JP2744653B2 - Diphenylmethylamine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel diphenylmethylamine derivative, In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a formyl group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group or a lower alkylsulfonyl group, and R ² represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, And a salt thereof, which represents a hydroxyl group, a nitro group, an amino group or a cyano group.

Conventionally, as a diphenylmethylamine derivative, for example, the following formula (The Journal of Organic Chemistry, vol. 53, pp. 2520-2525, 1988) represented by the following formula: The compound shown by (Chemical Abstracts, Vol. 98,
163553V, 1983), etc., but no pharmacological action of these compounds has been reported.

This time, the diphenylmethylamine derivative represented by the formula (I) has an excellent anti-inflammatory effect and is considered to be deeply involved in the inflammatory response of a living body. In particular, arachidonic acid is excellent in cyclooxygenase and / or lipoxygenase inhibitory activity, and has very little effect on inducing gastrointestinal disorders, and is promising as an anti-inflammatory, analgesic, antirheumatic agent, etc., which hardly involves gastrointestinal tract disorders. I found something. Furthermore, the present inventors have found that the diphenylmethylamine derivative of the formula (I) has an action of eliminating active oxygen in a living body.

The term "lower" throughout this specification means that the group or compound to which it is attached has less than 6 carbon atoms, preferably less than 4 carbon atoms.
Means less than or equal to

As used herein, the “lower alkyl group” or “lower alkoxy group”, the “lower alkylcarbonyl group”, the “lower alkoxycarbonyl group” and the lower alkyl moiety in the “lower alkylsulfonyl group” are linear and branched. Any of them, for example, methyl,
Ethyl, n-propyl, iso-propyl, n-butyl, s
Examples thereof include ec-butyl, iso-butyl, tert-butyl, and n-pentyl group.

Thus, examples of the "lower alkoxy group" include methoxy, ethoxy, and iso-propoxy groups.
"Lower alkylcarbonyl" includes, for example, acetyl,
Propionyl, butyryl group and the like are included, and the "lower alkoxycarbonyl group" includes, for example, methoxycarbonyl, ethoxycarbonyl group and the like, and the "lower alkylsulfonyl group" includes, for example, methanesulfonyl, ethanesulfonyl group and the like. Can be

Further, the “halogen atom” includes fluorine, chlorine and bromine atoms.

Representative examples of the compound of the formula (I) provided by the present invention are as follows.

(3,5-di-t-butyl-4-hydroxyphenyl)
Methylamine, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-chlorophenyl) methylamine, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-bromophenyl) methylamine, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-fluorophenyl) methylamine, (3,5-di-t-butyl-4-hydroxyphenyl)
(3-methylphenyl) methylamine, (3,5-di-t-butyl-4-hydroxyphenyl)
(2-methoxyphenyl) methylamine, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-methoxyphenyl) methylamine, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-isopropoxyphenyl) phenylmethylamine, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-hydroxyphenyl) methylamine, (3,5-di-t-butyl-4-hydroxyphenyl)
(2-hydroxyphenyl) methylamine, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-nitrophenyl) methylamine, (3,5-di-t-butyl-4-hydroxyphenyl)
(3-nitrophenyl) methylamine, (3,5-di-t-butyl-4-hydroxyphenyl)
(2-aminophenyl) methylamine, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-cyanophenyl) methylamine, (3,5-di-t-butyl-4-hydroxyphenyl)
Phenyl (methylamino) methane, (3,5-di-t-butyl-4-hydroxyphenyl)
Phenyl (formylamino) methane, (3,5-di-t-butyl-4-hydroxyphenyl)
Phenyl (acetylamino) methane, (3,5-di-t-butyl-4-hydroxyphenyl)
Phenyl (methoxycarbonylamino) methane, (3,5-di-t-butyl-4-hydroxyphenyl)
Phenyl (methanesulfonylamino) methane, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-fluorophenyl) (methylamino) methane, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-chlorophenyl) (ethoxycarbonylamino)
Methane, (3,5-di-t-butyl-4-hydroxyphenyl)
(2-methylphenyl) (formylamino) methane, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-methylphenyl) (acetylamino) methane, (3,5-di-t-butyl-4-hydroxyphenyl)
(3-methoxyphenyl) (formylamino) methane, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-methoxyphenyl) (ethoxycarbonylamino) methane, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-hydroxyphenyl) (methanesulfonylamino) methane, (3,5-di-t-butyl-4-hydroxyphenyl)
(2-hydroxyphenyl) (methylamino) methane, (3,5-di-t-butyl-4-hydroxyphenyl)
(2-nitrophenyl) (acetylamino) methane, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-aminophenyl) (ethoxycarbonylamino)
Methane, (3,5-di-t-butyl-4-hydroxyphenyl)
(4-cyanophenyl) (formylamino) methane.

The compounds of the above formula (I) can take the form of salts due to the basic amino groups present, examples of such salts being, for example, hydrochlorides, hydrobromides, sulphates, phosphorus salts Inorganic acid salts such as acid salts; organic acid salts such as acetate, propionate, succinate, malonate, maleate, lactate, tartrate, citrate, etc., among which are physiologically acceptable Salts which can be used are preferred.

Since the carbon atom to which two phenyl groups are bonded is an asymmetric carbon atom, the compound of the formula (I) has an optically active form (D
(L-form) or racemic form.

The compound of the formula (I) of the present invention can be produced, for example, by various routes shown in the following reaction formula A.

In the above formula, R ¹¹ represents a group defined for R ¹ other than a hydrogen atom and a formyl group, Ha 1 and X each represent a halogen atom, and R ² has the same meaning as described above.

In the above reaction formula A, the diphenyl ketone derivative of the formula (II) can be prepared by a method known per se, for example, JP-A-62-84051.
Can be converted to a diphenylmethylimine derivative of the formula (III).

The resulting diphenylmethylimine derivative of the formula (III) is hydrogenated in the presence of a white metal catalyst such as platinum, palladium or rhodium and preferably in the presence of an inducing acid such as acetic acid, or Reduction using acetic acid, tin-hydrochloric acid, or the like can lead to the compound of the formula (I) when R ¹ is a hydrogen atom, that is, the compound of the above (I-1).

The compound of formula (I-1) thus obtained is then of the formula
By reacting with a halide represented by R ¹¹ -X, for example, methyl iodide, ethyl iodide, acetyl chloride, propionyl chloride, ethyl chloroformate, methanesulfonyl chloride and the like in the presence of a base, the corresponding compound represented by the formula (I- The compound of 2) can be produced. The above reaction is usually carried out in a suitable inert solvent, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; halogenation such as dichloromethane, chloroform and carbon tetrachloride. Among hydrocarbons, the reaction can be carried out at about 0 ° C. to the reflux temperature of the reaction mixture, preferably at room temperature to the reflux temperature of the reaction mixture. Formula (I
The use ratio of the compound of the above formula R ¹¹ -X to the compound of the formula -1) is not particularly limited, but is generally at least 1 mol per 1 mol of the compound of the formula (I-1).
Preferably, it is suitable to use within a range of 1.05 to 5 mol.

Further, as a base that can be used, for example, potassium carbonate,
Examples thereof include sodium carbonate, triethylamine, pyridine, and dimethylaniline. These are at least 1 equivalent, preferably 1.1 to 1 mol, per 1 mol of the compound of the formula (I-1).
It can be used in a ratio of 5 equivalents.

When R ² represents an amino group or a hydroxy group, the amino group or the hydroxy group is temporarily protected in advance at the stage of the compound of the formula (II) or (III), and the reaction is terminated. It is desirable to be able to remove the protecting group later.

The compounds of the present invention can also be obtained by halogenating a diphenylmethanol derivative of formula (IV) to a diphenylmethyl halide derivative of formula (V), which is then converted to delepin (Delpin).
pine) is reacted with an amine of or formula NH ₂ -R ¹¹ is treated with concentrated hydrochloric acid from changing the hexamine salt according to the reaction formula (I
-1) or (I-2).

Halogenation of the diphenylmethanol derivative of the formula (IV) can be carried out in the same manner as in a method known per se for alcohols [for example, Experimental Chemistry Course, Vol. 20, Synthesis of Organic Compounds II, pp. 224 to 232 (1956). Nishi Maruzen)],
Examples of the halogenating agent that can be used include, for example, thionyl chloride,
And phosphorus oxychloride.

Some of the diphenylmethanol derivatives of the formula (IV), which are starting materials used in the halogenation, are novel compounds not described in the conventional literature, and include, for example,
It can be synthesized by reducing the diphenyl ketone derivative of the formula (II). Reduction is, for example, in an inert solvent such as diethyl ether, dipropyl ether, tetrahydrofuran, dimethoxyethane, dioxane,
It can be carried out by treating with a complex metal hydride such as lithium aluminum hydride.

Some of the diphenylmethyl halide derivatives of the formula (V) obtained by the above halogenation are also novel compounds which have not been described in the conventional literature.

The treatment of the compound of formula (V) according to the Delepine reaction is first carried out in a suitable inert solvent such as methanol, ethanol, dichloromethane, chloroform or the like at about 0 ° C. to the reflux temperature of the reaction mixture, preferably at a temperature near room temperature. ,
The reaction can be carried out by reacting the compound of the formula (V) with hexamine to form a hexamine salt of the compound of the formula (V), and then subjecting the obtained hexamine salt to hot treatment with concentrated hydrochloric acid.

The proportion of hexamine used for the compound of formula (V) is also not critical, but usually the compound 1 of formula (V)
It can be used in an amount of at least 1 mol, especially in the range of 2 to 5 mol, per mol.

The reaction between the compound of the formula (V) and the amine of the formula NH ₂ —R ¹¹ is carried out in the same manner as described above for the reaction of the compound of the formula (I-1) and the halide of the formula R ¹¹ —X. Whereby the compound of the formula (I-2) can be obtained.

Further, the compound of the formula (I) in which R ¹ represents a formyl group, that is, the compound of the formula (I-3) in the reaction formula A, is obtained by converting the diphenyl ketone derivative of the formula (II) into a formic acid according to a Leuckart reaction. Reaction with ammonium formate or urea in the presence or the diphenylmethyl halide derivative of formula (V) and formamide with formula (I-
The compound of formula (I-1), which can be prepared by reacting the compound of formula (1) with the halide of formula R ¹¹ -X in the same manner as described above, or can be prepared as described above, is an organic solvent. It can also be produced by reacting with formic acid under heating, preferably under reflux conditions.

Further, the compound of the formula (I-1) is obtained by hydrolyzing the compound of the formula (I-3) produced by the above-described Leucart reaction under an acidic condition, or the step (a) of Example 8 described later. The following formula which can be produced by the method described in In the formula, R ² has the same meaning as described above. The compound can also be produced by catalytic reduction or reduction using a complex metal hydrogen compound.

The compound of formula (I) thus obtained can be separated from the reaction mixture and / or purified by methods known per se, for example, by extraction, filtration, distillation, recrystallization, column chromatography, thin-layer chromatography, and the like. can do.

In the compound of formula (I) obtained as described above,
When R ² is a hydrogen atom, the hydrogen atom is converted to a conventional aromatic ring nitration method [for example, in Journal of Organic Chemistry (J. Org. Chem.), Vol. 31, 65-69).
Pp. (1966)], for example, the nitro group can be substituted by reacting with potassium nitrate in concentrated sulfuric acid. When R ² is a nitro group, the nitro group can be substituted by a conventional method [for example, Synthesis Collective
Volume I (Org. Synth. Coll. I), pp. 240-241 (1948)
Year)], the nitro group can be converted to an amino group by catalytic reduction, and when R ² is a bromine atom, the bromine atom can be converted to a non-amino group using a reaction known per se [eg, tetrahedron (Tetrahedron), Vol. 23, 3823-3827
(1967)], and can be converted to a cyano group by treatment with copper (I) cyanide.

When R ² represents a lower alkoxy group, the compound of formula (I) can be used, for example, in the absence of a solvent or in a suitable solvent such as tetralin, quinoline or the like, for example, pyridinium halide (eg, pyridinium chloride) or halogen. The lower alkoxy group can be converted to a hydroxyl group by treatment with a hydrofluoric acid (eg, hydrochloric acid, hydrobromic acid) or the like under heating at a temperature of, for example, about 150 to 200 ° C.

The formula (I) provided by the present invention described above.
The diphenylmethylamine derivative of
It has lipoxygenase and / or cyclooxygenase inhibitory activity in addition to potent anti-inflammatory activity, and has a very weak digestive disorder-inducing effect, so it is particularly useful as a new type of anti-inflammatory, analgesic and anti-rheumatic drug. It is. Further, the compound of the present invention has anti-asthma, anti-allergy,
Various pharmacological actions such as immunomodulation are expected, and in addition to anti-inflammatory drugs, analgesics, anti-rheumatic drugs, anti-asthmatic drugs, anti-allergic drugs,
It is also expected to be used as an immunomodulator, a therapeutic agent for skin psoriasis, and the like.

The excellent pharmacological action of the compound of the formula (I) of the present invention can be confirmed by the following experiments.

(1) Anti-inflammatory action Wistar (Wista) weighing 120-150 g fasted for 24 hours
r) A group of five male rats was used, and the right paw volume of each group was measured by a volume difference meter [manufactured by Ugo Basile], and the test drug was dissolved in a solvent (0.5% carboxymethylcellulose and 2.0%). A suspension or a solution in which Twin 80 was dissolved was orally administered. One hour after the oral administration of the test drug, a 1% carrageenyl solution in distilled water for injection was injected subcutaneously into the right footpad. Three hours later, the right paw volume was measured again. The increase volume (edema volume) of each individual right foot of each group was determined, and the edema inhibition rate of the test drug administration group with respect to the average increase volume of the solvent administration control group (this group used 10 mice) was calculated by the following formula. The average of each group was determined.

As a result, the compound of Example 1 was administered at a dose of 10 mg / kg to 49.3.
%, And the compound of Example 2 showed a 27.3% inhibition at a dose of 10 mg / kg.

(2) Analgesic activity Male ddY mice weighing 19 to 23 g are used as a group of 12 mice, and a test drug is orally administered to each dose at first. For oral administration, the test drug was dispersed in a solvent (aqueous solution in which 2% gum arabic was dissolved), and the suspension or solution was administered using a probe. One hour after the administration of the test, 0.65% acetic acid was intraperitoneally injected into the abdominal cavity.
The administration was performed in an amount of 1 ml / 10 g body weight, and the number of writhing generated over 20 minutes after the administration was measured. Vehicle-treated control group (this group were used 14 rats) seeking inhibition rate of the test drug administration group relative according to the following equation to calculate the ED ₅₀ values according to the minimum square method from that number.

As a result, the ED ₅₀ of the compound of Example 1 was 21.5 mg / kg.

(3) Lipoxygenase and cyclooxygenase inhibitory action The inhibitory action of the compound of the present invention on 5-lipoxygenase and cyclooxygenase activity was determined by Siege (Siege).
l) et al. [Prostaglandin
s), Volume 21, page 123 (1981)].

That is, leukocytes in the exudate collected from the pleural cavity of the rat in which carrageenin pleurisy was induced were suspended in 50 mM Tris-HCl buffer (pH 7.4) containing 100 mM sodium chloride. An aliquot of this leukocyte suspension was _incubated with the test drug, ¹⁴ C arachidonic acid, calcium _ionophore ( _A23187 ) and 1 mM calcium chloride for 2 minutes, and the ¹⁴ C arachidonic acid metabolite produced at that time was removed. Fractionation was performed by thin-layer chromatography (silica gel, plastic plate, developing solvent; hexane: diethyl ether: acetic acid = 40: 60: 2). After exposing the thin plate to an X-ray film, each arachidonic acid metabolite fraction was identified by comparison with a standard sample, and each corresponding fraction and other radioactive fractions were collected. Then, the radioactivity of each fraction was measured by a liquid scintillation counter, and the percentage of the radioactivity of each fraction relative to the total radioactivity was determined (production rate).

Using this product as an index, the inhibition rate of the test drug on the synthesis ability of each fraction was determined.

5-Lipoxygenase activity is 5S-hydroxy-6,8,
11,14-eicosatetraenoic acid (5-HETE) and 5S, 12R
The production of dihydroxy-6,8,10,14-eicosatetraenoic acid (5,12-diHETE) was used as an index, and the cyclooxygenase activity was determined to be 12-hydroxyheptadecatrienoic acid (HH
T) was used as an index.

All test drugs were dissolved in a 10% dimethyl sulfoxide solution. The final concentration of dimethyl sulfoxide in the assay system is 2.5%. As a result, the compound of Example 1 of the present invention showed 5-HE at concentrations of 23.7 and 20.7 μM.
The production of TE and 5,12-diHETE was inhibited by 50%, and 29.9 μ
At a concentration of M, HHT formation was inhibited by 50%. Also, the compound of Example 2 of the present invention inhibited the production of 5-HETE and 5,12-diHETE by 50% at the concentrations of 5.9 and 5.2 μM, and at the concentration of 23.1 μM.
HHT formation was suppressed by 50%.

(4) Inhibitory effect on granuloma formation Using Wistar male rats under anesthesia with sodium hexobarbital (100 mg / kg, ip), the back of the tablet was cut and the skin was pressurized and sterilized under the skin. .85
K, 9 mm diameter) were implanted on both the left and right sides, and 0.25 ml of oily procaine penicillin G (Wanyu Pharmaceutical, 300,000 units / ml) was intramuscularly injected.

After the test drug was implanted and a filter paper piece was implanted, it was orally administered once a day for seven consecutive days including that day, and on the day after the final administration, the filter paper piece and the granulation seeds formed around the filter paper piece were excised, and the temperature was reduced to about 60 ° C. At 24
After drying for an hour, the weight was measured, and the value obtained by subtracting the weight of the filter paper was taken as the dry granulation weight.

As a result, the compound of Example 1 of the present invention was 3 mg / kg, po
Dried granulation weight was significantly (p <0.05, n =
7-8) decreased.

(5) Stomach-damaging effect Six male Wistar rats weighing 120-150 g fasted for 24 hours were used as a group, and the test drug was orally administered in the same manner as in the above-mentioned anti-inflammatory effect test. After sacrifice, the stomach was removed, and the number of animals showing mucosal hemorrhage and submucosal damage was counted and calculated as the ratio to the number of animals used. As a result, the compound of Example 1 of the present invention did not show a clear dose-dependent gastrotoxic effect, and showed a dose of 300 mg / kg.
No gastric damage was observed even at the po dose.

Thus, the compound of the formula (I) of the present invention is orally or parenterally administered to humans and other warm-blooded animals (eg, intramuscular, intravenous, subcutaneous, rectal, etc.) as anti-inflammatory, analgesic, anti-rheumatic agents and the like. Administration) or topical administration.

When used as a medicament, the compounds of the present invention can be formulated in various forms suitable for oral, parenteral or topical administration. For example, the compounds of the present invention are non-toxic excipients, binders, lubricants, disintegrants, preservatives, isotonic agents, stabilizers, dispersants, antioxidants commonly used in this class of drugs. , Colorants, flavors, buffers, propellants, surfactants and the like.

Such drugs may be used in the form of tablets, capsules, granules, powders, fine granules, pills, troches, suppositories,
It can be prepared in any formulation such as ointment, patch, injection, syrup, aerosol and the like. Thus, non-toxic additives that can be used include, for example, starch, gelatin, glucose, lactose, fructose, maltose,
Magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, gum arabic, polyethylene glycol,
alkyl p-hydroxybenzoate, syrup,
Examples include ethanol, propylene glycol, petrolatum, carbowax, glycerin, sodium chloride, sodium sulfite, sodium phosphate, citric acid, dichlorodifluoromethane, 1,2-dichlorotetrafluoroethane, and sorbitan trioleate. The agent can also contain other therapeutically useful agents.

The dose of the compound of the present invention can be widely varied depending on the kind of human or other warm-blooded animals, the administration route, the severity of symptoms, the diagnosis of a doctor, and the like.
It can be 0.1 to 50 mg / kg, preferably 0.2 to 20 mg / kg per day. However, it is of course possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range, depending on the severity of the symptoms of the patient and the diagnosis of the doctor as described above. The above dose can be administered once or several times a day.

 Hereinafter, the present invention will be further described with reference to examples.

Example 1 16.3 g of 3,5-di-t-butyl-4-hydroxybenzophenone oxime and 3.0 g of acetic acid were dissolved in 500 ml of ethanol, 2 g of 10% palladium-carbon was added, and catalytic reduction was performed at room temperature and normal pressure for 48 hours. . After the reaction, the catalyst was removed, and ethanol was distilled off. Ethyl acetate was added to remove the precipitated acetate.
After washing with ethyl acetate, the obtained crystals are added to a solution of 10% sodium hydrogen carbonate (100 ml) and ethyl acetate (200 ml), and the mixture is stirred for 10 minutes. After the reaction, the organic layer is separated, washed with water and dried over magnesium sulfate. After removing magnesium sulfate, hydrochloric acid gas is passed through under ice cooling, and the precipitated blood crystals are collected and washed with ethyl acetate. The obtained crystals were recrystallized from methanol-ethyl acetate to obtain 10.0 g of (3.5-di-t-butyl-4-hydroxyphenyl) phenylmethylamine hydrochloride.

Melting point: 238-241 ° C Example 2 (3.5-di-t-butyl-4-hydroxyphenyl)
Dissolve 4.38 g of phenylmethylamine in 50 ml of toluene and add 8
Add 1.37 g of 5% formic acid and heat to reflux for 2 hours. After the reaction, toluene was distilled off, methylene chloride was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and water in that order, and dried over magnesium sulfate. After distilling off the methylene chloride, the residue was crystallized from petroleum ether to obtain 4.1 g of (3,5-di-t-butyl-4-hydroxyphenyl) phenyl (formylamino) methane.

Melting point: 124-127 ° C Example 3 6.2 g of 3.5-di-t-butyl-4-hydroxybenzophenone, 4.6 g of formic acid and 3.8 g of ammonium formate were stirred under 12 g.
The reaction is carried out at 0 ° C. for 2 hours, then at 180 ° C. for 3 hours. After the reaction, the mixture is cooled and extracted with ethyl acetate, washed with water and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (elution solvent, benzene: ethyl acetate (95: 5)), recrystallized from ether-hexane, and purified with (3,5-di-t-butyl). 1.4 g of (-4-hydroxyphenyl) phenyl (formylamino)) methane were obtained. This compound had the same physical properties as the compound obtained in Example 2.

Example 4 (3,5-di-t-butyl-4-hydroxyphenyl)
2 g of phenylmethylamine and 0.8 g of triethylamine are dissolved in 50 ml of dry diethyl ether, and 0.6 g of acetyl chloride is added dropwise with ice cooling and stirring. After the dropwise addition, the mixture is stirred at room temperature for 2 hours, water is further added, and after stirring, the organic phase is separated and dried over magnesium sulfate. After evaporating the solvent, the residue was washed with ether-
Recrystallized from hexane, (3,5-di-t-butyl-4
-Hydroxyphenyl) phenyl (acetylamino) methane 1.5 g was obtained.

Melting point: 98.9-100.2 ° C Example 5 (3.5-di-t-butyl-4-hydroxyphenyl)
3.1 g of phenylmethylamine and 1.2 g of triethylamine are dissolved in 100 ml of dry diethyl ether, and 1.2 g of ethyl chlorocarbonate is added dropwise with stirring under ice cooling. After the dropwise addition, the mixture is stirred at room temperature for 4 hours, and water is further added. After stirring, the organic phase is separated and dried over magnesium sulfate. After evaporating the solvent, the residue was washed with ether-
Recrystallization from petroleum ether gave 2.9 g of (3,5-di-t-butyl-4-hydroxyphenyl) phenyl (ethoxycarbonylamino) methane.

Melting point: 127.1-128.1 ° C Example 6 (3.5-di-t-butyl-4-hydroxyphenyl)
2.0 g of phenylmethylamine, 0.8 g of triethylamine and 0.8 g of methanesulfonyl chloride were treated in the same manner as in Example 5 to give 0.9 g of (3.5-di-t-butyl-4-hydroxyphenyl) phenyl (methanesulfonylamino) methane. Obtained.

Melting point: 138.3-139.0 ° C Example 7 (3.53-di-tert-butyl-4-hydroxy-4'-fluorobenzophenone oxime (4.43 g) in ethanol 200
Then, 4 ml of acetic acid is added, and catalytic reduction is carried out at a hydrogen pressure of 5 kg / cm ² and room temperature for 23 hours using 10% palladium-carbon as a catalyst. After the reaction, the catalyst is removed, the solvent is distilled off, and the residue is dissolved in ethyl acetate, washed with a 10% aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (elution solvent, benzene), and the obtained oil was converted into the hydrochloride by a conventional method to give (3,5-di-t-butyl-4-methyl-4-butyl). (Hydroxyphenyl) (4-fluorophenyl) methylamine hydrochloride
1.1 g were obtained.

Melting point: 131.1-133.0 ° C Example 8 (a) (3,5-Di-t-butyl-4-hydroxy-
2.5 g of 4'-methoxy) benzophenone oxime at 50 ° C
Dissolve in 40 ml of acetic acid in a water bath, slowly add 1.8 g of zinc dust, and react for 45 minutes. After removing the catalyst by filtration and concentrating the filtrate,
Add ice water and extract with ethyl acetate. After neutralization with a saturated aqueous solution of sodium hydrogencarbonate, washing with water and drying over magnesium sulfate. After distilling off the solvent, the residue is dissolved in chloroform and converted into a hydrochloride with hydrochloric acid-isopropanol. Chloroform is distilled off, n-pentane is added to crystallize, and 2,6-di-
t-butyl-4- [amino (4-methoxyphenyl) methylene] -2,5-cyclohexadien-1-one hydrochloride
2.13 g were obtained.

Melting point: 231-236 ° C (B) 1.0 g of 2,6-di-t-butyl-4- [amino (4-methoxyphenyl) methylene] -2,5-cyclohexadien-1-one hydrochloride was dissolved in 50 ml of ethanol,
Then, 0.4 g of palladium-carbon is added and catalytic reduction is carried out by a conventional method. After the reaction, the catalyst was removed by filtration and ethanol was distilled off. The residue was recrystallized from methanol-ethyl acetate to give (3,5-di-t-butyl-4-hydroxyphenyl) (4-methoxyphenyl). 734 mg of methylamine hydrochloride were obtained.

Melting point: 161.8-167.8 ° C Example 9 0.9 g of (3,5-di-t-butyl-4-hydroxy-2'-methyl) benzophenone oxime was dissolved in 20 ml of acetic acid, and 0.9 g of zinc powder was added with stirring at 40 ° C., followed by reaction for 1 hour.
After the reaction, insolubles were removed by filtration, and acetic acid was distilled off. The residue was dissolved in ethyl acetate, washed with a 10% aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (elution solvent, chloroform: methanol (95: 5)), and the obtained oil was converted into a hydrochloride by a conventional method to give (3,5-di-dichloromethane). t-butyl-
322 mg of 4-hydroxyphenyl) (2-methylphenyl) methylamine hydrochloride were obtained.

Melting point: 222.0-223.2 ° C (decomposition) Example 10 (a) 5 g of lithium aluminum hydride was suspended in 400 ml of dry diethyl ether, and a solution prepared by dissolving 20 g of 3,5-di-t-butyl-4-hydroxybenzophenone in 200 ml of dry tetrahydrofuran was added dropwise with stirring. Then, heat and stir for 30 minutes. After the reaction, 10% sulfuric acid is added under ice-cooling, the organic layer is separated, washed with water and dried over magnesium sulfate. After distilling off the solvent, the residue was recrystallized from ether-hexane to give (3,
15 g of 5-di-t-butyl-4-hydroxyphenyl) phenylmethanol were obtained.

Melting point: 121-123 ° C (b) Thionyl chloride (2 ml) was added to 1.5 g of (3,5-di-t-butyl-4-hydroxyphenyl) phenylmethanol under ice-cooling, followed by stirring at room temperature for 2 hours. After the reaction, excess thionyl chloride was distilled off to give (3,5-di-t-butyl-4).
-Hydroxyphenyl) phenylmethyl chloride was obtained.

(C) The chlorinated compound obtained in the above step (b) is treated with 5 ml of pyridine
And 1 ml of a 40% methylamine solution is added dropwise under ice-cooling, followed by stirring at room temperature for 1 hour. After the reaction, the reaction mixture is poured into ice water, extracted with ether, and the organic layer is washed with water and dried over magnesium sulfate. The solvent was distilled off, the residue was converted into a hydrochloride by a conventional method, and then crystallized from petroleum ether to give (3,5-di-t-butyl-4-hydroxyphenyl) phenyl (methylamino) methane hydrochloride 1.35. g was obtained.

Melting point: 182.1-182.7 ° C Example 11 0.3 g of sodium amide was suspended in 30 ml of anhydrous benzene,
Add 0.8 g of methylamine and heat for 3 hours. The reaction solution was cooled and obtained in the step (b) of Example 10 (3,5-di-
A solution of t-butyl-4-hydroxyphenyl) phenylmethyl chloride in 10 ml of benzene is added dropwise. After the dropwise addition, the mixture is heated for 3 hours, and the precipitated insoluble matter is filtered off. The filtrate is washed with water and dried over magnesium sulfate. The benzene is distilled off under reduced pressure,
The resulting compound was converted into a hydrochloride by a conventional method, and then crystallized from petroleum ether to obtain (3,5-di-t-butyl-4-hydroxyphenyl) phenyl (methylamino) methane hydrochloride. This compound showed the same physical properties as the compound obtained in Step (c) of Example 10.

Example 12 (a) (3,5-Di-t-butyl-4,4'-dihydroxy) benzophenone oxime (1.0 g) was dissolved in acetic acid (15 ml), and zinc dust (1.0 g) was gradually added thereto while stirring with water cooling. And stir for 1.5 hours. After the reaction, zinc was removed by filtration, the filtrate was concentrated, ice water was added, and the mixture was extracted with ethyl acetate. After neutralization with an aqueous solution of sodium hydrogencarbonate, washing with water and drying over magnesium sulfate. After evaporating the solvent, the residue is dissolved in ethyl acetate, and a hydrochloric acid-isopropanol solution is added to form a hydrochloride. After the solvent was concentrated, the residue was recrystallized from methanol-ethyl acetate to give 2,6-di-t-butyl-4- [amino (4-hydroxyphenyl) methylene] -2,5-cyclohexadien-1-one hydrochloride. 1.0 g of salt was obtained.

Melting point: 259.3-261.2 ° C (decomposition) (B) 0.8 g of 2,6-di-t-butyl-4- [amino (4-hydroxyphenyl) methylene] -2,5-cyclohexadien-1-one hydrochloride is dissolved in 40 ml of ethanol,
0.3 g of 10% palladium-carbon is added and catalytic reduction is carried out by a conventional method. After the reaction, the catalyst was removed by filtration, the solvent was distilled off, and the residue was recrystallized from methanol-ethyl acetate to give (3,5-di-t
0.52 g of -butyl-4-hydroxyphenyl) (4-hydroxyphenyl) methylamine was obtained.

Melting point: 172.0-174.9 ° C Next, production examples of a drug containing the compound of the present invention will be described.

Production Example A: Capsule Formula 1-a 50 mg capsule mg / capsule active ingredient 50 starch 30 lactose 27.8 magnesium stearate 2.2 110 mg Formula 1-b 100 mg capsule mg / capsule active ingredient 100 starch 60 lactose 55.6 magnesium stearate 4.4 220 mg The active ingredient is comminuted and the starch, lactose and magnesium stearate are admixed with it and mixed well into capsules.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Norio Yamamoto 201, Nakanoshima, Tama-ku, Kawasaki-shi, Kanagawa Prefecture (72) Inventor Katsuhiko Miyasaka 2-23-9 Mohridai, Atsugi-shi, Kanagawa Prefecture (72) Inventor Takashi Mikami Kanagawa 17-5, Sumiyoshidai, Midori-ku, Yokohama, Japan (72) Katsuhiko Miyazawa, 1198, Kamiodanaka, Nakahara-ku, Kawasaki, Kanagawa Prefecture (72) Motohiro Kobayashi 4-17-14, Takatsu-ku, Kawasaki, Kanagawa, Japan (72) Inventor, Hagiwara Masafumi 2232 Yanoguchi, Inagi, Tokyo

Claims (1)

(57) [Claims] (1) Expression In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a formyl group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group or a lower alkylsulfonyl group, and R ² represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or Or a salt thereof, which represents a hydroxyl group.