CS222694B2 - Method of making the thiazole derivatives - Google Patents

Abstract

Thiazoles of formula <IMAGE> and salts thereof, wherein R represents hydrogen or an acyl group, possess anti-inflammatory activity and have low toxicity. The compounds may be formulated as pharmaceutical compositions.

Description

* R ^{2 are} identical or cutting-alkyleneoxy means subs-substituted aryl or bsteroar ^ ZBY memory ^area and

R ³ represents rtLžáí jlifatiskou kartoxylovou mineral water of 2-6 carbon atoms not ^b corresponding salt, ester, AMD ntril or derivative thereof with a hydroxamic acid residue is Vasan on the thiazole ring by a carbon atom of its aliphatic chain and L addition · salts of these compounds acids.

According to British Patent No. 1,145,884 maa ± a compound of formula (A) in particular an anti-inflammatory effect. Examples of R ¹ and R * may be. is phenyl, optionally substituted by halogen, lower alkyl, lower alkoxy, nitro, amino, amino substituted, COOH, COOH, COOH, COOH, or trihaloethyl.

The anti-inflammatory effect of specific compounds of formula A against carrageenin-induced swelling of the hind leg of a rat is described in Brown et al., Jovurnal of Meeicinal ChernmiSry, 1974, Vol. 17, No. 11, pp. 1,177 to 1,111. 'When exploring. It was shown that the anti-inflammatory activity was greatest when the substituent ^R is 4-chlorophenyl. Preferred R ¹ and the ^phenyl subssituce of the ring in the 4-position plagued antiinflammatory effect. This means that subssituce methoxy and carboxy at position 4 substantially reduce the efficacy of the 'if subssituent ^R2 is ^{N-chlorphenyl} l.

It has now been shown to have a remarkable anti-inflammatory effect especially when administered topically. have some acid thiazol-5-acetic acids which are not specifically mentioned in the formula A in which R ^1, A tonylový ztytek substituted in the ^fourth Meanwhile, this thiazole-5-carboxylic acid group has low toxicity.

The invention relates to a process for the preparation of compounds of the formula I

(I) where

R represents a hydrogen atom or an acyl group, for example an alkanoyl group having 2 to 7 carbon atoms, preferably 2 to 7 carbon atoms, and salts thereof.

The meaning of R may be acetic, propionic, butyric, isobutyric, valeric or isovaleric.

The compounds of formula I form salts, for example acid addition salts such as hydrochloric and hydrobromic acid, or salts with alkali metal hydroxides such as sodium or potassium or alkaline earth metals such as calcium salts. These salts are prepared in a known manner.

The compounds of formula (I) have been investigated for their anti-inflammatory activity as described in Tenneii et al., Endocrinology ££, 62- (1965):

Female rats in groups of 10, Sprlgue-Dowldy strain of 60 to 70 gm were used. Ear swelling was induced by injection into both ears, and an irritant mixture consisting of 1. Croton oil, 20% pyridine, -% water and 74% Heteroethar, in control rats, only this blend without active ingredient was used. The tulle mixture is applied only once and only to the right ear. After 6 hours, the animals were sacrificed and a 9 mm diameter portion of the ear was removed and weighed. The anti-inflammatory effect of the test compound was expressed as the percentage of the mean potency increase in the ear of the control group and the ear of the group treated with the test compound. The relation can be expressed by the following equation:

(mean increase in hmmonooti (mean increase in mass vs. test staupin) ~ controls)% inhibition = 100 x -1 - ¹ ......> ^{1 11} (mean increase in mass in controls)

The results for some of the compounds of formula I are shown in the following table, together with the results of 3 experiments for the preferred compound of Brown et al. In J. Med. Chem. as cited above, in particular for 4- (p-chlorophenyl) -2-phenylthiazole-5-acetic acid (B):

Compound of Formula I

Dose% inhibition

R = H 50 16% 500 jug 33% 2.5 mg 86% 5 mg 92% R ₃ = COCH 50 <µg -14% 500 yug 41% 2.5 mg 85% 5 mg 100% R = COC ₄ H ₉ 50 pg 41% 500 jag 54% 2 »5 mg 71% Cl \ __ 5 mg 87% V - / CH ₂ COOH 50 pg -30,15 -7% \ = / N S 500 / µg 10, 35.52% Y Ph 2.5 mg 93.79, 89% (B) 5 mg 92, 93, 93 S.

All compounds have expressed anti-inflammatory activity of approximately the same order.

Toxicity of the compounds of Formula I was measured by oral administration to groups of 3 male and 3 female TFW strains under normal administration at various doses. The results obtained for a compound of formula I in which R represents a hydrogen atom and for a compound V as described in J. Med. Chem. are listed in the following table:

Number of deaths (hours after treatment) Dose mg / kg Formula I (B = H) Formula В 24 hours 5 dral 24 hours 7 days 450 0 0 2 3 675 1 1 3 6 1 012,5 1 1 3 6 1 518.8 1 1 2 4 2 278.1 0 0 3 3 3 417.2 0 0 5 6

These results indicate that 4- (p-chlorophenyl) -2- (p-hydroxyphenyl) thlazole-5-acetic acid is substantially less toxic than the corresponding 2-phenylanalogene in B.

The process for preparing a compound, vuorce I or salts jejich'adičních «acid consists in that reacting an alpha-haloketone of general vuorce II ^p - ^{c f} e ^ny hlo ^rl-CC-5 ClCH ² CCCB (II) hal where hal denotes a halogen atom and

B ⁹ unamené t <m in ^ 3 to alkyl of not ^b 'aralalkyl with thimidem general vuorce III

where.

^r6 unamené atom · hydrogens alkanol ^y nominal group having 2 and ^Z 7 atomec ^h carbons alk ^y l ^OR ζγζΙ ^ Ι ^p MCEM ^f VP ^ p ^ that ^B ® in the end product unamené alkyl or zrzlkyl ^p rovádí the dealk ^y lace ua vuniku compounds wherein ^R unamená 'H? v ^ p ^ that b ⁹ unamen ^alkyl no ^b of ζ ^ Ι ^! ^ is performed hyhnlýua ua vuniku composite in which b ⁹ unamen ^é hydrogen atom and ^p opřípadě a compound of vuorce I wherein B is a hydrogen atom acylated in the ammonia of a compound of formula I, wherein B is a C 2 -C 7 alkanoyl group and optionally a salt of the compound of formula I is further formed.

The process according to the invention is described in detail in British Patent No. 1,145,882.

The acylation of compounds of formula (I) in which B is hydrogen may be carried out by standard procedures in the post-treatment of the acyl group B-containing acylating agent, for example anhydride or halide, for example acid chloride.

Methods K for <^ r ^: s dealkylation are uésadně unémy, proceed nappíklad so that the ether ^yp of ^{OBI bromide,} iodine-Kem no ^{b b} r ^b oritým perfluorooctyl bromide. B® unamen ^E výtodou Altos! of from 1 to 4 carbon atoms, in particular methyl.

The resulting esters can be reacted in a suitable manner, for example by using an alkali metal hydroxide and acidifying.

The compounds of formula (I) may be formulated into a pharmaceutical composition which comprises as an active ingredient a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutical carrier. Any conventional carrier may be used. In the pharmaceutical composition obv regards ^Y, E o, solid or liquid carrier or mixture of solid or liquid carrier, · in some type of aerosol formulations can be a carrier gas.

The solid compositions encapsulate granular powders, tablets, capsules, for example in hard or soft gelatin, suppositories, and vaginal globules. The solid carrier may be one or more drugs, which may also act as flavorants, glidants, or infusions, fillers, compression molding agents, sticky flights, or pellets to facilitate the tablet. It may also be a covering or packaging material. In the case of powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier which is miscible in suitable proportions to the shape and size desired. Preferably, the precipitates and tablets comprise up to 99%

0.03 to 99%, preferably 1 to 80%, of the active ingredient. Suitable solid carriers are, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, deetrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.

The term composition includes the active ingredient together with the carrier and the coating, for example, to form the capsule in which the active ingredient, with or without the carrier, is provided with and associated with the carrier. The same is true of wafers.

Liquid formulations include, for example, emulsions, suspensions, solutions, syrups, elixirs with pressurized formulations. For example, the active ingredient is dissolved or suspended in a pharmaceutical liquid carrier, for example, water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain suitable additives, for example, solubilizers, emulsifiers, purifiers. preservatives stedidl ^ ohm ^LE tk ^{y P j} and j om ^m or occurrence SLI ^{p tnze,} a thickener, dyes, viscosity refliláMy, stabilizers regulators osamoického pressure. Suitable examples of liquid carriers for both oral and parenteral administration may be water, in particular containing the aforementioned additives, for example cellulose derivatives, preferably sodium crioxymethylcellulose sodium solution, alcohols, both polyhydric and polyhydric alcohols, for example glycerin with glycols with derivatives thereof. oils, for example, fractionated coconut oil with peanut oil. For enteral administration, the carrier can also be an aliphatic acid ester, for example, ethyl acetate with an ester. Sterile liquid carriers are used in the case of sterile liquid formulations for parennial administration. The liquid carrier for the pressurized compositions may be a halogenated hydrocarbon or other pharmaceutically acceptable carrier gas.

Liquid pharmaceutical compositions, for example, sterile solutions or suspensions, may be used for titrated, oral or subcutaneous injection. Sterile solutions may also be administered intravenously. If the compound has oral activity, it may be a cell in the form of a liquid or solid pharmaceutical composition.

Preferably, the pharmaceutical composition has the form of a monohydrate; dosage forms, for example tablets or capsules. In these forms, the foregoing is divided into single doses which contain the respective emissive active ingredients. This can be accomplished in various ways, such as powders, vials, ampoules, pre-filled syringes or plastic bags containing ksppiny. The capsule or tablet may contain a single dose, or multiple tablets may be taken at a time. The minor active ingredient in a unit dosage form can range from 0.5 to 750 mg or more as needed, with the active ingredient being at a distance. The invention also encompasses compositions in which the active ingredient is presented as a single dose without the carrier.

The invention also encompasses semi-solid or aerosol pharmaceutical compositions for administration by a compound of formula (I) or a salt thereof, in conjunction with a pharmaceutical carrier suitable for topical administration.

By a polysilicillating agent is meant a lotion, cream, ointment, paste, jelly or any other pharmaceutical or coimetic agent of similar consistency suitable for application to the skin. Examples of semi-solid formulations may be the dosage forms listed in Chapter 17 of The Theory of Sinds by Phrrmacy, Lschmsn, Li ebermanand Kanng, published by Les Snd Febiger (1970) in Chapter 67 of Reemi-tats PhaarnaacuUcal Sciences, 15th edition ( 1975), published by Mack PrUishing Comppny.

The topical formulation preferably contains 0.1 to 20 µmol of active ingredient. It may contain, for example, 0.5 to 10% by weight of active ingredient.

The carrier for topical formulations may be any carrier suitable for the manufacture of semi-solid. topical formulations or aerosol formulations for topical administration. Examples of suitable carriers for semi-solid formulations are listed in the above-mentioned publications of Lachman, HLeberaan and Kariga and in Chapter 67 of Remington ' s Pharmaceutical Sciences.

The carrier for the semi-solid composition may be, for example, a H 2 in-water emulsion, for example a soft and liquid paraffin in water. The carrier may also be an absorbent, for example a mixture of wool oil and soft paraffin. A third group of suitable carriers are water-miscible substances, for example mixtures of high and low molecular weight polyethylene.

When the composition is an aerosol for topical administration, the composition typically contains the active ingredient and a readily liquefied gas. Examples of readily liquefied gases are halogenated hydrocarbons and liquefied lower hydrocarbons, which are commonly used as propellants for all types of aerosols. A lower hydrocarbon is considered to contain a hydrocarbon having up to 6 carbon atoms.

In addition to the active ingredient and the carrier, the composition according to the invention may also contain other components, for example, antloxidizing agents, surfactants, emulsions, emulsifiers. perfumes, preservatives and solvents which contribute ^ p ^{^,} ^ i ^ A: i vll8inostei the product, as is required in the case of local administration.

In particular, pH-adjusting buffers can be used, for example in the range of 4 to 5.5, for example 4.8, so that the active ingredient can be kept in the free acid form. The composition may also contain other active ingredients.

By the use of the active ingredient formulations according to the invention, inflammations in warm-blooded animals can be treated by topically administering a plurality of compounds of the formula I which have an anti-inflammatory effect. Topical administration means administration to the external surface of the skin. In particular, the active ingredient may be administered in the form of any of the aforementioned topical fumacetic agents for topical administration.

The invention will be illustrated by the following! examples.

Example 1

4- (4-Chlorophenyl) -2- ( ^4- hydroxyphenyl) thaazole

4- (Chlorophenyl) -2 - (- methoxyphenyl) -1-thiazole-5-acetic acid in 1.26 g (3.5 µmol) was heated to reflux in a mixture of 10 ml of glacial acetic acid and 20 ml of ethyl acetate. mL of hydrobromic acid having a 48% yield for 4 hours. After cooling in 1 ml of the title compound, 1.03 g of the hydrobromide of the title compound is obtained. Crystals of ^ C ^ face the, ^ ^ ί αη with water and ether and dried Nu ^ ^d of results obtained product has a temperature ^Ta of the ² and 39 ^{out of 241} DEG ^C. with decomposition. · * '

N, 3.3%. N, Boom ions 18.7% * _9. Found: 47.7. SC, 31.1% H, 2.4% N. 19.2 S.

Example 2

4- (4-Chlorophoyl) -2- (4-hydroxyphenyl) thiazol-5-acetic acid 3-bromo-3- (4-chlorobenzoyl) propionic acid and 14.6 g of 4-hydroxythlobenzamide are formed at ⁸⁰ DEG. ^C in ⁵⁰ ml Ηοο ^^ οοιιοΙ ^. The reaction mixture is kept at this temperature for one hour and then cooled. poured into crushed ice. Pryžovvtý resultant product solidified, collected by filtration, this swill give ^F of i ^ Square 3 ^{1, 6 g of} the powder of tepLlt ^l Tani ¹⁸⁴ and ^{from 194} ° C .For moods.

This powder was allowed překrystalovet from water and isopropanol to afford 250 ^g · hemihydrate Xátky result, a temperature reading 19 ² to 19 ⁴ ° C with decomposition.

Analysis for C ^ HH ^ClNCl -S. H, 3.7; N, 3.9;

found: 57.7 ® C, 3.5% H, 3.6 ·% N.

Example · 3

2- (4-Acetoxyphenyl) -4- (4-chlorophenyl) thiazole-5-acetic acid

7.0 g (0.016 mol) of 4- (4-chlorophenyl) -2- (4-hydroxyphenyl) thiazole-5-acetic acid was extended ^beta results in 493 i ^(0, 3 mo ^{72 a) Copper} hydroxide with ^H oo ^{to a} concentration of ^0.1 N and cooled to 0 ° C. Acetic anhydride (1.5 ml, 0.016 mol) was added and the mixture was allowed to stand for 3 hours at room temperature. To the solution was added dilute hydrochloric acid, the resulting precipitate was oddiltiuje, washed with a small mnoostvím water, dried and recrystallized from meetletylketonu, ^No. COMES ^z is from ^I com ^and a ^colorless, solid léitka ^2.4 g výsletoé ^substances yo temperature reading ⁷⁷ to I ¹⁸⁰ ° C.

H, 3.64; N, 3.61. Found: C, 58.84; H, 3.64;

Found: 58.94 ® C · 3.87% H · 3.43% N.

Example 4

4- (4-Chloroenyl) -2- (4-valeryloxyphenyl) thiazole-5-ocoic acid

3.81 g (0.011 moo) of 4- (4-chloroethyl) -2- (4-hydroxyethyl) thiazole-5-acetic acid are dissolved in 55 ml (0.027 mm &lt; -1 &gt;) of sodium hydroxide with an end of 0.30 g. 2 N and cooled to 0 ° C. Then 2.0 g (0.011 mmol) of valeric anhydride was added and the reaction flask was vigorously shaken for 4 minutes. Dilute hydrochloric acid was then added and the resulting gummy product was extracted with chloroform. The chlorine opium was washed with water, separated, dried over magnesium sulfate to give a white solid.

1/4 hour with water at 50 ° C, then the mixture zfiltuije the solid-TX JSDI to give 3.68 g title product as a colorless solid diacrylate> and a temperature reading ¹⁹⁷ to ¹⁹⁹ ° C

Analysis for C22H2QC1NO4S:

calculated: % C, 61.46;% H, 4.69;% N, 3.26; found: C, 61.16; 4.61. «H, 3.11« N.

Example 5

4- (4R, 4R, 4R) -2- (4-Hydrosyl-ethyl) -thiazole-5-ocoic acid

The procedure is analogous to Example 2, but reacting methyl-3-brsyl-3- (4-chlorobenzoyl) prostate and 4-hydroxythioblnazide to give methyl-4- (4-chloroethyl) -2- (4-chloroethyl) -sulfonate. (1-methoxyphentyl) thiazole-5-acetate. The Tatb compound is hydrolyzed with 2 N sodium hydroxide to give the above product.

Example 6

4- (4-Sulfonylpentyl) -2- (4-hydrosylethyl) thiazole-5-acetic acid

2- (4-acetoxyphenyl) -4- (4-chlorophenyl) -thiazole-5- ₀ -acetic prepared according to Example 3 is hydrolyzed with 2 N sodium hydroxide, 'to give present title product.

Claims (4)

SUBJECT. OF THE INVENTION (I) wherein R is hydrogen or alkanoyl of 2 to 7 carbon atoms and 'sooi these compounds, characterized' in that reacting alpha-haoogenketon formula II ^p - ^c hlorf ^{у пу1-С0-СНСН} ₂ С00й ⁵ (II) Even ha) wherein Hal represents • halooenu and R5 'is hydrogen, alkyl or alrylalkyl with th.i oiamidem of the formula wherein is hydrogen atoanoytovou group having ^{2-7 h} atomec Uhl ^Cart with alkyl or 1 ^^ ^ ^ wherein in 'case an ^R ® wants to transfer the product is alkyl of not ^b ^ ^^ βΐ dealkylation is carried out to give compound e ^{N] y} Lyy ⁱⁿ which ^R represents ^a hydrogen leading and in case an ^R · ⁵ represents ^and alkyl or is hydrolyzed to form a compound wherein R is hydrogen and optionally a compound of formula I wherein R is hydrogen is acylated to form a compound of formula I wherein R is C 2 -C 7 alkanoyl and optionally forming a salt of a compound of formula (I). 2. Method of claim 1, vyznaačujczí \ in that a product of the formula II in which Hal is chlorine or bromine and R ⁵ has the abovementioned meaning. 3. The method according to claim 1 or 2, vyznaačJící by 'employing the compound of formula ^III _f vn ^IZ R are alkyl of ^{1 and} 4 ^h atomec uhHku. 4. The process of claim 1, wherein 3-O-3- (4-chlorophenyl) propionic acid is reacted with 4-hydroxythioenamide to give 4- (4-chlorophenyl) -2- (3-hydroxyl) acid. .beta.-thiazole-4-acetic.