Derivatives of substituted 4-phenylthiazole, the method of production thereof and pharmaceutical composition based on them

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds with antithrombotic activity. Disclosed are derivatives of substituted 4-phenylthiazole formula I, where the values of R1, A, R, are presented in the description, or their salts, as well as the method of production thereof and pharmaceutical composition thereof. New compounds and pharmaceutical composition are effective inhibitors of the aggregation of blood clots, in particular, are antagonists of the receptor GP IIb/IIIA. 4 C. and 10 C.p. f-crystals, 4 PL.

The invention relates to new derivatives of 2-amino-4-phenylthiazole and their salts, and method of production thereof and to pharmaceutical compositions based on them.

Compounds of the present invention differ from known derivatives of 1,3-thiazole its chemical structure and pharmacological properties. Thus, the compounds according to the invention have an affinity for the receptor fibrinogen complex of glycoprotein IIb/IIIa (GP IIb/IIIa); more specifically an object of the present invention is a new platelet aggregation inhibitors, receptor antagonists of GP IIb/IIIa ones patterns, active in parenteral and oral administration.

The influence of platelets on these pathological processes depends on their ability to form aggregates or clumps of platelets, in particular, on the walls of the arteries damaged by rupture of atheromatous plaques.

It is known that platelets play an essential role in maintaining homeostasis and in the pathogenesis of arterial thrombosis. It has been shown that activation of platelets, increasing during coronary thrombolyse, may affect reperfusion and cause re-blockage of arteries.

Clinical studies conducted with aspirin and ticlopidine showed that inhibition of aggregation, thrombosis is at risk groups.

Platelets are activated by a large number of agonists, as a result appear modified their form, and modification of the secretion of the contents of the granules and aggregation. Aggregation of platelets leads to the formation of clots.

Identified several endogenous agonists, such as adenosine-5-diphosphate (ADP), serotonin, arachidonic acid, platelet activating factor (FOP), epinephrine, thrombin or collagen.

Given that several endogenous agonists affect the activation of the function of platelets and their aggregation, the inhibitor, which would act against all agonists, would be a more effective protivotrevozhny agent than currently available drugs, which are products of acting specifically against a particular agonist.

Currently used agents against platelet aggregation are active only against one type of agonist. For example, aspirin is active against arachidonic acid, ticlopidine active against ADP inhibitors of thromboxane A2synthetase or antagonists of the receptor thromboxane A2or hirudin action is no activation of the membrane complex of Glycoproteins GP IIb/IIIa, which captures circulating fibrinogen by formation of a bridge between multiple platelets and, therefore, leads to platelet aggregation. In the last academic journals published interesting data in respect of substances which are antagonists of GP IIb/IIIa, for example, Drugs of the Fulure, 1994, 19/2/, 135-159; or 19/5/, 461-476 or even 19/8/, 757-764.

Glycoprotein Gp IIb/IIIa unstimulated platelets is not associated with soluble proteins. Conversely, it is known that GP IIb/IIIa on activated platelets bound with adhesive proteins such as fibrinogen, factor von Willebrand, fibronectin or vitronectin. The binding of fibrinogen and factor a background of Villebranda with GP IIb/IIIa causes platelet aggregation. The binding of fibrinogen is partly recognized by the sequence Atg-Gly-ASp (RGD), the total for adhesive proteins, which are fixed on the GP IIb/IIIa (Thromb. Res. 199, 72, 231-245).

Antagonists of GP IIb/IIIa became the object of patent applications, such as the European patent application EP-608858, EP-542363, EP-539343, EP-478363, EP-623595, international application WO 94/22910, and over the last few years were described antithrombotic properties inhibitors GP IIb/IIIa (see Drugs of the Future, above). Among the studied compounds monokrome, in N. Engl., J. Med., 1994, 330, 956-961. The results show that these products are of particular interest for the prevention of thrombosis and its complications. This product requires intravenous administration. However, among the studied today inhibitors GP IIb/IIIa some apparently have activity in oral introduction. This refers to such compounds as SC 54684, Z703-014, GR 144053, DMP 728 or BIBU - 104 (Zablocki, J. A. et al., Exp. Gpin Snvest Drugs., 1994, 3, 5, 449-455).

Therefore, the development of antagonists of GP IIb/IIIa, active in oral introduction, is a new and promising direction for the treatment of pathologies dependent platelet aggregation.

The objective of the invention is to satisfy the need for antiplatelet agent platelets that are specific to the GP IIb/IIIa, which inhibited the activation and platelet aggregation, regardless of the type of agonist that caused it, and would be active in oral introduction.

In addition, such an inhibitor should have a more efficient therapeutic properties than specific antagonists, known at the present time.

Thus, the present invention relates to the derivatives of thiazole, which are antagonists of complainti individually or in combination with other antithrombotic agents, such as anticoagulants and/or thrombolytics for the treatment of thromboembolic diseases and any pathologies that depend on them.

The present invention also refers to pharmaceutical compositions that contain at least one compound according to the invention and anticoagulants, such as warfarin, heparin, biopeptide, hirudin or argatroban, or antiagregant platelets such as aspirin, ticlopidine, or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or a mixture of these agents.

These compositions can be used for inhibition of platelet aggregation and thromboembolic disorders.

Compounds according to the present invention correspond to the following formula:

< / BR>
in which

R1is hydrogen, C1-C5-alkyl, C3-C6-cycloalkyl, aralkyl, the alkyl part of which contains 1 to 5 carbon atoms, alkoxycarbonylmethyl group or (alkoxycarbonyl) alkyl group in which the CNS and the alkyl parts contain 1-3 carbon atoms; carboxialkilnuyu group or (carboxyethyl)alkyl group in which the alkyl part/SUB>-C5is an alkyl group; alkoxybenzyl group, CNS part of which contains 1 to 5 carbon atoms; alkoxycarbonylmethyl group, in which CNS and alkyl parts contain 1 to 5 carbon atoms; carboxialkilnuyu group in which the alkyl part contains 1 to 5 carbon atoms; a group selected from phenyl and benzyl, unsubstituted or substituted in the aromatic nucleus C1-C5-alkyl, C1-C5-alkoxygroup, hydroxyl, halogen or trifluoromethyl; peredelnoj group; or (ii) signifies the ethylene group;

R is hydrogen, C1-C5is an alkyl group; aryl or aranceles group in which the alkyl part has 1 to 5 carbon atoms, these aryl and kalkilya groups are unsubstituted or substituted in the aromatic series, hydroxyl, C1-C3-alkoxygroup, C1-C3-alkanoyloxy, halogen, trifluoromethyl, or C1-C5-alkyl;

Y is hydrogen; a group-COOR2in which R2is C1-C5is an alkyl group, aryl or aranceles group in which the alkyl part has 1 to 5 carbon atoms, these aryl and kalkilya groups may be h is a or C1-C5; or one of their salts.

According to the invention under the aryl see, for example, the aromatic nucleus, for example, C6-C10in particular phenyl, 1-naphthyl or 2-naphthyl.

Aryl part Uralkalij groups (alkoxycarbonyl)alkyl and (carboxyethyl)-alkyl groups according to the invention preferably is an aromatic nucleus, for example, C6-C10, namely, phenyl, 1-naphthyl or 2-naphthyl.

Salts of compounds of formula (I) according to the present invention include salts derived from mineral or organic acids, which provides the Department or convenient crystallization of the compounds of formula (I), such as picric acid or oxalic acid, or optically active acid, for example, almond or camphorsulfonic acid, and pharmaceutically acceptable salts such as hydrochloride, bromohydrin, sulfate, acetate, acid sulfate, primary phosphate, methanesulfonate, methyl sulfate, maleate, fumarate, sulfonate, 2-naphthalenesulfonate, glycolate, gluconate, citrate, isetionate, benzoate, salicylate, ascorbate, tartrate, succinate, lactate, glutarate, toluensulfonate, ascorbate or salts with inorganic bases to form salts of Molochny is samaram compounds of formula (I), which may contain one chiral center, as well as to their salts.

Enantiomers and racemic mixtures of compounds of formula (I) are part of the invention.

In the present description, the alkyl or alkoxygroup are straight or branched. Alkyl groups are, for example, stands, ethyl, n-propylene, isopropyl, n-bootrom, Deut.-bootrom, or tert.-bootrom and alkoxygroup is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, Deut.-butoxy or tert.-butoxy.

Preferred are the compounds of formula (I) in which R is the stands or ethyl.

Another group of preferred compounds consists of compounds of the formula

< / BR>
in which A is a methylene group may monosubstituted, R1is hydrogen, methyl group, carboxialkilnuyu group or alkoxycarbonylmethyl group, a-COOR is the same as defined for (I) or their salts.

Another group of preferred compounds consists of compounds of the formula

< / BR>
in which A is a methylene group may monosubstituted,- COOR, R1and R2are as defined for (I), or one of their salts.


or one of their salts.

Even more preferred group of compounds of the formula

< / BR>
in which R1is hydrogen, carboxialkilnuyu group or alkoxycarbonylmethyl group, R is hydrogen, methyl or ethyl group, and Y is as defined for (1),

or one of their salts.

Particularly preferred compounds are:

a) methyl ester/4-{4-[4-(aminoiminomethyl)-phenyl]-1,3-thiazol - 2-yl-amino}-piperidine-1-yl/acetic acid,

b) /4-{ 4-[4-(aminoiminomethyl)-phenyl] -1,3-thiazol-2-yl-amino} - piperidine-1-1-yl/-acetic acid,

C) methyl ester/4-{4-[4-(amino-(N-ethoxycarbonyl)-methyl) -phenyl] -1,3-thiazol-2-yl-amino]-piperidine-1-yl/-acetic acid,

d) ethyl ester/4-{4-[4-(aminoiminomethyl)-phenyl]-1,3-thiazol-2 - yl-amino}-piperidine-1-yl/-acetic acid,

d) ethyl ester/4-{4-[4-(amino-(N-ethoxycarbonyl)-methyl)- phenyl] -1,3-thiazol-2-yl-amino]-piperidine-1-yl/-acetic acid,

e) /4-{4-[4-(aminoiminomethyl)-phenyl]-1,3-thiazol-2-yl-N - carboxymethyl-amino}-piperidine-1-yl/-acetic acid,

W) ethyl ester of 3-[N-{4-[4-(aminoiminomethyl)-phenyl]-1,3-thiazol - 2-yl} -N-/1-etoxycarbonyl-methylpiperidin-4-yl/-amino]-PR]-propionic acid,

and) ethyl ester of 3-[N-{4-[4-(aminoethoxyethanol)- phenyl]-1,3-thiazol-2-yl} -N-(1-ethoxycarbonylmethylene-4-yl) amino]-propionic acid, or one of their salts.

The present invention also relates to a method for producing compounds (I) from intermediates of formula (II).

This method comprises the stages consisting of:

(a) removing the protection of cyclic AMINOPHENYL the compounds of formula (II)

< / BR>
in which

R1matter listed for (I), and Z is a group protecting aminophenol, such as benzyl, to obtain the free amine of formula (III)

< / BR>
in which

R1matter listed for (I), and when Z is a benzyl, removing the protection can be carried out under the action of chloroformiate;

b) N-alkylation of the obtained compound of the formula (III) (i) or when interacting with a halide derivative of the formula:

X - A - COO - R, (1),

in which X is a nucleophilic group, such as tosyl or halogen, preferably chlorine or bromine, and A and R are as defined for (I), in a solvent selected among, for example, alkanols or dimethylformamide, in the presence of an alkaline agent such as an alkaline carbonate or treat is whether

RCOO-CH=CH-COOR (3)

in alkanol, where R is as defined for (I) obtaining the compounds of formula

< / BR>
in which

A, R and R1are as defined for (I),

(C) introducing the compounds obtained in the reaction of Pinner, interacting nitrile (IV) in acidic medium in alkanol to get imidate salt, which is then injected into interaction with an amine, such as ammonia, to obtain amidin formula

< / BR>
I when y = H

in which A, R and R1are as defined for (I), the compound obtained is a compound of formula (I) in which Y is hydrogen,

d) in some cases, the interaction of amidine obtained in stage (C),

(i) or chloroformiate formula

Ci - COO - R2,

in which R2is the same as defined for the compounds of formula (I), in a solvent such as dimethylformamide, in an alkaline medium, for example, in the presence of triethylamine or alkali carbonate to obtain a compound of the formula

< / BR>
which compound of formula (I) in which Y is-COO-R2and R1, R2A and R are as defined for (I);

(ii) or allermuir agent such as C-CO-R3 is-CO-R3, R1A and R are as defined for (I);

(d) in some cases, hydrolysis of the corresponding essential precursor obtained in stage (b), for example, in an acidic medium in the presence of hydrochloric acid to obtain the compound of formula (I) in which R is hydrogen, or one of their salts.

Intermediate compounds of formula (II) in which R1different from hydrogen, can be obtained from the corresponding compounds of the formula (II) in which R1is a hydrogen atom by reaction with a derivative of formula R1X, in which R1is as defined for (I), and X is a nucleophilic group, such as alkylsulfonate, arylsulfonate or halogen atom, or in the presence of a strong base such as an alkali hydride, e.g. sodium hydride, or such as tert.-butyl potassium, anhydrous solvent such as dimethylformamide or tetrahydrofuran, or by catalysis of the treatment phase (KOTH) solid-liquid in the presence of a catalyst treatment phases, for example, tetrabutylammonium, and base, for example potassium carbonate, in such an inert solvent like toluene.

In the case when R11= -CH2CH2-COOR4can be obtained from corresponding compounds of formula (II) in which R1is a hydrogen atom, by reaction type with Michael , -unsaturated compound of the formula CH2= CH-COOR4(R4is a hydrogen or C1-C2is an alkyl group) in KOF solid-liquid in the presence of a catalyst, for example, tetrabutylammonium, and base, for example potassium carbonate, in an inert solvent, such as toluene.

The intermediate compound (II) in which R1is hydrogen receive well-known to specialists in this area by, for example, by the method Hantzsch, Comprehensive Heterocyclic Chemistry, A. Katritzky, 1984, T. 6, from commercially available starting products or obtained by known methods.

The compounds of formula (II), (III) and (IV) and their salts are the original compounds, which are another aspect of the invention.

They can be represented by the following formula (Y):

< / BR>
in which

R1is the same as defined above, and L is hydrogen, a group Z or a group-A-COOR, and Z, A and R are as defined above.

The compounds of formula (I) include also t enemy on their radioactive isotopes, for example, tritium or carbon-14. Such labeled compounds are used in research work in the study of metabolism or pharmacokinetics, biochemical experiments as a ligand of the receptor. Presents a combination of the above reactions are as follows:

< / BR>
< / BR>
Given their antagonistic activity to fixation of fibrinogen with platelets, the compounds of the present invention may be useful for the treatment of humans and animals, in particular for the treatment and prevention of thrombotic disorders. Numerous examples of thrombotic disorders are known from the literature and include, for example, such diseases with the blockage of blood vessels, as myocardial infarction, angina, temporary ischemic complications, stroke thrombotic origin, atherosclerosis, peripheral artery disease, nephropathy, retinopathy, postoperative thrombosis, pulmonary embolism, venous thrombosis, and thrombosis and angioplasty.

Compounds according to the invention are also interesting and useful to prevent complications in the pre - and postoperative period, resulting in organ transplantation, in particular, heart and kidneys.

Compounds according to the s complex GP IIb/IIIa or other receptors. So, for example, compounds of the invention can be used to improve wound healing, to treat osteoporosis or rheumatoid arthritis.

Compounds of the invention may also be useful for the treatment of certain cancers and are useful to prevent or stop the development of cancer metastasis.

Another aspect of the invention relates to pharmaceutically acceptable salts of the compounds according to the invention for use in the treatment or prevention of thrombotic disorders, as well as for medicines containing them.

Compounds according to the invention were tested in biochemical and pharmacological experiments.

The pharmacological activity of the compounds (I) according to the invention was studied in experiments on platelet aggregation. These experiments were carried out on samples taken from human, baboon, dog, Guinea pig, rabbit, rat and mouse, and allowed to determine the activity of compounds in vitro. The activity in vivo of these products, administered intravenously or orally, was also measured in the baboon by the same method.

Platelet aggregation was induced in accordance with one of the following two protocols

is her appeal, Nature, 1962, 194, 927-929, modified by SAVI et al. , Now.Rev.Fr.Hematol 1993, 35, 115-119.

Platelet aggregation (human, dog, Guinea pig, rabbit, rat, mouse and baboon) was measured by turbidimetry 400 μl of plasma enriched with platelets (SWEAT), obtained by centrifugation selected whole blood with the help of 3.8% (9 vol./1 vol.) the solution triacrylate. 400 µl of the POT is placed in the cuvette of aggregometry under stirring (900 rpm) at 37oC. Aggregation initiated by adding 4 μl of an aggregating agent.

The Protocol aggregation whole blood by Diodati et.al.Circulation, 1992, 88, 1186-1193.

Platelet aggregation (dogs) measure the resistance unit of blood, the selected solution chirodini concentration of 100 µg/ml (9 vol./1 volume). Placed in the cuvette of aggregometry 0.5 ml of selected whole blood and 0.5 ml of 0.9% NaCl solution under stirring at 37oC, then the electrode is immersed in a cuvette. Aggregation was measured after activation 10 μl of a solution of an aggregating agent.

Studied aggregating agents were ADP (2.5 or at 6.25 μm), arachidonic acid (500 μm), collagen (12.5 µg/ml), thrombin (0.1 IU/ml) or PAF (0.5 µm). In the case of in vitro tests in cell injected 10 μl of 10% solution DMCO containing the of storytale.

Compounds according to the invention have activity against platelet aggregation at concentrations between 1 nm and 10 μm when using any aggregation agent.

After oral or intravenous administration of pharmacological activity can be observed in baboons for some compounds, administered intravenously or orally, at doses ranging from 0.01 to 100 mg/kg

The compounds of formula (I) are of low toxicity; their toxicity is compatible with their use as a drug for the treatment of the above diseases and disorders.

The compounds of formula (I) may enter into pharmaceutical compositions for administration to mammals, including humans, for treatment of the above diseases.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used at daily doses of 0.01 to 100 mg per kilogram of body weight of the mammal to be treated, preferably at daily doses of 0.01 to 5 mg/kg

For men dose may preferably range from 0.1 to 500 mg per day, more specifically, 2-500 mg depending on the age of the subject to be treated or the type treatment: preventive care who is in single doses, containing from 0.01 to 500 mg mostly 0.2 to 500 mg, preferably 0.2 to 200 mg of the indicated active agent per unit dose.

Therefore, an object of the invention is also pharmaceutical compositions as the active agent containing the above compounds. These compositions are prepared so that they could enter the oral or parenteral route.

In pharmacological compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal injection of the active ingredient can be introduced in a single form of introducing mixed with classical pharmaceutical carriers, to animals and people. The appropriate unit forms of introduction include forms for oral administration such as tablets, capsules, powders, granules and oral solutions or suspensions, forms for sublingual use and insertion through the mouth, forms for subcutaneous, intramuscular, intravenous or for insertion through the nose or in the eye and forms for rectal administration.

When preparing a solid composition in the form of tablets, the active principle is mixed with a pharmaceutical carrier, such as IELTS sucrose or other suitable materials, or you can process them so that they had prolonged activity or a slow release and that they release the active principle continuously in a predetermined quantity.

Get the drug in capsules by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard capsules.

A preparation in syrup or elixir may contain the active principle together with podslushivaet, preferably low-calorie, methyl paraben and propyl paraben as an antiseptic, as well as an agent, giving suitable taste and color.

Powders or granules, dispergirujutsja in the water can contain the active ingredient mixed with dispersing agents or wetting, or suspendresume agents, such as polyvinylpyrrolidone, as well as with edible additives or taste correctors.

For rectal injection use suppositories prepared with a binder, floating at rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral, intranasal or intraocular injection using aqueous suspensions, isotonic saline rest acceptable for example propylene glycol or botopical.

The active principle can also be formulated as microcapsules, possibly with one or more carriers or excipients.

The active principle may also be in the form of a complex with a cyclodextrin, for example -, or-cyclodextrin, 2-oksipropil- -cyclodextrin or methyl - - cyclodextrin.

The following preparations and examples illustrate the invention without limiting it.

Obtain intermediates of formula (II), (III) and (IV)

Preparation 1

N-(I-Benzylpiperidine-4-yl)-N'-tert.-butilhioscina (compound 1)

Dissolve 24,93 g of 4-amino-1-benzylpiperidine in 300 ml of dichloromethane, then added dropwise at room temperature of 16.7 ml of tert-utilizationand. The reaction mixture was stirred at room temperature for 5 hours, then add water and allow to settle. Separate the organic phase, dried over sodium sulfate and evaporated. The resulting residue is crystallized from petroleum ether to obtain white crystals, which melt at 137oC. Yield 88%.

Preparation II

Bromohydrin N-(I-benzylpiperidine-4-yl)-thiourea (preprogram the-4-yl)-N'-tert.-butultimately, the reaction mixture was stirred at room temperature for 4 hours, then poured into diethyl ether. Filtered the obtained crystals are washed them richly diethyl ether to obtain white crystals, melting at 120oC. quantitative Output.

Preparation III

Dibromide 4-{ 2-[2-[N-(1-benzylpiperidine-4-yl)-amino]-1,3 - thiazol-4-yl}-benzonitrile (compound 3, (II) with R1= H))

To 18,38 g bromhidrosis N-/1-benzylpiperidine-4-yl/-thiourea in 200 ml of methanol are added 12,46 g of 4-cyanobenzaldehyde, then heat the reaction mixture by boiling under reflux for 4 hours. Cooled to room temperature, then successively added 200 ml of diethyl ether, filtered, washed the residue with diethyl ether to obtain white crystals, melting at 280oC. Yield 86%.

Preparation IV

4-{ 2-[N-(I-Benzylpiperidine-4-yl)-N-methylamino]-1,3-thiazol-4-yl}- benzonitrile (compound 4.1, (II) with R1= CH3)

To 146 mg of sodium hydride (60% dispersion in oil) in suspension in 13 ml of N,N-dimethylformamide are added at room temperature, 1.3 g of 4-{2-N-(1-benzylpiperidine-4-yl)-amino] -1,3-thiazol-4-yl}-benzonitrile dissolved in 5 ml of N,N-dimatia, stirred the reaction mixture for 4 hours at room temperature, then poured in water and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel, elwira dichloromethane. Get yellow crystals, melting at 136oC. Yield 67%.

Oxalate ethyl ester 3-{N-(1-benzylpiperidine-4-yl)-N-[4- (4-cyanophenyl)-1,3-thiazolyl-2-yl]-amino}-propionic acid (compound 4.2, (II) with R1= -CH2-CH2-COOC2H5)

To 44,8 g of 4-{2-[N-(1-benzylpiperidine-4-yl)amino]-1,3-thiazol-4 - yl}-benzonitrile in 900 ml of toluene was added 25,92 ml ethyl acrylate, 32,98 g of potassium carbonate and 7.7 g of tetrabutylammonium, then the reaction mixture is refluxed for 24 hours. The reaction mixture is cooled, then add water and decanted. The organic phase is dried over sodium sulfate, then evaporated to dryness. The oil obtained is treated with isopropyl ether and filtered through a layer of silicon oxide, introducing diisopropyl ether. Evaporation of the filtrate gives the resin, which is then converted into the salt form by the addition of oxalic acid in acetone to obtain white crystals, melting at 225oC is l (compound 5.1, (III) with R1= H)

This compound is obtained when the effect of chloroformiate thus as described in Tetrahedron Letters 1983, 24, 31, 3233 - 3236, and more specifically, under the action of 1-chloroethyl of chloroformate according to J. Org. Chem., 1984, 49, 20181 - 2082.

Added to 18 g of 4-{2-[N-(1-benzylpiperidine-4-yl)-amino]-1,3 - thiazol-4-yl} -benzonitrile in 250 ml of 1,2 dichloroethane 6.2 g of 1,8-bidimensionality, then the reaction mixture cooled down to 0oC and gain of 10.4 ml of 1-chloroethylphosphonic, then stirred the reaction mixture for 30 minutes at this temperature, then refluxed for 3 hours. Is evaporated to dryness and treated the remainder of the 250 ml of methanol, then the mixture is refluxed for 2 hours. The reaction mixture is allowed to cool and add 250 ml of diethyl ether, then filtered, washed with diethyl ether and dried to obtain a beige crystals, melting at 266oC. Yield Of 87%.

Dichlorhydrate 4-{2-[N-(piperidine-4-yl)-N-methylamino]-1,3-thiazol - 4-yl}-benzonitrile (connection 5.2, (III) with R1= CH3)

This connection receive on the method of obtaining compounds of 5.1, by dibenzylamine 4-{ 2-[N-(1-benzylpiperidine-4-yl)-N-methylamino] -1,3-thiazol-4-yl} -benzonitrile. Get beige kepeiden-4-yl)-amino}-propionic acid (compound 5.3, (III) with R1= -CH2-CH2-COOC2H5)

This connection receive on the method of obtaining compounds of 5.1 by dibenzylamine ethyl ester 3-{N-(1-benzylpiperidine-4-yl)-N-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]- amino}-propionic acid. Get white crystals, melting at 140oC. Yield Of 70%.

Preparation VI

Methyl ester {4-[4-(4-cyanophenyl)-1,3-thiazol-2-yl-amino]- piperidine-1-yl}-acetic acid (compound 6.1, (IV) with R1= H, A = CH2and R = CH3)

Add to 14.8 g of dichlorhydrate 4-{2-[(piperidine-4-yl)-amino]- 1,3-thiazol-4-yl} -benzonitrile in 150 ml of N,N-dimethylformamide 17,75 g of potassium carbonate and 4.3 ml of methylpropanoate, the reaction mixture is heated at 50oC for 2 hours. Pour it into water, extracted with ethyl acetate and the organic phase is washed with water, then dried over sodium sulfate and concentrated in vacuo. The residue is crystallized in isopropyl ether, receive beige crystals, melting at 172oC. Yield 86%.

Ethyl ester of 3-{N-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-N-(1 - ethoxycarbonylmethylene-4-yl)-amino} -propionic acid (compound 6.2, (IV) with R1= -CH2-CH2-COOC2H5, A = CH2and R = C2H5)

This soedinenii)-1,3-thiazol-2-yl] -N-(piperidine-4-yl)amino}- propionic acid with ethylbromoacetate. Get colorless resin, yield 85%.

1H NMR spectrum (DMCO-d6) : of 1.16 (m, 6H), 1,73 is 1.96 (m, 4H), to 2.29 (m, 2H), 2,66 (m, 2H), 2,89 (m, 2H), 3,23 (s, 2H), 3,50 (m, 1H), 3,62 (m, 2H), Android 4.04 (m, 4H), 7,49 (s, 1H), 7,82 (d, J = 8,44 Hz, 2H), 7,98 (d, J = 8,44 Hz, 2H).

Preparation VII

Methyl ester 3-{4-[4-(4-cyanophenyl)-1,3-thiazol-2-ylamino]-piperidine-1-yl}-propionic acid (compound 7.1)

This connection receive Michael's reaction with a complex, unsaturated ether alcohol, according to the Organic Reaction, 1967, t/ 10, 173.

To 2 g of dichlorhydrate 4-[2-[(piperidine-4-yl/-amino]-1,3-thiazol-4 - yl}-benzonitrile in 30 ml of methanol was added 1,64 ml of triethylamine, then with 0.55 ml of methyl acrylate and the reaction mixture is refluxed for 1 hour. Then the reaction mixture is evaporated to dryness. The residue is purified by chromatography on silica gel, elute with a mixture of dichloromethane-methanol (95-5). Concentration of the fractions containing pure product, leads to white crystals with so pl. 154oC. Yield 72%.

Work on methods of preparation VI and VII, above, receive connections 6.3 = 7.2, described in table 1 below/

Example 1.

Hydrochloride methyl ester/4-{4-[4-(aminoiminomethyl)-phenyl]- 1,3-thiazol-2-yl-amino}-piperidine-1-yl/acetic acid

(1): Y by the reaction of Silver according to the Organic Functional Group Preparation, Sandler S. and W. Karo, 1989, 12, 111, Second Edition.

To 150 ml of methanol saturated with gaseous hydrogen chloride at a temperature of about 0oC add 10,33 g methyl ester [4-{4-(4-cyanophenyl)-1,3-thiazol-2-yl-amino} -piperidine-1-yl] -acetic acid (compound 6.1) and the reaction mixture is stored overnight at a temperature of 4oC. Evaporated to dryness without heating, then process the remainder of 150 ml of methanol and bubbled ammonia until alkaline pH. Then the reaction mixture is refluxed for 2 hours, then evaporated to dryness and purify the residue by chromatography on a column of silica gel, elwira a mixture of dichloromethane-methanol (8-2 by volume). Concentration of the fractions of pure product gives yellow crystals with so pl. 150oC. Yield 69%.

Example 2.

The hydrochloride of the ethyl ester of 3-[N-{4-[4-(aminoiminomethyl)-phenyl]- 1,3-thiazol-2-yl}-N-(1-ethoxycarbonylmethylene-4-yl)-amino]- propionic acid

(1): Y = H; -A-COOR = -CH2COOC2H5; R1= -CH2CH2COOC2H5< / BR>
A solution of 1.25 g of ethyl ester of 3-{N-[4-(4-cyanophenyl)-1,3 - thiazol-2-yl] -N-(1-ethoxycarbonylmethylene-4-yl)-amino} - propionic acid (compound 6.2) in 25 ml of ethanol is saturated at 0oC gaseous chlorite is therefore spend processing residue 40 ml of ethanol and the bubbling stream of ammonia until alkaline pH. Then the reaction mixture is refluxed for 2 hours, evaporated to dryness and purify the resulting residue by chromatography on a column of silica gel, elwira a mixture dichloromethane (8-2 by volume). Concentration of the fractions of pure product gives yellow crystals, melting at 156oC. Yield 76%.

Working according to the method of examples 1 and 2 above, get connection examples 3 to 17 described in table II below.

Example 18.

Trichlorohydrin/4-{4-[4-(aminoiminomethyl)-phenyl]-1,3-thiazol-2 - yl-amino} -piperidine-1-yl/-acetic acid

(1): Y = H; -A-COO-R = -CH2COOH; R1= H

To 20 ml of 6N hydrochloric acid are added 1 g of methyl ester hydrochloride/4-{ 4-[4-(aminoiminomethyl)-phenyl]-1,3-thiazol-2-yl-amino}- piperidine-1-yl/-acetic acid (example 1) and the reaction mixture is boiled for 5 hours under reflux. Is evaporated to dryness and the residue is crystallized from acetone to obtain white crystals with so pl. 216oC. Yield Of 96%.

Example 19.

Trichlorohydrin 3-[N-{4-[4-(aminoiminomethyl)-phenyl]-1,3-thiazol-2 - yl}-N-(1-carboxyethylidene-4-yl)-amino]-propionic acid

(1): Y = H; -A-COO-R = -CH2COOH; R1= CH2CH2COOH

To 25 ml of 6N hydrochloric acid was added 700 m is-4-yl)-amino] -propionic acid (example 2) and refluxed the reaction mixture for 5 hours. Is evaporated to dryness and the residue is crystallized from acetone, to obtain white crystals with so pl. 215oC. Yield 80%.

Work according to the methods of examples 18 and 19 above, get connection examples 20 to 30, are shown in table III below.

Example 31.

Methyl ester/4-{4-[4-(aminoethoxyethanol)-phenyl]- 1,3-thiazol-2-yl-amino}-piperidine-1-yl/-acetic acid

(1): Y = -COOCH2CH3; A-COO-R = -CH2COOCH3; R1= Y

To 1 g of the methyl ester hydrochloride/4-{4-[4-(aminoiminomethyl)-phenyl]-1,3-thiazol-2-yl-amino} -piperidine-1 - yl/-acetic acid (example 1) in 20 ml of N, N-dimethylformamide in the presence of 0.71 ml of triethylamine are added dropwise, maintaining the temperature of the mixture 0oC, 0.25 ml of ethylchloride, then the reaction mixture is left for 15 minutes at this temperature and then stirred for 3 hours at room temperature. The reaction mixture was poured into water and consistently spend extraction with ethyl acetate, washing the organic phase with water, drying over sodium sulfate and evaporation to dryness. The residue is crystallized from isopropyl ether, to obtain white crystals, melting at 194oC. Yield 76%.

Example 32.

Ethyl ester of 3-[N-{4-[4-(amino-(N-ethoxycarbonyl the OC2H5; -A-COO-R = -CH2COOC2H5, R1= -CH2CH2COOC2H5< / BR>
To 1.5 g of the hydrochloride of the ethyl ester of 3-[N-{4-[4-(aminoiminomethyl)-phenyl] -1,3-thiazol-2-yl} -N-(1 - ethoxycarbonylmethylene-4-yl)-amino]-propionic acid (example 2) in 20 ml of N,N-dimethylformamide in the presence of from 0.84 ml of triethylamine are added dropwise, maintaining the temperature of the mixture 0oC 0,29 ml ethylchloride. The reaction mixture is left for 15 minutes at this temperature, then stirred for 3 hours at room temperature. Pour the reaction mixture into water, then successively the extraction is carried out with ethyl acetate, washing the organic phase with water, drying over sodium sulfate and evaporation to dryness. The residue is crystallized from isopropyl ether, to obtain white crystals with so pl. 130oC. Yield 78%.

Work according to the methods of examples 31 and 32 above, get connection examples 33 - 41, described in table IV below, the interaction of the derivatives described in table II, with adequate chloroformiate formula Cl-COO-R2.

Below are some examples of possible formulations of a pharmaceutical composition:

Example 42. Dry gelatin capsules containing 50 mg AK is oz - 140 mg

Example 43. Tablets containing 75 mg of active substance:

Active substance - 75 mg 75 mg

Microcrystalline cellulose - 45 mg 43 mg

The corn starch modified - 22 mg 22 mg

Poloxamer (Pluronic F-38) 4 mg 4 mg

Colloidal silicon dioxide 3 mg 3 mg

Magnesium stearate 1 mg -

Gidrirovannoe castor oil per tablet weighing 150 mg - 3 mg

Example 44. Tablets containing 150 mg of active substance:

Active ingredient 150 mg 150 mg

Microcrystalline cellulose - 89 mg 85 mg

Modified maize starch - 45 mg 45 mg

Poloxamer (Pluronic F-68) 8 mg 8 mg

Colloidal silicon dioxide 6 mg 6 mg

Magnesium stearate 2 mg -

Gidrirovannoe castor oil for a tablet weight of 300 mg - 6 mg

Example 45. Gelatin capsule containing 5 mg of active substance:

Active substance - 5,00 mg

Microcrystalline cellulose - 276,50 mg

Modified maize starch - 50,00 mg

Talc 25 mg

Colloidal silicon dioxide 0.50 mg

Magnesium stearate - 1,00 MSU

1. Derivatives of substituted 4-phenylthiazole formula I

< / BR>
in which R1is hydrogen, C1-C5-alkyl, phenylalkyl, alkyl the alkyl group, in which the alkoxy and alkyl parts contain 1-3 carbon atoms; karboksilnoj group in which the alkyl part contains 1-3 carbon atoms;

And means (i) a methylene group, possibly mono - or disubstituted WITH1-C5is an alkyl group, alkoxycarbonyl group, in which CNS section contains 1-5 carbon atoms, alkoxycarbonylmethyl group, in which CNS and alkyl parts contain 1-3 carbon atoms; karboksilnoj group, the alkyl part of which contains 1 to 5 carbon atoms; a group selected from phenyl and benzyl, unsubstituted or substituted in the aromatic nucleus WITH1-C5-alkyl or halogen, or (ii) signifies the ethylene group;

R is hydrogen; C1-C5is an alkyl group; phenyl, unsubstituted or substituted in the aromatic cycle;

Y is hydrogen; a group-COOR2in which R2is1-C5is an alkyl group,

or one of their salts.

2. Connection on p. 1, in which Y is hydrogen; And a is methylene group may monosubstituted, and R1is hydrogen, methyl group, carboxialkilnuyu group or alkoxycarbonyl group, or one and the sing, perhaps monosubstituted, in which R2is as defined for (I), or one of their salts.

4. Connection PP.1-3, in which-A - is a group-CH2- or one of their salts.

5. Connection PP.1-4, in which R1is hydrogen, carboxialkilnuyu group or alkoxycarbonyl group; R is a hydrogen, methyl group or ethyl group, or one of their salts.

6. Connection PP. 1-5, in which R is a methyl or ethyl group.

7. The compounds of formula:

a) methyl ester of 4-{4-[4-aminoiminomethyl)-phenyl]-1,3-thiazol-2-yl-amino}-piperidine-1-yl/-acetic acid;

b) /4-{ 4-[4-aminoiminomethyl)-phenyl]-1,3-thiazol-2-yl-amino}-piperidine-1-yl/-acetic acid;

C) methyl ester/4-{4-[4-(amino)-(N-ethoxycarbonyl)-methyl)-phenyl] -1,3-thiazol-2-yl-amino}-piperidine-1-yl/-acetic acid;

d) ethyl ester of 4-{4-[4-aminoiminomethyl)-phenyl]-1,3-thiazol-2-yl-amino} -piperidine-1-yl/-acetic acid;

d) ethyl ester/4-{4-[4-(amino)-(N-ethoxycarbonyl)-methyl)-phenyl] -1,3-thiazol-2-yl-amino}-piperidine-1-yl/-acetic acid;

e) /4-{ 4-[4-aminoiminomethyl)-phenyl]-1,3-thiazol-2-yl-N-carboxymethyl-amino}-piperidine-1-yl/acetic acid;

g) the new acid,

C) 3-[N-{ 4-[4-(aminoiminomethyl)-phenyl]-1,3-thiazol-2-yl}-N-(1-carboxyethylidene-4-yl)-amino]-propionic acid;

and) ethyl ester of 3-[N-{4-[4-(amino-(N-ethoxycarbonyl)-methyl)-phenyl] -1,3-thiazol-2-yl}-N-(1-ethoxycarbonylmethylene-4-yl)-amino]-propionic acid, or one of their salts.

8. The compound according to any one of paragraphs.1-7 in the form of a racemic mixture, or a mixture of enantiomers, or one of their salts.

9. The compound according to any one of paragraphs.1-8, in which the compound of formula (I) is in the form of hydrochloride, bromhidrosis, sulfate, acetate, acid sulfate, primary phosphate, methanesulfonate, methyl sulfate, maleate, fumarata, sulfonate, 2-naphthalenesulfonate, glycolate, gluconate, citrate, isothionate, benzoate, salicylate, ascorbate, tartrate, succinate, lactate, glutarate, toluensulfonate, or is a salt of an inorganic base, for example alkali metal salt such as sodium salt.

10. The method of obtaining compounds of formula (I), characterized in that:

(a) deprotect cyclic AMINOPHENYL the compounds of formula (II)

< / BR>
in which R1is as defined for (I), and Z is a group protecting aminophenol, such as benzyl,

obtaining its a benzyl, the removal of protection can be carried out under the action of chloroformiate;

(b) alkylate obtained compound of the formula (III) in two ways:

(i) when interacting with a halide derivative of the formula:

X - A - COO - R, (1)

in which X is a nucleophilic group, such as tosyl or halogen, preferably chlorine or bromine, and R and a are as defined for formula (I),

in a solvent selected among, for example, alkanols or dimethylformamide, in the presence of an alkaline agent such as an alkaline carbonate or triethylamine;

(ii) either by reaction with Michael , -unsaturated complex ester of the formula

CH2= CH - COOR or

RCOO - CH = CH - COOR

in alkanol, where R is as defined for (I), to obtain a compound of formula IV

< / BR>
in which A, R and R1are as defined for (I);

(C) introducing the compound obtained in the reaction of Pinner, i.e. spend processing nitrile (IV) in acidic environment alkanols obtaining imidate salt, which is then injected into the reaction with an amine, such as ammonia, to obtain amidin formula

< / BR>
in which A, R and R1have the above values,

moreover, the compound obtained is a compound of four is th at the previous stage (i) or chloroformiate formula

Cl - COO - R2< / BR>
in which R2matter listed for formula (I),

in a solvent such as dimethylformamide, in an alkaline medium, for example, in the presence of triethylamine or alkali carbonate, to obtain the compounds of formula

< / BR>
which is a compound of formula (I), where Y is-COO-R2and R1, R2; A and R have the above values,

(d) and, if necessary, carry out the hydrolysis of the corresponding essential precursor obtained in stage (b), for example, in an acidic medium in the presence of hydrochloric acid, and obtain the connection formula (I) in which R is hydrogen, or one of its salts.

11. The compound of formula V

< / BR>
in which L is hydrogen, protecting group Z as defined for formula (II) in paragraph 10, or the group-A-COOR, where A, R and R1are as defined for (I) in paragraph 1,

or one of its salts.

12. Pharmaceutical composition having antithrombotic activity, containing the active principle and pharmaceutical additives, characterized in that it contains at least one compound according to one of paragraphs.1-9, in an effective amount.

13. The composition according to p. 12, characterized in that unity in one of the paragraphs.1-9.

14. The composition according to p. 12, characterized in that it contains 0.01 to 500 mg of the compounds according to one of paragraphs.1-9.

 

Same patents:

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,

with improved anthelminthic activity, and can be used in medicine for the treatment of larval and alveolar hydatidosis of hydatid cysts

The invention relates to a derivative of thiazolidinedione formula

,

where X is unsubstituted or substituted indayla, indolenine, asiandaily, asiandaily, imidazopyridine or imidazopyridine group; Y is an oxygen atom or a sulfur atom; Z-2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene, 2,4-dioxoimidazolidin-5-ylmethylene, 3,5-dioxoimidazolidin-2-ylmethylene or N-gidroksilaminopurina group; R is a hydrogen atom, an alkyl group, alkoxygroup, halogen atom, hydroxy-group, a nitrogroup, kalkilya group or unsubstituted or substituted amino group; and m is an integer from 1 to 5

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,

where X is unsubstituted or substituted indayla, indolenine, asiandaily, asiandaily, imidazopyridine or imidazopyridine group; Y is an oxygen atom or a sulfur atom; Z-2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene, 2,4-dioxoimidazolidin-5-ylmethylene, 3,5-dioxoimidazolidin-2-ylmethylene or N-gidroksilaminopurina group; R is a hydrogen atom, an alkyl group, alkoxygroup, halogen atom, hydroxy-group, a nitrogroup, kalkilya group or unsubstituted or substituted amino group; and m is an integer from 1 to 5

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FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

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