JPS61229848A - Novel compound, manufacture and medicinal compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to substituted amine phenols, processes for their preparation, pharmaceutical compositions containing them and their use as medicines.

[Conventional technology]

JP-A No. 56-29745 discloses the formula H Ra (in the formula, Ra is C mountain, CI or Not, and R6 is -
CH2CaHs) is disclosed. These compounds are indicated only as intermediates for the production of pharmacologically active benzoxazines.

[Summary of the invention]

A group of amine phenol derivatives, some of which are new, are involved in the production of the enzyme 5-lipoxygenase [an enzyme important in the production of spasmodic peptide leukotrienes (LTC, LTD, LTE) and inflammatory leukotrienes LTB4]. It was found to be active as an inhibitor of

These compounds also have inhibitory activity on 5R8-A production in vivo, and the symptoms of Shichiwara are associated with these mediators.
It is of value in the prevention and treatment of diseases controlled by cancer, such as asthma, rheumatoid arthritis, psoriasis and other allergic and inflammatory disorders.

According to the invention, the formula (II R.

. [In the formula, R1 is a straight chain or branched chain C1-6 alkyl, halogen, nitro, cyano, hydroxy, or COR6 (in the formula, R4 is a straight chain or branched chain C1-6 alkyl or aryl)] and: Bird is substituted or unsubstituted aryl, aralkyl, or heteroaryl; R5 is hydrogen or straight-chain or branched C alkyl; Melon is hydrogen, hydroxy, straight-chain, or Branched chain 01-6 alkyl, halogen, nitro, cyano, C1-, alkoxy, halo(01-6) alkyl: amino, carboxylic acid ester, carbonic acid, CORa, SRe, 5OtRa
.

and R5 is hydrogen, straight or branched chain 01-6 alkyl, substituted or unsubstituted benzyl, or COR6 (wherein R5 is as above); A pharmaceutical composition comprising a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier is provided.

As used herein, the term "aryl" includes phenyl; heteroaryl groups are typically 4- to 7-membered rings containing up to 4 heteroatoms selected from oxygen, sulfur, and nitrogen.

When R, is C8-6 alkyl it is preferably methyl, in-propyl or tertiary-butyl.

As COR, it would be, for example, acetyl or pendyl. Bromine or chlorine is a typical R substituent.

Suitably R7 is substituted or unsubstituted phenyl.

As a heteroaryl group it may be, for example, furan, thiophene, imidazole, inxazole or pyridine and may be substituted or unsubstituted. A suitable aralkyl group, which may also be substituted or unsubstituted, is benzyl.

Any suitable substituent of horse may be a straight or branched chain 01.6
Alkyl, hydroxy, halogen, nitro, cyano, C
1-, alkoxy, 10(01-6)alkyl, amine, carboxylic acid ester, carboxylic acid, COR,.

It is one or more groups selected from NHCORa -NHRa, N(Ra)t -Sθ几, or 5OtRa' (the formula Nakayama is the same as above).

Preferred substituents for R2 are C□~, alkyl, halogen,
Nitro, cyano, alkoxy such as methoxy, halo (C
□~6) Alkyl such as trifluoromethyl, amino,
Carboxylic acid ester, carboxylic acid, COR41 or NH
COR, (in the formula, X is the same as above).

A suitable carboxylic ester group is -COtR4, (wherein R
5 is the same as above).

Rttlt substituents are typically meta or para preferably para with respect to the -CH,- linking group.

Suitably R8 is hydrogen or when C1-6 alkyl is methyl.

A suitable halo(C,2,)alkyl group is trifluoromethyl. As 01-6 alkyl it is typically methyl or tertiary butyl and as CORII it is typically benzoyl. When 也 is other than hydrogen, it is preferably in the 6th position.

Preferably the melon is hydrogen.

A suitable acyl C0R6 group for R3 is -COCH8.

Preferably R5 is hydrogen.

R4 is typically methyl, ethyl or phenyl.

In formula (13, R is methyl, ethyl, iso-propyl, tertiary butyl,
benzoyl, chlorine or bromine; R, haphenyl, benzyl, furyl or thienyl; the seventh element is optionally methyl, isopropyl, cyano, methoxy, chlorine, bromine;
There are some compounds which may be substituted by fluorine, trifluoromethyl, hydroxy or nitro, R3 is hydrogen or methyl, is hydrogen or hydroxy, and R1 is hydrogen or benzyl.

Examples of compounds of formula (I) include:

2-phenylmethylamino-4-chlorophenol, 2
-Phenylmethylamino-4-methylphenol and its salts and solvates.

The compounds of formula (I) are new.

Therefore, according to the detailed invention, the formula (IA) (in the formula R,,R
,, R,, R2 and Rs are as defined for K in formula (I), and when R1 is methyl or chlorine, R5 is phenyl and R3 is hydrogen, melon is hydrogen, and crow is other than hydrogen. ) is provided.

Suitable and preferred substituents are as appropriate as described for formula (Il).

When the compounds of formula (IA) form salts (eg acid addition salts) or solvates (eg hydrates) these also form part of the invention.

The compound of formula CIA) or a salt or solvate of the Seven Straws is preferably in pharmaceutically acceptable or substantially pure form.

By pharmaceutically acceptable form we mean specifically of a pharmaceutically acceptable level of purity and free from the usual pharmaceutical excipients such as diluents and carriers and from substances that would be considered toxic at normal dosages. .

Substantially pure form is generally at least 50% (excluding normal pharmaceutical additives) preferably 75% and more preferably 90% pure.
% and more preferably 95% of the compound of formula (R) or a salt or solvate thereof.

One preferred pharmaceutically acceptable form is the crystalline form.

Pharmaceutically unacceptable salts or solvates of compounds of formula CIA) may be useful as intermediates in making the pharmaceutically acceptable compounds of the present invention.

Suitable pharmaceutically acceptable salts of this invention are acid addition salts.

Suitable acid addition salts of compounds of formula (IA) include pharmaceutically acceptable inorganic salts such as sulfates, nitrates, phosphates, phosphates,
hydrochlorides and hydrobromides and pharmaceutically acceptable organic acid addition salts such as acetates, tartrates, maleates, citrates, succinates, benzoates, ascorbates, methanesulfonates, Contains α-ketogel tarrate, α-glycerophosphate, and glucose-1-phosphate. Preferably the acid addition salt is hemisuccinate, hydrochloride, alpha-ketogel tarrate, alpha-glycerophosphate or glucose-1
- Phosphate special hydrochloride.

Examples of compounds of formula CIA) include:

2-((4-cyanophenyl)methylcoamino-4-methylphenol; 2-((4-methylphenyl)methylcoamino-4-methylphenol): 2-((4-methoxyphenyl)methylcoamino-4-
Methylphenol: 2-((4-chlorophenyl)methylcoamino-4-methylphenol: 2-((2-furyl)methylcoamino-4-methylphenol): 2-((3-trifluoromethylphenyl)methylcoamino-4-methylphenol ; 2-((4-fluorophenyl)methylcoamino-4-
Methylphenol: 2-((3,4-dichlorophenyl)methylcoamino-
4-methylphenol; 2-[(cheso-2-yl)methylcoamino-4-methylphenol: 2-((4-bromophenyl)methylcoamino-4-methylphenol: 2-((3-fluorophenyl)methylcoamino-4-
Methylphenol; 2-phenylmethylamino-4-iso-propylphenol: 2-phenylmethylamino-4-tertiary butylphenol: 4-pensoyl-6-(phenylmethylamino)resorcinol: 2-dibenzylamino-4- Methylphenol: 2-phenylmethylamino-4-chlorophenol: 2-phenylmethylamino-4-bromophenol: 2-phenylmethylamino-4-ethylphenol: 2-((4-nitrophenyl)methylcoamino-4) -Methylphenol: 2-((4-iso-propylphenyl)methylcoamino-4-methylphenol: 2-((4-hydroxy,diphenyl)methylcoamino-
4-Methylphenol: 2-phenylethylamino-4-methylphenol: and its salts and solvates.

The present invention provides a compound of the formula (■
) and CIA) are provided.

The hydrolysis reaction is suitably carried out in an organic solvent (eg methanol) in the presence of an excess of base (eg potassium or sodium hydroxide). The reaction was carried out under reflux at 30°C to 10°C.
It is carried out at a high temperature of 0°C.

The compound of formula (■) is a compound of formula (face h (wherein R1 and melon are as defined for formula (1)) and a compound of formula ([V) R].

? R, -CH-X may be prepared by reaction with a compound in which R1 and R3 are as defined for formula (I) and X is a halogen such as chlorine, bromine or iodine.

The reaction is suitably carried out in the presence of a base in an inert solvent (eg a mixture of ethanol and water). Suitable bases include sodium hydroxide and potassium hydroxide.

The reaction is carried out under reflux at an elevated temperature of 60°C to 100°C and may be prepared by reaction of a compound of formula (as defined for 11) with urea.

The reaction is carried out for 2 to 3 hours at 135°C to 320°C, preferably at 160°C.
It is carried out at high temperature of °C.

Compounds of formula (5) and M are known compounds or can be prepared from known compounds by known methods.

The present invention further provides compounds of formula (I) or (I
A method for producing the compound of A) is provided.

Suitable reducing agents include hydrogen or hydride reducing agents in the presence of catalysts such as palladium. The particular hydride reagent used will be selected according to Rt = R1-Rs and the nature of the horse. Examples of such reactants are NaBHsCN,
BtHa etc.

The reaction may be carried out in an organic solvent such as ethanol and if necessary at a low pH such as pl (1-2).

L 1AIH4 may also suitably be used in an ethereal solvent such as diethyl ether or tetrahydrofuran.

Moderate temperatures from 0<0>C to 60<0>C may advantageously be used.

Compounds of formula (to) may be prepared by the reaction of a compound of the above formula with a compound of formula (vm, where and R5 are as defined for formula (1) K).

The reaction is suitably carried out in an inert organic solvent such as toluene or an alcohol such as ethanol at an elevated temperature of 60 DEG C. to 150 DEG C., preferably under reflux. The water formed during the reaction when a water-immiscible solvent such as toluene is used is preferably removed using a trap.

The present invention provides a chemical compound (II) or (IA) in which hydrogen is hydrogen by the reaction of the compound of ■ and the compound of formula (2) under reducing conditions.
A method for producing a compound is provided.

For example, the reaction may be carried out in an organic solvent such as methanol at neutral pH.
may be carried out in the presence of a hydride reducing agent such as NaBH, CN. Moderate temperature, such as 0°C to 30°C, suitably 25°C
can be used. The reaction is carried out for a long time, for example 13 hours or more.

If hydrogen in the presence of a catalyst such as platinum or nickel is used as reducing agent then high temperatures e.g.
℃ and/or high pressures, suitably up to 10 atmospheres, are used.

The present invention combines a compound of Wenmu (■) Ru (wherein L-R4 and Rs are as defined for formula (1) and R2 is hydrogen or a hydroxy protecting group) and a compound of formula α■ as described above. A method is provided for preparing compounds of formula (1) or (IA) by reaction and subsequent removal of any hydroxy protecting groups if necessary.

Suitable hydroxy protecting groups R2 include benzyl groups, which may be substituted by groups such as nitro or methoxy, and so!
0 (including s).

The reaction is suitably carried out in the presence of a base such as potassium hydroxide or sodium hydride in an inert organic solvent such as N,N-dimethylformamide. High temperature e.g. 25℃~1
60°C is preferably used.

The reaction is also carried out in an aqueous solution at room temperature in the presence of a base such as IJium hydroxide.

Compounds of formula (■) and ([) are known compounds or can be prepared from known compounds by conventional methods.

The present invention further provides that by reduction of formula (ff) (wherein R+, R1-R4 and R4 are as defined for formula (i), and R8 is hydrogen or a group reducible to hydrogen) Methods are provided for making compounds of formulas (Il and CIA), where hydrogen is hydrogen or straight or branched chain 01-.alkyl.

Suitably R is benzoyl or benzyl or hydrogen which may be substituted by groups such as nitro or methoxy.

The reaction is carried out in the presence of a hydride reducing agent. The hydride reducing agent will be chosen taking into account any other reducible groups present. An example of a hydride reducing agent that can be used is BH
Contains s-THF (borane tetrahydrofuran), lithium aluminum hydride or borane dimethyl sulfide.

The reaction is suitably carried out in an inert solvent such as ether or tetrahydrofuran at a temperature of 0°C to 80°C.

Compounds 2) can be prepared by conventional methods from compounds of the above formula <[) in which R7 is hydrogen and R5 is hydrogen or straight or branched chain 01-6 alkyl.

For example, R? Compounds of formula ([) in which is hydrogen and tome is Mizutake or straight-chain or branched 08-6 alkyl, wherein R2 is as defined for formula (I) and Y is halogen, e.g. chlorine) in the presence of a base such as E t, N or pyridine: or the reaction of a compound of formula (where B is as defined for formula (11)) with an anhydride and an amine. or (wherein R5 is as defined for formula (II).

compound in the presence of conventional condensing agents such as dicyclohexylcarbodiimide (DCCI), diethyl azodicarboxylate/triphenylphosphine.

Compounds of the formulas (force, (b)) and (heel) are known compounds or are prepared from known compounds by conventional methods.

The present invention relates to compounds of the formula (xnt), where R+ -Rt, Ra and melon are as defined for formula (Il) and R4 is as defined for formula (vM), and 2〇〇 or a compound of formula
6 is provided.

Suitable reaction conditions are those conventionally used for acylation reactions.

The present invention further provides a compound of formula (XIV) L1 (wherein R,,1, and melon is as defined for formula (11) and R7 is as defined for formula (1'l)) and a compound of formula ( XV) react with a compound of R, -Z(XV) where Rs is as defined for formula (1) and Z is a metal ion or metal ion complex, and then if necessary A method is provided for making a compound of formula (I) or (IA) in which hydrogen is hydrogen by removing any protective base.

Suitable examples of Z are magnesium halide ions such as M
gBr+ and alkali metals such as lithium.

The reaction is suitably carried out in an inert organic solvent such as dry ether or benzene at reflux.

Compounds of formula (XIV) and (XV) are known compounds or are prepared from known arsenic materials by known methods.

Formula (
The compounds of No. 11 or CIA) can be obtained, if appropriate, in the form of salts and/or solvates. A pharmaceutically unacceptable salt or solvate may be converted to a pharmaceutically acceptable salt or solvate or to the compound itself. Compounds of formula (1) or (IA) may be converted to other such compounds by intramolecular transformation of appropriate substituents.

Compounds of formula (Il and CIA) are indicated as active therapeutic agents due to their inhibition of 5-lipoxygenase.

The invention therefore also describes the use of formulas (Il and (IA)
or a pharmaceutically acceptable salt or solvate thereof.

The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable compound of formula (1) and (IA) or a pharmaceutically acceptable salt or solvate thereof mixed or combined with a pharmaceutically acceptable carrier. .

Preferably, the pharmaceutical compositions of the invention are in unit dosage form and adapted for use in the medical or veterinary field. For example, these products may be in the form of a bank with instructions for use as an agent in the treatment or prevention of any of the aforementioned disorders.

Suitable dosage ranges for compounds of the invention will vary from compound to compound and will depend on the conditions being treated. It will also depend, among other things, on the absorption versus potency relationship and the mode of administration chosen. The compounds or compositions of the invention may be formulated for administration by any route, the preferred route depending on the disorder for which treatment is sought and preferably in unit dose form or for human patients to administer to themselves in a single dose. It is the shape.

Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration or for administration to the respiratory tract. Products should be designed to provide sustained release of the active ingredient.

The compositions may be in the form of tablets, capsules, packs, vials, powders, granules, troches, reconstituted powders, or foams such as solutions or suspensions or suppositories, for example. Compositions particularly suitable for administration to the respiratory tract and for topical administration are described in detail below.

Compositions suitable for oral administration include conventional additives such as binders such as syrup, gum arabic, gelatin, sorbitol, gum tragacanth or polyvinylpyrrolidone fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol. or a glycine tableting lubricant such as magnesium stearate; a disintegrant such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or a pharmaceutically acceptable hardening agent such as sodium lauryl sulfate.

Solid compositions may not be obtained by conventional methods such as mixing, filling, tabletting, etc. Repeated mixing operations may be used to distribute the active agent throughout these compositions employing large amounts of filler. When the composition is in the form of a tablet, powder or troche, any carrier suitable for formulating a solid pharmaceutical composition may be used, including magnesium stearin, starch, glucose, lactose, sugar, rice flour and chalk. It is.

The tablets may be coated by methods well known to normal pharmaceutical practice, particularly with enteric coatings. The composition may also be in the form of a digestible capsule of gelatin, for example, containing the compound together with a carrier or other additives if desired.

Compositions for oral administration as liquids include, for example, emulsions,
It may be provided in the form of a syrup or elixir or as a dry product which is reconstituted with water or other suitable medium before use. Such liquid compositions may contain conventional additives such as suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate, hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan monooleate or Arabica. Gum; aqueous or non-aqueous medium (
edible oils) such as almond oil, fractionated coconut oil, oily esters such as esters of glycerin, or propylene glycol or ethyl alcohol, glycerin,
Water or normal saline; preservatives such as methyl or propyl p-hydroxybenzoate or sorbin rR; and, if desired, conventional flavoring or coloring agents.

Compounds of the invention may also be administered by the parenteral route. In accordance with conventional pharmaceutical practice, the compositions may be administered rectally, for example as suppositories, or as aqueous or non-aqueous solutions in pharmaceutically acceptable liquids, such as sterile pyrogen-free water or parenterally acceptable oils or mixtures of liquids. , in an injectable form in a suspension or emulsion. The latter may contain bacteriostatic agents, antioxidants or other preservatives, buffers or solutes to make the solution isotonic with blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. . Such forms may be in unit dosage forms, such as ampoules or disposable injection devices, or in multi-dose forms, such as bottles from which appropriate doses are drawn, or solid forms or concentrates which can be used to prepare formulations for injection. It will be provided in

The compositions of the invention may also be suitably provided for administration to the respiratory tract as an aerosol or solution for nasal drops or nebulizers or in combination with an inert carrier such as 2-ctose or as a finely divided powder for inhalation alone. . In such cases the particles of active compound are suitably smaller than 50 microns, preferably l
O microns such as isoprenaline, isoethaline, salbutamol, phenylephrine and hiephethrine:
May include xanthine derivatives such as theophylline and aminophylline and corticosteroids such as glednisolone and adrenal stimulants such as ACTH.

For topical administration, the composition may be presented as an ointment, cream, lotion, gel, gel stick, spray, aerosol or skin paint.

For example, in any of the above formulations, a suitable dosage unit may contain 0.01 to 5 ooag of active ingredient via the oral route, more suitably 1 to 500 Ing, and 0.01 to 10 ng by inhalation.
It would be 11g. The effective dosage of a compound will depend on the particular compound used, the patient's condition and the number and route of administration, but will generally include the weight of the patient.
It is within the range of 9/day to 100 W/kli/day. For use in the treatment of inflammatory disorders, the compositions of the invention will preferably be in a form suitable for oral administration, such as tablets or capsules or bags containing reconstituted powders. A unit dose is generally 20
-10009 Preferably 30 to 500 to especially 50,10
0゜150.200,250,300,350,400
It will contain 450 or 500 Iv. The composition is 1 per day
administered more than 70 times, e.g. 2.3 or 4 times (per day)
) C1? For adults, the total daily dose is usually 100 to
It will be in the range of 3000m9. Also, the unit dose is 2-2
oIn9 active ingredient and, if desired, may be administered in multiple doses to achieve the daily dosages set forth above.

Within the dosage ranges mentioned above, no adverse toxicological effects have been demonstrated for the compounds of the present invention.

The present invention also provides effective and non-toxic amounts of formula (1) or (IA
) provides a method of treating allergic diseases or inflammatory conditions in humans or non-human animals comprising administering a pharmaceutically acceptable salt or solvate thereof.

The invention also includes the use of a compound of formula (I) or (IA), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the disorders mentioned above.

〔Example〕

The compounds of the invention, their preparation and their biological activity are illustrated in the Examples and pharmacological data below. Spear! The compounds shown in Tables 1 and 2 were prepared by methods similar to those described in Examples 1-6.

Example 1 5-Methyl-2(3H)-benzoxacillinone 2-amino-4-methylphenol (s, s g ).

53ff! mol) and urea (4 g, 6 rm-enyl) were heated at 160° C. for 2 hours each and cooled. The resulting solid was partitioned between 2N aqueous hydrochloric acid and diethyl ether. The organic solution was dried (M g S 04) and concentrated under reduced pressure and the resulting gray solid was purified by column chromatography on silica eluting with chloroform to give the title compound (&84, 9.
87%). Melting point: 131-3°C.

νmax(m)33sO,1790,174(m-”a
(CDC13): 2.27 (3H, s, G (J, 6.7
0-7.10 (3H,s, aromatic).

10.00 (IH, 8, NH) Actual value: C: 64.60: H: 4°60; N: 9.30
%.

C, H, No as C: 64.41 :H: 4.7
3:N: 9.39% Example 2 3-Phenylmethyl-5-methyl-2-benzoxacylinone 5-Methyl-2(3H)-benzoxacylinone (l#*s, 7m in ethanol (4od) mole) and benzyl bromide (L2σ, 9,7.35ff!-f-l) 8
Potassium hydroxide (0,
429#7. Heated to reflux in the presence of sm mol). The mixture was allowed to cool, and the resulting solid was collected by filtration and recrystallized from ethanol to give the title metal product (1.42 g, 89%) as a white solid. Melting point 123-4°C.

ymB x (Nil)1775.1760cIIL-'
(DMSO): 2.30 (3H-s-Q(a), 5-0
2(2H*5sG(2)-6-93(IH-d, d, J
=IHz, 8Hz, H-6), 7. os(IH, d, J
:=IHz, H-4).

7.23 (IH, d, 8Hz, H-7), 7.27-7
．． 40 (5H, m, aromatic).

Actual value: C near 5.59:)l:5.43:N:5.
9) C Near 5.29:H as %-CtsHtsNOt
:5.47:N:5゜Example 3 3-phenylmethyl-5-methyA- in 2-phenylmethylamino-4-methylphenomethanol (4omt)
Benzoxacylinone (5 g, 21 mmol) and potassium hydroxide (7i, 0.126 mol) were heated under reflux for 1 hour. The solvent was removed under reduced pressure and the residue was transferred to water and neutralized with aqueous sodium bicarbonate. The resulting solid was collected by filtration and further purified on silica column 1, Chromadog 2 column, eluting with chloroform to yield the title compound (1,5,9,38%) as a pale yellow solid.

The solid was transferred to diethyl ether and converted to its hydrochloride salt with HCI gas, which was EtOH:EttOVc.
more recrystallized. Melting point 133-4°C.

νrnax (zru) 3120.2740, 15657y
-'.

' (DMSO): 2.13 (3H,s, CH3
), 4, 42(2H,s,Q(,), 7.0
2 (2H, s, H-4, 6), 7, 22 (IH,
s, H-7), 7.20-7.50 (5H, m.

aromatic), 9.20-11.60 (3H, br s
, OH, NF (1■, replaceable).

Actual measurements: C: 67.13: H: 6.47: N: 5.
60%, C,4H,, C as CINO: 67.3
3:H: 6.48:N: 5.61%.

Example 4 2-(4-cyanobenzylidene)amino-4-methylphenol 2-amino-4-methylphenol (1,9)7.

15.3 mmol) and 4-cyanobenzaldehyde C2gj15.3 mmol) in toluene (z5d) for 4 hours.
The mixture was heated under reflux in a vacuum chamber, and the water produced was removed using a Dean, And, Stoke, and trap. The solution was allowed to cool, and the resulting solid was collected by filtration, washed with toluene, and then washed with Et
, was recrystallized from OK. Title compound (3,09,9,8
6%) as a yellow solid. Melting point: 152-3°C.

1'maX (A/u) 3400.2220.1620.
1500.1245CIIL-'.

δ (DMSO): 2.25 (3H, s, CH3), 6.
80-7. x7 (3H, m, aromatic).

7.95 (2H, d, J=8Hz, aromatic), 8.25
C2H, d, J = 8 Hz, aromatic), 8.87 (IH
, s , CH=) -8,97 (IH-s , OH* exchange reaction).

Actual value C: 76.31:H:5.15:N:11.9
2%-CIIHI! N! C near 6.25 as 0:
H: 5.12: N: 11.86%.

Example 5 2-((4-cyanophenyl)methylcoamino-4-methylphenol 2-(4-cyanobenzylidene)amino-4-methylphenol (1,
acidified to pI (1) with a suspension of 8fi, 7.67F 1 mol) and sodium cyanoborohydride (0,5,9,7,6
111 mol) in portions.

The reaction mixture was brought to pHt by addition of ethanolic hydrogen chloride.
I kept it at 2.

After 1 hour, the mixture was poured onto ice and neutralized with aqueous sodium bicarbonate solution, and the resulting solid was collected by filtration. Et, O
The title compound (1.14 g) was recrystallized as a white solid from
, 63%). Melting point 137S138°C.

νmax (visit) 3500-2800 (br),
3330, 2225, 15201M-”.

δ(yviSO): 2-07 (3He s −σ
ls) -4,40(2H-d-J" 6Hz e
1D-5,42 (IH, t, J=6Hz, NH, exchangeable), 6.13 (IH, d.

J = 1, 5Hz, H-3), 6, 24 (IH
, d , d , J = 1.5Hz, 8Hz, H-5
).

6, 62 (IH, d, J = 8Hz, H-6)
, 7.55 (2H, d, J = 8Hz, aromatic),
7.78 (2H, d, J=8Hz, aromatic), 9
．． 08 (ILs#OH, replaceable).

Actual value C: 75.63:H:6.04:N:11.8
6%, C111H14N20 as C near 5.6
0:H:5.92SN:11.76%.

Example 6 2-((4-Methylphenyl)methylcoamino-4-methylphenol 2-amino-4-methylphenol (493, lit, 40 mmol) and 4-methylbenzaldehyde (481, lit, 40 mmol) at 25°C for 13 hours.
' (Z 519 , 40 mmol). The reaction mixture was poured into HtO (250 mZ) and CH, CI
.

(3X50-) and dry the combined extracts (M
gSO4). Concentration in vacuo gave a red oil which was purified by column chromatography on silica eluting with CHICIt. The main components were treated with ethanolic hydrogen chloride to remove ethanol, and the resulting solid was recrystallized from ethyl acetate/petroleum ether (40-60°C) to give the title compound as its hydrochloride (5,079, 48%). I got it.

Melting point: 172-4°C.

νmax (M/) 3100, 2740.1630.15
65.1520cm.

a (DMSO)2.16 (3B, s, C[-1s)
, 2.30(3H,s,CH,), 4.39(2H
.

s, CH,), 7. O door, 50 (7Hzm + aromatic)
, 10.00-11.00 (3H, br s, N)
I2■, OH2 replaceable).

Actual value C: 68.36: H near, 04: N: 5.45
:C1:13.48%, C1,H.

C as ClN0:68.30:)I:6.88:N:
5.31:C1:13.44%.

Example 17 2-(α-Methylbenzyl)amino-4-methylphenol This compound was prepared by a method similar to that described in Examples 4-6 and was obtained as its hydrochloride. Melting point 1
36-7°C (ethanol).

Actual value C: 68.14: H: 6.84: N: 5.30:
C1: 13.22%'.

C,5H,,C as ClN0: 6B, 30:H:6
．． 88:N:5.31:C1:13.44%.

Example 13 2-phenylmethylamino-4-methylphenol (2
-benzoylamino-4-methylphenol) in dry*THF (somj) (Seha) [Help.

Kimi, Acta (He, 1v, Chim, Acta) 19
80, 63.

9) 2-benzoylamino- produced by method 6]
4-Methylphenol (520 da, '!-3 mmol)
was treated with lithium aluminum hydride (2601 v, 6.5 mmol) at room temperature with stirring under nitrogen for 4 hours. H2O (0,1g), 10% aqueous NaOH (0,1
ytl ) and H, O (1 ml) were added to the reaction mixture sequentially and the resulting solid was removed by filtration and Et! 0(2X 2
s d ) and the combined F solution was concentrated. The resulting solid was transferred to a 2N HCI aqueous solution and the solution was adjusted to pH
CH was adjusted with 84C saturated NaHCOs aqueous solution.
Extracted with Clg (3×50 rnl). The combined extracts were dried (MgSO4), concentrated in vacuo, and the resulting solid was purified by chromatography on silica, eluting with CH, CI, to give the title compound in average yield, which was consistent with the authentic sample. Example 19 2-phenylmethylamino-4-methylphenol (
2-Benzoylamino-4-methylphenol Ω-benzoate) 2-Benzoylamino-4-methylphenol α-benzoz-) prepared from 2-amino-4-methylphenol and benzoyl chloride in dry THF (50 mJ)
(600 IR9,1,812 Fi mol) was heated at room temperature with optional stirring for 3 hours.
0 m9, 7.9 mmol). Saturated NaHCOa
Aqueous solution (zom/) was added slowly and the duplicates were separated. The aqueous phase was extracted with Et20 (3X 20 mA) and the combined organic phases were washed with HtO (2011!j), dried (Mg 804) and concentrated under reduced pressure.CH,CI.

The solid obtained was purified by column chromatography on silica eluting with K to give the title compound (270 mg, 7
0%) was obtained and showed the same physical and analytical spectral properties as the authentic sample as its hydrochloride salt.

Example 29 4-Penzoyl-6-(phenylmethylamino)sorcinol Hydrochloride This compound was prepared from 4-benzoyl-6-amylresosinol in a manner similar to that described in Examples 4-6. Melting point: 2095211°C.

Measured values: C: 67.59: H: 5.26: N: 3.97
%, as C,H□ClNOs(”:67.51:
H: 5.10: N: 3.94%.

Example 30 2-Dibenzylamino-4-methylphenol A solution of 2-amino-4-thylphenol (1132 g, 0.1 mol) in 2N aqueous NaOH (50 ml) was dissolved in benzyl bromide (17, 1J.

1 mol). The mixture was converted into Et, o(210
The combined extracts were extracted with 2 NaOH aqueous solution (50 mj), then water (50 mj) and dried (MgSOJ L). Concentration under reduced pressure gave a colored oil which was extracted with hexane: Et, O (4:0 ml). Purified by column chromatography on silica, eluting with 1/V).

The main components were dissolved in Et, OK and treated with ethereal hydrogen chloride. The resulting precipitate was collected by filtration, washed with Et20 and recrystallized with EtOH to give the title compound (11,811,69%) as its hydrochloride. . Melting point 197-2
00℃.

Actual value: C near 3.29: H: 6.44: N: 4.0
2:C1:10.06%.

C,,H,,ClN0,o,25H,0 as C near 3.24:H:6.58;N:4.06;C1:
10.29%.

Minor components from the chromatographic separation were transferred to Et, 0 and treated with ethereal hydrogen chloride to give a white solid which was collected by filtration and recrystallized from ethanol. This compound showed a significant increase in 2-phenylmethylamino-4-methylphenol hydrochloride (1
,55! i, 7%). Melting point 131
~2℃.

Actual value: C: 67.14: H: 6.56: N: 5.3
2:C1:14.22.

C14H16CIN) as C:67.33:H:6.
48:N:5.61:C1:14.20.

Pharmacological data (1) RBL-1s-lipoxygenase, JaKsch 1K (Be, x-,
-2 Kushitsuk, F, F, San (F, F, 5un)
, L, M.

Lee (L, M, Lee), Eng A, x A, Sternhoff CM.

M, 5tejnhoff), 19 s o, &quot;
high octane b, high #fishi, reply, com, (Bi
ochem+Biophys, Res.

Corrm, ) 95, 103) 17) Method: Injecting 5-riboxygenase enzyme into RBL-IM cells 10.
000.9 Manufactured as a supernatant liquid. 10,000.
i9 supernatant was diluted with homogenization buffer to equal L5-45X10' cells/Ill4C & to 2mM relative to CaC1z IC. 0.51 was placed in a tube and incubated for 2 minutes at 29° C. with the desired concentration of compound in ethanol or 5d of ethanol.

Next K(1-"C) arachidonic acid was added to the buffer to give a final concentration of 6.3 μM and α2 μCi per incubation. The reaction was continued for 2 min at 29°C. The reaction was stopped by the addition of Isu acetate and kept on ice. Add chilled 0.51 ml of water-cooled saline and 1004 ml of 2N formic acid and mix the mixture 2X
Extracted with 211Lt of chloroform. The extracts were stored under N2 at -20°C until analysis by chromatography. The activity was determined by 5-HETE and 5,12-diHETE&
C was measured as a % of the total radioactivity found and inhibition was calculated as the decrease in the formation of the sum of these two species during compound-treated incubations with respect to control incubations.

biological results

Claims (15)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 is a straight chain or branched chain C_1_-_6 alkyl, halogen, nitro, cyano, hydroxy, or CO
R_6 (in the formula R_6 straight chain or branched chain C_1_-_6
R_2 is substituted or unsubstituted aryl, aralkyl or heteroaryl; R_3 is hydrogen or straight-chain or branched C_1-_6 alkyl; R_4 is hydrogen, hydroxy , straight chain or branched chain C_1
＿～＿6 Alkyl, halogen, nitro, cyano, C_1
___~_6 alkoxy, halo(C_1_~_6)alkyl; amino, carboxylic acid ester, carboxylic acid, COR_
6, SR_6, SO_2R_6, NHCOR_6 or N
HR_6 (in the formula, R_6 is as above); and R_5 is hydrogen, linear or branched C_1_-_6 alkyl, substituted or unsubstituted benzyl, or COR_6 (in the formula, R_6 is as above) or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier. (2) R_1 is methyl, iso-propyl, tert-butyl,
The composition according to claim (1), which is acetyl, benzyl, bromine or chlorine. (3) The composition according to claim (1) or (2), wherein R_2 is substituted or unsubstituted phenyl, furan, thiophene, imidazole, isoxazole, pyridine, or benzyl. (4) R_2 is a straight chain or branched chain C_1_-_6 alkyl, hydroxy, halogen, nitro, cyano, C_1
___~_6 alkoxy, halo(C_1_~_6)alkyl, amino, carboxylic acid ester, carboxylic acid, COR_
6, NHCOR_6, NHR_6, N(R_6)_2,
SR_6, SOR_6 or SO_2R_6 (R_6 in the formula
The composition according to any one of claims 1 to 3, wherein the composition is substituted with one or more groups selected from the group consisting of the same as above. (5) The composition according to any one of claims (1) to (4), wherein R_3 is hydrogen or methyl. (6) Claim No. (1) in which R_4 is hydrogen, trifluoromethyl, methyl, tert-butyl or benzoyl.
The composition according to any one of items 1 to 5. (7) The composition according to any one of claims (1) to (6), wherein R_5 is -COCH_3 or hydrogen. (8) Formula (I) (wherein R_1 is methyl, ethyl, isopropyl, tert-butyl, benzoyl, chlorine or bromine, and R_2 is phenyl, benzyl, furyl or thienyl, and they are methyl, iso-propyl, propyl, cyano, methoxy, chlorine,
Optionally substituted by bromine, fluorine, trifluoromethyl, hydroxy or nitro, R_3 is hydrogen or methyl, R_4 is hydrogen or hydroxy, and R_5 is hydrogen or benzyl. The composition according to any one of the ranges (1) to (7). (9) A claim in which the compound of formula (I) is selected from 2-phenylmethylamino-4-chlorophenol, 2-phenylmethylamino-4-methylphenol, and pharmaceutically acceptable salts and solvates thereof. The composition according to range (1). (10) Formula ( I A) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I A) (In the formula, R_1, R_2, R_3, R_4 and R_5 are the formulas in claims (1) to (8) As defined for (I), when R_1 is methyl or a base, R_2 is phenyl, R_3 is hydrogen, and R_4
is hydrogen and R_5 is other than hydrogen) or a salt or solvate thereof. (11) The compound is 2-[(4-cyanophenyl)methyl]amino-4-methylphenol; 2-[(4-methylphenyl)methyl]amino-4-methylphenol; 2-[(4-methoxyphenyl) Methyl]amino-4-
Methylphenol; 2-[(4-chlorophenyl)methyl]amino-4-methylphenol; 2-[(2-furyl)methyl]amino-4-methylphenol; 2-[(3-trifluoromethylphenyl)methyl] Amino-4-methylphenol; 2-[(4-fluorophenyl)methyl]amino-4-
Methylphenol; 2-[(3,4-dichlorophenyl)methyl]amino-
4-methylphenol; 2-[(thien-2-yl)methyl]amino-4-methylphenol; 2-[(4-bromophenyl)methyl]amino-4-methylphenol; 2-[(3-fluorophenyl) ) methyl]amino-4-
Methylphenol; 2-phenylmethylamino-4-iso-propylphenol; 2-phenylmethylamino-4-tert-butylphenol; 4-benzoyl-6-(phenylmethylamino)resorcinol; 2-dibenzylamino-4-methyl 2-phenylmethylamino-4-chlorophenol; 2-phenylmethylamino-4-bromophenol; 2-phenylmethylamino-4-ethylphenol; 2-[(4-nitrophenyl)methyl]amino-4 -Methylphenol; 2-[(4-iso-propylphenyl)methyl]amino-4-methylphenol; 2-[(4-hydroxyphenyl)methyl]amino-4
-Methylphenol; 2-phenylethylamino-4-methylphenol; and salts and solvates thereof. (12) A compound according to claim (10) or (11) in pharmaceutically acceptable and/or substantially pure form. (13) (a) When R_5 is hydrogen, formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R_1, R_2, R_3 and R_4 are formula (I)
(b) When R_5 is hydrogen, the formula (VI) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI) (where R_1, R_2, R_3 and R_4 are Formula (I)
(as specified for) (c) When R_5 is hydrogen, formula (V) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Compounds of (V) and formula (VII) ▲ Numerical formulas, chemical formulas, There are tables, etc.▼ (VII) By reacting the compound of (VII) under reducing conditions, (d) formula (VIII) ▲ There are mathematical formulas, chemical formulas, tables, etc. (as defined for formula (I) and R_7 is a hydrogen or hydroxy protecting group) is reacted with a compound of formula (IV) If necessary, by removing any hydroxy protecting group R_7 (e) Formula (IX) when R_3 is hydrogen and R_5 is hydrogen or straight or branched chain C_1_-_6 alkyl ▲Mathematical formula, chemical formula , tables, etc.▼(IX) (In the formula, R_1, R_2, R_4 and R_5 are the formula (I)
(f) When R_5 is COR_6, formula (XIII) ▲There are mathematical formulas, chemical formulas, tables, etc.▼( XIII) (where R_1, R_2, R_3 and R_4 are the formula (I)
(R_7 is a hydrogen or hydroxy protecting group) and formula (X) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Compounds of (X) or formula (X I ) ▲ Numerical formulas, chemical formulas, tables, etc. etc. ▼ by reacting with a compound of (X I ) and then removing any hydroxy protecting group R_7 if necessary, or (g) when R_5 is hydrogen, formula (XIV) ▲ mathematical formula, chemical formula , tables, etc.▼(XIV) (wherein R_1, R_2 and R_4 are as defined for formula (I) and R_7 is hydrogen or a hydroxy protecting group) and the compound of formula (XV) R_3-Z(XV ) in which R_3 is as defined for formula (I) and Z is a metal ion or metal ion complex and then removing any hydroxy protecting group R_7 if necessary. A process for producing a compound according to claim 1, wherein the compound is optionally obtained by forming a salt and/or solvate of the compound. (14) Used for the treatment of the human or animal body, particularly for the treatment or prevention of allergic diseases such as asthma, hay fever, rhinitis or allergic eczema, or for the treatment of inflammation such as arthritis and psoriasis Claim No. (1) A compound of formula (I) or (IA) according to any one of items 1 to 11, or a pharmaceutically acceptable salt or solvate thereof. (15) A compound of formula (I) or (IA) according to any one of claims (1) to (11) for the manufacture of a drug for the treatment of allergic or inflammatory diseases; Uses of pharmaceutically acceptable salts or solvates thereof.