The way to obtain 2-substituted 4-(3-tert-butyl-4 - hydroxyphenyl)-thiazolo


(57) Abstract:

Usage: in medicine as pharmaceuticals. The inventive product 2-substituted 4-(3-tert-butyl-4-hydroxyphenyl)-thiazole f-ly I, where R1-C1-C5- alkyl; R2-H, C1-C3- alkyl, A - (CH2)nCR3R4- ; -CH=CR3-(CH2)mor-CH=N-O-(CH2); R3and R4- H, C1-C2- alkyl, n = 1 to 4; m = 0 to 3; z - tetrazol or the residue of f-crystals: -C (-0)-x, where X is hydroxyl or a residue of f-crystals: R5O or R6R7-N, where R5- alkyl, C1-C4is unsubstituted or substituted by hydroxyl, C1-C3- alkoxyl, C1-C3- alkylaminocarbonyl; R6and R7is hydrogen, C1-C6- alkyl. Reagent 1: thiazolidin. Reagent 2: diakidoy ether phosphonic acid f-crystals II (R9O)2P(=O)-CHR3-(CH2)m. Reaction Conditions: a strong Foundation. The connection structure of f-crystals I.

The invention relates to organic synthesis and concerns a method for obtaining 2-substituted 4-(3-tert-butyl-4-hydroxyphenyl)-thiazolo having a high therapeutic activity in the treatment of inflammatory, especially rheumatic diseases.

The subject of the invention is a method of obtaining new substituted thiazolo General formula

in which

R1represents a saturated linear or branched C1-C5is an alkyl group,

R2represents a hydrogen atom or an alkyl residue with 1 to 3 C-atoms,

A represents the -CH=N-O-(CH2)n-,

R3and R4the same or different and represent a hydrogen atom, or an alkyl residue with the number of C-atoms to 2 and

m is a number 0-3, and

n is a number from 1 to 4, and

Z represents a group of tetrazole or a residue of the formula


X denotes a hydroxy-group or a residue of the General formula R5O-, or R6R7N-, and R5means having a linear or branched chain, substituted if necessary by hydroxyl,1-C3-alkoxy or C1-C3-alkylamino-group1-C4is an alkyl residue, R6and R7the same or different and represent a hydrogen atom having a linear or branched chain WITH1-C6is an alkyl residue or for the case where R6means a hydrogen atom or a C1-C4is an alkyl residue, R7represents hydroxy, C1-C3-alkoxy - or tetrazol-5-yl group, or X together with the structural elements A- (C=O)- represents the residue of General formula

as well as physiologically compatible salts of these compounds.

The method according to the invention differs in that thiazolidin General formula II

is subjected to condensation with dialkylamino ether phosphonic to the-C3is an alkyl residue with obtaining compounds of General formula I

in which R1, R2, Z, R3and R5have the above significance, or thiazolidin General formula II is subjected to condensation with 3-halogenopyrimidines formula IV

together with ether phosphine or phosphoric acid in the presence of a strong base to obtain the compounds according to the invention of the formula I

and R1, R2, R8and Z have the abovementioned meanings, or thiazolidin General formula II is condensed with hydroxylamine of formula V

H2N-O-(CH2)n--X in which X and n have the specified values by obtaining the compounds according to the invention I

and, if necessary, the obtained compound of formula I is subjected to catalytic portirovaniyu.

Used as intermediate products thiazolidine General formula II can be obtained an advantageous manner by turning the corresponding 2-halo-1-phenylalaninol with dialkoxysubstituted, such as diethoxyacetate. To highlight the aldehyde is heated corresponding acetal with diluted mineral acids as hydrochloric acid or sulfuric acid.

It is preferable to obtain the compounds of formula I assetcontrol R3means a hydrogen atom or methyl and R5and R9mean ethyl residue, if known to the expert standard conditions. In the preferred embodiment, is used as a solvent dimethylformamide and as the Foundation of sodium hydride, and the reaction is carried out at the boiling point of the solvent.

The preferred embodiment of the method are also turning with 3-halogenopyrimidines formula IV, especially those in which Hal represents a bromine atom, with a phosphine, as triphenylphosphine, to the corresponding Quaternary phosphonium salts, and in the case when R8= hydrogen, to protect the free amide nitrogen compound IV pretreated azetiliruet by means such as acetic anhydride. These intermediate stage without further processing can usually turn an ordinary reaction Wittig standard ways with aldehydes of formula V. it is particularly advantageous was the heated components of the reaction in an inert solvent, especially ethanol, as ethanol or dimethylformamide, in the presence of a base as triethylamine, sodium alcoholate or potassium, sodium hydride or potassium or sodium hydroxide or potassium. The reaction is carried out is around 60-80aboutC.

Transformation with hydroxylamino General formula V are implementing best way with equimolar quantities of the components of the reaction in aqueous-alcoholic solution, but also in other inert solvents, as pyridinedimethanol and alcohols as methanol, ethanol and various propanol and butanol, and also mixtures of these solvents. While hydroxylamine derivative of the formula VIII are useful in the form of their acid additive salts, as hydrochloride, hydrobromide or sulfates. In this case, it is recommended to add at least the stoichiometric amount of acid binding agent, for example, hydroxides or carbonates of alkali metals or organic base like triethylamine. The reaction is carried out at temperatures between approximately 20aboutC and the boiling point of the solvent, preferably between 40 and 70aboutC.

Compounds according to the invention of General formula I, as they contain carboxylate group can form salts with inorganic and organic bases. Therefore, and such salts are included in the scope of the invention. Preferred salts with inorganic bases, especially physiologically not cause fear salts of alkaline metal is rmula I and their corresponding salts according to the invention on the basis of their valuable pharmacological properties, particularly suitable for use as active substances in medicinal products, especially in such tools for the treatment of inflammatory rheumatic diseases. You can appoint one or, for example, in the form of microcapsules, in mixtures with one another or in combination with suitable auxiliary substances and/or substances-carriers.

Medicines are at least of the compounds of formula I and/or at least one of their respective salts or contain at least one of these active substances together with a pharmaceutically suitable and physiologically compatible substances-carriers, diluents and/or other auxiliary substances.

Medicines on the basis of the compounds according to the invention can be used orally, rectally or, if necessary, parenteral, and prefer oral administration.

Suitable solid or liquid galenovye ready forms are, for example, granules, powders, pills, tablets, microcapsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, and preparations with delayed release of active ingredients, which used conventional AIDS such as substance-media tools e substances or agents of dissolution. As commonly used excipients should be called such. magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, and one - or polyvalent alcohols, such as glycerin.

Preferably pharmaceutical receive and administered in dosage units, with each unit as the active components contains a certain dose of at least one compound according to formula I and/or at least the corresponding salt. When the solid dosage units, tablets, capsules, coated tablets or suppositories, this dose can be approximately up to 800 mg, but preferably approximately from 100 to 500 mg.

For treatment of suffering from inflammatory rheumatic diseases of the adult patient - depending on the effectiveness of the compounds of the formula I and/or the corresponding salts - man shows daily doses of approximately 100-2000 mg of active substance, preferably 300-1100 mg, oral appointment. Under certain conditions it is possible, however, to assign a higher or lower day and repeatedly taking a smaller dosage units, as multiple doses at specific intervals.

Finally, the compounds of formula I and the corresponding salts when receiving the above-mentioned herbal preparations can be applied together with other suitable active substances, for example, animacionnymi means, inhibitors accumulation of platelets, analgesics and other steroid or nesteroidnymi anti-inflammatory drugs.

The structure of these compounds was determined by elemental analysis and infrared spectra, and spectra ofIH-nuclear magnetic resonance. Obtained in the following examples and obtained in a similar manner the compounds of formula I are summarized in table.1.

P R I m e R 1. Complex ethyl ester 3-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)- thiazol-2-yl]-acrolein acid.

11). 4-(3,5-di-tert-Butyl-4-hydroxyphenyl)-2-formilleza.

90 g (0.27 mol) of 2-bromo-1-(3,5-di-tert-butyl-4 oksifenil)-ethanol from stage A1) and 42.4 g (0.26 mol) of detoxificated was stirred in 200 ml ethanol for 30 min at room temperature. After removal of the solvent under reduced pressure the residue was treated with 200 ml of complex ethyl EF is and was dissolved to highlight the aldehyde group in 1500 ml of acetone, was mixed with 230 ml of 4 N. hydrochloric acid and was stirred 2 h at room temperature. After neutralization with the help of Na2CO3solution precipitation, which after filtering off again recrystallized from petroleum ether.

Output and 63.4 g (77% of theory)

The melting point of 99-100aboutC.

WITH18H23NO2S (mol. m 317,5).

Calculated, %: C 68,10; N 7,30; N To 4.41; S 10,10.

Found, %: C 67,86; H 7,29; N 4,35; S Becomes 9.97.

12). Complex ethyl ester 3-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-thiazol-2-yl]-acrolein acid.

In a solution of 31.7 g (0.1 mol) of the aldehyde from stage 1) and 23.3 g (0.1 mol) of a compound teeterboro ether fosfornokislye acid in 400 ml of dry dimethylformamide are introduced with stirring parts of 6.6 g (0.22 mol) of 80% sodium hydride, and the reaction temperature support through the cooling water is below the 30aboutC. After 3 hours stirring at room temperature and after the addition of 375 ml 4 N. sulfuric acid is extracted several times complex ethyl ester of acetic acid. United ether phases are extracted by shaking 2 times respectively with 300 ml of a saturated solution of NaHCO3, washed with water, dried over sulfate LASS="ptx2">

The output of 33.3 g (86% of theory).

The melting point of 126-127aboutC.

C22H29NO3S (mol. m 387,5).

Calculated, %: M 68,18; N Rate Of 7.54; N 3,61; S 8,27.

Found, %: C 67,87; N 7,66; N 3,59; S 8,31.

P R I m e R 2. 3-[4-(3,5-di-tert-Butyl-4-hydroxyphenyl)-thiazol-2-yl-methylidene]- pyrrolidin-2-it.

16.0 g (91 mol) 3-bromperidol-2-it was heated in 30 ml of acetic anhydride for 1 h to a boil. After evaporation of the reaction mixture under reduced pressure to dryness the residue was dissolved in 50 ml of tetrahydrofuran and after the addition to 26.2 g (0.1 mol) of triphenylphosphine was heated for 5 h with the phlegm. Then again the danger, the residue was dissolved in 300 ml of ethanol and mixed with 24,7 (78 mol) of the aldehyde from example 2 b1) and 27 ml (0.26 mol) of triethylamine. After 2 hours of heating the mixture to 70aboutWith the yellow precipitate was filtered and washed with ethanol. Dissolved mass of crystals and mother liquor in approximately 2 l of chloroform, washed several times with saturated sodium chloride solution, dried over Na2SO4and the day, the chloroform phase up to a third. In case of prolonged exposure of deposited yellow crystals.

The output of 24.7 g (81% of theory).

The melting point 244-245aboutC.

P R I m e R 3. 2-[4-(3,5-Di-tert-Butyl-4-hydroxyphenyl) -thiazol-2-yl-methylidene)-aminooxy]-acetic acid.

To a solution of 15.9 g (0.05 mol) of the aldehyde from example 11) in 200 ml of methanol is instilled at the same time with stirring, a solution of 6.4 g (0.05 mol) of karboksimetoksimetilguanina in 20 ml of water and 2 g (0.05 mol of sodium hydroxide in 200 ml of water. After further 1,5-hour stirring at 50aboutWith methanol largely distilled off in vacuo, and the residue is repeatedly extracted with complex ethyl ester of acetic acid. The United extracts washed with water, dried over Na2SO4, and evaporated in vacuum. Oily residue after treatment with petroleum ether (40-60about(C) becomes crystalline.

The output of 13.8 g (71% of theory).

The melting point 178-180aboutC.

WITH20H26N2O4S (mol. m 390,5).

Calculated, %: 61,52; N. Of 6.71; N 7,17; S 8,21.

Found, %: C 61,44; N 6,85; N Of 6.96; S 8,02.

P R I m e R 4. 2-[4-di-tert-Butyl-4-hydroxyphenyl)-thiazol-2-yl)methoxy] -2-methylprop - peony acid.

41). 4-(3,5-di-tert-Butyl-4-hydroxyphenyl)-2-hydroxymethylimidazole.

117,8 g (0.36 mol) of 2-bromo-1-(3,5-di-tert-butyl-at room temperature. The resulting crystals are filtered and washed with a small amount of ethanol. For removal of hydroxy-group 139,4 g selected benzilovogo ester (melting point 198-199aboutWith as hydrobromide) absorb in 600 ml of ethanol, mixed with 45.6 g (0.69 mol) of 85% potassium hydroxide in 30 ml of water and additionally stirred for half an hour at room temperature. After that, the mixture was concentrated, mixed with water and repeatedly extracted with acetic ether. The United extracts after drying over Na2SO4mixed with hydrochloric acid in ethanol, and ethanol precipitated in the form of hydrochloride.

The output of 78.6 g (65% of theory).

The melting point of 185-186about(As hydrochloride).

WITH18H26ClNO2S (mol. m 355,9).

Calculated, %: C 60,74; N. Of 7.36; Cl 9,96; N 3,94; S 9,01.

Found, %: C 60,49; N 7,56; CL Of 10.05; N Of 6.96; S 9,05.

42). 2-[4-(3,5-di-tert-Butyl-4-hydroxyphenyl)-thiazol-2-yl-methoxy]-2-methylpropan vacillate.

9.6 g (0,031 mol) of the alcohol stage 41in free base form is mixed with 6.0 g (0.15 mol) of powdered sodium hydroxide in 44 ml of acetone and heated suspension to phlegmy. Then buried 4.8 g (0.04 mol) of chloroform in 10 ml of acetone and settled between simple diisopropyl ether and water. The organic phase is separated, and the aqueous phase after the secondary simple extraction with ether, acidified with concentrated hydrochloric acid to pH 2 and several times extracted with methylene chloride. The United extracts methylene chloride is dried, filtered and concentrated. The residue is purified by chromatography on a column of silica gel (90-130), solvent: methylene chloride:methanol (50:1), with a small amount of petroleum ether (40-60about(C) is brought to crystallization.

Yield 3.1 g (26% of theory).

The melting point of 158-159aboutC.

WITH22H31NO4S (mol. m 405,6).

Calculated, %: C 65,16; N. Of 7.70; N 3,45; S To $ 7.91.

Found, %: C 65, 03; N 7,89; N 3,37; S 7,81.

P R I m e R 5. 3-[4-(3,5-di-tert-Butyl-4-hydroxyphenyl)-thiazol-2-yl]-propionamido - xnova acid.

In a solution of 6.7 g (to 18.6 mmol of 3-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-thiazol-2-yl] -propionic acid in 250 ml of methylene chloride added at 0aboutWith the first 1.4 g of dimethylformamide, then with 5.2 g (42 mmol) of oxalic acid dichloride and stirred for 1 H. With the instillation of a solution of 7.7 g (111 mmol) of hydroxylamine-hydrochloride in 65 ml of tetrahydrofuran and 13 ml of water and 11.2 g (111 mmol) of triethylamine raise the reaction temperature to 30about3and NaCl, dried over Na2SO4and concentrated in vacuum. After addition of petroleum ether (40-60about(C) the residue solidifies.

Yield 3.8 g (55% of theory).

The melting point 182-183aboutC.

C20H28N2O3S (mol. m USD 376.6).

Calculated, %: C 63,80; N 7,50; N 7,44; S Charged 8.52.

Found, %: C 63,95; N To 7.61; N 7,42; S 8,63.

The compounds of formula are given in table.1.

Pharmacological tests

The test compounds according to the invention of the formula I on the anti-inflammatory effect, the influence of immunopathological processes, decontamination oxygen radicals properties and the effect of arachidonic acid metabolism produced in the following models and bioassays.

Rheumatoid arthritis to determine the effect of anti-inflammatory action (see tab.2).

Studies were performed according to the method of Pearson (Arthrit. Rheum. 1959, 2, 44). As experimental animals served male rats of Wistar strain-Lewis c weighing between 130 and 200 G. of the Test compound was administered in doses of 50 mg per 1 kg of body weight once a day from the 1st to the first drug. Each specimen and control group consisted of 8 animals. As a criterion of validity was a decrease in the percent increase of the legs compared with the untreated control group. Values U50was determined graphically from the curve of action dose.

As a comparative drug in this and the following study included 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthiazole - i.e., the compound of the formula

CH for U.S. patent 4535165.

Anti-inflammatory effect on the 5th day.

Braking immunopathological processes.

It is generally accepted that the progressive course of inflammatory rheumatic diseases is caused, mainly, immune system disorders, therefore, more causal therapy can succeed only with such medications that suppress these immunopathological processes.

a). Rheumatoid arthritis (option Perper).

Described in paragraph 1 of the experiment, animals were treated only with 1-th to 12-th experimental day. After-free treatment interval of 9 days is the volume of the left and right hind paws on the 21st day (see tab. 3). In this test classic nesteroidnyi against the technical inflammatory phase immunopathological processes. Then, the results clearly demonstrate the superiority of the compounds according to the invention of the formula before comparative drug from the U.S. patent 4535165, which in the modification Perper rheumatoid arthritis shows only nameeeee action.

b). Reversible passive Arthus reaction.

As experimental animals served Sprague-Dawley-rats male weighing between 100 and 120 g, which were divided into groups respectively for 8 animals. Animals were given 1 h after oral purpose of the test substance 0.5 mg of antibody in 0.1 ml of sodium chloride solution under a sole injection into the left hind paw. After 4 h was measured reaction Artus court, and as the measuring action parameter was the change in percent increase paws compared with the control group, which received only neutral, the basis of the medicinal product.

According to the table.4, for example, the following compounds according to the invention are distinguished as strong inhibitors of the reaction of the market.

3. Action as a trap radicals and inhibitors of arachidonic acid metabolism.

a). The properties of the trap radicals.

Test in this test, which can Ohm the reaction of the compounds according to the invention with a stable radical 1,1-diphenyl-2-picryl-Hydrosila (DRRN) observed at 20aboutWith using optics. The rate constant and reaction orders n were defined in the table.5 graphically in the usual way.

b). The arachidonic acid metabolism.

The inhibitory effect of the compounds according to the invention on catalyzed by cyclooxygenase and lipoxygenase the cleavage of arachidonic acid in vitro was measured by means described in Weithmann and Alpermann, Arzneim.-Forsch. 1985, 35, 947 test systems:

In microsomal system cyclo-oxygenase (fraction from sheep seminal vesicles, the firm Paesel, Frankfurt, Germany) measured catalyzed by cyclooxygenase prostaglandin synthesis from arachidonic acid. The coenzyme is the adrenaline, the transformation of which adrenochrome see at 492 nm with a spectral photometer. In the system of lipoxygenase in vitro incubated CIS-9-CIS-12-linoleic acid with lipoxygenases (L 7127, the company Sigma, Deisenhofen, Germany) and trace at 234 nm using optics occurring during the oxidation of the formation of conjugated double bonds.

Inhibitory effect or required for 50% inhibition of enzyme activity concentrations of inhibitor (IC50-values) were determined for the following examples of the invention:

Lipoxygenase (enzyme)

Collagenase (microsome assay)

Example 7: at 100 mmol: 65% inhibition.

Example 8: in 100 mmol: 75% inhibition.

Example 16: IC50: = 34 mmol.

In addition, the substances according to the invention as inhibitors of metabolites of arachidonic acid were also characterized at the cellular systems of leukocytes in vitro. For detection of lipoxygenase metabolites were incubated stimulated calcium-ionophores And 23187 (70 Ámol/l) neutrophils14C-arachidonic acid (81 Ámol/l) and quantify formed after 15 min at 37aboutWith the main metabolites such as 5-hydroxyacetone acid with four unsaturated bonds (5-NET) and have more anti-inflammatory action leukotrien4(LTB4), after separation by HPLC method using regiomontana (PL.6). Accordingly determined the effect on anti-inflammatory metabolites of arachidonic acid and thromboxane LTB4made with fat cells of rats cultures (table.7).

The effect of the compounds according to examples 5 and 6 on the activity of LTB4- or 5-NET formation in human neutrophils (n is the number of dimensions).

The effect of different concentrations of connections on p is 2-SUBSTITUTED 4-(3-TERT-BUTYL-4-HYDROXYPHENYL)-THIAZOLO General formula I

< / BR>
where R1- saturated linear or branched C1- C5is an alkyl group;

R2is hydrogen or C1- C3is an alkyl residue;

A - intermediate chain of General formula


where R3and R4- same or different, hydrogen or alkyl residue with the number of carbon atoms up to 2;

n = 1-4;

m = 0 - 3;

Z - tetrazol or the residue of General formula


where X is a hydroxy-group, or a residue of the General formula R5O - or R6R7N - , and R5- linear or branched, unsubstituted or substituted by hydroxyl, C1- C3- alkoxyl or C1- C3- alkylaminocarbonyl C1- C4-alkyl;

R6and R7- same or different, hydrogen, a linear or branched C1- C6- alkyl residue, or for the case where R6is hydrogen or C1- C4is an alkyl residue, R7is hydroxy, C1- C3- alkoxy or tetrazol-5-yl group, or X with the structural elements - And - (C=O) represents a residue of the formula

< / BR>
and the physiologically compatible salts of the compounds of General formula I, where X is hydroxy or gidroksilaminopurina,

distinguishing the th acid of General formula III


where R9- C1- C3is an alkyl residue,

obtaining compounds of General formula I

< / BR>
where R1, R2, R3And Z have the above values,

or 3-halogenopyrimidines General formula IV

< / BR>
together with ether phosphine or phosphoric acid in the presence of a strong base to obtain the compounds of General formula I

< / BR>
where Z, R1, R2have the specified values;

R8is hydrogen,

or with hydroxylamine of the General formula V


where X and n have the specified values,

obtaining compounds of General formula I

< / BR>
if necessary, the resulting compounds of General formula I is subjected to catalytic hydrogenation.


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9 cl, 5 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex