JPH0214328B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to pharmaceutical compositions containing pharmacologically active thiazole compounds and their uses. British Patent No. 1145884 describes compounds represented by the following general formula and acid addition salts thereof. [In the formula, R ¹ and R ² are the same or different,
Substituted aryl group (heterocyclic aryl group), R ³
is a lower aliphatic carboxylic acid having 2 to 6 carbon atoms or a salt, ester, amide, nitrile or hydroxamic acid derivative thereof, and R ³ is bonded to the thiazole ring at a carbon atom of the aliphatic chain. According to British Patent No. 1145884, compound (A) is described to have pharmacological effects, particularly anti-inflammatory effects. Specific examples of R ¹ and R ² include unsubstituted phenyl, halogen, lower alkyl,
lower alkoxy, nitro, amino, substituted amino,
Mention may be made of phenyl substituted with mercapto, alkylthio, alkylsulfonyl or trihalomethyl. Brown et al. reported on the anti-inflammatory effect of a specific compound represented by formula (A) on carrageenil-induced edema in rat hindpaws (Brown et al.
etal, J.Med.Chem., 1974, Volume 17, No. 11, 1177~
(See page 1181). Considering the relationship between the structure of the compound and its pharmacological activity, it is said that the anti-inflammatory effect was the highest when R ² was 4-chlorophenyl. However, it is said that when the preferred R ¹ is substituted with a phenyl group at the 4-position of the phenyl ring, the anti-inflammatory effect is reduced. Thus, even if R ² is 4-chlorophenyl, the activity is substantially reduced in both cases where R ¹ is 4-methoxy- and 4-carboxy-substituted phenyl. The present inventors have discovered that a series of thiazole-5-acetic acids not specifically disclosed among the above general formula (A) (R ¹ is 4-substituted phenyl) surprisingly have a remarkable anti-inflammatory effect. I found out. The present invention next provides a pharmaceutical composition containing a compound represented by the general formula and a salt thereof. [In the formula, R is a hydrogen atom or an acyl group, for example,
It is an alkanoyl group having 2 to 7 carbon atoms, preferably 2 to 5 carbon atoms, and more specifically, acetyl,
propionyl, butyryl, isobutyryl, valeryl and isovaleryl] The compounds () may form salts, for example addition salts with acids such as hydrochloric acid, hydrobromic acid, alkali metal salts (such as sodium or potassium salts). ),
Includes alkaline earth metal salts (calcium salts, etc.). These salts are manufactured by conventional methods. The anti-inflammatory effect of the compound () used in the present invention was evaluated using the method of Tonelli et al.
Endocrinology, Vol. 77, p. 625 (1965)). Female rat (Sprague-Dawley strain, weight 60-70
g) was used in each group of 10 animals. A stimulant was applied to both ears to induce ear edema. The stimulant consists of a mixture of 1% cod oil, 20% pyridine, 5% water and 74% diethyl ether. This stimulant mixture is then applied once to the right ear only, with or without test compound. 6 hours later,
The animals were killed, and both ears were cut into 9 mm diameter pieces and their weights were measured. The anti-inflammatory effect of the test compound was expressed as the percentage difference in mean ear weight increase between the treatment group and the control group, as shown in the following formula: Suppression rate (%) = (average weight increase of treatment group) - (average weight increase of control group) / (average weight increase of control group) x 10
0 The test results for representative compounds of formula () are shown in the table below. For comparison, Brown et al. (J.
The test results (three tests) of 4-(p-chlorophenyl)-2-phenylthiazole-5-acetic acid (B), which is considered to be a preferable compound according to the literature of Med.Chem., are also shown.

[Table] Toxicity of compound () without fasting
The test was conducted by oral administration to TFW mice (one group: 3 males and 3 females). The results are shown in the following table for the compound of formula () (R=H) and the above compound (B) as a control.

[Table] As is clear from the above results, the compound 4-(p-chlorophenyl)-2-(p-chlorophenyl) used in the present invention
-Hydroxyphenyl)thiazole-5-acetic acid has significantly lower toxicity than the corresponding 2-phenyl analogue (B). The compounds used in the present invention are manufactured in a variety of ways, for example British Patent No. 1145884 and
Examples include the method described in No. 1262292. That is, the compound () and its salt used in the present invention are produced by the following method. (a) General formula The α-haloketone represented by the general formula (In the formula, R is the same as above.) or (b) the general formula [In the formula, R is the same as above] A compound represented by the above is subjected to a dehydration reaction, or (c) a compound in the general formula () in which R is a hydrogen atom is acylated to lead to a compound in which R is an acyl group, or ( d) General formula [In the formula, R ⁴ means an alkyl or aralkyl group] The compound represented by the following is dealkylated to lead to a compound in which R in the general formula () is a hydrogen atom, or (e) a compound represented by the general formula [In the formula, R is the same as above, R ⁵ is a hydrogen atom, an alkyl or aralkyl group, provided that both R and R ⁵ are not hydrogen atoms] A mono- or di-ester represented by the following is hydrolyzed. Methods (a) and (b) above are described in British Patent Nos. 1145882 and 1262292. Acylation of the compound () (R═H) is carried out in a conventional manner using an acylating agent in which the acyl group R is in the form of an anhydride or an acyl halide (for example, chloride). Dealkylation in method (b) is carried out by a known method, for example, by treating the ether compound with hydrogen bromide, hydrogen iodide, boron tribromide, or the like. Preferred R ⁴ is alkyl having 1 to 4 carbon atoms, especially methyl. Hydrolysis of compounds of formula () is also carried out in known manner, for example by treatment with an alkali metal hydroxide followed by acidification. The pharmaceutical composition of the present invention consists of a compound of formula () or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. As pharmaceutical carriers, known carriers used in the preparation of conventional pharmaceutical compositions can be used, which are generally liquid or solid carriers, or mixtures thereof. Gaseous carriers are also used in aerosol type compositions. Solid compositions include powders, granules, tablets, capsules (such as hard and soft gelatin capsules), suppositories, and petals. As the solid carrier, for example, one or more substances are used which also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, compression aids, binders, disintegrants, etc. Also included are capsule-forming substances. In the case of powders, a finely divided carrier is used, which is mixed with the finely divided active substance. In the case of tablets, the active substance is mixed with a carrier having the desired compressibility and compressed into the desired shape and size. In powders and tablets, the active substance may be up to 99%, e.g. 0.03-99%,
It is preferably used in a blending amount of 1 to 80%. Preferred solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting wax, ion exchange resin, and the like. As used herein, the term "composition" includes encapsulations of the active substance in an encapsulation as a carrier (with or without other carriers), as well as so-called cassiers (with or without other carriers) in which the active substance is encapsulated in wafers, etc. cachets). Liquid compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs, pressurized solutions, etc., in which the active substance is present in a pharmaceutically acceptable solvent such as water, an organic solvent or a mixture thereof or a pharmaceutically acceptable oil or fat. It is prepared by dissolving or suspending it in an acceptable liquid carrier. The liquid carrier may also include other suitable pharmaceutically acceptable additives, such as solubilizers, flavorants, suspending agents, fillers, colorants, viscosity modifiers, stabilizers, osmotic pressure modifiers, and the like. sell. Examples of liquid carriers for oral or parenteral administration include water (particularly an aqueous solution containing additives such as the above-mentioned cellulose derivatives, preferably a sodium carboxymethyl cellulose solution), alcohols (monohydric alcohols, glycerin, glycols, etc.). (including alcohols) and derivatives thereof, oils (eg, fractionated coconut oil, peanut oil), and the like. Carriers for parenteral administration also include oily esters such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are also used in sterile liquid compositions for parenteral administration. Liquid carriers for pressurized solutions include halogenated hydrocarbons and other pharmaceutically acceptable propellants. Liquid compositions such as sterile solutions or suspensions are used as injections, such as intramuscular, intravenous or subcutaneous injections. Sterile solutions may also be administered intravenously. Orally effective compounds are administered orally in the form of liquid or solid compositions. Preferred pharmaceutical compositions are in unit dosage form, e.g.
tablets or capsules. In such unit dosage form, the composition is divided into unit doses containing appropriate quantities of the active component and packaged in unit dosage form. Examples include powder sachets, vials, ampoules, pre-prepared syringes, liquid-containing casseries, and the like. The unit dosage form may be, for example, an individual capsule or tablet itself, or it may be the appropriate number thereof in a packaged form.
The amount of active ingredient per unit dose varies depending on the activity of the active ingredient and individual requirements, but ranges from 0.5 mg to
Selected from the 750mg range. The present invention also encompasses formulations containing only the active compound in unit dosage form without the use of a carrier. The present invention also includes a topically applied semisolid or aerosol pharmaceutical composition consisting of the active compound () or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable topical carrier. By semisolid pharmaceutical compositions are meant ointments, creams, salves, pastes, jellies and other pharmaceutical or cosmetic compositions that can be applied to the skin. Examples of semi-solid compositions can be found in “The Theory and practice
of Industrial Pharmacy, Lachman,
Lieberman and Kanig” (Lea and Febiger
(1970)) and “Remington’s
Pharmaceutical Sciences” 15th edition (1975)
(published by Mack Publishing Co), Chapter 67. The topical composition of the present invention contains about 0.1% active ingredient.
(wt%, same below) ~ about 20%, preferably about 0.5
% (more preferably about 1%) to 10%. The carriers used in the topical compositions of the present invention are those used in the preparation of conventional topical semisolid or aerosol compositions. For example, suitable carriers for semisolid compositions include Lachman, Lieberman &
Kanig's literature and Remington's
Pharmaceutical Sciences, such as those based on oil-in-water emulsions (such as aqueous emulsions of soft and liquid paraffin)
can be mentioned. Also included are absorbent-based carriers, such as mixtures of cotton fat and soft paraffin, as well as water-miscible bases, such as high and low molecular weight polyethylene glycols. When used as a topical aerosol, a composition consisting of the active ingredient and a readily liquefiable gas is used. Such liquefiable gases are well known as propellants in the aerosol field. Examples include halogenated hydrocarbons and liquefied lower hydrocarbons (hydrocarbons having up to 6 carbon atoms). In addition to the active ingredients and carriers described above, the composition of the present invention includes antioxidants, buffers, emulsifiers, fragrances,
Other additives suitable for topical application such as preservatives, solvents, etc. may also be included. In particular, buffers may be used to adjust the PH of the composition between 4 and 5.5 (eg, 4.8) to maintain the active ingredient in the free acid form. The composition may also contain other active ingredients. Additionally, the present invention provides a method of treating inflammation in a warm-blooded non-human animal by topically applying an effective amount of the compound () to the animal. By "topical application" is meant application to the external skin surface, and the active ingredient is used in the form of a composition as described above. Next, the compounds used in the present invention will be explained in more detail with reference to Examples. Example 1 Production of 4-(4-chlorophenyl)-2-(4-hydroxyphenyl)thiazole-5-acetic acid: 4-(4-chlorophenyl)-2-(4-methoxyphenyl)thiazole-5-acetic acid 1.26g
(3.5 mmol) in ¹⁰ cm of glacial acetic acid and 48% hydrobromic acid
Reflux in 20 cm ³ of the mixture for 4 hours. After cooling, 1.03 g of crystals of the hydrobromide salt of the title compound are obtained. The crystals are collected, washed with water and ether, and dried. Melting point 239-241℃ (decomposed) Elemental analysis: C ₁₇ H ₁₂ ClNO ₃ S・HBr Calculated value (%): C, 47.8; H, 3.1; N, 3.3; Ionic bromine, 18.7 Actual value (%): C, 47.7; H, 3.1; N, 2.4; ionic bromine 19.2 Example 2 Preparation of 4-(4-chlorophenyl)-2-(4-hydroxyphenyl)thiazole-5-acetic acid: 3-bromo-3- 27 g of (4-chlorobenzoyl)propionic acid and 14.6 g of 4-hydroxythiobenzamide are heated to 80° in 50 ml of dimethylformamide. The reaction mixture is kept at the same temperature for 1 hour and, after cooling, poured onto ice. Take the resulting gummy solid and wash with water to obtain 31.6 g of powder. Melting point 184
-194 DEG C. (dec.) This is recrystallized from aqueous isopropanol to yield 25.4 g of the hemihydrate of the title compound. Melting point 192-194℃ (decomposition) Elemental analysis: C ₁₇ H ₁₂ ClNO ₃ S・1/2H ₂ O Calculated value (%): C, 57.55; H, 3.7; N, 3.9 Actual value (%): C, 57.7 ; H, 3.5; N, 3.6 Example 3 Production of 2-(4-acetoxyphenyl)-4-(4-chlorophenyl)thiazole-5-acetic acid: 4-(4-chlorophenyl)-2-(4- Hydroxyphenyl)thiazole-5-acetic acid 7.0g
(0.016mol) in 493ml of 0.1N sodium hydroxide solution
(0.372 mol) and cooled to 0°C. Add 1.5 ml (0.016 mol) of acetic anhydride to this and keep at room temperature for 3 hours. Dilute hydrochloric acid is added to the resulting solution, and the resulting precipitate is collected, washed with a small amount of water, dried, and recrystallized from methyl ethyl ketone to obtain 2.4 g of the title compound as a colorless solid. Melting point 177-180℃ Elemental analysis: C ₁₉ H ₁₄ ClNo ₄ Calculated value (%): C, 58.84; H, 3.64; N, 3.61 Actual value (%): C, 58.94; H, 3.87; N, 3.43 Example 4 Production of 4-(4-chlorophenyl)-2-(4-valeryloxyphenyl)thiazole-5-acetic acid: 4-(4-chlorophenyl)-2-(4-hydroxyphenyl)thiazole-5 -3.81g of acetic acid
(0.011mol) in 55ml of 0.2N sodium hydroxide solution
(0.027 mol) and cooled to 0°C. Add 2.0 g (0.011 mol) of valeric anhydride to this and shake vigorously for 4 minutes. Dilute hydrochloric acid is added and the resulting gum is extracted with chloroform. The chloroform layer is washed with water, separated and dried over magnesium sulfate to give a white solid. This solid was stirred in water at about 50°C for 25 minutes, filtered and dried to produce the title compound 3.68 as a colorless solid.
Take g. Melting point: 197-199℃ Elemental analysis: As C ₂₂ H ₂₀ ClNO ₄ S Calculated value (%): C, 61.46; H, 4.69; N, 3.26 Actual value (%): C, 61.16; H, 4.61; N, 3.11 Example 5 Production of 4-(4-chlorophenyl)-2-(4-hydroxyphenyl)thiazole-5-acetic acid: In the same manner as in Example 2, 3-bromo-3-(4
-chlorobenzoyl)methyl propionate and 4-
By reacting with hydroxythiobenzamide, 4
-(4-chlorophenyl)-2-(4-hydroxyphenyl)thiazole-5-methyl acetate is obtained.
Hydrolysis of this compound with 2N sodium hydroxide gives the title compound. Example 6 Production of 4-(4-chlorophenyl)-2-(4-hydroxyphenyl)thiazole-5-acetic acid: 2-(4-acetoxyphenyl)-4-(4- Hydrolysis of (chlorophenyl)thiazole-5-acetic acid with 2N sodium hydroxide gives the title compound. Example 7 Preparation of 4-(4-chlorophenyl)-2-(4-hydroxyphenyl)thiazole-5-acetic acid: 3-bromo-3-(4-chlorobenzoyl)propionic acid and an equivalent amount of 4-hydroxythio 4-(4-chlorophenyl)- by stirring benzamide in isopropyl alcohol containing sodium carbonate.
4-hydroxy-2-(4-hydroxyphenyl)
Obtain -2-thiazoline-5-acetic acid. This compound is heated and dehydrated to obtain the title compound.

Claims (1)

[Claims] 1 Formula () [In the formula, R means hydrogen or an acyl group] An anti-inflammatory pharmaceutical composition comprising a thiazole compound or a pharmaceutically acceptable salt thereof. 2. The pharmaceutical composition of item 1 above, wherein the R group is alkanoyl having 2 to 7 carbon atoms. 3. The pharmaceutical composition according to item 1 above, wherein the compound of formula () is 4-(4-chlorophenyl)-2-(4-hydroxyphenyl)thiazole-5-acetic acid or a pharmaceutically acceptable salt thereof. 4 The compound of formula () is 2-(4-acetoxyphenyl)-4-(4-chlorophenyl)thiazole-5-acetic acid or 4-(4-chlorophenyl)-2
-(4-valeryloxyphenyl)thiazole-
The pharmaceutical composition according to item 1 above, which is 5-acetic acid or a pharmaceutically acceptable salt thereof.