JPS63185924A - Lipoxygenase-inhibiting agent - Google Patents

Abstract

PURPOSE:To obtain an anti-inflammatory agent containing a phenolic derivative and its salt in combination with other phenolic derivative and its salt as active components. CONSTITUTION:The objective anti-inflammatory agent contains (A) a compound of formula I (R<1b> is carboxyl, cyano, carbamoyl, nitro, sulfamoyl, etc.; R<2> and R<3> are 1-6C alkyl) and its salt and (B) a compound of formula II (R<4> and R<5> are 1-6C alkyl; R<6> is H or 1-6C alkyl; R<5> and R<6> may together with bonding benzene ring form a condensed ring; Aa is H, 1-6C alkylsulfonyl, 1-6C alkoxycarbonyl, etc.; when R<6> is H, Aa is not H, carboxy-1-6C alkyl, etc.) and its salt as active components. The agent is useful for the remedy of diseases such as asthma, bronchitis, psoriasis, cardiovascular insufficiency, myocardial infarction, etc. It has long duration of activity and no side effect.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel lipoxygenase inhibitor containing a phenol derivative.

Broiled rice Nagaishi U.S. Patent No. 37871 74@, No. 3905761@,
No. 3953508, No. 4008043, No. 4008
No. 999, No. 4042627, No. 4054147,
No. 4112229, No. 4170452, No. 4200
No. 432, No. 4222958, No. 4233241,
No. 4496590, No. 4510139, No. 4515
No. 980 and JP-A-50-88040, JP-A-59-
No. 27329, Izv. Akad. Nauk
SSSR.

3er. Khim. , 1971, 609, and Zh.

Obshch. Khim. , 55,648 (1985
) describes various phenol derivatives. However, the above-mentioned prior art documents do not disclose at all that these phenol derivatives have a lipoxygenase inhibitory effect.

DISCLOSURE OF THE INVENTION The present inventor has repeatedly researched certain phenol derivatives and found that these have a lipoxygenase inhibitory effect, which is not disclosed in the above-mentioned prior art documents, and therefore inhibit the production of lipoxygenase metabolites. Based on this, the present inventors have found that the present invention is useful in treating diseases such as asthma, bronchitis, dry skin, cardiovascular system insufficiency, and myocardial infarction, and have completed the present invention.

That is, the present invention provides (a) general formula R3 [wherein R1b is carboxyl group, cyano group, carbamoyl group, hydroxyC+ Cs alkyl group, C1Cs alkoxycarbonyl CI Ce alkyl group, carboxyC+ Cs alkyl halogeno-substituted C+ Cs alkyl] group, C1-C6 acyl group, CI Cs alkylthio group, phenylthio group, CI C6 alkylsulfonyl group, amino group, halogen atom, CI-C6 alkoxy group,
It represents a phenyl group or an unsubstituted phenyl group having 1 to 3 substituents selected from a hydroxyl group and a C1-C6 alkyl group.

R2 and R3 are the same or different and represent a CI-C6 alkyl group. ] Phenol derivatives and their salts represented by (b) the general formula [wherein R4 and R5 are the same or different and CI Ce
It represents an alkyl group, and R6 represents a hydrogen atom or a CI Cs alkyl group. Further, R5° and R6 may be bonded to each other to form a fused ring together with the benzene ring to which they are bonded. Aa is a hydrogen atom,
CI Cs alkylsulfonyl group, CI Cs alkoxycarbonyl group, piperidinocarbonyl group, phenyl CI CB alkylcarbamoyl group, CI (1
2-alkylcarbamoylurbonyl group, carboxyl group, CI Cs acyl group,
CI Cs alkylcarbamoyl group and 03 CB
C2 Cs alkenyl group with a group selected from cycloalkylcarbamoyl groups, C3 C8 as substituents
CI having a group selected from cycloalkylcarbamoyl, CI Cs alkylcarbamoyl, [engineering C+ Cs alkylcarbamoyl, piperidinocarbonyl, morpholinocarbonyl and hydrazinocarbonyl group]
Ce alkyl group, carboxy C+-C6 alkyl group,
CIC6 alkoxycarbonyl C+ Ce alkyl group, CI C6 alkyl group, carboxyl group, CI
Cs alkoxy group, halogen atom, or -NR 7R8
a group (R7 is a hydrogen atom or a CI Cs alkyl group, and R8a is a CI Cs alkyl group, a CI Cs alkyl group having a phenyl group as a substituent), an engineering group, and a CI Ce alkyl group as a substituent a benzoyl group, a C1 C6 acyl group which may have a CI Cs alkoxycarbonyl group as a substituent, a CI Cs alkylsulfonyl group or a phenylsulfonyl group). However, the sharpening group Aa in which R6 is a hydrogen atom is a hydrogen atom, carboxy CI 06 alkyl group, C+Cs alkoxycarbonyl C+ Cs alkyl group, CI Cs alkyl group, carboxyl group, CI
It must not be a Cs alkoxy group or a halogen atom. The present invention relates to a polyoxygenase inhibitor characterized by containing a phenol derivative represented by the following and its salt as an active ingredient.

The phenol derivatives of general formulas (1) and (2), which are the active ingredients of the lipoxygenase inhibitor of the present invention, include some of the compounds described in the above-mentioned prior art documents. This was discovered for the first time by the present inventor.

In addition, the compounds of general formulas (1) and (2) of the present invention have a long duration of action, have almost no gastric cyst-forming action or renal damage action, and have low toxicity.

Among the compounds of general formulas (1> and (2) of the present invention,
The following general formula [wherein R4, R5 and R6 have the same meaning as in general formula (2), Aa is a hydrogen atom, C+ Ce alkoxy group, C+ Cs alkoxycarbonyl C1'C
s alkyl Ce alkyl group, halogen atom or C+ Cs alkoxycarbonyl C2 Ce alkenyl group. It is preferable to use a compound represented by the following as an active ingredient.

Representative examples of the compound of general formula (2-1>) are as follows.

02,3.6-Dolimethyl-4-(4-methoxyphenylamino)phenol 02,3.6-Dolimethyl-4-(4-methoxycarbonylmethylphenylamino)phenol 02,3.6-
Dolimethyl-4-(4-methylphenylamino)phenol 02, 3.6-Dolimethyl-4-(4-chlorophenylamino)phenol o2-methyl-4-phenylamino-5.6,7.

8-tetrahydronaphthol o2-methyl-4-(4-methoxycarbonylmethylphenylaminolahydronaphthol 02, 3.6-drimethyl-4-phenylaminophenol 03-(4-hydroxy-2.3.5-trimethylphenylamino) In Ethyl Cinnamate Suimei 11m, examples of C+Ce alkyl groups include straight chain or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups. can.

Examples of the phenyl C+ Cs alkyl group include benzyl, 1-phenylethyl, 2-phenylethyl, 3-
Phenylpropyl, 2-phenyl-1-methylethyl,
Examples include 4-phenylbutyl, 2-phenyl-1,1-dimethylethyl, 5-phenylpentyl, and 6-phenylhexyl groups.

Examples of the 01 C6 alkoxy carbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups.

Examples of the C+Cs acyl group include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl groups.

CI Cs alkylcarbamoyl, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, pendelcarbamoylcycloalkylcarbamoyl, cyclopropylcarbamoylhexylcarbamoyl, cycloheptylcarbamoyl, Cscycloalkylcarbamoyl group.

As the alkylcarbamoyl group, the above-mentioned CI
In addition to the Cs alkylcarbamoyl group, for example, C7C+ such as heptylcarbamoylnonanylcarbamoyl, 2-methyloctylcarbamoylcarbamoyl, dodecanylcarbamoyl group, etc.
An example is a 2-alkylcarbamoyl group.

Examples of the piperidinocarbonyl group include 1-piperidinocarbonyl, 2-piperidinocarbonyl, 3-piperidinocarbonyl, and 4-piperidinocarbonyl.

Examples of the phenyl C+ Cs alkylcarbamoyl group include benzylcarbamoyl, 1-phenylethylcarbamoyl, 2-phenylethylcarbamoyl 2-phenyl-1-methylethylcarbamoyl, 4-phenylbutylcarbamoyl, 2-phenyl-1,1-dimethylethylcarbamoyl Examples include rubamoyl, 5-phenylpentylcarbamoyl, 6-phenylethylcarbamoyl, and the like.

Examples of C2C8 alkenyl groups include vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl,
3-butenyl, 1-pentenyl, 2-pentenyl, 3-
Examples include pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl groups.

Morpholinocarbonyl groups include, for example, 2-morpholinocarbonyl and 3-morpholinocarbonyl substituents, such as CI -Methylbenzoyl, 3-ethylbenzoyl, 4-propylbenzoyl, 4
Examples include -butylbenzoyl, 3-pentylbenzoyl, 4-hexylbenzoyl, and the like.

Examples of the CI Cs acyl group which must have a CI 06 alkoxycarbonyl group as a substituent include, in addition to the above-mentioned CI Cs acyl group, examples include methoxycarbonylacetyl, ethoxycarbonylacetyl, 3-(methoxycarbonyl)propionyl, 3 Examples include -(ethoxycarbonyl)propionyl and 2-(methoxycarbonyl)propionyl groups.

CI Ce alkylsulfonyl groups include, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, te
Examples include rt-butylsulfonyl, pentylsulfonyl, and hexylsulfonyl groups.

Halogen atoms include fluorine, chlorine, bromine and iodine atoms.

Examples of hydroxy CI 06 alkyl groups are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-1-methylethyl, 1-hydroxybutyl. , 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 1
-Hydroxypentyl, 2-hydroxypentyl, 3-
Examples include hydroxypentyl, 4-hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl, 2-hydroxyhexyl, and 6-hydroxyhexyl groups.

Examples of the Q+ Cs alkoxycarbonyllkyl group include methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, hexyloxycarbonylmethyl, 1-methoxycarbonylethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl. , 2-
Methoxycarbonylbutyl, 4-methoxycarbonylbutyl, 3-methoxycarbonylpentyl, 5-methoxycarbonylethyl, 4-methoxycarbonylbutyl! Examples of lehexyl, 6-methoxycarbonylethyl, 4-ethoxycarbonylbutyl, 3-(1-butoxy)carbonylpropyl, 6-(1-propoxy)carbonylhexylcarboxyC+ Cs alkyl groups include, for example, carboxymethyl, 1-carboxy Ethyl, 2-carboxyethyl 3-carboxypropyl, 2-carboxybutyl, 4-
Examples include carboxybutyl, 3-carboxypentyl, 5-carboxypentyl, 5-carboxyhexylxyl, and the like.

Specific examples of halogeno-substituted CI Cs alkyl groups include:
For example, fluoroethyl, difluoromethyl, trifluoroethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, 1-libromomethyl, iodomethyl, short methyl, triiodomethyl, 1-fluoroethyl, 2-fluoroethyl, 1,
2-difluoroethyl, 2,2-difluoroethyl, 1
, 2-dichloroethyl, 2,2-dichloroethyl, 2-
Chloro-2-fluoroethyl, 2-bromoethyl, 2,
2-dibromoethyl, 2,2.2-trifluoroethyl, 1,3-difluoropropyl, 3,3,3-trifluoropropyl, 3,3-dichloropropyl, 2,4-dibromobutyl, 4.

4,4-tribromobutyl, 4,4-difluorobutyl, 3,5-dichloropentyl, 5,5-difluoropentyl, 5,5.5-trifluoropentyl, 6,6-dibromohexyl, 6,6. Examples include a rottrifluorohexyl group.

Specific examples of CI Cs alkylcarbonyl groups include:
For example, acetyl, ethylcarbonyl, 1-propylcarbonyl, 2-propylcarbonyl, 1-butylcarbonyl, 2-butylcarbonyl, tert-butylcarbonyl, 1-pentylcarbonyl, 2-pentylcarbonyl, 3-pentylcarbonyl, 1-hexyl carbonyl,
Examples include 2-hexylcarbonyl and 3-hexylcarbonyl groups.

Examples of the CI CB alkoxy group include methoxy,
Examples include linear or branched alkoxy groups such as ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups.

Furthermore, as specific examples of the phenyl group having 1 to 3 of the above groups as substituents, the following groups can be exemplified.

2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-
Bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2,
4-difluorophenyl, 2,4-dichlorophenyl,
2,4゜rotrifluorophenyl, 2,4.6-dolichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2゜4-dihydroxyphenyl, 2,4.6-dolihydroxyphenyl enyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,
3,5-di(trifluoromethyl)phenyl, 2-carboxymethylphenyl, 3-carboxymethylphenyl, 4-carboxymethylphenyl, 2,4-dicarboxymethylphenyl, 2-ethoxycarbonylmethylphenyl, 3-ethoxycarbonyl Methylphenyl, 4-ethoxycarbonylmethylphenyl, 2,4-jethoxycarbonylmethylphenyl, 2.4.6-driethoxycarbonylmethylphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,4. 6-trimethoxyphenyl, 3,4.5-trimethoxyphenyl, 2
-1hexyphenyl, 4-ethoxyphenyl, 2,4
-jethoxyphenyl, 2,4.6-Drie-1-xyphenyl, 2,4.6-doricarpoxymethylphenyl,
2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 2,4-dimethylphenyl, 2-(1
-carboxyethyl)phenyl, 3-(1-carboxyethyl)phenyl, 4-(1-carboxyethyl)phenyl, 2,4-di(1-carboxyethyl)phenyl,
2-(2-carboxyethyl)phenyl, 3-, (2-
Carboxyethyl)phenyl, 4-(2-carboxyethyl)phenyl, 2,4-di(2-carboxyfer)
Phenyl, 2-methylthiophenyl, 3-methylthiophenyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2,4.6-trimethylthiophenyl, 3
, 4.5-trimethylthiophenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2,4
-diaminophenyl, 2,4.6-triaminophenyl, 2-phenylthiophenyl, 3-phenylthiophenyl, 4-phenylthiophenyl, 2-(1-pentylthio)phenyl, 3-(1-pentylthio)phenyl, 4
-(1-pentylthio)phenyl, 2,4-di(1-pentylthio)phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,4,6-drimethyl Phenyl, 2-(1-
butyl)phenyl, 3-(1-butyl)phenyl, 4-
(1-butyl)phenyl, 2,4-di(1-butyl)phenyl, 2,4,6-tri(1-butyl)phenyl, 3
-chloro-2-hydroxyphenyl, 4-chloro-2-
Hydroxyphenyl, 5-chloro-2-hydroxyphenyl, 6-chloro-2-hydroxyphenyl, 4-chloro-3-hydroxyphenyl, 5-chloro-3-hydroxyphenyl, 2-(3-carboxypropyl)phenyl, 3 - (3-carboxypropyl)phenyl, 4-
(3-carboxypropyl 4-di(3-carboxypropyl)phenyl, 2-hydroxy-4-carboxymethylphenyl, 2-hydroxy-5-carboxymethylphenyl 2-hydroxy-6
-Carboxymethylphenyl 3-hydroxy-5-carboxymethylphenyl 2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 3,5-
Dicarboxyphenyl, 2-chloro-6-carboxyphenyl, 4-chloro-6-carboxyphenyl, 2-chloro-4-carboxyphenyl, 3-chloro-5-carboxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3.

5-dicyanophenyl, 2,4.6-tricyanophenyl, 4-methyl-2-carboxyphenyl, 6-methyl-2-levoxyphenyl, 2-methyl-4-carboxyphenyl, 3-methyl-5 -carboxyphenyl,
4-hydroxy-3-carboxyphenyl, 4-hydroxy-2-carboxyphenyl, 6-hydroxy-2-
carboxyphenyl, 2-hydroxymethylphenyl,
3-Hydroxymethylphenyl, 4-hydroxymethylphenyl, 2,6-di(hydroxymethyl)phenol 12,4,6-tri(hydroxymethyl)phenyl, 2
-(2-hydroxyethyl)phenyl, 3-(2-hydroxyethyl)phenyl, 4-(2-g droxyethyl)phenyl, 3,5-di(2-hydroxyethyl)phenyl, 2-(1-hydroxyethyl) Phenyl, 3-(
1-hydroxyethyl)phenyl, 4-(1-hydroxyethyl)phenyl, 2,4-di(1-hydroxyethyl)phenyl, 2,4.6-tri(1-hydroxyethyl)phenyl, 2-(3- hydroxypropyl)phenyl, 3-(3-hydroxypropyl)phenyl, 4
-(3-hydroxypropyl)phenyl, 3,5-di(
3-hydroxypropyl)phenyl, 2,4-di(3-
hydroxypropyl)phenyl, 2-(4-hydroxybutyl)phenyl, 3-(4-hydroxybutyl)phenyl, 4-(4-hydroxybutyl)phenyl, 2,4
-di(4-hydroxybutyl)phenyl, 2-(1-hydroxyisopropyl)phenyl, 3-(1-hydroxyisopropyl)phenyl, 4-(1-hydroxyisopropyl)phenyl, 2,6-di(1-hydroxyisopropyl) ) phenyl, 2-chloro-6-hydroxymethylphenyl, 3-chloro-6-hydroxymethylphenyl, 4-chloro-6-hydroxymethylphenyl, 2
-chloro-4-hydroxymethylphenyl, 2-chloro-5-hydroxymethylphenyl, 2-hydroxy-4
-(2-hydroxyethyl)phenyl, 2-hydroxy-5-(2-hydroxyethyl)phenyl, 2-hydroxy-6-(2-hydroxyethyl)phenyl, 3-hydroxy-5-(2-hydroxyethyl)phenyl ,6
-Methyl-2-(hydroxymethy)phenyl, 5-
Methyl-2-(hydroxymethyl)phenyl, 4-methyl-2-hydroxymethyl)phenyl, 2-methyl-
4-(hydroxymethyl)phenyl group, etc.

The compounds of the present invention can be produced, for example, by the methods shown in the following reaction schemes.

<Reaction scheme-1> 3R3 (5) ('l) [R1b in the formula
, R2 and R3 are the same as above. ] The condensation reaction shown in the above reaction scheme-1 is carried out by reacting the benzquinone derivative (3) in the presence of a halide Lewis acid such as aluminum chloride, ferric chloride, titanium tetrachloride, tin chloride, or zinc chloride. and the aniline derivative (4), which also serves as a dispersant, in an inert organic solvent such as 1,2-dichloroethane, chloroform, toluene, benzene, etc., at room temperature to about 120°C.
It is carried out by reacting at a temperature of . An inert organic base such as pyridine or triethylamine may also be added to the above reaction system as a dispersing agent. The ratio of the benzoquinone derivative (3) and the aniline derivative (4) to be used is not particularly limited, but the latter is usually used in an amount of about 1 to 10 times the former, preferably about 1 to 3 times the molar amount. is desirable.

In addition, the reaction using titanium tetrachloride in the above is described, for example, in the Journal of Organic Chemistry [J
, Ora, Chem, 32, 3246 (1976)]
H. Weingarten (1. Wein (l.
It can be carried out according to the method of Arten et al.

The above-mentioned condensation reaction can be carried out using known methods such as Ni-Riker (A) and H-Kessler (Tol).
．． Tetrahydrone (Tetr
ahedron), Vol. 23, p. 3723 (1967
(2013) and the method described in J.-Fuiguelas et al.
Journal of Organic Chemistry (J, 01fJ.

Chem.), 36.3497 (1971). More specifically, the above condensation reaction is carried out using acetic acid, boron trifluoride ethyl ether [(02-15)2
0.BF3] or the like as a catalyst, compound (4) is used in an amount of 1 to 5 times the molar amount of compound (3), and the compound (4) is used without a solvent or for example, tetrahydrofuran (THF>, ethyl ether, etc.).
dioxane, chloroform, 1,2-dichloroethane,
In a suitable solvent such as benzene, toluene, xylene, etc., about 3
It is carried out in a temperature range of 0-200°C.

Compound (5) obtained as described above can be subjected to the subsequent reduction reaction without being isolated from the reaction system, but may of course be isolated.

The reduction reaction can be carried out according to a conventional method, for example, by transferring the above reaction product into THF and adding a 2 to 50 times molar amount of sodium hydrosulfide (Na2S204>aqueous solution. 5) has R1
Depending on the type of substituent of group b, for example, a method using zinc dust in acetic acid, a method of catalytic hydrogenation using palladium-carbon or platinum dioxide as a catalyst in a solvent such as ethyl acetate, alcohol, THF, or water, or THF. It can also be added by a method using sodium borohydride (NaBHz) in a mixture of and water.

Furthermore, in the compound (1) of the present invention, Rlb is hydroxy C
A compound in which Rlb obtained according to the above method is a phenyl group having a +Ce alkyl group is carboxyC1C
e Compound (1) which is a phenyl group having an alkyl group or a phenyl group having a C+ 06 alkoxycarbonyl C+ -06 alkyl group, for example, ethyl ether,
Compound (1) which is reduced with about 1 to 7 times the molar amount of lithium aluminum hydride (L!Al2H4) in a suitable solvent such as THF, or where R1 is a phenyl group having a C1-C6 acyl group. For example, methanol, ethanol,
Isopropatool and these and T I-IF.

In a suitable solvent such as a mixed solvent with dioxane etc., about 1.5
It can also be obtained by reduction with ~5 times the molar amount of NaBHa.

Furthermore, instead of the benzoquinone derivative (3), a compound of the general formula: [wherein R4, R5 and R6 have the same meanings as above]. ] Using a compound represented by the following, further aniline derivative (4)
Instead, the general formula [wherein Aa has the same meaning as above] is used. ] The compound of the present invention represented by the general formula (2) can be produced in the same manner as described above except for using the amine represented by the formula (2).

In the above reaction, the raw materials benzoquinone derivatives (3) and (6), aniline derivative (4) and amine (7) are all known or can be produced according to known methods.

Reaction Scheme-2> (2b) [In the formula, R4, R5 and R6 are the same as above. B is -Nl-
IR7 (in the formula, R7 is the same as above), carboxy C+
Cs alkyl group, carboxyl group, carboxy substituted C2
06 indicates an alkenyl group. C is -NR7R81) group (
R7 is the same as above. R8b is CI Cs as a substituent
Indicates a benzoyl group that may have an alkyl group, a CI Cs acyl group that may have a CI C6 alkoxycarbonyl group as a substituent, a CI C6 alkylsulfonyl group, or a) engineeredylsulfonyl group. ), ICt
Cs alkoxycarbonyl group, phenyl CI C
6 alkylcarbamoyl group, CI C12 alkylcarbamoyl group, C3C8 cycloalkylcarbamoyl group, CI 06 alkylcarbamoyl as a substituent, C
I02 having a group selected from C6 alkoxycarbonyl and C3Cs cycloalkylcarbamoyl groups
C6 alkenyl group, having as a substituent a group selected from 03 C8 cycloalkylcarbamoyl CI Cs alkylcarbamoyllkoxycarbonyl, phenyl C+ Cs alkylcarbamoyl, piperidinocarbonyl, morpholinocarbonyl and hydrazinocarbonyl group (l CB alkyl group shows.

However, when R6 is a hydrogen atom, C is not necessarily a CI Ce alkoxycarbonyl C+ Cs alkyl group. ] According to reaction scheme-2, acylation of compound (2a),
Compound (2b) can be obtained by amidation, sulfonylation or esterification reaction.

The above acylation and sulfonylation reactions are carried out on the compound (2a) in which group B is an amino group.

By acylation, a compound of the general formula (2b), in which the group C is a group -NR7R8b (wherein R7 is the same as above, and R8b is a benzoyl group which may have a CI Cs alkyl group as a substituent) or Cs C as a substituent
e CI that may have an alkoxycarbonyl group
Cs indicates an acyl group. ) can be obtained.

Further, by sulfonylation, a compound of the general formula (2b), which shows a group Cffi group -NR7R8b (wherein R7 is the same as above, and R8b represents a CI Cs alkylsulfonyl group or a phenylsulfonyl group) compound can be obtained. The above acylation reaction and sulfonylation reaction are each carried out as follows.

That is, the acylation reaction is carried out in an inert solvent using a suitable acylating agent. Examples of the acylating agent include CI-C6 acyl halides such as acetyl chloride, acetyl bromide, propionyl chloride, butyryl chloride, isobutyryl chloride, valeryl chloride, isovaleryl chloride, pivaloyl chloride, and heptanoyl chloride; CI Cs alkoxycarbonyl C+ Cs acyl halide 20+ Cs alkyl group such as monoethyl malonic acid chloride, monomethyl malonic acid chloride, monomethyl succinic acid chloride, monopropyl geltar acid chloride, monoethyl adipic acid chloride, monomethylsperic acid chloride, etc. Optionally substituted benzoyl chloride, etc. can be used. As the inert solvent, TI-IF, ethyl ether, chloroform, dichloromethane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), etc. can be used. The acylation reaction generally proceeds well in the presence of a suitable base such as triethylamine, pyridine, collidine, etc. at a temperature range of about -20°C to 30°C. The ratio of the acylating agent to the raw material compound can be determined as appropriate, but it is usually selected from the range of about 1 to 3 times the mole, preferably about 1 to 1.1 times the mole.

The sulfonylation reaction can be carried out in the same manner as the acylation reaction described above using a suitable sulfonylation agent in the same inert organic solvent in the presence of a base. Examples of the sulfonylating agent used here include CI C6 alkanesulfonylhalide sulfonyl chloride such as methanesulfonyl chloride, ethanesulfonyl chloride, butanesulfonyl chloride, and hexanesulfonyl chloride, benzenesulfonyl halide such as benzenesulfonyl bromide, and the like.

In addition, the amidation reaction shown in the above reaction scheme-2 is carried out using the group B
is a carboxyl group, a carboxyC+-C6 alkyl group,
Compounds that are carboxy02G6 alkenyl groups (2
a) will be implemented. By this amidation reaction, when group B is a carboxyl group, general formula (2
In b), compounds are obtained in which the LSC represents a phenyl Ct Cs alkylcarbamoyl group, a CI -CI 2 alkylcarbamoyl group or a 03 C8 cycloalkylcarbamoyl group. Group B is carboxy C+ Cs
When it is an alkyl group, in the general formula (2b), group C is a substituent such as 03 CB cycloalkylcarbamoyl, C1-06 alkylcarbamoylphenyl CI C
Compounds exhibiting a CI Cs alkyl group with a group selected from 6-alkylcarbamoylidinocarbonyl, morpholinocarbonyl and hydrazinocarbonyl groups can be obtained. Further, when the group B is a carboxy C2 C6 alkenyl group, a compound in the general formula (2b) in which the group C represents a C2 Cs alkenyl group having a CI Cs alkylcarbamoyl group as a substituent can be obtained.

The above-mentioned amidation reaction can be carried out using a normal amide bond forming reaction, such as an acid halide method, a mixed acid anhydride method, an activated ester method, a N
, N'-dicyclohexylcarbodiimide diethyl (DEPC) method, etc. To be more specific about the diethyl cyanophosphate method, the method involves using, in a suitable solvent such as DMF, THF, or ethyl acetate, about 1 to 1.5 times the molar amount of the corresponding amine relative to compound (2a); For example, C1-CI2alkylamine,
Using phenyl C+-06 alkylamine, C3 C8 cycloalkylamine, hydrazine, morpholine, piperidine, etc., about 1 to 1.2 times the molar amount of diethyl cyanophosphate and about 1 to 5 times the molar amount of an organic amine such as triethylamine, This is carried out using pyridine or the like. The reaction can be carried out by stirring at a temperature of typically 0 to 30°C for about 2 to 20 hours.

In addition, C+ in which the group C has a hydrazinocarbonyl group
In the compound (2b) which is a Cs alkyl group, group B is C+
It can also be obtained by reacting compound (2a), which is a Cs alkoxycarbonyl C+ -C6 alkyl group, with hydrazine hydrate. More specifically, the reaction is usually carried out in an alcohol solvent such as ethanol, methanol, tert-butanol, etc. using about 50 to 300 times the molar amount of hydrazine hydrate and heating to the boiling point temperature of the solvent for about 1 to 20 hours. It is done by doing.・In general, the esterification reaction of compound (2a) shown in Reaction Scheme-2 is performed when group B is a carboxyl group, carboxy GI Cs
This is demonstrated for compounds that are alkyl groups and carboxyC2C6 alkenyl groups. By this esterification reaction, when the group B is a carboxyl group, a compound in which the group C in the general formula (2b) represents a C+ Cs alkoxycarbonyl group is obtained, and when the group B is a carboxyl (l Cs alkyl group, the general formula In (2b), the group C has a C1Cs alkoxycarbonyl group as a substituent
A compound exhibiting a Cs alkyl group (wherein R6 is not a hydrogen atom) is obtained.

Furthermore, when the group B is a carboxy02G6 alkenyl group, in the general formula (2b), the group C has a CI Cs alkoxycarbonyl group as a substituent.
A compound exhibiting 6 alkenyl groups is obtained.

The esterification reaction can be carried out using conventional methods such as hydrochloric acid, sulfuric acid,
A method of heating and reacting compound (2a) with C1Cs alcohol in the presence of an acid catalyst such as p-toluenesulfonic acid, (C2Hs)20.BF3, etc., and a method of reacting compound (2a) with C1Cs alcohol by about 1 to 10 times the molar amount relative to compound (2a). in the presence of a basic compound such as pyridine, triethylamine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, etc., in an inert solvent such as DMF, hexamethylphosphoric triamide (HMPA). , a method of reacting about 1 to 10 times the molar amount of C1C6 alkyl halide [counter compound (2a)] in a solvent such as dimethyl sulfoxide (DMSO), pyridine, chloroform, dichloromethane, THE, ethyl acetate, benzene, toluene, etc. It can be implemented by

In addition, in general formula (2a), B is a carboxyl group, -
A compound having an NHR7 group, a carboxyC+Cs alkyl group, and a carboxy02G6 alkenyl group can be produced according to the method shown in Reaction Scheme-1 above.

<Reaction scheme-3> 5 Re (2C) 5 R8 (2d) (In the formula, R4, R5 and R6 are the same as above. D is C -NR7R group (R7 is the same as above. R8c is C + C
s indicates an acyl group or a benzoyl group). E is -N
R7R8d group (R7 is the same as above. R8d is C+ C
s represents an alkyl group or a benzyl group). ] According to the method shown in the above reaction scheme-3, the compound (2C
Compound (2d) can be obtained by the reduction reaction of ). The reduction reaction can be preferably carried out using LiA9Hz in an inert solvent such as ethyl ether or TI-IF.

The amount of LiA9Hz is usually about 1 to 10 times the molar amount of compound (2C), and the reaction generally proceeds at a temperature in the range of about 0.degree. C. to the boiling point of the solvent.

In addition, in general formulas (1) and (2), the compound having a carboxy CI Cs alkyl group or carboxyl group as a substituent on the benzene ring may be a corresponding appropriate ester compound as a starting material, such as C1-06 alkoxycarbonyl C+ It can be obtained by subjecting a compound having a -C6 alkyl group, a C+CB alkoxycarbonyl group, etc. on a benzene ring to a hydrolysis reaction. This hydrolysis reaction can be carried out under a wide range of conditions for ordinary hydrolysis reactions, such as those described by E.L.E.

L, EIiel) et al.'s method [0raanic 5yn
theses.

IV, 169 (1963)].

That is, by reacting a Nisder compound as a starting material with a suitable acid such as hydrochloric acid or hydrobromic acid at a temperature of room temperature to about 120°C without a solvent or in a suitable solvent such as acetic acid, the reaction on the benzene ring is performed. A compound having a carboxyC+Cs alkyl group or a carboxyl group as a substituent can be obtained. The proportion of the ester compound to be used is not particularly limited, but it is usually preferably from a catalytic amount to about 10 times the molar amount.

The compounds of the present invention that can be easily isolated and purified by the reactions shown in the above reaction schemes can be easily isolated and purified by conventional separation methods. Examples of such separation methods include solvent extraction, recrystallization, and column chromatography. etc. can be exemplified.

Furthermore, the compound of the present invention thus obtained can be easily converted into a pharmaceutically acceptable wrinkled 7JO salt by subjecting it to an addition reaction with a suitable acidic compound according to a conventional method.
The acid addition salts have pharmacological activity similar to the free form of the compounds of the invention, and the invention also encompasses such acid addition salts.

Examples of acidic compounds that form the above acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and benzenesulfonic acid. Examples include organic acids. Furthermore, among the compounds of the present invention, those having a free carboxyl group may be treated with alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and other copper salts. These also have the same pharmacological activity as the isolated form of the compound of the present invention, and are therefore included within the scope of the present invention.

The compounds of the present invention are usually used in the form of common pharmaceutical preparations. The formulation is prepared using commonly used diluents or excipients such as fillers, intensifiers, binders, humectants, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquid , suspending agents, etc.),
Examples include ointments. When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran disintegrants such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc. 4. Absorption enhancers such as ammonium base and sodium lauryl sulfate,
Humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid;
Lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol can be used. If necessary, the tablets may be coated with a conventional coating, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, or multilayered tablets. When forming an emulsion, a wide variety of carriers conventionally known in this field can be used, such as glucose, lactose, starch,
Excipients such as cocoa butter, hydrogenated vegetable oil, kaolin, and talc,
Binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaran and agar can be used. When forming into a suppository, a wide variety of carriers conventionally known in this field can be used, such as polyethylene glycol, cocoa butter, higher alcohols, esters of higher furcols, gelatin, semi-synthetic glycerides, and the like. Capsules are prepared by mixing the compound of the present invention and various carriers according to known methods, and preparing hard gelatin capsules,
It can be obtained by encapsulating it in soft gelatin capsules or the like. When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and when formed into these forms, diluents commonly used in this field may be used. For example, water, aqueous lactic acid solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated instearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used. In addition,
In this case, sufficient salt, glucose or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and conventional solubilizing agents, buffers, soothing agents, etc. may be added. good. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary. When forming into a paste, cream or gel form, white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as diluents.

The amount of the compound of general formulas (1) and (2) or a salt thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited and is appropriately selected from a wide range, but usually 1 to 70% of the total composition. It is better to use the top percentage.

The method of administering the pharmaceutical preparation of the present invention is not particularly limited, and is determined depending on various preparation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, emulsions, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, are administered alone intramuscularly, subcutaneously, subcutaneously, or intraperitoneally. Suppositories are administered rectally.

The dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc.
Usually, the active ingredients, compounds of general formulas (1) and (2), should be administered in an amount of about 0.5 to 500 ma per 1 kg of body weight per day, and the preparation should be administered 1 to 4 times a day. Can be administered separately.

! --Eggplant 1-1 Examples will be given below to explain the present invention in more detail.

Example 1 Preparation of 2.6-tert=butyl-4-(4-fluorophenylamino)phenol 2.6-tert
- 2.2 g of butyl-1,4-benzoquinone and 3.3 g of p-fluoroaniline were dissolved in 60 ml of THE,
Collenium' (C2Hs >20-BF30.3111Q) was added and refluxed for 6 hours. Cold welding, 50 ml of water was added, and then Na 2320420 (L of water 150 + n2 solution was added,
Add to the air temperature for about 15 minutes until the red color of the reaction mixture disappears.
Stirring was continued for a minute. Thereafter, it was transferred to water, extracted with ethyl ether, and the organic mixture was washed with saturated saline, and the l1fL
The crude product obtained by drying and concentrating with magnesium oxide (MgSOa) was purified by silica gel column chroma 1 hegelafy (ethyl ether:hexane = 1:10) to obtain 2 g of the target compound.

The physical properties of the obtained Compound 1 are shown in Table 1.

Examples 2 to 23 Compounds 2 to 11 shown in Table 1 were produced in the same manner as in Example 1.

In addition, the free bases of Compounds 12 to 23 were prepared in the same manner, and a 4N solution of hydrogen chloride in ethyl acetate was added to each of them.
and 1q of each of the target compounds in the form of hydrochloride.

Table 1 shows the physical properties of each compound obtained.

Example 24 4-(3-carboxyphenylamino)-2°6-tert-butylphenol? < 2.6-sheet t
ert-butyl-1,4-henzoquinone 6.6 (],
] m-Aminobenzate 6:\i4,20 and 6 drops of acetic acid were stirred for 2 hours at 150-160'C. After cooling, approximately 50 mQ of water was added to the reaction mixture, and TH
Add E200Iq and add Na 2520i 50! I
A solution of 300ml of water was added to the mixture at room temperature, and the mixture was stirred with a ladle for 15 minutes until the red color faded.Then, the mixture was transferred to water and extracted with vinegar. -1] Real Q of stratification! 11, and purified by silica gel column chromatography (dichloromethane:THF=5:1) to obtain the target compound 6.
．． 7g is IH.

The obtained compounds (raw) are shown in Table 1 with Compound No.

24.

Examples 25-30 In the same manner as in Example 24, each compound shown as Compounds 25-29 in Table 1 was obtained.

In addition, the free @ group of Compound 30 was prepared in the same manner, and a 4N solution of hydrogen chloride in ethyl acetate was added thereto to obtain the target compound 19 in the form of a hydrochloride.

Example 31 Production of 2.6-tert-butyl-4-(3-hydroxymethylphenylamino)phenol hydrochloride tert-butylphenol 1.
Dissolve 8 g in THF30 and add the solution to L! A
It was added dropwise to a suspension of 1.7 CI of QHa in 150 ml of ethyl ether at air temperature with stirring, and then the reaction mixture was
．． It was refluxed for 5 hours. Cold welding, S water engineering chill ether, then excess L! using water! The AQHt was carefully decomposed and the organic layer was separated, dried over Mg5Ot, and expanded. The obtained crude product was dissolved again in 100 mQ of ethyl ether, and 6zQ of a 4N hydrogen chloride solution in ethyl acetate was added thereto.
The precipitated crystals were collected, washed with ethyl ether, and evaporated to obtain 1.5 g of the target compound.

The physical properties of this compound are shown in Table 1 as Compound 31.

Examples 32-40 Compound 3 shown in Table 1 was prepared by the same operation as in Example 31.
I got 2-40.

Example 41 2.6-sheet tart-bougie roux 4-', 3-<1
-hydroxyethyl)phenylamino]phenol 1'
Preparation of A-acid salt 4-(3-acetylphenylamino),-2,6-tert-butylphenol (compound 10) 1(II) obtained in Example 10 was mixed with 17ff!Q of ethanol.

and T I-I F 3 mQ, and added Na B Hz 200 mQ to this with water cooling and stirring. :Slowly add I,
The reaction mixture was then stirred for 1 hour. The reaction mixture was transferred to water and extracted with ethyl ether. The separate layer was washed with 10% Na 23204 aqueous solution until the yellow-red color of the 0-layer faded, then washed with saturated saline, dried over ~1g5Ot, and concentrated to about 100ml. Add 6 ml of a solution of 4.N hydrogen chloride in ethyl acetate, separate the precipitated crystals, wash with ethyl ether, and air dry to obtain 1 g of the target compound.

The physical properties of this compound are shown in Table 1 below as Compound 41.

Table 1 In addition, in the above Table 1 and the following table, the coupling constant (J)
Unless otherwise specified, the unit of is r l-I Z j, and [1-j3uj indicates tert-butyl base.

Example 42 2. Preparation of 6-tert-butyl-4-(4-dimethylaminophenylamino)phenol dihydrochloride [Compound 42] 2. 6-tert-butyl-1,4-benzoquinone 2. 2.6 g of 13 and N,N-dimethyl-1,4-phenylenediamine were dissolved in 60 mQ of THF, 30.3 g of (C2Hs)20-BF was added thereto, and the mixture was heated under reflux for 7 hours. The crude product obtained by concentration was purified by silica gel column chromatography (ethyl ether:hexane=1:5) to obtain reddish-purple crystals.

This was diluted with 150 mQ of THF, and the resulting solution was heated to 150 mQ of Na2320t 21CI water at room temperature. r+i2
The solution was added and stirred for 10 minutes. Then, water was added, extracted with ethyl ether, and the organic layer was dried (MgSOa>
and concentrated. The obtained oil was dissolved in a small amount of ethyl ether, 3 4N hydrogen ihydride in ethyl acetate solution was added thereto, and the precipitated crystals were counted. These crystals were recrystallized from ethanol-diethyl ether. Target compound 1.
8g was obtained.

Table 3 shows the physical properties (melting point and 1t (NMR value)) of the obtained compound.

Examples 43 to 51 Production of Compounds 43 to 51 In the same manner as in Example 42, the target compounds (
Compounds 43 to 51) were "JAMed."

Table 3 shows the physical properties of each compound obtained.

Example 52 Production of ethyl 3-(4-hydroxy-2,3,5-trimethylphenylamino)cinnamate hydrochloride [Compound 52] 0.73 mQ of titanium tetrachloride was added to a solution of 2.2 mQ of pyridine in 60 mf2 of dichloroethane. The mixture was heated and stirred at 90°C for 20 minutes, and 2.3.6-drimethyl-1,4
- 2 g of benzoquinone and 3 q of ethyl 3-aminocinnamate hydrochloride were added and heated roughly at 90° C. for 30 minutes. The solvent was distilled off under reduced pressure and concentrated, and the oily reaction mixture was purified by silica gel column chromatography (ethyl ether:hexane=1=9→1:4) to produce a red-yellow oil. 1g was obtained.

Dissolve this in THF150n++2, add a solution of Na2S20410 (J in 150mQ water) at room temperature,
Stirred for 0 minutes. Then, water was added, extracted with ethyl acetate, and the organic layer was washed with water, dried (MqSOt), and concentrated.
The obtained oil was dissolved in ethyl ether, 1 ml of a 4N hydrogen chloride solution in ethyl acetate was added, the precipitated salt was counted, and further recrystallized from ethanol-ethyl ether to obtain 0.75 g of the target compound.

Table 3 shows the physical properties of the obtained compound.

Example 53 4-(4-benzoylaminophenylamine) = 2,6
-tert-butylphenol hydrochloride [compound 5
3] Production of 4-(4-aminophenylamino)-2,6-sheet
rt-butylphenol (free base of compound 14>1.
5 g of chloroform was dissolved in 100 ITIQ of chloroform, 538 m of triethylamine (J) was added under water cooling, and then 748 m of benzoyl chloride was added, and the mixture was stirred at ¥ temperature for 1.5 hours. Then, water was added, extracted with chloroform, and the organic layer was dissolved in M Q
Dry with SOa. After concentration, silica gel column chromatography (ethyl ether:hexane=1:1)
Dissolve the resulting oil in a small amount of ethyl ether, add 4N hydrogen chloride in ethyl acetate solution, collect the precipitated crystals, and recrystallize from ethanol-ethyl ether. Thus, 1.79 of the target compound was obtained.

Table 3 shows the physical properties of the obtained compound.

Examples 5/1 to 57 Production of Compounds 54 to 57 In the same manner as in Example 53, the target compounds (
Compounds 54 to 57) were produced.

Table 3 shows the physical properties of each compound.

Example 58 2.6-tert-butyl-4-(2-phenylsulfonylaminephenylamino)phenol hydrochloride [
Preparation of Compound 58] (1) 2.6-tert-butyl-1,4-benzoquinone 19 and 0-phenylenediamine 0.80 were dissolved in TH
F50m[,: dissolve, kot'L ni(C2H5)20
-BF30.15mQ was added, and the mixture was heated under reflux for 15 hours.

A cold solution of Na2320!20CI in water 2501TIJ2 was added, stirred at air temperature for 30 minutes, and extracted with ethyl acetate. The organic layer was dried with MCJS Ot, concentrated, and the resulting product was purified by silica gel column chromatography (ethyl ether:hexane = 1:5) to obtain 4-(2-aminophenylamino)-2. 1 g of 6-tert-butylphenol was obtained as an oil.

(2) Dissolve 1 g of 4-(2-aminophenylamino)-2,6-tert-butylphenol obtained in (1) above in 10 ml of DMA, and cool with water to dissolve 1.28 g of pyridine.
CJ, then pensene sulfonyl chloride 570m!
1] and stirred at air temperature for 1.5 hours. Then, water was added, extracted with chloroform, and the organic layer was dried with MqSOt. After concentration, the oil obtained by purification by silica gel column chromatography (chloroform:hexane = 1:1) was dissolved in a small amount of ethyl ether, and 3 ml of a 4N hydrogen chloride solution in ethyl acetate was added thereto. 1 g of compound was obtained.

Table 3 shows the physical properties of the obtained compound.

Example 59 Production of Compound 59 In the same manner as in Example 58, the target compound (Compound 59) listed in Table 2 was produced.

Table 3 shows the physical properties of the obtained compound.

Example 60 2. Preparation of 6-tert-butylphenol 4-(2-ethoxycarbonylphenylamino)phenol hydrochloride [Compound 60] 4-(2-carboxyphenylamino-tert-butylphenol (Compound 25) 1Q
! Dissolved in 5m DMF (2), added 500mg of potassium carbonate and 350mg of ethyl bromide, and stirred at +1 for 20 hours.Then, the reaction mixture was diluted with 10% Na23204
The mixture was transferred to an aqueous solution and extracted with ethyl acetate, and the organic layer was washed with water, dried (MCJSOt), and concentrated with W. The obtained oily substance was purified by silica gel column chromatography (ethyl ether:hexane=1:5), then dissolved in ethyl ether, and 4N hydrogen chloride dissolved in ethyl acetate was added.
2 ITl12 was added and the crystals were taken along to obtain 0.75 CI of the target compound as pale yellow crystals.

Table 3 shows the physical properties of the obtained compound.

Example 61 4-(2-benzylaminocarbonylphenylamino)
-2.6-diCrt-butylphenol [compound 6
1] Production of 4-(2-carboxyphenylamino)-2,6-tart-butylphenol (compound 25) 1q.
Dissolve in F20mG and add benzylamine 340mG under water cooling.
g and 570 mq of DEPC were added, and a solution of 330 mg of triethylamine in DMF5rpA was added over 20 minutes, and the reaction mixture was then stirred at room temperature for 20 hours. The reaction mixture was transferred to water, extracted with ethyl acetate, the organic layer was washed with water, dried (MQSO4) and concentrated, and the resulting crude product was subjected to silica gel column chromatography (
Ethyl ether:hexane - target compound (1.1Cl as white crystals) q.

Table 3 shows the physical properties of the compounds listed above.

Examples 62 to 75 Compounds 62 to 75 shown in Table 2 were produced in the same manner as in Example 61.

The physical properties of each compound obtained are also listed in Table 3.

Example 76 Preparation of 2,6-tert-butyl-4-(4-hydrazinocarbonylmethylnoenylamino)phenol [Compound 76] 2,6-tert-butyl-4-(4-ethoxycarbonylmethyl phenylamino)phenol (compound 6
) 2.4Q was dissolved in 25 mQ of hydrazine hydrate and ethanol, and heated at 100'C for 40 minutes.

The reaction mixture was transferred to water, extracted with ethyl acetate, and the first layer was washed with 10% aqueous Na23204 solution, then water, and dried (M
gSO4), Q-contracted. The obtained crystals were recrystallized from ethyl ether:hexane='l:/l to obtain the target compound 1.
．． 8 g was obtained as white crystals.

Table 3 shows the physical properties of the obtained compound.

Example 77 4-(4-benzylaminophenylamino)=2,6-
Tert-butylphenol dihydrochloride [Compound 7
7] made) old L! AQ Ha 4 66m! ;l T H F
4-(4-benzoylaminophenylamino)-2.6-di-butylphenol (free base of compound 53>1.7c+) was suspended in THFHF at 30 mL under cooling with water. , and then refluxed for 5.5 hours.

A cold solution of 5 g of Na2 32 04 12 in 60 ml of water was added, and the mixture was stirred at air temperature for 10 minutes. Then, water was added, extracted with ethyl ether, and the organic layer was dissolved in M gSO
4, dried and shrunk. The obtained oil was dissolved in a small amount of ethyl ether, 2 mQ of a 4N hydrogen chloride solution in ethyl acetate was added thereto, and the precipitated crystals were collected by filtration.

The crystals were recrystallized from isopropanol-ethyl needle to obtain the target compound 45 (E'l) as white crystals.

Table 3 shows the physical properties of the obtained compound.

Example 78 Compound 78 shown in Table 2 was produced in the same manner as in Example 77.

The physical properties of the obtained compound are also listed in Table 3.

Table 2 Table 5 R6 Examples 79 to 97 Compounds listed as Compounds 79 to 97 in Table 4 below were obtained in the same manner as in Example 52 using appropriate starting materials.

Table 4 also lists the physical properties of each compound obtained.

Example 98 2,6-tert-butyl-4-(3-hydroxy-4-methoxyphenylamino)phenol hydrochloride (
Preparation of Compound 98) The title compound was obtained in the same manner as in Example 1 above.

Melting point: 190'C or higher (decomposition)' H-NMR spectrum (DMSOds) δ1.3
7 (s, 18H), 3.71 (s, 3H), 6.54 (d, J=3Hz, 1H), 6.68 (d
d, J=8Hz, 3t-1z,'IH)6.85 (d
, J=8Hz, 1t-1>, 7.02 (s, 2H) Example 99 2.6-tert-butyl-4-(3-carboxy-4-chlorophenylamino)phenol hydrochloride (Compound 99) Preparation of the title compound was obtained in the same manner as in Example 24 above.

Melting point: 199-201°C or higher (decomposition)' H-NM
R spectrum (DMSO-ds) δ1.37 (s,
18H), 6.88 (s, 2H), 6.96 (dd, J=10Hz, 3Hz, 1H), 7.23 (d, J=10Hz, 1H>, 7, 32
(d, J=3 t12.1H>Example 1
00 4-(4-carboxymethylphenylamino-2.3.
Production of 6-drimethylphenol hydrochloride (compound 100) 4-(4-methoxycarbonylmethylphenylamino)
-2.3.6-drimethylphenol (compound 86
), 7.2 mQ of 36% hydrochloric acid, and 14.2 mQ of acetic acid was heated at 50° C. for 14.5 hours. After cooling the reaction mixture to room temperature, the precipitated crystals were counted, washed with acetonitrile, and dried to obtain 1.6 g of the target compound. The mother liquor was concentrated under reduced pressure, and the resulting solid was treated in the same manner as above to further obtain the target compound 0.4Q.

Table 5 shows the physical properties of the 1q compound.

Examples 101 to 104 Compounds 101 to 104 listed in Table 5 were obtained in the same manner as in Example 100 above.

Table 5 shows the physical properties of each compound obtained.

The results of pharmacological tests using the compounds of the present invention are shown below.

(1) 5-lipoxygenase inhibition effect Cell preparation and measurement of 5-lipoxygenase activity are carried out by G.
The method of G. M. Bokoch and P. W. Reed [J. Biol, Chem, 256.415
6 (1981) Ko and Ochi et al.'s method [J, Biol
,Chem,.

258.5754 (1983)].

That is, 2% casein was administered intraperitoneally to guinea pigs, and 14
After ~16 hours, the mice were exsanguinated, and the peritoneal cavity was washed to collect infiltrated cells. The cells were suspended at a concentration of 2.5x107 cells/m12 in phosphorus-M1 buffer containing 1mM CaC (22 and 5.5mM glucose).
After incubation at 'C for 2 minutes, each concentration of analyte was added and further incubated for 2 minutes.

Then 10μM ionophore A23187 followed by 1
0 μM 14G-arachidonic acid was added. After incubation for 3 minutes, the reaction was stopped by adding 0.2M citric acid and the product was extracted with ethyl acetate. The extract was spotted on a thin plate, and after development, arachidonic acid, 5(S)-hydroxy-6,8,11,14-eicosatetraene M (
5-HETE> and other parts were scraped off, and 14C was counted using a scintillator. The inhibitory activity of the sample was expressed as the inhibition rate relative to the 5-HETE production rate of the control.

The results are shown in Table 7.

Table 7 In Table 7, NDGA is nordihydroguaiaretic acid.
ticacid).

Formulation Example 1 Compound 91 200mg glucose
250mCJ distilled water for injection
Compound 91 and glucose are dissolved in an appropriate amount of 5 ml of distilled water for injection, then injected into a 5 mQ ampoule, and after purging with nitrogen, autoclaving is performed at 121° C. for 15 minutes to obtain an injection with the above composition.

Formulation example 2 Compound 91 100g Crystalline cellulose (trade name: [Avicel pH101, manufactured by Asahi Kasei Corporation) 40CJ cornstarch 30g Stearic acid management 2g Total amount 172g Hydroxypropyl methylcellulose (trade name rTc-5J, Shin-Etsu Chemical Co., Ltd.) ) 100 polyethylene glycol 3q dye
0.3C] Di-awakened titanium 0.2g Water 8'6.5g Total amount 100g Compound 91. Crystalline cellulose, cornstarch, and magnesium stearate are taken and mixed, and then tableted using a machine with a padding radius of 10 mm. The obtained tablets are coated with a film coating agent consisting of TC-5, polyethylene glycol 60001 castor oil, and ethanol to produce film-coated tablets having the above composition.

Formulation example 3 Compound 91 2g Purified lanolin 5g White beeswax 5g White petrolatum 88CJ all @
Heat 100g beeswax to make it liquid, then add compound 9
1. Add purified lanolin and white petrolatum, warm until it becomes liquid, and stir until it begins to solidify to obtain an ointment with the above composition.

(that's all)

Claims (1)

[Claims] [1] (a) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (1) [In the formula, R^1^b is a carboxyl group, cyano group, carbamoyl group, nitro group, sulfamoyl group, hydroxyC_1-C_6 alkyl group, C_1-C_6 alkoxycarbonyl C_1-C_6 alkyl group, carboxyC_
1-C_6 alkyl group, halogeno-substituted C_1-C_6 alkyl group, C_1-C_6 acyl group, C_1-C_6 alkylthio group, phenylthio group, C_1-C_6 alkylsulfonyl group, amino group, halogen atom, C_1-C
A phenyl group or an unsubstituted phenyl group having 1 to 3 substituents selected from a _6 alkoxy group, a hydroxyl group, and a C_1-C_6 alkyl group. R^2 and R^3 are the same or different and represent a C_1-C_6 alkyl group. ] Phenol derivatives and their salts represented by (b) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (2) [In the formula, R^4 and R^5 are the same or different and C_1-
C_6 represents an alkyl group, R^6 is a hydrogen atom or C_1
-C_6 represents an alkyl group. Furthermore, R^5 and R^6 may be bonded to each other to form a condensed ring with the benzene ring to which they are bonded. Aa is a hydrogen atom,
C_1-C_6 alkylsulfonyl group, C_1-C_6
Alkoxycarbonyl group, piperidinocarbonyl group, phenyl C_1-C_6 alkylcarbamoyl group, C_1
-C_1_2 alkylcarbamoyl group, C_3-C_8
Cycloalkylcarbamoyl group, C_1- as a substituent
C_6 alkoxycarbonyl group, carboxyl group, C_
C_2-C_6 alkenyl group having a group selected from 1-C_6 acyl group, C_1-C_6 alkylcarbamoyl group and C_3-C_8 cycloalkylcarbamoyl group, C_3-C_8 cycloalkylcarbamoyl, C_1-C_6 alkylcarbamoyl, phenyl as a substituent C_1-C_6 alkyl group, carboxyC_1-C_6 alkyl group, C_1-C_6 having a group selected from C_1-C_6 alkylcarbamoyl, piperidinocarbonyl, morpholinocarbonyl and hydrazinocarbonyl group
6 alkoxycarbonyl C_1-C_6 alkyl group, C
_1-C_6 alkyl group, carboxyl group, C_1-C
_6 alkoxy group, halogen atom, or -NR^7R^
8^a group (R^7 is a hydrogen atom or a C_1-C_6 alkyl group, and R^8^a is a C_1-C_6 alkyl group, a C_1-C_6 alkyl group having a phenyl group as a substituent, a phenyl group, a substituted Indicates a benzoyl group that may have a C_1-C_6 alkyl group as a group, a C_1-C_6 acyl group, a C_1-C_6 alkylsulfonyl group, or a phenylsulfonyl group that may have a C_1-C_6 alkoxycarbonyl group as a substituent. . However, when R^6 is a hydrogen atom, the group Aa is a hydrogen atom,
Carboxy C_1-C_6 alkyl group, C_1-C_6
Alkoxycarbonyl C_1-C_6 alkyl group, C_
1-C_6 alkyl group, carboxyl group, C_1-C_
It must not be a 6-alkoxy group or a halogen atom. ] A lipoxygenase inhibitor characterized by containing a phenol derivative represented by the following and its salt as an active ingredient.