JPS5852250A - 2-aminophenol derivative, its preparation, and remedying agent containing said derivative as active component - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI[R<1> is 1-6C straight-chain or branched alkyl or group of formula II (R<2> is H, halogen, lower alkyl, lower alkoxy, carboxyl, etc,; n is 0, 1 or 2); X is halogen; Y is oxo or hydroxyimino] and its pharmacologically permissible acid addition salt. EXAMPLE:3-Amino-5,4'-dichloro-2-hydroxybenzophenone. USE:Useful for the prevention and remedy of allergic tracheal, bronchial or pulmonary diseases, allergic shock, or various inflammatory diseases. It has 5- lipoxygenase-inhibiting and cycloxygenase-inhibiting activities, and controls the biosynthesis of leucotriene, etc. PROCESS:The compound of formulaIcan be prepared by selectively reducing the compound of formula III, and if necessary, converting the resultant compound to oxime.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 5-lipoxygenase (5-1ipoxygenase).
nase) inhibitory activity and cyclooxygenase (cyc
Novel 2 with looxyge-nase) inhibitory activity
- An aminophenol derivative, a method for producing the same, and a pharmaceutical product containing the derivative as an active ingredient. More specifically, it strongly inhibits the activity of 5-lipoxygenase, which is involved in the first step in a series of in-vivo reactions in which various leukotrienes are biosynthesized from arachidonic acid. Various prostaglandins (Pros
It also strongly inhibits the activity of cyclooxygenase, which is involved in the first step in the series of in-vivo reactions in which taglandin is biosynthesized. The present invention relates to a novel 2-amine phenol derivative effective for the prevention and treatment of various inflammations caused by sexual shock or allergies, and various inflammations caused by prostaglandins, a method for producing the same, and a pharmaceutical containing the same as an active ingredient.

In the area of prostaglandin (hereinafter abbreviated as PG) research, several important discoveries have been made one after another over the past few years. Therefore, there have been major changes in the flow of PG research and development in recent years.

Newly discovered or newly determined PGs
Among Sophia, PG eF peroxide (PG e
ndoperoxides, j i.e. P(1, G 2
and PGE1), thromboxa7A2 (Tbr
omboxane A2, hereinafter abbreviated as TXA 2 . ) Prostacyclin
, i.e. PGI2) and leukotrienes G, D and E
(Hereinafter, each will be abbreviated as LTC, LTD, and TE.). In addition to these compounds, all of the PG families, including the well-known fiPGs, are biosynthesized in vivo using arachidonic acid as a common parent, and therefore the entire metabolic pathway starting from arachidonic acid is synthesized in vivo. Arachidonic acid cascade (Ayachi-do)
nate cascade). For a detailed explanation of each pathway and the pharmacological properties of each product, see History of Medicine, 114. 378 (1980), 9°C.

462 (1980), 114,866 (1980)
:same.

1065 (1980) and 12.1105 (1
980) etc.

In the arachidonic acid cascade, cyclooxygenase acts on arachidonic acid to generate PGG2. Furthermore, each fiPG, such as prostaglandin Fz, 6 (hereinafter abbreviated as PGF24), prostaglandin E2 via PGE1.
(hereinafter abbreviated as PGE2), PGI2, TxA2, etc., and lipoxygenase acts on arachidonic acid to produce hydroperoxyeico-satetraenoic acid.
Hydroxyeicosatetraenoic acid (hereinafter abbreviated as HPETE)
acid, hereinafter abbreviated as HETE. ) or the route leading to leukotrienes.

The former route is well known and will not be discussed in detail here. For more information, please see Shin Katori et al. f! , Prostaglandin (1978), published by Kodansha.

Regarding the latter pathway, it is known that various compounds are produced according to the phase path shown in the diagram IK.

Arachidonic acid is metabolized by a well-known pathway, that is, a pathway via PGene r peroxide, and is also metabolized by a completely different pathway by lipoxygenase. That is, arachidonic acid and lipoxygenase, e.g.
-Lipoxygenase.

12-lipoxygenase or 15-lipoxygenase acts to produce 5-HPETE 12-HPETE 15-hp! 1ITa is generated. In these HPETEs, hydrogen peroxide groups are converted to hydroxyl groups by peroxidase, resulting in 5-HETE,
12-HETE or 15-HETE is produced, but
I and TA are also produced from 5-HPETE. LT
Leukotriene B (hereinafter abbreviated as LTB) or LTC is produced from A enzymatically or non-enzymatically, or by glutathione-8-) transferase. LTC is γ-glutamipolytrans and LTDK is converted by butidase. It has recently been revealed that LTD is further metabolized to KLTE [Biochem
.

Biophys, Rag, Gorrvnun-,
91, 1266 (1979) and Prostaglan
din4 19(5), 645 (1980)].

LTC and LTD are respectively well-known SRS (slow reacting 5ubst
ance) or S RS-A (slow re
acting 5ubstance of anaphy
laxia) It became clear that K was the same [P
roc, Natl, Acad, Sci, US
A, 76h4275 (1979), Biochem,
Biophys, Res.

Gommun, 9'L 1266 (1979)
, Proc., Natl.

Acad, Sci, USA, 77, 2014 (1
980), Natura 285. 104 (198
0) see]. Therefore, the pharmacological properties of these leukotrienes can be understood as the pharmacological properties of SR8 or 5R8-A.

The name SR8 was used by Feldberg et al. for the pulmonary flow of copra toxin or the substance released when copra toxin was incubated with egg yolk, which slowly constricts the isolated guinea pig ileum and its effect lasts for a long time. [J
, Ph)'5io1. ．． 94. 187 (1938
)reference〕. Furthermore, Kellaway et al. showed that 5BS-A was released when the lungs of sensitized guinea pigs were sensitized with the antigen, and demonstrated for the first time a relationship between 5R8-A and allergic reactions (Quant, J.

EXP, Physiol-* 5 convex 121 (19
40)].

In addition, Brocklehurst reported that when an antigen was applied to a surgically removed lung section of a patient with bronchial asthma for whom a specific antigen was known, histamine and 5R8-A were released.
5R8-A strongly contracts bronchial muscles, and this contraction is not relieved by antihistamines, so 5R8-A plays an important role in bronchial constriction during asthma attacks.
(Progr, Al
6. 539 (1962)].

5R8-A, subsequently obtained from a piece of lung tissue from one person, constricts the bronchial ring in a normal person [Int, Arch-A
llerg)'App1. Irrrnunol-e
38. 217 (1970)], the 5Rs of rats.
When 8-A is administered intravenously to guinea pigs, an increase in pulmonary airway resistance is observed [J, Cl1n.

Invest, 55. 1679 (1974)], 5) When injected into the skin of guinea pigs, rats, and monkeys, is-A increases the permeability of blood vessels to light (Adova et al.
nees in Immunolog7. 10. 10
5 (1969), J. Aller-gy C11n
, Immunol, 621. 371 (19
78), Prostaglandin6.19(5),
779 (1980), etc.]. In addition, 5R3-A is released due to immune reaction.
, calcium ionophore (calcium ionophore)
SR3 is classified as SR3 when it is released without being affected by an immune reaction such as treatment, but there are many similarities between the two types of K, and it is thought that there is a strong possibility that they are the same substance.

Based on these many research results, various leukotrienes (LTG%LTD, LTE, and leukotrienes whose structures may be further determined in the future) biosynthesized from arachidonic acid through LTA are now known to be effective in allergic tracheal tract infections. It is also considered to be an important factor involved in the development of bronchial or pulmonary diseases, allergic shock, and various types of allergic inflammation.

Furthermore, PC has traditionally been shown to be an important chemical mediator in inflammatory responses.
) is believed to be. For example, PGH has a vasodilatory effect that increases vascular permeability, and a carcinogenic effect5.
It has been reported that it has antipyretic effects and leukocyte migration effects (Shin Katori et al., Prostaglandin (1978),
Published by Kodansha], and PGI2 alone does not increase blood vessel permeability, but it has been reported that it has the effect of enhancing the vascular permeability-enhancing effect of histamine [
Prosta-grandins, 15.557 (1
978)]. More recently, it has been reported that K, which suppresses these effects of PG, is more effective in inhibiting cyclooxygenase activity and simultaneously inhibiting VC5-lipoxygenase activity [Biochemieal Pharmac
ology, 2 & 1959 (1979) and Europ.
ean Journal of Phar-macol
ogy, 66, 81 (1980)].

Therefore, the present inventors have discovered that this method inhibits the activity of 5-lipoxygenase in vivo and also inhibits the activity of cyclooxygenase. As a result of intensive research to find compounds that are effective in preventing and treating inflammation, we have discovered a compound that achieves this objective and completed the present invention.

That is, the present invention relates to the general formula [wherein R1 is a stone or branched alkyl group having 1 to 6 carbon atoms, or the general formula (wherein R2 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a carboxyl group] represents a group, an amino group, a carbamoyl group (i.e. -00N) 12), a sulfamoyl group, i.e. -SO2NH2 or a nitrile group, and n represents 0.1 or 2. ), 5x represents a halogen atom, and Y represents an oxo group (i.e., U) or a hydroxy, -OH, diimino group (i.e., 11).

The present invention relates to 2-amine phenol derivatives represented by the following formulas and pharmaceutically acceptable (non-toxic) acid addition salts thereof.

In general formula (1), the linear or branched alkyl group having 1 to 6 carbon atoms represented by R1 includes methyl, ethyl, propyl, phtyl, pentyl, hexyl and isomers thereof, and preferred alkyl groups are Methyl, ethyl, propyl, butyl, pentyl or hexyl groups, and a particularly preferred alkyl group is hexyl group.

In the general formula (1), the halogen atom represented by X includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a preferable halogen atom is a chlorine atom or a fluorine atom.

In general formula (II), the halogen atom represented by R2 includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a preferred halogen atom is a chlorine atom or a fluorine atom.

In the general formula (Ill), the lower alkyl group represented by R2 includes straight-chain or branched-chain alkyl groups having 1 to 4 carbon atoms, i.e., methyl, ethyl, propyl, butyl groups, and isomers thereof, and are preferred. Alkyl groups are methyl or ethyl groups.

In general formula (II), the lower alkoxy group represented by R2 includes stone or branched alkoxy groups having 1 to 4 carbon atoms, -f, methoxy, ethoxy, zolopoquine, butoxy groups, and isomers thereof. , preferred alkoxy groups are methoxy or ethoxy groups.

In the general formula (Ill), the group represented by formula 1 -(CHz)n- includes a single bond, a methylene group, and an ethylene group, with a single bond being preferred.

Among the compounds represented by the general formula (11), preferred compounds include +1+Ri or methyl, ethyl, propyl, butyl, k-methyl or hexyl group, X represents a chlorine atom or a fluorine atom, and Y represents an oxo group or a hydroxyimino group. and (tt) a group in which R1 is represented by the general formula (II) (wherein R2 represents a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, an ethyl group, a methoxy group, or an ethoxy group, and n is 0 ).
A compound in which X represents a chlorine atom or a fluorine atom and Y represents an oxo group or a hydroxyimino group.

According to the present invention, in the compound represented by the general formula (1) in which Y represents an oxo group, that is, the general formula 0H, all symbols have the same meanings as above. ) is a compound represented by the general formula (in which all symbols have the same meanings as above). ．． e hydrogen gas in the presence of a catalyst such as radium on carbon, or iron, zinc, tin or stannous chloride and hydrochloric acid, or titanium trichloride in the presence of benzene or benzene and tetrahydrofuran, or sodium sulfide in water or a hydrous alcohol; It can be easily obtained by a reaction using ammonium sulfide, aqueous ammonia and hydrosulfide.

Using a compound represented by the general formula (in the formula, all symbols have the same meanings as above), the compound represented by a button is used in a mixed acid of nitric acid and sulfuric acid, nitric acid and sulfuric acid in acetic acid, or It can be easily obtained by a method using a common nitration reagent such as nitric acid in acetic acid.

The compound represented by the general formula ([V)] is obtained by subjecting the compound represented by the general formula (wherein, All symbols including -f have the same meaning as above.)
It can be obtained by converting the methoxy group attached to the 1-position of the compound shown by into a hydroxy group.

Acylation by the Friedel-Crafts reaction is well known, for example, in inert organic solvents such as carbon disulfide, nitrate, chloroform, methylene chloride, carbon tetrachloride, petroleum benzine, aluminum chloride, aluminum bromide, etc. , tin tetrachloride.

Iron trichloride, zinc chloride, boron trifluoride, hydrofluoric acid,
In the presence of a catalyst such as sulfuric acid, phosphorus pentoxide, phosphoric acid, polyphosphoric acid, polyphosphoric acid ester, iodine, etc.

An acylating agent such as an acyl halide, an acid anhydride, an acid ester, or an acid amide is used, and the reaction is usually carried out at the reflux temperature of the solvent. The product obtained by the Friedel-Crafts reaction is usually a mixture of the compound represented by the general formula (Vl) and the compound represented by the general formula, but the reaction conditions can be controlled depending on the type of group represented by R1. By doing so, only the compound represented by the general formula can be selectively obtained.

The method of converting the methoxy group of the compound shown in the general formula (C) to a hydroxyl group is well known, for example, by heating in acetic acid using hydrobromic acid or a mixture of hydrobromic acid and hydroiodic acid. This is done by refluxing.

Furthermore, among the compounds represented by the general formula, compounds other than those in which R1 represents a group represented by the general formula (II) and R2 represents a lower alkoxy group are defined by the general formula [wherein, X has the same meaning as above] , R4 has 1 carbon number
~6 linear or branched alkyl groups or general formula (I
It can also be obtained by subjecting a compound represented by I) (where n is the same as above) to a Fries rearrangement reaction. This reaction is well known, and for example, aluminum chloride or titanium tetrachloride, 80' to 200 in the presence of a Friedel-Crafts catalyst, in an inert organic solvent, such as methylene chloride, or in free solvent, preferably free of solvent.
This is done by heating to C temperature.

The compound represented by the general formula 2) can be obtained by subjecting the compound represented by the general formula (in the formula, X has the same meaning as above) to 〇-resyllation. Methods for acylating phenols are well known, for example by acylating the corresponding acids in an inert organic solvent such as methylene chloride or without solvent in the presence of a tertiary amine such as pyridine or triethylamine at temperatures below room temperature. This is carried out using 10 hydrides or acid anhydrides.

The compound represented by the general formula M and the compound represented by the general formula 1 are themselves known compounds or known compoundsff
:Can be more easily controlled than VC.

Furthermore, according to the present invention, a compound represented by the general formula (1) in which Y represents a hydroxyimino group, that is, a compound represented by the following formula (wherein, the symbol "done" has the same meaning as above) is , can be obtained by converting a compound represented by general formula (IA) into an oxime. Oxime formation is well known, for example, by reaction with hydroxyamine hydrochloride in the presence of sodium or potassium carbonate in an inert organic solvent such as methanol or ethanol at room temperature to the reflux temperature of the solvent. can get.

The acid addition salt of the 2-aminophenol salt conductor represented by the general formula (1) can be prepared by adding the compound represented by the general formula (1) to the compound represented by the general formula (1) in a suitable solvent. Suitable acids 1 Inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, nitric acid 5 or acetic acid, lactic acid,
Tartaric acid, benzoic acid, citric acid.

It can be obtained by reacting organic acids such as methanesulfonic acid, ethanesulfonic acid, hensensulfonic acid, toluenesulfonic acid, and isethionic acid in theoretical amounts.

Preferably, the acid addition salt is a non-toxic salt.

Here, non-toxic salts are relatively harmless to animal tissues and when used in therapeutically necessary amounts, the effective pharmacological properties of the compound represented by the general formula It refers to salts of the anion such that they are unimpaired. The salts are preferably water-soluble. Suitable acid addition salts include, for example, hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, etc. Inorganic rR salts such as acid salts, nitrates, or acetates.

Lactate, tartrate, benzoate, citrate, methanesulfonic acid 1m, ethanesulfone ellffl, Hensensulfone #! t4if, toluene sulfone 112
and organic acid salts such as isethionate.

Since the compound represented by the general formula (1) and its pharmaceutically acceptable acid addition salt have an activity of inhibiting 5-lipoxygenase and an activity of inhibiting cyclooxygenase,
It is effective in controlling the biosynthesis of leukotrienes and various PGs in mammals including humans. For example, in a laboratory experiment, in a screening system using guinea pig polynuclear leukocytes (the experimental method will be described later), the 50% inhibitory concentration for 5-lipoxygenase and the 50% inhibitory concentration for cyclooxygenase are 3-amino-5,4' -dichloro-2-hydroxybenzophenone at 1 μM and 3 μM, respectively, and 6-amino-4'-chloro-5-fluoro-2-hydroxybenzophenone at 1 μM and 2 μM, respectively, in both cases at extremely low concentrations. It was found to inhibit enzyme activity.

Screening using polynuclear leukocytes includes the following KI,
I went. That is, 50mM IJ acid buffer (pH 7,
4) After incubating 1 ml of reaction solution Q containing 1 mM calcium chloride, guinea pig polynuclear leukocytes (4 x 107 cells) and the compound of the present invention at 67C for 5 minutes, 1.8 nmol labeled with radioactivity (14Q) was added.
of arachidonic acid (2,2X 105 dpm) was added to start the enzymatic reaction. After incubation for 5 minutes at 37c 0.31 ether-methanol-1M citric acid (30
:4:1) mix and add 20μ of the organic layer.
t was spotted on a thin layer plate and developed using a mixed solution of ether-petroleum ether-acetic acid (85:15:0.1) as a developing solvent to separate each product. The activity of 5-lipoxygenase increases the amount of 5-HETE produced by 1, and the activity of cyclooxygenase increases the amount of 5-HETE produced by 5.8.
．． 10-Hebutatrienoic acid (HHT)
or t a y hoki”j y B 2 (T X B
2) ()IHT and IJTXB2! '17 rakhi r
It is known as one of the final products in the cyclooxygenase-related system of the acid cascade. ]
Calculation by measuring the production amount of 5-HETE
and HHT *? ,=l! The concentration of the compound of the present invention required to inhibit TXBz production by 50% was defined as the 50% inhibitory concentration for 5-lipoxygenase and the 50% inhibitory concentration for cyclooxygenase, respectively.

Controlling the biosynthesis of leukotrienes and prostaglandins is important for allergic tracheal and bronchial or pulmonary diseases in mammals including humans, especially humans.
It is effective in the prevention and treatment of allergic shock and various types of allergic inflammation, as well as various types of inflammation caused by prostaglandins. For these purposes systemic K is usually used.

For example, it can be administered orally, enterally or parenterally.

The dosage varies depending on the age, symptoms, therapeutic effects, administration method, treatment time, etc., but it is usually preferably 0.1 my orally.
The dose is administered in the range of 500 μg, and when urgent treatment is required, the dose is intravenously administered in the range of 1 μII to 1 μg or continuously injected intravenously in the range of 0.1 μg to 0.1 μg/hour. Ru.

Solid compositions for oral administration include tablets, pills, powders, and granules. In such (6) body compositions, one or more active substances are combined with at least one inert diluent, such as calcium carbonate, potato starch, dextrin, alginic acid, lactose, mannitol, glucose, cocoa butter. mixed. The composition is prepared according to a conventional method using additives other than an inert diluent.
For example, a lubricant such as magnesium stearate and/or a disintegrant such as fibrin calcium gluconate may be included. Tablets or pills may be coated with sugar, gelatin, enteric agents, films, or coated with two or more layers, if desired.

Liquid compositions for oral administration include pharmaceutical emulsions, solutions, suspensions, syrups, elixirs, and commonly used viscous diluents such as water, fluids, etc. Contains paraffin. In addition to inert diluents, the compositions may also contain adjuvants such as humectants, suspending agents, sweeteners, flavoring agents, aromatics, and preservatives.

Compositions according to the invention for oral administration include a diluent,
Also included are capsules of absorbable material, such as gelatin, containing one or more active substances with or without excipients.

Solid compositions for rectal administration σ) include suppositories containing one or more active substances and formulated in a manner known per se.

Products for parenteral administration according to the invention may include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, ethanol, vegetable oils such as olive oil, and injectable organic acid esters such as ethyl oleate and sorbitan esters. Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These are sterilized, for example, by filtration through a bacteria-retaining filter, addition of a disinfectant, or irradiation. They may also be prepared as sterile solid compositions and used in sterile water or sterile injectable bath media before use.The proportion of active substance in the pharmaceutical compositions of the invention may vary. It is necessary to set the amount of harm so that a dose suitable for the desired therapeutic effect can be obtained.
-Yes. Of course, the composition divided into several units = r may be administered at once. Generally, for a product to be administered by injection there is usually at least 0.025 weight! Contains 1% active substance, I/CM for daily administration, contains at least 0.1% active substance.

Preferred 2-aminophenol derivatives included in the present invention include, for example, 6-acetyl-2-amino-4-chlorophenol, 2-amino-4-chloro-6-propionylphenol, and 2-amino-6-butylylphenol. 4-chlorophenol, 2-amino-4-chloro-6-antanoylphenol, 2-amino-4-chloro-6-hexanoylphenol, 2-amino-4-chloro-6-heptanoylphenol, 6- Cetyl-2-amino, no-4-fluorophenol, 2-amino-4-fluoro-6-propionylphenol, 2-amino-6-butyl-4-fluorophenol, 2-amino-4-fluoro-6--! ntanoylphenol, 2-amino-4-fluoro-6-hexanoylphenol, 2-amino-4-fluoro-6-heptanoylphenol, 6-amino-5-chloro-2-hydroxybenzophenone, 6-amino-5 , 4'-dichloro-2-hydroxybenzophenone, 6-amino-5-chloro-4'-fluoro-2-hydroquinpene/phenone, 6-amino-5-chloro-2-hydroxy-4'-methylbenzophenone, 6- Amino-5-chloro-4'-ethyl-2-hydroxybenzophenone, 6-amino-5-chloro-2-hydroxy-4'-methoxybenzophenone, 6-amino-5-chloro-4'-ethoxy-2-hydroxy Inzophenone r 6-amino-5-fluoro-2-hydroxybenzophenone, 3-amino-4'-chloro-5-fluoro-2-hydroxy is inzophenone, 3-amino-5,4/-, >fluoro- 2-Hydroxy is nzophenone, 6-amino-5-fluoro-2-hydroxy-4'-methylbenzophenone, 3-amino-4'-ethyl-5-fluoro-2-hydroxyincifhenone, 3-amino-5- Included are fluoro-2-hydroxy-4'-methoxyinsiphenone, 3-amino-4'-ethoxy-5-fluoro-2-hydroxybanzophenone, their oxime compounds, and their acid addition salts.

Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples, but the present invention is not limited to these Examples. In addition, rT L GJ, rI RJ, I in Reference Examples and Examples
N M 1' (The symbols J and rMassJ represent "thin layer chromatography,""infrared absorption spectrum,""nuclear magnetic resonance spectrum," and "mass spectrometry," respectively. The proportions of solvents listed indicate volume ratios, the solvent in parentheses in rTLcJ indicates the developing solvent, rI RJ is measured by the tablet method, unless otherwise specified. If there is no deuterochloroform (cDcz3)
Measured in solution.

Reference Example 1 4-chlorobenzoic acid 4-chlorophenyl ester 2.2.9 g of triethylamine was added to 2.8 g of 4-chlorophenol dissolved in 5 QrLt of methylene chloride, cooled in an ice water bath, and diluted with 4-chlorobenzoic acid (4-chlorophenyl ester) in 5 tl'. 6.8g of chloride was slowly added dropwise.After the addition, the cooling bath was removed and the reaction mixture was stirred at room temperature for 60 minutes.Water was added to dissolve the salt, and the organic layer was dissolved in 2N hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous solution of sodium bicarbonate. The mixture was washed successively with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 5.87.9 as crude crystals having the following physical properties.

NMR: δ = 8.0O (2H, d), 7.36 (2H,
d), 7.26 (2H, d), 7.10 (2H, a).

IR Niji=3095.1740.1590.1480.
1400.1285.1270.1205.1170.
1160.1090.1075.1010.870.8
45.815.800.750 -10 Mass: m/e =266 (M”), 169.1
10° The following compound was obtained in the same manner as in Reference Example 1.

(a) 4-chlorobenzoic acid 4-fluorophenyl ester (4-chlorophenol used in Reference Example 1 was replaced with 4-fluorophenyl ester)
There was 2.46 g of fluorophenol.

Yield ii: 5.46g NMR: δ = 7.98 (2H, d), 7.38 (2H,
d) 7,3-6.9 (4H,m).

Engineering R: υ=3100.1760.159011500.
1400°1295.1280.1240.1190.
1090°1080.1070.1010.875.8
55.820.755cIIL-1°Mass: m/e =250 (M”), 176.1
39.111゜(b) Hebutane # 4-chlorophenyl ester (heptanoyl chloride 6.27 in place of 4-chlorobenzoylchloride F used in Reference Example 1)
G is 6 shi. ) Yield: 5.9.9 NMR: J = 7.9 (2H, d), 7.2 (2H, d)
, 2.4(2H,t).

IR Niji=3090.1765.1590cIrL-1
゜Mas s : m/e= 242,240 (M+)
Reference Example 2 A mixture of 2 g of 5.4'-cyclo-2-hydroxyinsiphenone ester compound (produced in Reference Example 1) and 2.8 II titanium tetrachloride was stirred at 1150C for 18 hours, and the reaction mixture was heated in an ice water bath. While cooling, 50 Hj of methylene chloride was added to crush the solid, and further 201 parts of water and 10 parts of 6N hydrochloric acid were added and the mixture was stirred well and then separated.

The organic layer was washed with saturated brine, dried over anhydrous sulfuric acid and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solution of methylene chloride-n-hexane (2:3) as the eluent to obtain the title compound 1.49 as yellow crystals having the following physical properties. .

TLC (methylene chloride; n-hexane:/=1:1
): Rt=0.6°NMR: δ=11.63 (IH, s), 7.8 to 7.2
(5H,m), 6.93 (Formula 2 d).

IR Niji=3400.6030.1660.1595.
1460.1400.1625.1285.1235.
122.0.1175.1090.1010.955.
945.900.845.860.785 cm-'.

Mass: m/e = 266 (M”), 260.1
54.169.111.99° The following compound was obtained in the same manner as in Reference Example 2.

(a) 4'-chloro-5-fluoro-2-hydroxybenzophenone [Reference Example 1 (instead of the ester compound used in Reference Example 2)
Ester compound 4.47f9 produced in a) was used.

] Yield: 3.64!9 TLC (methylene chloride: n-hexane = 1:1): Rf
=0.44°NMR: δ-11,82 (IH,s), 7.6-6.6
(7H,m).

IR:l/=3440.6080.1665.1600
,1585.1560.1470.1420.1695
．． 1340°1285.1250.1230.1180
．． 1125.1095.1015.975.890.8
7o1840.825.790 side-1 Mass: m/e =250 (M”), 215.1
69.111゜(b) 4-chloro-2-heptanoylphenol [ester compound produced in Reference Example 1(b) instead of the ester compound used in Reference Example 2 1.819
& was used, and the reaction temperature was 100C. ] Yield: 1
．． 6yO NMI (: δ = 11.8 (IH, s), 7.7 (IH,
d), 7.5 (IH, dd), 6.8 (IH, d), 2
．． 9 (2H, t).

Mass: m/e=242,240 (M+).

Reference Example 6 5-Chloro-2-hyrroxy 4'-methoxyhanzophenone Under nitrogen atmosphere, add salt (k aluminum 12.819) to methylene chloride 501, stir for 15 minutes, cool to OC, and then add p-methoxyin. Zoyl chloride 13.64
g was added dropwise and stirred at room temperature for 15 minutes. Next, p-chloroanisole 101 dissolved in 5Qmt of methylene chloride was added dropwise to the reaction solution and stirred for 18 hours. The reaction mixture was transferred into a mixture of ice water and hydrochloric acid, and extracted with methylene chloride. The extract was washed with an aqueous sodium bicarbonate solution, dried over sodium chloride, and concentrated under reduced pressure. The residue was recrystallized from cyclohexane to give the title compound 8 with the following physical properties.
．． 6g was obtained.

TLC (benzene): Rf=0.46°NMR: δ-1
1,82 (IH, s), 7.9-6.9 (7H, m)
, 3.92 (3H, s).

Engineering R Niji = 1620.1590.1560.1460
．． 1625.1605.1250.1260.1210
．． 1165.1020.955.940.840.86
0.785c+n-”.

Mass: m/e=262 (M”).

Reference Example 4 5,4'-Dichloro-2-hydroxy-6-nidrobenzophenone Benzophenone compound 1.4.9 (produced in Reference Example 2) was dissolved in 5 g of acetic acid under heating and heated to room temperature. After cooling, one drop of concentrated sulfuric acid was added, and then 330 μ of concentrated nitric acid (60%) was added dropwise over 20 minutes. The reaction mixture was stirred at room temperature for 5 minutes, cooled on ice, a mixture of methylene chloride and ice water was added, and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was eluted with methylene chloride-n-hexane (1:1).
) was purified by silica gel column chromatography using a mixed solution of 1.
5 g of crystals were obtained.

TLC (methylene chloride): Rf=0.5°NMR:
δ-11,82(IH,s), 8.17(1)(,d)
, 7.63 (2H, d), 7.62 (IH, a), 7.
43 (2H, d).

IR Niji=ri420.3180.3090.1655.
1615.1585.1530.1480.1445.
1405.1315.1280.1245.1160.
1090.1010.980.905.890.845
．． 830.780.730cm-to Mass: m/e = 311 (M”), 294.2
76.264.199.159.111° The following compound was obtained in the same manner as in Reference Example 4.

(a) 4-chloro-6-hebutanoyl-2-nitrophenol [phenol compound σ used in Reference Example 4] 1.28 g of the phenol compound produced in Pleading Example 2(b) was used instead. ] Yield: 1.419°NMR: δ = 11.5 (IH, s), 8.05 (IH,
d), 7.7 (IH, d), 3.0 (,2H, t).

Ma s s : m/e = 287.285 (M+)
.

(b) 5-chloro-2-hydroxy-3-nitrobenzophenone [Instead of the phenol compound used in Reference Example 4, 1.23 g of 5-chloro-2-hydroxyinciferone (commercial product: manufactured by Wako Junkuwa) was added. Using. ]Yield: 1.3g.

Melting point: 56° ~ 58tZ' NMR: δ = 11.23 (IH, g), 8.13 (IH
,d), 7.90-7.15 (6H,m).

IR Niji=3600~6515.6075.1665.
1660.1605.1590.1525.1440.
1395.1610.1270.1240.1160.
9 5.895.805.765.720.695.6
45cIL-l.

Mass: m/e = 279.278, 277 (M+)
, 276.267.260.105.77° Reference Example 5 4'-Chloro-5-fluoro-2-hydroxy-6-nitrobenzophenone Benzophenone compound 3,9 (produced in Reference Example 2(a) ] was dissolved in acetic acid 10111Z under heating, and concentrated nitric acid (
60%) 1.3.9 was slowly added dropwise over 20 minutes. After stirring at room temperature for 30 minutes, a mixture of methylene chloride and ice water was added while cooling with water, and the mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was eluted with methylene chloride-n-
The title compound 2.99.9 was purified by Kagel column chromatography using a mixed solution of hexane (1:1) to obtain the title compound 2.99.9 as yellow crystals having the following physical properties.

TLG (methylene chloride): Rf = 0.58°NMR: δ
= 1(11,8(IH,s) 7.90(IH,
dd), 7.65C2H,d), 7.40(2H,d)
, 7.7-7.2 (IH, m).

IR Niji=3450.3225.3100.1655.
1600.1585.1570.1540,1485.
1455.1425.1650.1610.1290.
1250.1220.1155.1095.1005.
955.885.850.800.775.755cI
IL-'.

Mass: m/e = 295 (M”), 260.2
47.184.139.111° The following compound was obtained in the same manner as in Reference Example 5.

(a) 5-chloro-2-hyVroxy4′-methoxy6-nitroRnzophenone (1.3 g of the benzophenone compound produced in Reference Example 3 was used instead of the benzophenone compound used in Reference Example 5,
Furthermore, 10Kt of methylene chloride was added during the reaction. ) Yield: 1.2,9° TLG (Hanzen): Rf = 0.22° NMR: δ = 1
1.23 (IH,s), 8.30~8.15 (IH
, m), 7.90-7.60 (3H, m), 7.1~
6.9 (2H, m), 3.90 (3H, m).

Engineering Rniji=5200.6100.1640.1600.
1525.1415.1400.1285.1250.
1160.1020.975.840α-10 Mass: m/e = 307 (M”).

Example 1 6-amino-s,4/-,:)chloro-2-hydroxybenzophenone nitrobenzophenone compound (produced in Reference Example 4)
Dissolve 370■ in ethanol 10W11, chloroform 1117! , and further palladium on carbon (content = 10%)
After adding 50 II kg, hydrogen gas was blown into the mixture while stirring at room temperature for 2 hours. After the reaction is complete, remove the catalyst by filtration.
Solution e was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methylene chloride as an eluent to obtain crystals of the title compound 70■ having the following physical properties.

Melting point: 91° to 94'c (decomposes).

TLC (methylene chloride): Rf=0.3t! S.

NMR: δ=12.0 (IH, wide 8), 7.62<
2H, d), 7.50 (2H, d), 6.87 (2H,
s), 3.84 (2H, wide s).

IR Niji=3460.6320.6050.2925.
1620.1600.1560.1460.1395.
1665.1660.1615.1275.1225.
1195.1180, 1095.1040.1020.
920.855.845.820.785.765.7
65.715 -1゜Mass: m/e =283.281 (M+), 17
1.169.141.169.116.111° The following compound was obtained in the same manner as in Example 1.

(a) 6-amino-4'-chloro-5-fluoro-2-
Hydroxybenzophenone (nitrobenzophenone compound 50 produced in Reference Example 5 instead of the nitrobenzophenone compound used in Example 1)
0■ was used. ) Yield: 400■.

Melting point: 124°-127C.

TLC (methylene chloride): Rf = 0.48°NMR: δ
= 11.85 (IH, wide 8), 7.62 (2H, d
).

7.48 (2H, d), 6.75 (IH, aa), 6.
56 (IH, aa), 4.03 (2H, wide S).

Engineering R Niji = 5480.3640.6060.2960.
1630.1600.1590.1560.1475.
1440.1400.1685.1665.1280.
1220.1195.1180.1120,1095.
1o45.1015.1000.855.845.86
5.785ctn-”.

Maas: m/e = 267.265 (M+), 153
．． 139.125.111.97゜Example 2 6-amino-5-chloro-2-hydroxybenzophenone hydrochloride In the same manner as in Example 1, a nitrobenzophenone compound [
Produced in Reference Example 4(b). ] Using 2233m, 3
-Amino-5-chloro-2-hydroxy obtained crystals of nzophenone, and further added the obtained compound to ethanol 101
2N hydrochloric acid 421 was added dropwise at room temperature. The reaction solution was concentrated to obtain the title compound 65W having the following physical properties.
I got J.

Melting point = 93° ~ 95C0 TLC (chloroform:ethanol-19:1):Rf
= 0.80°NM) ((CDCt, + acetone-d6 solution): δ = 7
84-7.37 (5H, m), 6.91 (IH, d),
6486 (IH, d).

Engineering R Niji = 3470.6330.1615.1590
．． 1455.1655.1605.1270.1220
．． 1185.1170.1015.905.855.7
95.765.695.660cIIL-1゜Ma s
s arrv'e = 249.247.170.1
68.148.112.104.77.76° In the same manner as in Example 2, the following compound was obtained.

(a) 2-amino-4-chloro-6-heptanoylphenol salt #! In place of the nitrobenzophenone compound used in Example 11112, the nitrophenol compound 240 prepared in Reference Example 4(a) was used. ] Yield: 62~.

NMR: δ = 12.2 (I H,s ), 10.0
(3H, wide 8), 7.9 (IH, d), 7.7. (
IH, d), 2.9 (2H, t).

IR Niji=3400.3600~2650.1650.
1620.1570 cm-1゜Mass: m/e = 302.300゜Example 6 3-Amino-5-chloro-2-hydroxy-47-methoxy is nitrophenone hydrochloride suspended in 4 nt of water at room temperature. is a ndzophenone compound [produced in Reference Example 5(a)]. ] 21 of concentrated ammonia water was added to 165W, 1.4 g of sodium hydrosulfide dissolved in 61 was added all at once, and tetrahydrofuran was added to completely dissolve, followed by stirring for 15 minutes. The reaction mixture was extracted with chloroform, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Dissolve the residue in ethanol and add concentrated hydrochloric acid to
．． After adding 2alt and concentrating, the mixture was dissolved in ethanol again, treated with activated carbon, concentrated under reduced pressure and dried to obtain the title compound 106■ having the same physical properties.

Melting point: 125°-135C.

TLG (methylene chloride): Rf = 0.52° NMR (dimethyl sulfoxide-ds solution): δ = 80 ~ 7.6 (
3H,m), 7.6-7.0 (3H,m), 3.9
2 (3H, s).

Erniji = 3420.3320.2770.2580
．． 1660.1590.1555.1440.1605
．． 1250゜1160.840.780.615crr
L-1゜Mass: m/e = 277 (M”), 169
゜Example 4 3-amino-4'-chloro-5-fluoro-2-hydroxybenzophenone oxime hydrochloride ethanol 501
LIK-dissolved aminobenzophenone compound [Example 1
Manufactured in (a). 1 g of hydroxyamine hydrochloride and 11 sodium carbonate were added to QIIf7 and heated under reflux for 6 hours. After the reaction was completed, it was cooled, ethanol was removed, chloroform and water were added, and the mixture was extracted with chloroform. The extract was saturated. Wash with salt water and anhydrous sulfuric acid) +7
After drying with aluminum, the residue was concentrated under reduced pressure to obtain 794mQ of crude crystals. The obtained product was dissolved in ethanol and concentrated hydrochloric acid 0.241
1 g was added, concentrated, and dried under reduced pressure. The obtained hydrochloride was dissolved in ethanol and treated with activated carbon.
The title compound, which is recrystallized from a mixed solvent of diethyl ether (1:2) and has the following physical properties, melting point: 186° ~
191C (decompose).

TLG (methylene chloride:methanol-10:1):Rf
= 0.56° NMR (methanol-d4 solution): δ = 7.56 (2H
, d), 7.33 (2H, d), 7.26 (dd to 1)
, 6.64 (IH, dd).

Engineering R Niji = 3400.6250.6060.2900
(wide range), 2580.1590.1550.1470
．． 1410.1695.1640.1285.1225
．． 1200.1160.1095.1050,1015
．． 995.880.840.805.795.750 Low 1°Mass: m/e=280(M”), 262.1
51.169.126.126.111.97゜Example 5 Ro-ryo minnow 5,4'-dichloro-2-hydroxybenzophenone 5g, cellulose magnesium gluconate (disintegrant) 200cm, magnesium stearate (lubricant) 1
00 ■ and 4.7 g of crystalline cellulose were mixed in a conventional manner.
The tablets were compressed to obtain 110 tablets containing [5[)11119 active ingredients in one tablet.

Claims (1)

[Scope of Claims] 1. General formula [wherein R1 is a linear or branched alkyl group having 1 to 6 carbon atoms, or general formula (wherein R2 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy represents a group, carboxyl group, amino group, carbamoyl group, sulfamoyl group or nitrile group, n represents 0, 1 or 2), X represents a halogen atom, and Y represents an oxo group. Or it represents a hydroxyimino group. ] A 2-amine phenol derivative or a pharmaceutically acceptable acid addition salt thereof. 2. The compound according to claim 1, wherein R1 is a straight chain or branched alkyl group having 1 to 6 carbon atoms. 3. The compound according to claim 2, wherein the compound is 2-amino-4-chloro-6-heptanoylphenol or its hydrochloride. 4. The compound according to claim 1, wherein R1 is a group represented by the general formula (in which n and R2 have the same meanings as in claim 1). 5. The compound according to claim 4, wherein R2 is a hydrogen atom. 6. The compound according to claim 5, wherein the compound is 6-amino-5-chloro-2-hydroxybenzophenone or its hydrochloride. 7. The compound according to claim 4, wherein R2 is a halogen atom. 8. The compound according to claim 7, wherein the compound is 6-dichloro-2-hydroxybenzophenone or a hydrochloride thereof. 9. The compound according to claim 7, wherein the compound is 6-amino-4'-chloro-5-fluoro-2-hydroxybenzophenone or its hydrochloride. 10. The compound according to claim 8g7, wherein the compound is 6-reminor-4'-chloro-5-fluoro-2-hydroxybenzophenone oxime or its hydrochloride. 11. Claims in which R'' is a lower alkoxy group
1. . Compound described in Disciple Item 4. 12. The compound has the general formula 136 according to claim 11, wherein 6-amino-5-chloro-2-hydroxy-4'-methoxy is nzophenone or its hydrochloride [wherein R1 has 1 to 1 carbon atoms] 6 straight or branched alkyl group or general formula (in the formula, %R2 is a hydrogen atom), rogene atom, lower alkyl group, lower alkoxy group, carboxyl group, amino group,
It represents a carbamoyl group, a sulfamoyl group or a nitrile group, and n represents 0% 1 or 2. ), where X represents a halogen atom. ] The compound represented by is subjected to a selective reduction reaction to obtain a compound represented by the general formula % (in the formula, R1 and X have the same meanings as above), and if desired, the obtained general 2 represented by the general formula (wherein, Y represents an oxo group or a hydroxyimino group, and R1 and X have the same meanings as above), which is characterized by converting the compound represented by the formula (IA) into an oxime. - A method for producing an aminophenol derivative. 14 General formula % Formula % [In the formula, R1 is a straight or branched alkyl group having 1 to 6 carbon atoms, or the general formula (wherein R2 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a carboxyl n represents 0.1 or 2. ), X represents a halogen atom, and Y represents an oxo group or a hydroxyimino group. ] A therapeutic agent for leukotriene-induced diseases, which contains a 2-aminophenol derivative or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. 15. General formula represents an amino group, a carbamoyl group, a sulfamoyl group, or a nitrile group, n represents a group represented by 0, 1 or 2), or represents a halogen atom, and Y represents an oxo group or a hydroxyimino group. A therapeutic agent for prostaglandin-induced inflammation, which contains a 2-aminophenol derivative or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.