JPH0441425A - 5-lipoxygenase inhibitor - Google Patents

Abstract

NEW MATERIAL:A 4-aminophenol derivative expressed by formula I (R<1> and R<2> are lower alkyl, lower alkanoyl or cycloalkyl; R<3> is H or lower alkyl; R<4> is naphthyl, naphthyloxy or heterocyclic group which may be substituted with lower alkyl or diphenyl-lower alkyl; Y is single direct bond, lower alkylene or lower alkenylene) or salts thereof. EXAMPLE:4-(2-Furoyl)amino-2,6-dimethylphenol. USE:A 5-lipoxygenase inhibitor having much better antiallergic and anti- inflammatory action than those of well-known inhibitors. PREPARATION:An aniline compound expressed by formula II (ZO is OH which may be protected) or a salt thereof and a carboxylic acid compound expressed by formula III, a salt or a reactive derivative thereof are subjected to condensing reaction and the OH-protecting group, as necessary, is removed to afford the objective compound expressed by formula I.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to 5-lipoxygenase inhibitors.

(Prior art) SRS-A (Slow Reacting 5u
bstance ofAnaphylaxrs) is
It is a causative substance of various allergic reactions with physiological effects such as contraction of bronchial smooth muscle and enhancement of vascular permeability, and its main body is known to be leukotrienes (LT) C4, D, , E, etc. It has been found that LTB4, which has a strong leukocyte migration effect, is involved in various inflammatory diseases.

Furthermore, it is known that 5-lipoxygenase is involved in the biosynthesis of LT from arachidonic acid.
As a therapeutic agent for diseases caused by, for example, 4-(2-
(5-methyl)thiazolyl amino)-2,3-di(te
It has been reported that rt,-butyl) phenol and the like are useful (Japanese Patent Application Laid-open No. 67023).

(Problems to be Solved by the Invention) The present invention provides a 5-lipoxygenase inhibitor that has even more excellent anti-allergic and anti-inflammatory effects than such conventionally known 5-lipoxygenase inhibitors. be.

(Means for Solving the Problems) The present invention uses a novel 4-aminophenol derivative represented by the following general formula (1) or a pharmacologically acceptable salt thereof as an active ingredient.

(However, R' and R2 are a lower alkyl group, a lower alkanoyl group or a cycloalkyl group, R'' is a hydrogen atom or a lower alkyl group, R4 is a naphthyl group which may be substituted with a lower alkyl group or a diphenyl lower alkyl group, (Naphthyloxy group or heterocyclic group, Y represents a single bond, lower alkylene group or lower alkenylene group.) 4-Aminophenol derivative (1) and its pharmacologically acceptable salts are excellent 5-lipoxygenases. It has an inhibitory effect and is useful for the treatment and prevention of various allergic diseases involving LT.

Specific examples of the active ingredient of the present invention include general formula (■), where R4 is a naphthyl group, a naphthyloxy group, a pyrrolyl group, a pyrrolidyl group, a pyridyl group, a piperidyl group, an imidazolyl group, a piperazyl group, a furyl group, a tetrahydrofuryl group. group, thienyl group, tetrahydrothienyl group, morpholyl group, thiazolyl group, thiazolidinyl group, indolyl group, quinolyl group, isoquinolyl group, benzothienyl group or benzothiazolyl group (these groups are substituted with a lower alkyl group or a diphenyl lower alkyl group) Examples include compounds that are

Among these, compounds in which R4 is a naphthyl group, a naphthyloxy group, an N-lower alkylpyrrolyl group, a pyridyl group, an imidazolyl group, an N-diphenyl lower alkylpiperazyl group, a furyl group, a tetrahydrofuryl group, a thienyl group, 2-lower alkylthienyl group, morpholino group,
It is a compound of a thiazolyl group, an indolyl group, a quinolyl group, an isoquinolyl group, or a benzothienyl group.

Further, compounds in which R4 is a naphthyl group, an N-lower alkylpyrrolyl group, a pyridyl group, a furyl group, a tetrahydrofuryl group, a thienyl group, a 2-lower alkylthienyl group, a thiazolyl group, an indolyl group, or a quinolyl group are more preferable from the viewpoint of medicinal efficacy. , isoquinolyl group, diphenyl lower piperazyl group or henzochenyl group.

In the present invention, preferred examples of lower alkyl groups, lower alkanoyl groups, cycloalkyl groups, lower alkylene groups, and lower alkenylene groups each have 1 to 4 carbon atoms.
Examples include an alkyl group having 2 to 5 carbon atoms, an alkanoyl group having 2 to 5 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkylene group having 1 to 4 carbon atoms, and an alkenylene group having 2 to 4 carbon atoms.

4-aminophenol derivative (
Examples of the pharmacologically acceptable salts in 1) include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, and aluminum salts. In addition, when R4 is a nitrogen-containing heterocyclic group, the 4-aminophenol derivative (I) can be an inorganic acid addition salt such as hydrochloride, hydrobromide, sulfate, acetate, oxalate, benzene sulfone. It can also be used as an organic acid addition salt such as an acid salt.

The 5-lipoxygenase inhibitor of the present invention can be administered either orally or parenterally, and formulations for parenteral administration include, for example, injections, ointments, aerosols, etc. Preparations for oral administration include tablets, capsules, granules, syrups, emulsions, suspensions, and the like.

4-aminophenol derivative (
The dosage of 1) or a pharmacologically acceptable salt thereof varies depending on the route of administration, age, weight, condition, type of disease, etc. of the patient, but is generally in the range of 0.3 to 300 μ/kg/day. is preferred.

4-aminophenol derivative (
1) is the general formula (where ZO represents an optionally protected hydroxyl group, R
1, R1 and R3 have the same meanings as above. ) An aniline compound or its salt represented by the general formula % formula % (
) (However, R4 and Y have the same meanings as above.) When the carboxylic acid compound, its salt, or its reactive derivative is subjected to a condensation reaction, and ZO is a protected hydroxyl group, the product It can be produced by removing the hydroxyl protecting group from .

In addition, among the target compounds (1), compounds in which Y is a lower alkylene group having 2 or more carbon atoms have the general formula (wherein, Yl represents a lower alkenylene group, and RIR2, R:l and R4 have the same meanings as above. ) can also be produced by reducing the compound shown.

Furthermore, among the 4-aminophenol derivatives (1), R
A compound in which 4 is a nitrogen-containing heterocyclic group optionally substituted with a lower alkyl group or a diphenyl lower alkyl group and Y is an ethylene group has the general formula (however, R1, R2 and R3 have the same meaning as above) %() (where R5 represents a substituted or unsubstituted nitrogen-containing heterocyclic group) is subjected to an addition reaction with an acryloylamino compound or a salt thereof represented by It can also be manufactured by

The condensation reaction between the aminophenol compound (II) or a salt thereof and the carboxylic acid compound (I[[) or a reactive derivative thereof can be carried out according to a conventional method for peptide synthesis. For example, when using a reactive derivative (e.g., acid halide, mixed acid anhydride, active ester) of carboxylic acid compound (I[I), the condensation reaction is carried out in a suitable solvent with or without a deoxidizing agent. can be implemented.

On the other hand, condensed RZ of aminophenol compound (II) or its salt and carboxylic acid compound (III) or its salt
The R3 combination reaction can be carried out, for example, in the presence or absence of a condensing agent. All of the above condensation reactions proceed suitably in an appropriate solvent under ice-cooling to heating.

When ZO is a protected hydroxyl group, the subsequent removal of the protecting group can be carried out according to an appropriate conventional method depending on the type of the protecting group.

Moreover, the reduction reaction of compound (1-a) can be carried out according to a conventional method. For example, the reduction reaction can be carried out by catalytic reduction in the presence of a Raney nickel, Raney cobalt or palladium based catalyst, and can also be carried out using an alkali metal borohydride in a lower alkanol.

The reaction between acryloylamino compound (IV) and compound (V) can be suitably carried out in a suitable solvent under heating.

Experimental Example 1 An enzyme solution containing 5-lipoxygenase was prepared from cultured basophilic leukemia cell line RBL1 cells of 5-1 poxy-gelat, and radioactive in the presence of indomethacin, calcium chloride, adenosine triphosphate, and the test substance. A certain amount of the 0 reaction solution, which was reacted with labeled arachidonic acid as a substrate, was spotted on a thin layer, developed and separated, and the enzymatic reaction product 5-HET, E (5-hydroxyeicosatetraenoic acid) fraction was irradiated. The activity was measured as an indicator of 5-lipoxygenase activity. The 5-lipoxygenase inhibitory activity of the test substance was expressed as the concentration IC5o (μM) at which the reaction in the control test was inhibited by 50%.

[Biocbimica eL [1iophysic
[Method of M. Furukawa et al. described in acLa Vol. 795, p. 458, (1984)] The experimental results are as described in Tables 1 to 3 below.

Table 1 Table 2 Table 2 C4 was subjected to solvent extraction and quantified by radioimmunoassay. The inhibitory effect of the test substance on leukotriene C4 production was expressed as % inhibition at a sample concentration of 10-'M.

The experimental results are shown in Tables 4 to 6 below.

Table 4 *: ph represents a phenyl group.

Experimental Example 2 0 Ikotriene C4 The lungs of a guinea pig sensitized with ovalbumin were cut into small pieces.
Table of leukotrienes produced by reaction with ovalbumin in the presence of the test substance and indomethacin Experimental Example 3 PAFtt I・Kami・The test substance was administered intraperitoneally to the mouse, and 30 minutes later, LD! .

A corresponding amount of l'AP was administered via the tail vein, and PAF was administered.The compounds in Table 7 below showed a survival rate of 100χ when administered intraperitoneally at 30 mg/kg.

Table 7 shows puromycin aminonucleoside (PAN)
100 μ/kg of the drug was administered intravenously to induce proteinuria.
On the 6th day of administration, the amount of protein in the urine was measured.

Thereafter, (6th day of PAN administration) 100 μ/kg of the sample [suspended in 5 Id of physiological saline using a small amount of non-ionic surfactant (Tween 80)] was administered intraperitoneally, and 1 day after administration of the sample, the urine Protein excretion was measured.

The experimental results are shown in Table 8 below.

Table 8 Experimental Example 4 PAN Frose SD male and female rats Body weight = 180 to 220 g) *: Instead of the sample suspension, the same amount of physiological saline was administered.

**: Represents the number of days after PAN administration.

Experimental Example 5 Anti-rat glomerular basement membrane antibody serum prepared from domestic rabbits was
It was administered to male and female rats (body weight: 170-215 g) through the tail vein to induce nephritis. Immediately after antibody administration and 6 hours later, 50 mg/kg of the specimen [5 ynl of physiological saline using a small amount of nonionic surfactant (Tween 80)] was added.
[Suspension]] was administered once. For the next 9 days, the same amount of specimen was intraperitoneally administered once in the morning and once in the afternoon, and the amount of protein excreted in the urine was measured 10 days after the start of antibody administration.

The experimental results are shown in Table 9 below.

Table 9 Experimental Example 6 P, aCneSll ° Force 1 7-week-old male B a I b / c mice were treated with Propionibacterium acnes (Propionibacterium acnes ).
erium acnes) was intravenously administered, and approximately one week later, lipopolysaccharide (LPS) was administered intravenously.
) 1 μg was additionally administered intravenously to induce acute liver failure.

The sample was prepared at 100 μ/kg (1 hour before LPS administration).
(suspended in 10 ml of distilled water using a small amount of nonionic surfactant (Tween 80)) was orally administered.

Glutamic virvic transaminase (GPT) and glutamic oxaloacetic transaminase (GOT) activities in serum were measured 6 hours after LPS administration.

The mortality rate after 24 hours was also examined.

The experimental results are shown in Table 1O below.

*: Instead of the sample suspension, the same amount of physiological saline was administered each time.

Table □10 *: Instead of the sample suspension, the same amount of distilled water was administered.

Umbrella*: Expressed in carmen units.

Production Example 1 To a suspension of 1.5 g of 4-amino-2,6-dimethylphenol in 30 yd of dichloromethane under an argon atmosphere, 979 μm of sodium hydrogen carbonate and 30 d of water were added at room temperature, and 171 g of 2-furoyl chloride was added with stirring. Add. The mixture is stirred for 5 minutes and then extracted with chloroform. The extract is washed with 10% hydrochloric acid and then with water, dried and concentrated. The residue was recrystallized from isopropyl ether-isopropyl alcohol to obtain 1.9 g of 4-(2-furoyl)amino-2,6-dimethylphenol.

M, p, 139.5-141.0@C Production Example 2 2°0 g of 4-amino-2,6-dimethylphenol and 10 Illl of tetrahydrofuran! 1.97 g of isonicotinic acid and 400 g of butanol were added to the solution under an argon atmosphere.
Add +ag. Then, while cooling with water, 3.61 g of dicyclohexylcarbodiimide was added and stirred for 4 hours. The precipitate was collected by filtration, suspended in 10% hydrochloric acid, and washed with chloroform to remove dicyclohexylurea. Pour the aqueous layer with potassium carbonate.
H5, the precipitate was collected by filtration, and recrystallized in chloroform-methanol to give 4-isonicotinoylamino-2,6-
1.95 g of dimethylphenol are obtained.

Furthermore, the filtrate obtained by removing the precipitate from the reaction solution is diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution to remove butanol. After washing with water and drying, the solvent was distilled off and the residue was recrystallized from chloroform-methanol to obtain an additional 790 μ of 4-isonicotinoylamino-2,6-dimethylphenol.

M, P, 243-244''C Production Example 3 128 µm of 2-thienylcarboxylic acid was dissolved in 3 ml of a7tonitrile under water cooling, and 303 mg of triethylamine,
Next, 207 mg of diethyl phosphorochloridate was added, and after stirring for 30 minutes, 201 cm of 4-amino-2,6-dinitylphenol was added and reacted at room temperature. After the reaction, ice pieces were added, followed by 5% aqueous sodium hydrogen carbonate solution, the precipitated crystals were collected by filtration, washed with isopropyl ether, and the residue was recrystallized from ethyl acetate to give 4-(2-
150 mg of thienylcarbonyl)amino-2,6-dinitylphenol are obtained as white crystals.

M, p, 190-191.5 @C Production Examples 4-30 The corresponding raw material compounds are treated in the same manner as in any of Production Examples 1-3 to obtain the compounds listed in Tables 11-13 above.

Table 11 (Note) R3: Methyl group in Production Example 20, Production Examples 21 to 2
4 is hydrogen atom Table 13 Table (Note) Y: Ethylene group "A" in Production Example 25 Trans vinylene group in Production Examples 26 to 30 Production Example 31 trans-4-(3-(2-furyl)acryloylcoamino- 2.5 g of 2,6-dimethylphenol is catalytically reduced in 30 ml of ethanol and 30 d of tetrahydrofuran in the presence of 1.0 g of 10% palladium-carbon at room temperature and normal pressure. After the reduction, the palladium-carbon is removed by filtration. After distilling off the solvent, the residual aroma was subjected to silica gel column chromatography [solvent: chloroform-methanol (20:1)]
4-(3-(2-tetrahydrofuryl)propionylcoamino-2,6-dimethylphenol)
Obtain 2g.

M, p, 88.5-90,0°C Production Example 32 Trans-4-(3-(2-naphthyl)acryloylcoamino-2,6-dimethylphenol was treated in the same manner as Production Example 31 to produce 4 - (3-(2-naphthyl)propionylcoamino-2,6-dimethylphenol is obtained.

M, p, 165-166.5°C (ethyl acetate-hexane) Production example 33 trans-4-(3-(2-furyl)acryloylcoamino-2,6-dimethylphenol 2°3g, sodium borohydride A mixture of 2.6 g of powdered tellurium and 3.2 g of powdered tellurium is refluxed with stirring in 1 OOm 9. of ethanol for 15 hours. After cooling, insoluble matter is filtered off and the filtrate is concentrated. The residue is dissolved in 20 m2 of acetic acid and diluted with water. The precipitated crystals were collected by filtration to give 4-(3-(2-furyl)propionylcoamino-2).
, 2.15 g of 6-dimethylphenol were obtained.

M, p, 121-123'C Production Examples 34 and 35 The corresponding raw material compounds were treated in the same manner as Production Example 33 to produce the following 1st
The compounds listed in Table 4 are obtained.

Table 14 Production Example 36 (1) 4-Amino-2,6-dimethylphenol and acrylic acid chloride are treated in the same manner as in Production Example 1 to obtain 4-acryloylamino-2,6-dimethylphenol.

M, P, 210.5-213°C (2) Above (1
1.01 g of 4-(diphenylmethyl)piperazine are reacted in 15 ml of ethanol at 60 DEG C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give 4-(3-(4-(diphenylmethyl)piperazino)propionyl)amino-2,
6-dimethylphenol is obtained quantitatively.

M, p, 178-180'C Production Examples 37 and 38 The corresponding raw material compounds were treated in the same manner as Production Example 36 to obtain the following 1st
The compounds listed in Table 5 are obtained.

Table 15 Reference Example 1 (1) Add triethylamine to a methylene chloride solution of 50 g of 2-n-propylphenol, and then add a methylene chloride solution of acetyl chloride under water cooling, stir, wash, dry, and distill the solvent. leave Chlorobenzene and then aluminum chloride were added to the residue and refluxed. After cooling,
Add ice chips to the reaction solution, make it alkaline with a 10% aqueous sodium hydroxide solution, and stir at room temperature to decompose the aluminum complex. Next, the pH was adjusted to 4 with 10% hydrochloric acid, extracted with ether, washed, dried, and concentrated under reduced pressure. The residue was separated and purified using a silica gel column to obtain 6-acetyl-
30.1 g of 2-(n-propyl)phenol are obtained as an oil.

(2) Copper nitrate (n) trihydrate is stirred with acetic anhydride at room temperature to form a complex. On the other hand, the above complex is added to a solution of 14 g of the product obtained in (1) above in acetic anhydride under water cooling. After stirring at room temperature, the mixture was poured into ice water, extracted with ethyl acetate, washed, dried, and the solvent was distilled off. The residue was purified with a silica gel column to obtain 10 g of 6-acetyl-4-nitro-2-(lopropyl)phenol.
is obtained as an oil.

(3) Add tin chloride dihydrate to an ethanol solution of 10 g of the product obtained in (2) above, and reflux.

After cooling, 5% aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, washed, dried, the solvent was distilled off, the residue was converted into a hydrochloride, and 6-acetyl-4-amino-2-(n-propyl) was obtained. Phenol/hydrochloride 8.

Obtain 7g.

m, p, 217-219°C (decomposition) Reference Example 2 (1) A sodium nitrite aqueous solution was added to a mixture of 6.8 g of 2,3.6-)limethylphenol, acetic acid, dimethylformamide, and water under water cooling. After dropping and stirring at the same temperature,
The precipitated crystals were collected by filtration, dried, and recrystallized from isopropyl ether-〇-hexane to obtain 756 g of 2°3.6-)dimethyl-4-nitrosophenol.

m, p, 181-183 °C (decomposition) (2) Add 1 to an ethanol solution of 5.0 g of the product obtained in (1) above.
Add 0% hydrochloric acid and iron powder, reflux, and then filter. The filtrate was extracted with ethyl acetate under alkaline conditions, washed, converted to hydrochloride, concentrated, and further washed with ether to obtain 2.3.6-
) Obtain 3.7 g of trimethyl-4 huminophenol hydrochloride.

m, p, 303°C (degradation) (Effect of the invention) The 5-lipoxygenase inhibitor of the present invention, based on its excellent enzyme activity inhibition effect, inhibits 5R3-A, L'r”Am caused by various causes. ,B.

, C4, D4, and other LT biosynthesis. In addition, the 4-aminophenol derivative that is the active ingredient has low toxicity; for example, 2000 mg of 4-(3-thienylcarbonylamino 12.6-dimethylaminophenol)
/kg was administered orally and intraperitoneally to mice, and no deaths were observed even after observation for 2 days.

Therefore, the 5-lipoxygenase inhibitor of the present invention
Various allergic and inflammatory diseases caused by T., such as bronchial asthma, allergic rhinitis, urticaria,
It can be effectively used to treat, alleviate symptoms of, and/or prevent dry skin, gout, arthritis, nephritis, hepatitis, and the like.

Claims (1)

[Claims] 1. General formula▲ Numerical formula, chemical formula, table, etc.▼ (However, R^1 and R^2 are a lower alkyl group, a lower alkanoyl group, or a cycloalkyl group, and R^3 is a hydrogen atom or A lower alkyl group, R^4 is a naphthyl group, a naphthyloxy group, or a heterocyclic group which may be substituted with a lower alkyl group or a diphenyl lower alkyl group, and Y represents a single bond, a lower alkylene group, or a lower alkenylene group. .) A 5-lipoxygenase inhibitor comprising a 4-aminophenol derivative or a pharmacologically acceptable salt thereof as an active ingredient. 2, R^4 naphthyl group, naphthyloxy group, pyrrolyl group, pyrrolidyl group, pyridyl group, piperidyl group, imidazolyl group, piperazyl group, furyl group, tetrahydrofuryl group, thienyl group, tetrahydrothienyl group, morpholyl group, thiazolyl group, Thiazolidinyl group, indolyl group,
The 5-lipoxygenase inhibitor according to claim 1, which is a quinolyl group, an isoquinolyl group, a benzothienyl group, or a benzothiazolyl group (including cases where these groups are substituted with a lower alkyl group or a diphenyl lower alkyl group). 3, R^4 is a naphthyl group, naphthyloxy group, N-lower alkylpyrrolyl group, pyridyl group, imidazolyl group, N
-diphenyl lower alkylpiperazyl group, furyl group, tetrahydrofuryl group, thienyl group, 2-lower alkylthienyl group, morpholyl group, thiazolyl group, indolyl group, quinolyl group, isoquinolyl group or benzothienyl group 5-Lipoxygenase inhibitor. 4. Claim 1 which is an anti-allergic agent and/or an anti-inflammatory agent
, 2 or 3. 5. Claim 1, which is a therapeutic/preventive agent for bronchial asthma, allergic rhinitis, urticaria, psoriasis, gout, arthritis, nephritis, and hepatitis.
, 2, 3 or 4.