5 ml of chloroform. The extract was dried under nitrogen gas and then mixed with chloroform: methanol (2: 1).
And the method of Jackic et al. (Biachen. B
iophys. Res. Commun. 95,103
(1980)), thin layer chromatography (T
LC, Kieselgel 60F ₂₅₄ ).
5-Hydroxyeicosatetraenoic acid (5-HETE)
Was measured with a liquid scintillation counter (LSA-900, manufactured by Aloka Co., Ltd.) to determine the inhibition rate of 5-HETE biosynthesis in the drug-added group with respect to the control group, and then the 5-lipoxygenase activity 50% inhibitory concentration (IC ₅₀ ) Was asked. The test drug was dissolved in dimethyl sulfoxide (DMSO) and diluted before use. The results are shown in Tables 1, 2, and 3 below.

Test Example 2: Membrane Stabilizing Action The method of Schwartz et al. (Int. Arch. Allerg)
y30, 67 (1966)). That is,
10 ml of Hank's solution containing 10 units / ml of heparin was intraperitoneally administered to the rat, the abdomen was massaged for 2 minutes, and the cell suspension in the abdominal cavity was collected. The cells were washed 3 times with PBS containing 0.1% bovine serum albumin (BSA), and then washed 4x10.
^It was adjusted to ⁵ cells / ml. 50 μl of the test drug solution was added to 50 μl of this cell suspension, reacted at 37 ° C. for 5 minutes, and further diluted to a titer of 1:40 with anti-ovalbumin (Egg
Alubumin) rat serum 50 μl and 10 mg
50 μl of ovalbumin / ml was added, and the mixture was incubated at 37 ° C for 10
Let react for minutes. The reaction was stopped by cooling with ice, the cells were stained with neutral red, and the number of degranulated cells was counted under a microscope to measure the membrane stabilizing effect. The results are shown in Table-1.

[0069]

[Table 1]

Test Example 3: Histamine Antagonism After separating the contralateral membrane-like part of the trachea isolated from the guinea pig, it was separated into segments perpendicular to the running, and the three were continuously separated at 37 ° C Tyrode's solution (NaCl). : 137 mM, K
Cl: 2.7 mM, CaCl: 1.8 mM, MgC
_{l 2: 1.1mM, NaHPO 4:} 0.4mM, NaH
A Magnus tube filled with CO ₃ (12.0 mM, glucose: 5.6 mM) was suspended by applying a load of 0.5 g.
A 95% O ₂ -5% CO ₂ mixed gas was passed through the Magnus tube to contract the contraction of smooth muscle with an isotonic transducer (TD).
-112S, Nihon Kohden) via polygraph (JD-1
12S, Nihon Kohden). The test drug was incubated for 5 minutes before the addition of 3 × 10 ⁻⁵ M histamine dihydrochloride (Wako Pure Chemical Industries, Ltd.). The results are shown in Table-2.

[0071]

[Table 2]

Test Example 4 TX Synthesis Inhibitory Action The TXA ₂ synthase activity was measured using a thromboxane synthase kit (Funakoshi: Eldan Tech). That is, human platelet microsome fraction 0.97
mg was suspended in 1 ml of 50 mM Tris-0.1 M sodium chloride buffer (pH 7.5), ice-cooled 0.1 ml was dispensed into a sample tube, and a test drug was added. 25 this
Pre-incubation was performed for exactly 3 minutes at 0 ° C, 2 µl of ice-cooled 0.05 mg / ml PGH ₂ / acetone solution was added, and then incubation was performed at 25 ° C for exactly 3 minutes. Two
After 10 μl of 5 mM FeCl ₂ solution was added to stop the reaction, the mixture was allowed to stand at room temperature for 15 minutes, then at 4 ° C. for 10 minutes, 1000
Centrifuged at G. The amount of TXB ₂ in the supernatant was determined by the radioimmunoassay (RIA) method (thromboxane B ₂ [ ³ H]).
RIA Kit: NENResearch Product
It was quantified by ts) and was generated by adding only the solvent in which the test drug is dissolved. The inhibitory rate of the test drug was calculated by setting the amount of TXB ₂ to 100%. The test drug was dissolved in DMSO or purified water and diluted before use. It should be noted that the experiment is 3 for the same concentration
The results are shown in Table-3.

[0073]

[Table 3]

As is clear from the above test results, the compounds of the present invention not only inhibit 5-lipoxygenase but also inhibit TXA ₂ synthase, histamine antagonism,
It also has a membrane stabilizing effect on histamine-releasing mast cells, and is expected to act as a drug (antiallergic agent) for treating and treating allergic diseases.

When the compound of the present invention is used as an antiallergic agent for treating or treating a patient, the compound is orally or parenterally (intravenous, subcutaneous, intramuscular injection, etc.), rectal or topical. Can be administered to the patient (inhalation).
The dosage at that time can be varied according to the severity of the patient's symptoms, age, weight, sex, etc., the judgment of the doctor, the administration route, etc., but generally 0.1-9 mg / Kg body weight / day, It is preferably within the range of 2 to 6 mg / Kg body weight / day.

Upon administration, the compound of the present invention is combined with a pharmaceutically acceptable excipient or diluent in various preparations such as tablets, capsules, dragees, granules, powders, syrups, injections, suppositories, It can be formulated into a form such as an inhalant.

Excipients or diluents that can be used include lactose, starch, crystalline cellulose, mannitol, maltose, calcium hydrogen phosphate light anhydrous silicic acid, calcium carbonate starch polyvinylpyrrolidone, hydroxypropyl cellulose, ethyl cellulose, carboxymethyl cellulose, Examples thereof include gum arabic.

[0078]

EXAMPLES The present invention will be described in more detail with reference to Examples, Reference Examples and Test Examples.

Reference Example 1 Synthesis of 3,5-diacetoxy 2-naphthoic acid 1.14 g of 3,5-dihydroxy-2-naphthoic acid
(5.6 mmol) and acetic anhydride (1.4 g, 13.9 mmol) were dissolved in pyridine (30 ml), and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed under reduced pressure. The residue is ethyl acetate 100
It was dissolved in 50 ml of saturated potassium hydrogen sulfate solution, washed twice with 50 ml of saturated potassium hydrogensulfate solution and 50 ml of saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (eluent 5% methanol-dichloromethane) to obtain 1.5 g of the title compound (yield 93%).

Reference Example 2 Synthesis of 3-hydroxy-5- (3-pyridyloxy) -2-naphthoic acid 2-1 Synthesis of 3,5-dihydroxy-2-naphthoic acid benzyl ester 3,5-dihydroxynaphthoic acid 3 g (14.7 mmol)
Is dissolved in 100 ml of ethanol, and sodium hydroxide 62 is added.
0 mg (14.7 mmol) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure. Acetonitrile 1 on the residue
00 ml, benzyl bromide 2.57 g (14.7 mmol) and tetra-n-butylammonium hydrogensulfate 500 mg (1
(4.7 mmol) was added and the mixture was heated under reflux overnight. After completion of the reaction, the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue is purified by silica gel chromatography,
4.2 g of the title compound was obtained (yield 97%).

2-2 Synthesis of 3-hydroxy-5- (3-pyridyloxy) -2-naphthoic acid benzyl ester 3,5-dihydroxynaphthoic acid benzyl ester 50
0 mg (1.7 mmol) was dissolved in 100 ml of acetonitrile, 434 mg (3.4 mmol) of 3-picolyl chloride and 235 mg (1.7 mmol) of potassium carbonate were added, and the mixture was stirred for 7 hours. After the reaction was completed, the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography to obtain 480 mg of the title compound (yield 73
%).

2-3 3-Hydroxy-5- (3-pyridyloxy) -2-naphthoic acid Dissolved in 50 ml of a mixed solution of 500 mg (1.3 mmol) of the compound obtained above and ethanol-water (10: 1). , 72.8 mg (2.6 mg) of potassium hydroxide were added, and the mixture was heated under reflux for 2 hours. After completion of the reaction, the solvent was neutralized with 5% hydrochloric acid, and the solvent was removed under reduced pressure. The residue is poured into water and the crystals are collected by filtration to give the title compound 3
50 mg was obtained (yield 90%).

Reference Example 3 Synthesis of 3,5-dimethoxy-2-naphthoic acid 3-1 3,5-Dimethoxy-2-naphthoic acid methyl ester 3,5-dihydroxy-2-naphthoic acid 2 g (9.8 mm)
ol) was dissolved in 50 ml of anhydrous dimethylformamide, and 1.5 g (29.4 mmol) of sodium hydride was added to the solution.
Stir for 0 minutes. After stirring, 4.9 g (34.
(3 mmol) was added and the mixture was stirred overnight. After completion of the reaction, water was added to the solution and the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography to obtain 2.35 g of the above compound (yield 98%).

3-2 3,5-Dimethoxy-2-naphthoic acid The above compound was obtained in a yield of 90% according to the method of Reference Example 2-3.

Reference Example 4 Synthesis of 5- (2-thienylmethylthio) pentanamine 2 g (17.5 mmol) of 2-thiophenemethanol was dissolved in 15 ml of dimethylformamide, and 800 mg of 60% sodium hydride (60% sodium hydride under ice cooling under a nitrogen stream). 20 mmol) was added and stirred. After the generation of hydrogen was completed, a solution of 6.5 g of N- {5- (2-benzoxazolylthio) pentyl} phthalimide dissolved in 30 ml of DMF was added dropwise, and the mixture was stirred under ice cooling for 3 hours and at room temperature for 60 hours. After completion of the reaction, pour in ice water,
After extraction with benzene, the benzene layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography and N-
4.84 g of {5- (2-thienylmethylthio) pentylphthalimide was obtained (yield 80%).

Then, 2 g of the phthalimide compound (5.79)
mmol) was dissolved in 30 ml of methanol, 435 mg (8.7 mmol) of hydrazine hydrate was added, and the mixture was heated under reflux for 1 hour and a half. After cooling, the generated precipitate was filtered, the precipitate was washed with ether, and the filtrate and the washing liquid were combined. The solvent was distilled off, ether was added to the residue, and the operation was repeated until precipitation did not occur. The above-mentioned 5- (2-thienylmethylthio) pentanamine 1.1
8 g was obtained (yield 95%).

NMR (δ, CDCl ₃ ); 1.40 to 1.45 (2H, m),
1.56 ~ 1.61 (2H, m), 1.71 (2H, s), 2.50 (2H, t, J = 6Hz), 2.6
9 (2H, t, J = 7Hz), 3.92 (2H, s), 6.91 ~ 6.93 (2H, m), 7.20 (1
H, dd, J = 5 Hz, 2 Hz) Reference Example 5 Synthesis of 3- (2-thienylmethylthio) propanamine Instead of N- {5- (2-benzoxazolylthio) pentyl} phthalimide used in Reference Example 4, N-
The same reaction was carried out using {3- (2-benzoxazolylthio) propyl} phthalimide to obtain the title compound (yield 78%).

NMR (δ, CDCl ₃ ); 1.41 (2H, br-s), 1.7
2 (2H, t, J = 6Hz), 2.56 (2H, t, J = 6Hz), 2.78 (2H, t, J = 6Hz),
3.93 (2H, s), 6.91 ~ 6.93 (2H, m), 7.20 (1H, dd, J = 6Hz, 2H
z) Reference Example 6 Synthesis of 1- (2-aminoethyl) -4-benzhydrylthiopiperidine Dissolve in benzhydrylthiol 278 mg (1.39 mmol) dimethylformamide 10 ml, and under ice-cooling, nitrogen stream under 60% hydrogen. 60.7 mg (1.39 mmol) of sodium were added. After the generation of hydrogen was completed, a solution of 262 mg (1.39 mmol) of N-acetyl-4-methanesulfonyloxypiperidine dissolved in 10 ml of dimethylformamide was added dropwise, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue is purified by silica gel chromatography,
N-acetyl-4-benzhydrylthiopiperidine 23
0 mg was obtained (60% yield).

Next, 200 mg (0.81 mmol) of N-acetyl-4-benzhydrylthiopiperidine was dissolved in 10 ml of methanol, and a solution of 40 mg (1.0 mmol) of sodium hydroxide dissolved in 10 ml of water was added, followed by heating under reflux for 10 hours. did. After the reaction was completed, the solvent was removed under reduced pressure. The residue was extracted with chloroform, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography to obtain 225 mg of 4-benzhydrylthiopiperidine (yield 98%).

Further, 227 mg (0.8 mmol) of 4-benzhydrylthiopiperidine and 262 mg (1.4 mmol) of N- (2-bromoethyl) phthalimide were dissolved in 15 ml of methyl ethyl ketone, and 220 mg of anhydrous potassium carbonate was dissolved therein.
(1.6 mmol), 226 mg of sodium iodide (1.5 mm
ol) was added and the mixture was heated under reflux for 8 hours. After the reaction was completed, the solvent was removed under reduced pressure. The residue was extracted with chloroform, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography to obtain 237 mg of N- {2- (4-benzhydrylthiopiperidinyl) ethyl} phthalimide (yield 65
%).

Furthermore, the obtained phthalimide compound was treated with hydrazine hydrate in the same manner as in Reference Example 8 to obtain 1- (2-aminoethyl) -4-benzhydrylthiopiperidine (yield 92 %).

NMR (δ, CDCl ₃ ); 1.57 to 1.70 (4H, m),
1.84 ~ 1.90 (2H, m), 1.95 ~ 2.02 (2H, m), 2.34 (2H, t, J = 6H
z), 2.44 to 2.51 (1H, m), 2.72 to 2.80 (2H, m), 5.22 (1H,
s), 7.19 to 7.33 (6H, m), 7.41 to 7.44 (4H, m) Reference Example 7 N- (2-aminoethyl) -N '-{2-
Synthesis of (2-thienylmethylthio) ethyl} piperazine 2- (2-thienylmethylthio) ethanol 925 mg
(6.3 mmol), triethylamine 765 mg (7.6 mm)
ol) was dissolved in 20 ml of ethyl acetate and 800 mg of methanesulfonyl chloride dissolved in 10 ml of ethyl acetate under ice cooling.
(7.0 mmol) solution was added dropwise, and the mixture was stirred at room temperature for 1 hour.
After the reaction was completed, the insoluble matter was filtered. Formylpiperazine 2.15 (19.0 mmol) was added to the filtrate, and the mixture was heated under reflux for 7 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue is purified by silica gel chromatography,
N-formyl-N '{2- (2-thienylmethylthio)
1.27 g of ethyl} piperazine was obtained (yield 75%).

Then, N-formyl-N'-2-{(2-
Thienylmethylthio) ethyl} piperazine 1 g (3.7
mmol) was dissolved in 10 ml of methanol, a solution of 178 mg (4.4 mmol) of sodium hydroxide dissolved in 10 ml of water was added, and the mixture was heated under reflux for 10 hours. After the reaction was completed, the solvent was removed under reduced pressure. The residue was extracted with chloroform, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue is purified by silica gel chromatography, N
800 mg of-{2- (2-thienylmethylthio) ethyl} piperazine was obtained (89%).

Further, N- {2- (2-thienylmethylthio) ethyl} piperazine was treated in the same manner as in Reference Example 29,
The above N- (2-aminoethyl) -N '-{2- (2-thienylmethylthio) ethyl} piperazine was obtained (yield 7
5%).

NMR (δ, CDCl ₃ ); 1.63 (2H, s), 2.40〜
2.6 (14H, m), 2.77 (2H, t, J = 6Hz), 3.96 (2H, s), 6.90 ~ 6.
92 (2H, m), 7.20 (1H, d, J = 3Hz) Reference Example 8 Synthesis of 2- [N-methyl-N '-{2- (2-thienylmethylthio) ethyl} amino] ethanamine According to Reference Example 31. From 2- (2-thienylmethylthio) ethanol, the above 2- [N-methyl-N '-{2- (2-
Thienylmethylthio) ethyl} amino] ethanamine was obtained.

NMR (δ, CDCl ₃ ); 1.54 (2H, br-s), 2.2
0 (3H, s), 2.41 (2H, t, J = 6Hz), 2.57 to 2.60 (4H, m), 2.74
(2H, t, J = 6Hz), 3.95 (2H, s), 6.87 ~ 6.93 (2H, m), 7.20 (1
H, dd, J = 3 Hz, 1 Hz) Example 1 Synthesis of N- {5- (2-thienylmethylthio) pentyl} -3,5-diacetoxy-2-naphthamide 3,5-diacetoxy-2-naphthoic acid 260 mg ( 0.
(9 mmol) was dissolved in 20 ml of dichloromethane, 161 mg (1.35 mmol) of thionyl chloride was added, and the mixture was heated under reflux for 1 hour and the solvent was distilled off. The residue was dissolved in 20 ml of dichloromethane, sodium carbonate 159 mg (2.7 mmol), water 15
ml was added. To this mixture was added 5- (2-thienylmethylthio) -pentanamine (194 mg, 0.9 mmol) under ice cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was extracted with dichloromethane, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography to obtain 306 mg of the above compound (yield 70%). The physical properties are shown in Table 5, Example 1.

Examples 2 and 3 The compounds shown in Examples 4 and 3 of Table 4 below were produced in the same manner as in Example 1. Physical properties of the compound are shown in Table 5, Examples 2 and 3.

Example 4 N- [2- {4- (thienylmethylthio) ethyl-1-piperazinyl} ethyl] -5-
Synthesis of Acetoxy-3-hydroxy-2-naphthamide 3,5-diacetoxy-2-naphthoic acid 375 mg (1.
3 mmol) was dissolved in 20 ml of dichloromethane, 238 mg (2.0 mmol) of thionyl chloride was added, and the mixture was heated under reflux for 1 hour.
The solvent was distilled off. The residue was dissolved in 20 ml of dichloromethane, which was added to 133 mg (1.3 mmol) of triethylamine,
N- (2-aminoethyl) -N '-{2- (2-thienylmethylthio) ethyl} piperazine 349 mg (1.3 mm
ol) and 20 ml of dichloromethane were added dropwise, and the mixture was stirred for 1 hour at room temperature. After completion of the reaction, the mixture was extracted with dichloromethane, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography to obtain 467 mg of the above compound (yield 70
%). Physical property values are shown in Table 5, Example 4.

Examples 5 to 19 The compounds shown in Examples 4 to 19 in Table 4 below were prepared in the same manner as in the method described in Example 4 above. Physical properties of the compound are shown in Table 5 Examples 5 to 19.

Example 20 N- [2- {4- (2-thienylmethylthio) ethyl-1-piperazinyl} ethyl]
Synthesis of 3,5-dihydroxy-2-naphthamide 3,5-diacetoxy-2-naphthoic acid 408 mg (2.
0 mmol) was dissolved in 20 ml of dichloromethane, and N-hydroxysuccinimide 235 mg (2.00 mmol) and dicyclohexyl carboxylic diimide 422 mg (2.00 mmol).
Was added for 1 hour and stirred at room temperature, and then dissolved in 20 ml of dichloromethane, N- (2-aminoethyl) -N- {2- (thienylmethylthio) ethyl} piperazine 699 mg (2.0
mmol) was added dropwise, and the mixture was further stirred for 2 hours at room temperature. After completion of the reaction, the mixture was extracted with dichloromethane, washed twice with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. 20 ml of acetonitrile was added to the residue and filtered, and the solvent was distilled off. The residue was purified by silica gel chromatography to obtain 632 mg of the above compound (yield 67%). The physical property values are shown in Table 5 Example 20.

Examples 21 to 34 In the same manner as in Example 20, the compounds shown in Table 21, Examples 21 to 34 below were prepared. The physical properties of the compound are shown in Table 5, Examples 21 to 34.

Example 35 Synthesis of N- [2- {4- (benzhydryloxy) piperidino} ethyl] -3,7-dihydroxy-2-naphthamide 408 mg of 3,7-dihydroxy-2-naphthoic acid (2.
0 mmol) was dissolved in 20 ml of dichloromethane, and N-hydroxysuccinimide 235 mg (2.00 mmol) and dicyclohexyl carboxylic diimide 422 mg (2.00 mmol).
Was stirred for 1 hour at room temperature, 620 mg (2.0 mmol) of 1- (2-aminoethyl) -4- (benzhydryloxy) piperidino dissolved in 20 ml of dichloromethane was added dropwise, and the mixture was further stirred for 2 hours at room temperature. .. After completion of the reaction, the mixture was extracted with dichloromethane, washed twice with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. 20 ml of acetonitrile was added to the residue and filtered, and the solvent was distilled off. The residue was purified by silica gel chromatography to obtain 725 mg of the above compound (yield 73%). Physical properties are shown in Table 5, Example 35.

Examples 36 to 39 In the same manner as in Example 35, the compounds shown in Table 4, Examples 36 to 39 below were prepared. The physical properties of the compound are shown in Table 5, Examples 36 to 39.

Example 40 Synthesis of N- [2- {4- (benzhydryloxy) piperidino} ethyl] -5- (2-pyridylmethoxy) -3-hydroxy-2-naphthamide 5- (2-pyridylmethoxy) ) -3-Hydroxy-2-
Naphthoic acid 591 mg (2.0 mmol) was added to dichloromethane 2
Dissolved in 0 ml, 235 mg of N-hydroxysuccinimide
(2.0 mmol), dicyclohexyl carboxylic diimide 4
After adding 22 mg (2.00 mmol) and stirring for 1 hour at room temperature,
1- (2-aminoethyl) -4- (benzhydryloxy) piperidine 620 dissolved in 20 ml dichloromethane
mg (2.0 mmol) was added dropwise, and the mixture was further stirred for 2 hours at room temperature. After completion of the reaction, the mixture was extracted with dichloromethane, washed twice with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. 20 ml of acetonitrile was added to the residue and filtered, and the solvent was distilled off. The residue was purified by silica gel chromatography to obtain 632 mg of the above compound.
Obtained (yield 67%). Physical properties are shown in Table 5, Example 40.

Examples 41 to 43 In the same manner as in Example 40, the compounds shown in Examples 4 to 43 of Table 4 below were prepared. The physical properties of the compound are shown in Table 5, Examples 41 to 43.

Example 44 Synthesis of N- {5- (2-thienylmethylthio) pentyl} -3,5-dihydroxy-2-naphthamide 1.2 g (2.5 mmol) of the compound of Example 1 was dissolved in 40 ml of methanol. A solution prepared by dissolving 346 mg (2.5 mmol) of potassium carbonate in 5 ml of water was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, extracted with chloroform, washed with water and saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel chromatography to obtain 853 mg of the above compound (yield: 85
%). Physical properties are shown in Table 5, Example 44.

Examples 45 to 71 The compounds shown in Examples 45 to 71 in Table 4 below were prepared in the same manner as in Example 44. Physical properties of the compound are shown in Table 5 Examples 45 to 71.

Example 72 N- [2- (4-benzhydrylpiperazino) ethyl] -3-hydroxy-5- (3
Synthesis of 3-pyridylmethoxy) -2-naphthamide 3-hydroxy-5- (3-pyridylmethoxy) -2-
Naphthoic acid dicyclohexylamine salt 19.1 g (4
0.0 mmol) was added to triethylamine 11.2 ml (80.0
mmol) and 500 ml of anhydrous methylene chloride and dissolve at -20 ° C.
Then, 9.6 ml (80.0 mmol) of pivaloyl chloride was dissolved in 10 ml of anhydrous methylene chloride and added dropwise, and the mixture was stirred for 2 hours.
Then, 17.4 g (56.0 mmol) of 2- (4-benzhydrylpiperazino) ethanamine was dissolved in 20 ml of anhydrous methylene chloride and added dropwise, and the mixture was further stirred for 2 hours. The reaction mixture was washed with water and then saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is methanol 6
Dissolved in 00 ml, 16.56 g of potassium carbonate (120.
160 mmol of an aqueous solution of 0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate (1000
ml), washed with water, saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to obtain 18.3 g of the above compound (78%). The physical properties of the compound are shown in Table 5, Example 72.

Examples 73 to 80 In the same manner as in Example 72, the compounds shown in Tables 4 to 73 below were prepared. The physical property values of the compound are shown in Table 5, Examples 73 to 80.

[0110]

[Table 4]

[0111]

[Table 5]

[0112]

[Table 6]

[0113]

[Table 7]

[0114]

[Table 8]

[0115]

[Table 9]

[0116]

[Table 10]

[0117]

[Table 11]

[0118]

[Table 12]

[0119]

[Table 13]

[0120]

[Table 14]

[0121]

[Table 15]

[0122]

[Table 16]

[0123]

[Table 17]

[0124]

[Table 18]

[0125]

[Table 19]

[0126]

[Table 20]

[0127]

[Table 21]

[0128]

[Table 22]

[0129]

[Table 23]

[0130]

[Table 24]

[0131]

[Table 25]

[0132]

[Table 26]

[0133]

[Table 27]

[0134]

[Table 28]

[0135]

[Table 29]

[0136]

[Table 30]

[0137]

[Table 31]

[0138]

[Table 32]

[0139]

[Table 33]

[0140]

[Table 34]

[0141]

[Table 35]

[0142]

[Table 36]

[0143]

[Table 37]

[0144]

[Table 38]

[0145]

[Table 39]

[0146]

[Table 40]

[0147]

[Table 41]

[0148]

[Table 42]

[0149]

[Table 43]

[0150]

[Table 44]

[0151]

[Table 45]

[0152]

[Table 46]

[0153]

[Table 47]

[0154]

[Table 48]

[0155]

[Table 49]

[0156]

[Table 50]

[0157]

[Table 51]

[0158]

[Table 52]

[0159]

INDUSTRIAL APPLICABILITY The naphthoic acid derivative represented by the general formula (I) in the present invention has a 5-lipoxygenase inhibitory action, a TXA ₂ synthetic oxygen inhibitory action, a membrane stabilizing action of histamine-releasing mast cells and histamine. It is a compound that has an antagonistic action and can be a therapeutic agent for allergic diseases.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location A61K 31/44 AED 7252-4C 31/445 7252-4C 31/495 7252-4C 31/55 7252- 4C C07D 213/30 213/32 213/34 233/60 102 103 103 295/12 AZ 307/38 307/42 333/16 333/18 333/20 (72) Inventor Tetsuaki Yamaura 4-chome Shimochiai, Shinjuku-ku, Tokyo 6-7 Fuji Rebio Co., Ltd. (72) Inventor Eri Kojima 4-6-7 Shimoochiai, Shinjuku-ku, Tokyo Fuji-Rebio Co., Ltd. (72) Yasushi Higashi 4-6-7 Shimochiai, Shinjuku-ku, Tokyo No. Fuji Rebio Co., Ltd.

Claims (1)

[Claims] 1. A general formula: A naphthoic acid derivative represented by the formula (in the formula, R ₁ , R ₂ and R
₃ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group, a hydroxyalkyl group, a lower alkoxyalkyl group, a lower alkanoyloxyalkyl group or an aralkyloxy group, R ₄ is a hydrogen atom or A lower alkyl group, R ₅
Is a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group, and X is —CH (R ₆ ) —
A group represented by, a cyclic alkylene group, a divalent nitrogen-containing heterocyclic group, a cyclic alkylamino group, or a group represented by —N (R ₇ ) — or —NH—R ₈ —, wherein R ₆ And R
₇ is a hydrogen atom or a lower alkyl group, R ₈ represents a cyclic alkylene group, or R ₆ or R ₇ may combine with R ₄ to form an alkylene group having 1 to 3 carbon atoms, Y _{is, -S (O) p -,} - (CH 2) n -, - O
-Or a single bond, Z represents a substituted or unsubstituted alkylene group, or a single bond, Q is 0 to 1, _L is 0 to 4, m is 0 to 8, and n is 0 or 1. And P is 0-2. ).