JPS6267022A - Anti-inflammatory agent - Google Patents

Abstract

PURPOSE:An anti-inflammatory agent, containing a p-aminophenol drerivative or an acid addition salt thereof and capable of sufficiently and powerfully inhibiting both cyclooxygenase and 5-lipoxygenase and precisely suppressing both of acute and chronic inflammations. CONSTITUTION:An anti-inflammatory agent containing a compound expressed by formula I (R<1> and R<2> are H, alkyl or phenyl; R<3> and R<4> are lower alkyl) or an acid addition salt thereof, e.g. 3, 6-di-tert-butyl-4-[(5-methyl-2-thiazolyl) amino]phenol, etc. The dosage form thereof is a parenteral agent, e.g. injection, etc., or oral agent,e.g. tablet, etc. The dose is 0.01-10g/human/day, preferably 0.02-5g/human/day. The compound expressed by formula I which is an active constituent is obtained by consending a benzoquinone derivative expressed by formula II with an aminothiazole derivative expressed by formula III and reducing the resultant compound expressed by formula IV.

Description

[Detailed description of the invention] 17)! ■ Shito” The present invention relates to a novel anti-inflammatory agent.

In recent years, the involvement of arachidonic metabolites in inflammation has been revealed. That is, arachidonic acid, which is a component of phospholipids present in cell membranes, is liberated from cell membranes by various stimuli, such as inflammatory stimuli, antigen-antibody reactions (immune stimulation), etc., and is first metabolized by cyclooxygenases and lipoxygenases, resulting in various It is converted into the substance of Prostaglandins (PG) metabolically produced by the above cyclooxygenase, especially PGE2 and PGI
2, as well as hydroperoxyeicosatetraene (HPE), which is sequentially produced by the above lipoxygenases.
TE)1. Hydroxyeicosatetraene 1 (HETE)
) II, especially 5-HPET by 5-lipoxygenase
It has been revealed that O icotriene (LT) jl, which is produced via E, is particularly related to inflammation.

On the other hand, conventionally known anti-inflammatory drugs such as indomethacin and ibuprofen have the effect of specifically inhibiting the above-mentioned cyclooxygenase and are effective against acute inflammation, but they are effective against rheumatoid arthritis, etc. PG and L have not been shown to have sufficient effects on chronic inflammation.
For the treatment of chronic inflammation, which is predicted to be related to T and includes hives, it is thought that drugs that have the effect of inhibiting 5-lipoxygenase as well as inhibiting the above-mentioned cyclooxygenase are effective. Anti-inflammatory drugs are expected to serve as new anti-inflammatory agents.

I will.

An object of the present invention is to provide a new anti-inflammatory agent that can sufficiently strongly inhibit both cyclooxygenase and 5-lipoxygenase, which is desired in the field, and can accurately suppress both acute inflammation and chronic inflammation. .

As a result of intensive research, the present inventors have found that a series of p-7 minofenol derivatives represented by the following general formula (1) or their pharmacologically acceptable acid addition salts have the desired enzyme inhibitory activity. and based on this, they have discovered that it has anti-inflammatory activity, and have now completed the present invention.

That is, the present invention is directed to the general formula [wherein R1 and R2 are the same or different and represent a hydrogen atom, an alkyl group, or a phenyl group, and R3 and R4 each represent a lower alkyl group. ] The present invention relates to an anti-inflammatory agent characterized by containing a p-aminophenol derivative represented by the following or a pharmacologically acceptable acid addition salt thereof.

In the above general formula (1), examples of the lower alkyl group include linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl. In addition to the above-mentioned examples of lower alkyl groups, examples of the alkyl group include heptyl, octyl, nonyl, decyl, undecyl,
dodecyl, tridecyl, tetradecyl, pentadecyl,
Examples include alkyl groups such as hexadecyl, octadecyl, nonadecyl, and eicosyl groups.

The p-7 minofenol derivative represented by the above general formula (1), which is used as an active ingredient in the anti-inflammatory agent of the present invention, includes some known compounds (US Pat. No. 3,299,087;
However, the above-mentioned patent specifications only mention that the compounds described in these patents are heavy water compounds that can be used as antioxidants; There is no mention of any action or 5-lipoxygenase activity inhibitory action, and of course there is no suggestion that these compounds are useful as anti-inflammatory agents.

The active ingredient compound represented by general formula (1) of the present invention is:
Including those described in the above patent specifications, they can be produced, for example, by the method shown in Reaction Scheme-1 below.

<Reaction Scheme-1> In formula C, R1, R2, R'3 and R4 are the same as above. ] According to reaction step-1, benzoquinone derivative (2) and 7
The active ingredient compound (1) of the present invention can be obtained by a condensation reaction with the minothiazol derivative (3) and a subsequent reduction operation.

In the above, the aminothiazole derivative (3) can be obtained by a known method [The Chemistry of Heterocyclic Compounds (J, V, M
etzgerl! , 7he Chemistry o
fHeterocyclic Coa+pounds)
, 341.1979, John Wiley
& 5ons Inc.].

The above condensation reaction is described in the Journal of Organic Chemistry (J, Oro, Che).

The method of Weingarten et al., described in Vol. 32, p. 3246 (1967), same journal.

36, p. 3497 (1971) or the method of Tetrahedron, vol. 23, 372.
Reike (Reike) described on page 3 (1967)
r) It can be carried out according to the method of et al. That is, the above-mentioned synthetic reaction is carried out using a compound (2
) is used in an amount of 1 to 5 times the molar amount of compound (3), and the mixture is heated at room temperature in an appropriate solvent such as no solvent or an inert organic solvent such as 1.2 to dichloroethane, chloroform, benzene, toluene, tetrahydrofuran, and dioxane. ~about 20
It is carried out in a temperature range of 0° C., thus obtaining compound (4).

Compound (4) obtained as described above can be subjected to the subsequent reduction reaction without being isolated from the reaction system, but may of course be isolated.

The reduction reaction can be carried out according to a conventional method, for example, by using sodium hydrosulfide or zinc and acetic acid, and the compound (1) of the present invention is obtained by this reaction.

Further, the active ingredient compound represented by the general formula (1) of the present invention can also be produced, for example, by the method shown in the following reaction scheme-2.

[Reaction scheme-2] <5) (6) (In the formula, R1, R
2, R3 and RA are the same as above.

X represents a halogen atom and A represents a carbonyl group which may be protected. ) In the above, halogen atoms refer to fluorine, chlorine, bromine and iodine atoms. Carbonyl groups that may be protected include, in addition to carbonyl groups, di-lower alkyl acetal residues such as dimethyl acetal, methyl ethyl acetal, diethylacetal, dipropylacetal, dibutyl acetal, diethylacetal, diethylacetal, and ethylene acetal. Examples include cyclic acetal residues such as , trimethylene acetal, and tetramethylene acetal.

The method shown in Reaction Scheme-2 is a method in which a thiourea derivative of general formula (5) and a compound of general formula (6) are reacted to form a thiazole ring.

Compound (5) used here can be obtained by a known method. [Neftekhimiya (5haulvo et al., Neftekhimiya), vol. 21.

See page 467 (1981)].

When using a compound of general formula (6) in which A is a carbonyl group, the above reaction is carried out in an inert organic solvent such as water, methanol, ethanol, tetrahydrofuran, dioxane, acetic acid, etc. at about 50 to 150°C, preferably Approximately 80~
This is carried out by allowing the compound (5) to act on the compound (6) at a temperature of 100°C. Compound (5) and compound (
There is no particular limitation on the ratio of use with 6), but there are usually
Compound (6) is preferably used in an amount of about 1 to 5 times, preferably about 1 to 2 times, by molar amount relative to 5).

In addition, in the above reaction, when compound (6) in which A is a protected carbonyl group is used, the reaction can be carried out using a suitable solvent such as p-toluenesulfonic acid, pyridine hydrochloride, sodium hydrogen sulfate, sulfuric acid, phosphoric acid, polyphosphoric acid, etc. It is desirable to carry out the reaction by adding an acid or the like to compound (6) as a catalyst ffl.

The target compounds obtained by each of the above reactions can be easily isolated and purified by conventional separation means such as solvent extraction, recrystallization, column chromatography, etc.

Furthermore, the active ingredient compound (1) of the present invention can be made into a pharmaceutically acceptable acid addition salt by subjecting it to an addition reaction with a suitable acidic compound, and the present invention also includes such acid addition salts. It can be used as an active ingredient. Examples of acidic compounds that can form the above-mentioned acid addition salts include hydrochloric acid,
Inorganic acids such as sulfuric acid, phosphoric acid, hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid,
Examples include organic acids such as benzoic acid.

The anti-inflammatory agent of the present invention is formulated into a formulation containing an effective layer of the above-mentioned active ingredient compound (1) or a pharmacologically acceptable acid addition salt thereof. The formulation forms include formulations suitable for parenteral administration, such as injections (subcutaneous, intravenous, intramuscular, intraperitoneal injections), ointments, suppositories, aerosols, etc., depending on the route of administration, and tablets. capsules, granules, emulsions,
Examples include forms suitable for light administration such as syrups, solutions, emulsions, and suspensions, and preparation into these forms can be carried out according to conventional methods.

The above-mentioned tablets, capsules, granules, emulsions, etc. for oral administration may contain excipients such as white sugar, lactose, glucose, starch, mannitol, etc.; syrup, gum arabic, gelatin, sorbitol, tragacanth, methylcellulose, polyvinylvinylidene. Binding agents such as starch, carboxymethyl cellulose or its calcium salt, microcrystalline cellulose, polyethylene glycol, etc.; Lubricating agents such as talc, magnesium or calcium stearate, silica; Wetting agents such as sodium laurate, glycerol, etc. It is prepared using Injections, solutions, emulsions, suspensions, syrups, and aerosols can be prepared using, for example, water, ethyl alcohol, isopropyl alcohol, propylene glycol,
Solvent for dissolving active ingredients such as 1,3-butylene glycol and polyethylene glycol; sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, hydrogenated polyoxyethylene ether of mustard oil, lecithin, etc. Surfactants; suspension agents such as carboxymethyl sodium salts, cellulose derivatives such as methylcellulose, natural gums such as tragacanth and gum arabic; preservatives such as esters of roseoxybenzoic acid, benzalkonium chloride, sorbate, etc. It is customarily prepared using as appropriate. Suppositories are prepared using, for example, polyethylene glycol, lanolin, coconut oil, and the like.

The clinical dosage of the anti-inflammatory agent of the present invention is based on the patient's age, weight,
Although it varies depending on sensitivity, degree of disease, etc., the usually effective dosage is approximately 0.01 to 10 g of active ingredient per day for adults.
, preferably in an amount of about 0.02 to 5a. Of course, amounts outside the above range can also be used if necessary.

1--1-11 Hereinafter, synthesis examples of the active ingredient compound of the present invention will be given as practical examples, followed by pharmacological test examples and formulation examples.

Example 1 2.6-tert-butyl-4-((5-methyl-
Preparation of 2-thiazolyl)aminocophenol2.6-tert-butyl-1,4-benzoquinone2.2oo and 2-amino-5-methylthiazole3.
43 in 111#L of anhydrous dichloroethane 60ml,
0.55 WIJ of titanium tetrachloride was added to this, and the mixture was heated under reflux for 14.5 hours. The mixture was cooled to room temperature, and a solution of sodium hydrosulfide 40a in 150 ml of water was added, followed by stirring for 2 hours. Insoluble materials were removed, the solution was separated, and the aqueous layer was further extracted with dichloromethane. Combine the organic layers and wash with saturated saline, iii! Dried over sodium chloride and concentrated. The crude product was purified by silica gel column chromatography (ether:hexane-3N) to obtain the target compound 1.070.

The physical properties of the obtained compound are shown in Table 1 as compound N001.

Examples 2-9 Compound No. shown in Table 1 in the same manner as Example 1.

2 to 9 were produced.

Example 10 2. Preparation of 6-tert-butyl-4-((5-hexyl-2-thiazolyl)aminocophenol) 3.5-bis(1,1-dimethylethyl)-4-hydroxyphenylthiourea 2 .OOg, α-bromooctylaldehyde dimethyl acetal 1.81 (+ and ρ-
Add 0.06a of toluenesulfonic acid hydrate to vinegar 11
2- and heated at 90°C for 1 hour. After concentrating the reaction mixture, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated warm water, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (ether:hexane-1=3) to give the target compound of 1.56! I got II.

The physical properties of the obtained compound are shown in Table 1 as No. 10.

Examples 11 to 13 Compound No. 1 shown in Table 1 was prepared in the same manner as in Example 10.
1 to 13 were produced.

Table 1 -Bu t -13u (t -Bu: t-butyl group) <Pharmacological test> 1 Nidichlorooxygenase inhibitory effect Preparation of sheep seminal gland microsomes as a crude enzyme solution and measurement of cyclooxygenase activity is the method of Kanmoto et al. (
Proc, Nat, A cad, sci,,t
J.S.A.

71.3645 (1974) and J. Biol.

Chew, 251.2629 (1976)).

The specimen was added to the microsome solution and incubated at 24°C for 2 minutes, followed by the addition of the substrate μC-arachidonic acid. After incubating for an additional 2 minutes, ether-
The reaction was stopped with a mixture of methanol and 0.2M citric acid (30:4:1), and the cyclooxygenase product was extracted. The extract was spotted on a thin plate, and after development, arachidonic acid, PGE2 and other parts were scraped off, counted with a scintillation counter, and cyclooxygenase activity was calculated. The inhibitory activity of the sample was compared to that of the control PGE.
It was expressed as the inhibition rate relative to the 2 production rate.

The results are shown in Table 2.

Modulation of the 2:5-lipoxygenase inhibitory effect in and fenestration of 5-lipoxygenase activity was performed using the method of Bokoch et al. (J.

Biol, Chem, 256.4156 (198
1)) and the method of Ochi et al. (J, Biol, Ch.
ew,,258.

5754 (1983)).

Intraperitoneal administration of 2% casein to guinea pigs, 14-16
The animals were killed by exsanguination for a while, and the peritoneal cavity was washed to collect infiltrated cells. The cells were suspended at a concentration of 2.5 x 10' cells/- in phosphorous WaS solution containing 1 s M CaCO2 and 5.5 M glucose. This 1B cell suspension was heated at 30°C.
After incubation for 2 minutes, each concentration of specimen was added and further incubated for 2 minutes. Then 10 μM ionophore A23187 followed by 10 μM
M"C-7 rachidonic acid was added. After 3 minutes of incubation, 0.2M citric acid was added to stop the reaction, and the product was extracted with ethyl acetate. The extract was spotted in a thin layer, and after development, Arachidonic acid, 5-HETE and other moieties were scraped off, and mQ was counted using a scintillator.The inhibitory activity of the sample was expressed as the inhibition rate relative to the 5-HETE production rate of the control.

The results are shown in Table 2.

3: Rat carrageenan paw edema method S, D, male rat strain (170-1900, fasted) 1μ
m! Using the method of Winter et al. (Proc, Soc, l:xp, 3io1.M
ed.

111.544 (1962)).

One hour after oral administration of the specimen, 1% carrageenin solution 0.1
112 was injected subcutaneously into the right leg of the chicken. The fixed volume after 3 hours was measured, and the increase from the value before carrageenan treatment was expressed as the edema rate, and the inhibition rate was determined by comparing it with the control group.

The results are shown in Table 2 below.

Table 2 However, in Table 2, NDGA refers to nordihydroaletic acid (N0rdihydrOOuaiare).
tt+CaC1d), and 08 of the cyclooxygenase inhibition rate (%) of test N005 is the inhibition rate when 100 μM is used.

From Table 2 above, the active ingredient compounds of the present invention all have cyclooxygenase inhibitory activity and 5-lipoxygenase inhibitory activity with low If, and furthermore, they strongly suppress rat carrageenan paw edema, which is an acute inflammation model, when administered orally. I understand that. Therefore, it is useful as a new anti-inflammatory agent.

Formulation Example 1 Preparation of tablets 100g of compound N002, lactose 55! I+ and 41TJ of dried potato starch were mixed, the mixture was kneaded with 20 cups of water, and then extruded through a 16-mesh screen.
It was dried at 40°C and granulated. Next, 4 g of magnesium stearate was mixed uniformly and tableted to prepare a tablet containing 1000 g of Compound No. 2 in 2001Q.

Formulation Example 2 Preparation of Capsules 196 g of granules obtained in the same manner as in Formulation Example 1 were mixed with 4 g of magnesium stearin, and each 200so was filled into No. 2 hard capsules.
Hard capsules containing 10 On of No. 2 were prepared.

(Above) Agent: Eiji Saegusa, Patent Attorney 1985 Special Revision Application No. 207439 2 Title of Invention: Anti-Inflammation^1] 3
/.

) 1 n & (1) IIIJ (M Holding: 1 7ff 1 person/'-” Otsuka Pharmaceutical Factory Co., Ltd. 4 Agent Voluntary person 6 Amended Section 7 of “Detailed Description of the Invention” in the Specification to the Song Dynasty Contents Amendment Content 1: ``Related J'' is corrected to ``1 related'' on page 2, lines 14-15 of the specification.

2 Specification, page 11, line 17 1. : [Correct oxalic acid j to be ``benzenesulfonic acid.''

(that's all)

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 are the same or different, hydrogen atom,
It represents an alkyl group or a phenyl group, and R^3 and R^4 each represent a lower alkyl group. An anti-inflammatory agent comprising a p-aminophenol derivative represented by the following formula or a pharmacologically acceptable acid addition salt thereof.