Thiazolinone-2-substituted quinolines

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on CDK1 kinase. In formula I , R1 is hydrogen or R2-(X)n-; X is a lower alkylene or cyclic lower alkylene; R2 denotes ; where denotes phenyl; cycloalkyl containing 3-6 carbon atoms; 4-6-member heterocycloalkyl ring having 3-5 carbon atoms and 1-2 oxygen atoms; R5, R6 and R7 are independently selected from a group containing hydrogen or halide; R4 is hydrogen or -(O)k(CH2CH2O)y-R10; R19 is hydrogen; R20 is hydrogen or -C(O)-R11; R10 and R11 is a lower alkyl; n and k are equal to 0 or 1; y is an integer from 0 to 3.

EFFECT: obtaining a pharmaceutical composition with inhibitory effect on CDK1 kinase, containing one or more of the disclosed compounds.

15 cl, 10 ex

 

This invention provides derivatives thiazolidinedione quinoline with the replacement of the quinoline ring in the 2nd position, which is shown CDK1 (cyclin-dependent kinase) antiproliferative activity and applicable as anticancer agents.

Cyclin-dependent kinases cdks are serine-threonine protein kinases that play a key role in the regulation of transitions between different phases of the cell cycle, such as moving from the resting stage in the G1(the gap between mitosis and the beginning of DNA replication in the new cycle of dividing cells) to S (the period of active DNA synthesis), or the transition from the G2for phase Meters, in which there is active mitosis and cell division (see, for example, the collection of articles in Science, 274, 1996, s-1677; Ann.Rev.Cell Dev. Biol., 13, 1997, pp.261-291). CDK complexes formed by the Association of regulatory cyclenbuy subunit (e.g., cyclin a, B1, B2, D1, D2, D3 and E) and the catalytic subunit of the kinase (such as CDK1, CDK2, CDK4, CDK5 and CDK6). As their name implies, CDK kinases are absolute dependence on subunit cycline for their phosphorylation substrate of targets and different function kinase/ticinovic steam to regulate the passage through a specific phase of the cell cycle.

From the above it follows that these protein kinases are a class of proteins (enzymes), regulating RA is personal cellular functions. This is achieved by phosphorylation of certain amino acids in protein substrates, leading to a conformational change in the protein substrate. The conformational change modulates the activity of the substrate or its ability to interact with other binding partners. Enzymatic activity of protein kinases is the speed with which the kinase attaches a phosphate group to a substrate. It can be measured, for example, by determining the amount of substrate converted into product, as a function of time. Phosphorylation of the substrate occurs in the active centre of the protein kinase.

Thanks to the above properties, these kinases play an important role in the passage of the signal transduction of growth factor that leads to cell proliferation, differentiation and migration. The fibroblast growth factor (FGF) and vascular endothelial growth (VEGF) has been identified as important mediators of angiogenesis induced by tumor. Of VEGF activates endothelial cells, passing the signal through two high-affinity receptor, one of which is a receptor domain containing kinase as an insert (CRA). (See Hennequin L.F., etc., J. Med. Chem. 46, n 6, 2002, s). FGF activates endothelial cells, passing the signal through FGF-receptor (FRFR). Solid tumors require the formation of new blood vessels (angiogenesis) on the I growth. Accordingly, inhibitors of receptor FRFR and the CRA, preventing signal transduction growth and thus slow or prevent angiogenesis, applicable as agents to prevent or treat solid tumors.

Because CDK kinases, such as CDK1, are the main activators of cell division, CDK1 inhibitors can be used as antiproliferative agents. These inhibitors can be used for therapeutic intervention, leading to suppression of unregulated cell cycle progression.

According to the invention, it has been shown that the compound of the formula:

in which

R1means hydrogen, lower alkyl, aryloxyalkyl lower alkyl, -C(O)2[CH2CH2O]p-R9, -[CH2CH2O]V-R8or R2(X)n-;

X means lower alkylene, replacement lower alkylene, cyclosiloxanes lower alkylene, aryl-substituted lower alkylene, carboxyterminal lower alkylene, imidazolidinyl lower alkylene, mono - or dialogization lower alkylene, aminosilanes lower alkylene, mono - or di-lower alkylaminocarbonyl lower alkylene or imidazolidinyl lower alkylene;

R2 means

means Ari is inoe ring; cycloalkyl containing 3-6 carbon atoms; 4-6-membered geteroseksualnoe ring containing 3-5 carbon atoms and 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, or 5-6-membered heteroaromatic ring containing 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;

R5, R6and R7independently selected from the group consisting of hydroxy, lower alkylsulfonyl, replacement of lower alkyl, hydrogen, lower alkyl, halogen, perforamance lower alkyl, lower alkoxy, amino, mono - or di-lower alkylamino, or when two of the substituents R5, R6and R7attached to adjacent carbon atoms of the ringthese two deputies together with the adjacent attached carbon atoms to form an aryl ring; 3-6-membered cycloalkyl; 4-6-membered geteroseksualnoe ring; 4-6-membered heteroaromatic ring; specified geteroseksualnoe ring and a specified heteroaromatic ring containing 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur;

R4means hydrogen, -(O)k(CH2CH2O)y-R10,

or-O-(CH2)nR14

R19means hydrogen;

R20means hydrogen, ISSI alkyl or-C(O)-R 11;

means aryl ring; cycloalkyl containing 3-6 carbon atoms; 4-6-membered heterocyclic alkyl ring containing 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; or a 5-6-membered heteroaromatic ring containing 1-2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;

R8and R9independently mean hydrogen or lower alkyl;

R10and R11mean lower alkyl;

R14means perversioni lower alkyl;

R17and R18independently signify hydrogen, lower alkyl or -(CH2)z-C(O)OR11;

n and k denote integers from 0 to 1;

w, y and z denote integers from 0 to 3;

p means an integer from 0 to 6; and

v and m denote integers from 1 to 6;

or N-oxide compounds, where R2contains nitrogen in the heteroaromatic ring, sulfones, where R2contains sulfur in heterocyclicamines ring or heteroaromatic ring;

or their pharmaceutically acceptable salts, which inhibit the activity of CDK kinases, especially CDK1.

These agents of the invention and pharmaceutical compositions containing such agents applicable in the treatment of various diseases or medical conditions associated with uncontrolled or unwanted cell proliferation, t is such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative diseases and cardiovascular diseases.

Inhibition and/or modulation of activity of CDK kinases, in particular, CDK1, compounds of this formula and compositions containing these compounds makes them useful in the treatment of diseases mediated by kinase activity, in particular as anticancer agents in the treatment of various types of cancer.

As here indicated, the compounds of formula I are potent antiproliferative agents and therefore applicable to mediation and/or inhibiting the activity of CDK kinases, including CDK1, representing, thus, the antitumor agents for the treatment of cancer or other diseases related to uncontrolled or abnormal cell proliferation.

Among the preferred compounds of formula I are compounds corresponding to the formula

in which R1' means hydrogen or lower alkyl or lower alkoxyalkyl, and R4, R19and R20have the meanings indicated above, or

their pharmaceutically acceptable salts and compounds of formula

in which R1means R2'-(X')n-;

n, R4, R19and R20have the values specified above, the

X means lower alkylene, replacement lower alkylene, cyclosiloxanes lower alkylene or mono - or dialogization lower alkylene;

R2' means

means aryl ring, cycloalkyl ring containing 3-6 carbon atoms, a 4 to 6 membered geteroseksualnoe ring containing 3-5 carbon atoms and 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, and 5-6-membered heteroaromatic ring containing 1-2 heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen,

R5' and R6' are independently selected from the group consisting of hydroxy, lower alkylsulfonyl, replacement of lower alkyl, hydrogen, lower alkyl, halogen, perfluorinated lower alkyl, lower alkoxy, amino, mono - or di-substituted lower alkyl amino;

or N-oxide compounds in which R2' contains nitrogen in the heteroaromatic ring, sulfones, in which R2' contains sulfur in heterocyclicamines ring or heteroaromatic ring;

or their pharmaceutically acceptable salts.

In compounds I and I-B, where R1, R1", R2and X contain aryl radical, the preferred aryl is phenyl. As used here, the term halogen includes all four halogen is, such as chlorine, fluorine, bromine and iodine.

As used in the specification, the term "lower alkyl", alone or in combination, means monovalent promoteyou or branched saturated hydrocarbon group containing one to six carbon atoms, such as methyl, ethyl, n-propyl, ISO-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and the like.

The term "cycloalkyl" means a cyclic lower alkyl, which form a 3-6-membered unsubstituted monovalent saturated hydrocarbon ring. Preferred cycloalkyl substituents are cyclopropyl, cyclobutyl, cyclohexyl, etc.

The term "lower alkoxy group" means promoteyou or branched alkoxygroup formed from lower alkyl containing one to six carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.

The term "aryl" means a monovalent mono - or bicyclic unsubstituted aromatic hydrocarbon ring, such as phenyl or raftiline, and phenyl is preferred.

The term "heteroseksualci" means a 4-6-membered monocyclic saturated ring containing 3-4 carbon atoms and one or two heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur. The preferred heterocycle the definition of alkyl groups include morpholinyl, tetrahydrothiopyran or tetrahydropyranyl.

The term "heteroaromatic ring" refers to a monovalent 5 - or 6-membered monocyclic aromatic ring containing 4-5 carbon atoms and 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur. Preferred heteroaromatic groups are thiophenyl, thiazole, pyridinyl, furanyl etc.

The term "cyclic lower alkylene" means a bivalent cycloalkyl group, as defined above.

The term "lower alkylene" means divalently saturated premiani or branched hydrocarbon Deputy containing one to six carbon atoms.

The term "aryl-substituted lower alkylene" means the lowest alkylenes group, as defined above, substituted, preferably one-deputizing aryl group as defined above. Examples are benzyl, 1-phenylethyl or 2-phenylethyl.

The term "carboxyterminal lower alkylene" refers to the lower Allenova Deputy with carboxylation.

The term "replacement lower alkylene" refers to the lower alkalinous group, substituted, preferably one-deputizing, hydroxy-group, and where describes imidazolidinyl lower alkylen, this implies lower alkylenes group, as defined here above, semese the ing amide Deputy.

The term "mono - or dialogization lower alkylene" refers to the lower Allenova Deputy, as described above, monosubstituted or disubstituted by one or two atoms of the carbon chain of the lower alkylene, where specified by the Deputy is halogen.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "mono - or disubstituted by lower alkylamino Deputy lowest alkylene" refers to the lower alkylene, as described above, which is mono - or Disaese one or two carbon atoms of the chain lower alkylene mono - or di - lower alkylamino-group.

The term "aminosilanes lower alkylene" describes the lower alkalinity Deputy, as defined above, substituted, preferably monosubstituted, by the amino group.

The term "imidazolidinyl lower alkylene" refers to the lower Allenova Deputy, as defined above, substituted by one position aminogroups.

The term "imidazolidinyl lower alkylene" refers to the lower Allenova Deputy, as defined above, substituted by one position aminogroups.

The term "aryloxy" refers to aryloxyalkyl, where aryl is defined above. The preferred aryl group is phenyl and the preferred arroceros is fenoxaprop.

The term "perfluorinated lower alkyl"means any of the lower alkyl group, in which all the hydrogen atoms of the lower alkyl group substituted or replaced by fluorine. To the preferred perfluorinated lower alcelam include such groups as performer, pentafluoroethyl, heptafluoropropyl etc. and triptorelin group is most preferred.

The term "pharmaceutically acceptable salt" refers to conventional acid-additive salts or basic additive salts which retain the biological effectiveness and properties of the compounds of formulas I, II, III, IV and V and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of the acid additive salts include derivatives of inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and derivatives of organic acids, such as p-toluenesulfonate acid, salicylic acid, methanesulfonate acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid and the like. Examples of primary additive salts include derivatives of hydroxides of ammonium, potassium, sodium and Quaternary ammonium, such as Tetramethylammonium hydroxide. Chemical ol the rotation of the pharmaceutical compounds (i.e. drugs) in salt is well known to experts in the field of pharmaceutical chemistry and carried out with the aim of obtaining improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, for example, N. Ansel and others, Pharmaceutical Dosage Forms and Drug Delivery Systems (6th ed., 1995), it. 196 and 1456-1457.

According to the invention, the compounds of formula I can be obtained in accordance with reaction scheme 1, in which, unless specifically otherwise agreed, R1, R4, R19and R20have the meanings given here above.

Scheme 1

In accordance with the invention the compound of formula II is introduced into the reaction Knoevenagel with the compound of the formula III-A (rodanim (2-thioxothiazolidin-4-one)) to obtain the compounds of formula IV. Any terms traditionally used in the reaction of Knoevenagel, can be used for this condensation. Typically this reaction is carried out at the boiling temperature in the presence of alkali metal acetate and acetic acid.

In the next stage of synthesis of substituted received thiazolidin formula IV is treated meteorous agent for methylation of tigraphy in the compound of formula IV to obtain the compounds of formula V. Preferred meteorous agent is methyl iodide. The reaction is carried out in the body of the ical amine, such as diisopropylethylamine (DIEA). The reaction temperature and pressure are not essential in carrying out this reaction, and it can be carried out at room temperature and atmospheric pressure. In fact, any of the terms commonly used for the methylation of tigraphy, can be applied.

In the next stage of synthesis of the compound of formula V is introduced into reaction with the compound of the formula VI, receiving compound of formula I. the Compound of formula VI is an amine, and when carrying out this reaction can be applied to any of the methods traditionally used to replace tighrope on the amino group. In accordance with one of the sections of this substitution is performed by reaction of the compound of formula VI with the compound of the formula V in the presence of a conventional solvent, such as acetonitrile. In General the reaction is carried out in the presence of an amine base, such as diisopropylethylamine.

On the other hand, the compounds of formula I can be obtained by reaction of the compound of formula II with the compound of the formula:

in which R1has the meaning given above.

To obtain the compounds of formula I, the reaction of the compound of formula VII with the compound of the formula II is carried out in high-boiling organic solvent such as benzene or toluene, at high temperatures from 150°C to 250°C in a closed sistematikis way this reaction is carried out at high temperatures and pressures. This reaction is particularly advantageous when it is desirable to obtain the compounds of formula I in which the group R contains halides in the chain or in the ring R. the Compound of formula VII can be obtained by direct substitution reaction of compounds of formula VIwhere R1has the meaning given above, with a compound of formula III-A. substitution Reaction is usually carried out in the presence of activator thienyl thienyl group in the compound of formula IX in the presence of an amine base. One of the preferred activators is Duhlata mercury. The reaction is carried out in an inert organic solvent. Can be applied to any conventional inert organic solvent, such as acetonitrile, methylene chloride, etc. with the use of such amine base, as diisopropylethylamine. Temperature and pressure are not essential for this reaction, and it can be carried out at room temperature and atmospheric pressure. For carrying out this reaction can be used any traditional method of substitution thienyl group with the amine.

The compounds of formula VI, in which R1means X and x is the replacement lower alkylene can be obtained from the corresponding amino acids or esters AMI is ocelot recovering the alkali metal borohydride. On the other hand, these replacement lower alkylene compounds can be obtained from the corresponding esters cyanocobalamin acid recovery with lithium aluminum hydride. Recovery makes the cyano in the amino group and ester group in the hydroxyl group. This recovery should take place before the reaction of the compound of formula VI with the compound of the formula V.

On the other hand, the compounds of formula VI, in which R1means R2X and X means carboxyterminal lower alkylene, imidazolidinyl lower alkylene or imidazolidinyl lower alkylene, can be directly converted into the compounds of formula I by reaction of the corresponding compounds of formula VI with the compound of the formula V or with the compound of the formula III-A, as described above.

Where ringormean N-oxide in the nitrogen cycle which forms the ringorthese N-oxides can be formed from the Quaternary ring nitrogen atom oxidation. Can be applied by any conventional method of oxidizing Quaternary ring nitrogen atom in the N-oxide. The preferred oxidizing agent is meta-chlormadinone acid (MJNBK).

The compound of the formula I, in which R1means hydrogen, can be obtained by reactions which th Knoevenagel the compounds of formula II with the compound of the formula VII to obtain the compounds of formula IV. This condensation can be carried out in any conditions, the usual reaction of Coverages. Typically this reaction is carried out at the boiling temperature in the presence of alkali metal acetate and acetic acid. The reaction of Knoevenagel the compounds of formula VII with the compound of the formula II in which R20means-C(=O)-R11, R20forms an amide. This amide hydrolyzing with getting amine in the 2-position of the compounds of formula I in which R20means hydrogen. The base used in the reaction of Knoevenagel, hydrolyzes the amide group to the corresponding amine.

In accordance with the invention, the compound of formula II in which R4means hydrogen, i.e. the compound of the formula

where R19and R20have the meanings specified above,

can be obtained from the compounds of formula

the reaction is shown in scheme 2, where R19and R20have the values specified above.

Scheme 2

The compound of formula X, which can be obtained from 4-itanyone with 3-ethoxyacrylate, cyclist in the compound of formula XI by the action of sulfuric acid. Typically this reaction is carried out in an inert solvent such as dichloromethane. The cyclization is carried out on an alpha, beta-unsaturated double tie is in the ether group of the compounds of formula X using sulfuric acid In the course of this cyclization temperature and pressure are insignificant, the cyclization reaction can be conducted at room temperature and atmospheric pressure.

Cyklinowanie compound of formula XI containing oxazolidine, can be translated in a chlorinated compound of formula XII by treatment gloriouse agent such as phosphorus oxychloride. Usually the use of such high-boiling liquid glorieuses agent as phosphorus oxychloride, preferably. By boiling the reaction mixture is the transformation of the carbonyl group in chlorine with high yields. Any terms that are commonly used for the conversion of the carbonyl group in chlorine, may be used in carrying out this reaction. In the next stage of this reaction, the compound of formula XII is introduced into reaction with ammonium hydroxide to obtain the compounds of formula XIII. Reaction with ammonium hydroxide is carried out under pressure at a temperature of 100-200°C., preferably at a temperature of 150°C for 1-4 hours If this is desirable, secondary amine with substituents R19and R20can be obtained by reaction of compounds of formula XII with substituted amine, or any of the usual methods of conversion of the primary amine to secondary amine with a lower alkyl. 2-Imidazolidinone compound of formula II-A with the Deputy-C(=P)R11can be obtained by reaction of the compound with a primary amine group with acylchlorides. In the next stage of the synthesis of the compound is ormula XIII was transformed into a compound of formula II-A, using the reaction formirovaniya for the conversion of the iodide Deputy SNO phenyl ring. The reaction is carried out by the interaction of the compounds of formula XIII with carbon monoxide in the presence of diphenylpropylamine (dpp) and the substrate, using palladium acetate as the catalyst. When carrying out the reaction of carbon monoxide is added to the reaction mixture under pressure at a temperature of 60-100°C. Using, as a rule, the pressure of 70-80 psi. For carrying out this transformation can be applied to any ordinary way to turn the halogen in the aldehyde group in the phenyl ring by using a reaction with carbon monoxide.

Synthesis of 2,4-disubstituted compounds of the formula I, the intermediate of formula

where R20' means-C(=O)-R11, a R4and R11have the meanings given above,

can be carried out in accordance with the following reaction scheme 3, where R20' and R4have the values specified above.

Scheme 3

The compound of formula XVII can be obtained from compounds of formula XVI (obtaining compounds XVI described in example 2) by reaction of compounds of formula XVI with a reactive derivative of carboxylic acid of the formula R11-C(=O)-OH, where R11has the meaning specified above.

Any conventional methods of transformation amino is in amides by reaction with activated carboxylic acid derivatives, such as galodamadruga or anhydrides may be used for this reaction. The compound of formula XVII containing the hydroxy-group, can be converted into a compound of formula XVIII by reaction of the hydroxy-group of compounds of formula XVII with a halogen substituent R4if it is desirable to introduce the substituent in position 4 of the compounds of formula I. This reaction is carried out by introducing the appropriate halide in the interaction with the compound of the formula XVII at the boiling point of the inert organic solvent used as the medium. In carrying out this reaction can be applied to any conventional method of interaction between the hydroxy group was alkylated with halide. At the last stage of this synthesis of the compound of formula XVIII is converted into a compound of formula II-B, using the reaction formirovaniya to turn idgroup in Deputy SNO phenyl ring. This reaction can be performed as described herein previously, the interaction of the compounds of formula XVIII with carbon monoxide in the presence of a base and using tetrakis(triphenylphosphine)palladium catalyst at a temperature of 60-140°C. When carrying out the reaction of carbon monoxide is added to the reaction medium under pressure. Usually use the pressure of 40-80 psi. Any conventional method of formirovaniya halide group in the aldehyde phenyl ring using R the stocks and carbon monoxide can be used to convert compounds of the formula XVIII compound of formula II-B.

Among the compounds of formula I and those of its parts, which include the compounds of formula I-A and formula I-B, preferred are those compounds in which the aryl groups of the aryl substituents means preferably phenyl.

Preferred among members of the class of compounds of formula I-A are those compounds of formula I-A in which R1means hydrogen. Particularly preferred representatives of this class of compounds are those compounds in which R4means -(O)k(CH2CH2O)y-R10.

In this case, the compounds in which R20means-C(=O)-R11especially preferred.

A preferred representative of the compounds of formula I-B is the class of those compounds in which n is 0 and R2' means cycloalkyl ring lower alkyl, especially cyclopropyl. Among this class of compounds, preferred are those compounds in which R4means -(O)k(CH2CH2O)y-R10.

In this class of compounds in which R20means-C(=O)-R11especially preferred.

Another part of the invention is the compounds of formula I-B in which n is 1 and x is the lowest alkylen, replacement lower alkylene, cyclic lower alkylene or mono - or dihaloalkanes the config lowest alkylen. In this case, R4preferably means -(O)k(CH2CH2O)y-R10.

In this preferred part especially preferred are compounds in which R20means-C(=O)-R11.

The pharmaceutical compositions of the invention may, alternatively or in addition to the compound of formula I, include as an active ingredient, pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds and metabolites. Such compounds, prodrugs, multimer, salts and metabolites sometimes are referred to here as "active agents" or "agents".

In the case of solid agents specialists it is clear that the proposed compounds and salts may exist in different crystal or polymorphic forms, all of which are assumed in the text of the present invention and in the form of the invention.

A therapeutically effective amount of the active agents of the invention can be used for the treatment of diseases mediated by modulation or regulation of protein kinase CDK1. "Effective amount" implies the amount of agent that significantly inhibits proliferation and/or prevents de-differentiation of eukaryotic cells, for example cells of humans, insects, plants the deposits, fungi, and which is effective for the specified applications, for example for special therapeutic treatment.

The amount of this agent corresponding to this number will vary depending on several factors such as the particular compound, disease state and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can be defined in the usual way known in the art, in accordance with the specific circumstances of this case, including, for example, a particular assigned to the agent, the type of administration, the condition treated, and the subject or host that is treated. "Treatment" means at least reducing the extent of the disease in the subject such as a mammal (e.g. human), due, at least in part, by the activity of CDK1 protein kinase; prevention of a pathological state in a mammal, in particular, in cases where the mammal is predisposed to a painful condition, but it is not yet diagnosed as present; modifying or inhibiting the disease condition and/or alleviating the disease condition.

The present invention also aims at developing methods of modulating or inhibiting the activity of protein kinase CDK1, for example, in tissue mlekopitayushchie is about, by introducing him agent of the invention. Antiproliferative activity of agents easily measured by various known methods, for example, using culture of whole cells in MTT (MTT-time) analysis. The active agents of the present invention as modulators of the activity of protein kinase CDK1 can be measured by any means available to specialists, including analyses of in vivo and/or in vitro. Examples of suitable assays for activity measurements include described in International Publication no WO 99/21845; Parast and others, Biochemistry, 37, 1998, s-16801; Connell-Crowley and Harpes, Cell Cycle: Materials and Methods (Michele Pagano, ed, Springer, Berlin, Germany), 1995: International Publication no WO 97/34876 and International Publication no WO 96/14843. These properties can be estimated, for example, using one or more biological procedures in the following examples.

The active agents of the invention can be packaged in the pharmaceutical compositions described below. The pharmaceutical compositions of the invention include effectively modulating, regulating, or inhibiting amount of the compounds of formula I and an inert pharmaceutically acceptable carrier or diluent. In one section of the pharmaceutical compositions effective levels of the agents of the invention are picked so that effective levels provided therapeutic effect, which consists in antipol peratively abilities. The term "effective level" means a level at which proliferation is inhibited or limited. These compositions are prepared in the form of a unit dose, appropriate for the method of administration, for example, parenteral or oral administration.

The agent of the invention can be administered in the traditional dose form, obtained by a combination of therapeutically effective amounts of the agent (for example, the compounds of formula (I) as the active ingredient with suitable pharmaceutical carriers or diluents according to conventional procedures. These procedures may include mixing, granulating and crushing or dissolving the ingredients, which is more suitable for the desired product.

Applied pharmaceutical media may be both solid and liquid. Examples of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, gum Arabic, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. The carrier or diluent may also include material extended or gradual release, known in the art, such as glycerol monostearate or distearate glycerol alone or with a wax, ethylcellulose, hypromellose, methyl methacrylate, and the like.

Various who's pharmaceutical forms may be used. So, if you use a solid carrier, the preparation can be tableted, placed in a hard gelatin capsule in powder form or pill or be in the form of a tablet or pellet. The amount of solid carrier may vary. If you use a carrier liquid, the drug may be in the form of a syrup, emulsion, soft gelatin capsule, sterile solution for injection or suspension in an ampoule or vial or nonaqueous liquid suspension.

To obtain a stable water-soluble dose form pharmaceutically acceptable salt claimed in the invention the agent may be dissolved in an aqueous solution of an organic or inorganic acid. If a soluble salt form is not available, the agent can be dissolved in a suitable co-solvent or combinations of solvents.

It should be understood that the actual doses of agents used in the compositions of the present invention will vary according to the usage of an individual complex, use an individual compositions, method of administration and the place, the body's "master" and the disease requiring treatment. The optimal dose for a given set of conditions can be set by experts in this field using conventional tests used to determine doses on the basis of experimental data for the agent.

Compo is icii of the present invention can be obtained by known methods to obtain pharmaceutical compositions for example, using conventional techniques of cooking, such as mixing, dissolving, granulating, production drops, grinding, emulsification, inkapsulirovanie, linking and lyophilization. The pharmaceutical compositions can be included in the dosage form in the traditional way using one or more physiologically acceptable carriers that can be selected from fillers and additional substances that facilitate the translation process of the active compounds in pharmaceuticals, pharmaceutically applicable.

For oral administration the compounds can be easily converted into a dosage form by a combination of compounds with pharmaceutically acceptable carriers known in the art. Such media are capable of forming compounds of the present invention in the form of tablets, pills, coated tablets, capsules, liquids, gels, syrups, thick mixtures, suspensions and the like, for oral ingestion patients undergoing treatment. Pharmaceutical preparations for oral use can be obtained using solid filler in the mixture with the active ingredient (agent), optionally grinding the resulting mixture and the mixture of granules, after adding suitable additional materials, if necessary, to obtain tablets or domestic is its content drops.

The invention is further illustrated by the following accompanying working examples, which in no way limit the scope of the invention.

Examples

Example 1

5-[1-(2-Aminoquinoline-6-yl)meth-(Z)-ilidene]-2-((1R,2S)-2-phenylcyclopropane)thiazole-4-one; compound with triperoxonane acid.

Obtaining 3-ethoxy-N-(4-itfinal)acrylamide

To a solution of oxalicacid (40 g, 0,555 mol) was slowly added at 0°C ethylenically ether (105,6 g, 0.84 mol) and the mixture was stirred for 2 h at 0°C and 12 h at room temperature. After removing part of the solvent on a rotary evaporator the black mixture was heated at 120°C for 30 minutes After removal of the solvent on a rotary evaporator and then vacuum oil pump was obtained in the form of a black liquid 3-ethoxyacrylate (69,9 g), which is directly used in the next reaction stage without further purification.

To a mixture of 4-joanina (14 g, 64 mmol) and pyridine (10.5 ml, 128 mmol) in methylene chloride (85 ml) was added 3-ethoxyacrylate (10 g, 75 mmol). After stirring for 5 h were additionally added 3-ethoxyacrylate (5 g, 38 mmol) and pyridine (10.5 ml, 64 mmol). After stirring for 2 days the reaction mixture was washed with water (3×100 ml), dried over MgSO4and concentrated, produces the 3-ethoxy-N-(4-itfinal)acrylamide as a black oil (11,32 g, 56%). LC-MS m/e 318 (MN+).

Getting 6-iodide-1H-quinoline-2-it

Sulfuric acid was slowly added to 3-ethoxy-N-(4-itfinal)acrylamide (11.3 g, 36 mmol) under stirring. After stirring for 3 h the reaction mixture was slowly poured into ice (~300 g). The precipitate was collected by filtration, washed with water and dried. After flash chromatography (Merck silica gel 60, 230-400 mesh mesh, 0%-15% methanol in methylene chloride for 40 min) was isolated 6-iodide-1H-quinoline-2-he (of 7.23 g, 75%) as a black solid. LC-MS m/e 272 (MN+).

Getting 2-chloro-6-athineon

A mixture of 6-iodide-1H-quinoline-2-it (6,23 g, 23 mmol) and phosphorus oxychloride (25 ml) was heated at boiling in the atmosphere N2within 2 hours After cooling, the solvent was removed on a rotary evaporator and then vacuum oil pump. Then was slowly added to a saturated solution of sodium bicarbonate (100 ml). The solid is collected by filtration, washed with a saturated solution of sodium bicarbonate, water, dried and obtained 2-chloro-6-Athinais (5,78 g, 87%) as a black solid. LC-MS m/e 290 (MN+).

Getting 6-iodohydrin-2-ylamine

A suspension of 2-chloro-6-athineon (1 g, 3.46 mmol) in ammonium hydroxide (28%, 20 ml) was heated at 140°C for 3 days in a vacuum tube. The village is E. cooling the solvent was removed on a rotary evaporator. The solid is collected by filtration, washed with water, dried and received 6-athineon-2-ylamine (0,78 g, 84%) as a black solid. LC-MS m/e 271 (MN+).

Getting 2-aminoquinoline-6-carbaldehyde

A mixture of 6-athineon-2-ylamine (200 mg, of 0.74 mmol), triethylamine (0.26 per ml, of 1.85 mmol), diphenylpropylamine (dpp, 17 μl, 0,074 mmol) and palladium (II) acetate (17 mg, 0,074 mmol) in dry N,N-dimethylformamide (4 ml) was stirred in an atmosphere of carbon monoxide in a vacuum tube at 75 psi at room temperature for 10 minutes After adding tigecycline (of 0.53 ml, 1.5 mmol) and the mixture was stirred in an atmosphere of carbon monoxide at 75 psi for 4 h at 80°C. Then the reaction mixture was allowed to cool to 25°C, and then were extracted with methylene chloride (2×50 ml). The combined organic layers are then washed with water (3×50 ml), dried over sodium sulfate, filtered and concentrated in vacuum. After flash chromatography (Merck silica gel 60, 70-230 mesh, ethyl acetate) was obtained 2-aminoquinoline-6-carbaldehyde (30 mg, 24%) as a solid.

Getting 2-((1R,2S)-2-phenylcyclopropane)thiazole-4-it.

To a suspension of the hydrochloride of (1R,2S)-2-phenylcyclopropane of 0.85 g, 5 mmol) and rhodanine (2-thioxothiazolidin-4-it) (0.68 g, 5 mmol) in acetonitrile (20 ml) was added at room te is the temperature, N,N-diisopropylethylamine (DIEA) (2,61 ml, 15 mmol) and Then this solution was cooled to 0°C. and to it in two portions over a period of 10 min was added dichloride of mercury (1.35 g, 5 mmol). After adding the suspension was allowed to warm to room temperature and was stirred for 2 days. The obtained black solid substances were filtered through a plate of cellite and washed with ethyl acetate (500 ml). From the filtrate solvent was removed in vacuum and the solid residue was diluted with water (100 ml) and ethyl acetate (100 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with saline and dried over anhydrous magnesium sulfate. After filtration of the drying agent and removal of the solvent in vacuo was obtained a crude residue, which was purified using column chromatography on a Biotage silica gel, receiving 0,474 g (yield 42%) of 2-((1R,2S)-2-phenylcyclopropane)thiazole-4-it is in the form of a white amorphous solid: EI-HRMC (mass spectrometry high-resolution electron ionization) m/e calculated for C12H12N2OS (M+) 232,0670 found 232,0665.

Getting 5-[1-(2-aminoquinoline-6-yl)meth-(Z)-ilidene]-2-((1R,2S)-2-phenylcyclopropane)thiazole-4-it, the connection with triperoxonane acid

To a suspension of 2-aminoquinoline-6-carbaldehyde (30 mg, 0,174 mmol) and 2-((1R,2S)-2-phenylcyclopropane)is eazol-4-it (26 mg, 0.11 mmol) in toluene (1 ml) was added benzoic acid (3 mg, to 0.011 mmol) and piperidine (3 ál, to 0.011 mmol). The mixture was heated to 150°C. in microwave oven for 20 minutes After cooling to room temperature was filtered, the solid was washed with toluene and dried. The crude product was purified HPLC (sorbent for obremeniaet HPLC With 18, 10%-90% acetonitrile in water over 10 min)to give 5-[1-(2-aminoquinoline-6-yl)meth-(Z)-ilidene]-2-((1R,2S)-2-phenylcyclopropane)thiazole-4-one, compound with triperoxonane acid (36 mg, 84%) as a yellow solid substance. LC-MS m/e 271 (MN+).

Example 2

5-(2-Amino-4-ethoxyquinoline-6-ylmethylene)-2-[2-(3-forfinal)ethylamino]thiazole-4-one

Obtain 6-bromo-1H-benzo[d][1,3]oxazin-2,4-dione

A solution of 2-amino-5-bromobenzoyl acid (280 g, 1.3 mol) in acetonitrile (1.3 l) was heated to 50-55°C. was Added dropwise simultaneously pyridine (206 g, 2,61 mol) and a solution of triphosgene (128,8 g, 0.43 mol) in dichloromethane (720 ml). After complete addition, the mixture was stirred at 50-55°C for another 2 h solvent was Removed under reduced pressure and added water. The precipitate was separated by filtration, washed successively with water and chilled dichloromethane and then dried in vacuum, obtaining the desired product 6-bromo-1H-benzo[d][1,3]oxazin-2,4-dione (304 g, 98%). This substance is used and in the next stage without additional purification.

Obtaining 2-amino-6-bronchioles-4-ol.

A solution of 6-bromo-1H-benzo[d][1,3]oxazin-2,4-dione (90 g, 0,373 mol) in N,N-dimethylformamide (DMF) (400 ml) was added to a solution of malonitrile (37 g, 0.41 mol) and triethylamine (41,4 g, 0.41 mol) in DMF (150 ml) at 50-60°C. the Reaction mixture was stirred at 50-60°C for 30 minutes then Poured the reaction mixture into ice-cold 0,2n. HCl (400 ml), the precipitate was filtered and dried in vacuum. Then it was dissolved in 8h. KOH (2 l) and the solution was heated for 40 hours After cooling to room temperature the mixture was neutralized with HCl and the resulting precipitate was filtered and dried in the air, getting 2-amino-6-bronchioles-4-ol as a pale yellow solid (95 g, 97%). This substance was used in the next stage without additional purification.

Obtaining N-(6-bromo-4-hydroxyquinolin-2-yl)ndimethylacetamide

A mixture of 2-amino-6-bronchioles-4-ol (29,4 g, 0.12 mol), acetic anhydride (36,7 g, 0.36 mol) and sulfuric acid (20 ml) in glacial acetic acid (300 ml) was boiled for 30 minutes the Mixture was allowed to cool to room temperature, then poured into water. The precipitate was filtered and dried, obtaining the product N-(6-bromo-4-hydroxyquinolin-2-yl)ndimethylacetamide in the form of a brown solid (32 g, 93%). This product is used in the next stage without additional about isdi.

Obtaining N-(6-bromo-4-ethoxyquinoline-2-yl)ndimethylacetamide

A mixture of N-(6-bromo-4-hydroxyquinolin-2-yl)ndimethylacetamide (32 g, 0,114 mol), ethyl iodide (26,77 g, 0,171 mol) and potassium carbonate (130 g, 0,912 mol) in acetonitrile (250 ml) was boiled for 2 h, then the solvent was removed, and the residue triturated with water. The precipitate was isolated by filtration and dried, obtaining N-(6-bromo-4-ethoxyquinoline-2-yl)ndimethylacetamide in the form of a pale yellow solid (28 g, 80%). This product is used in the next stage without additional purification.

Obtaining N-(4-ethoxy-6-formylindole-2-yl)ndimethylacetamide

A mixture of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) and sodium formate (5 g, 48 mmol) in acetonitrile (30 ml) was saturated with nitrogen. A solution of N-(6-bromo-4-ethoxyquinoline-2-yl)ndimethylacetamide (2.5 g, 8,12 mmol) in DMSO (30 ml) was added through a rubber septum. The vessel was kept in an atmosphere of carbon monoxide (50 psi) and heated to 120°C for 30 min, then the mixture was cooled to room temperature, the acetonitrile was removed under reduced pressure, was added water and the resulting precipitate was filtered, dried, obtaining the desired aldehyde N-(4-ethoxy-6-formylindole-2-yl)ndimethylacetamide in the form of a pale yellow solid (0.8 g, 40%).

Getting 5-(2-amino-4-ethoxyquinoline-6-ylmethylene)-2-[2-(3-forfinal)ethylamino]thiazole-4-it

A solution of N-(4-ethoxy-6-formylindole-2-yl)ndimethylacetamide (example 2E, 50 mg, 0,19 mmol) in acetic acid (1.5 ml) was treated with 2-[2-(3-forfinal)ethylamino]thiazole-4-one (69 mg, 0.29 mmol) and sodium acetate (63 mg, 0.77 mmol) in a microwave synthesizer at 180°C for 60 min, was added water (0.5 ml) and the reaction mixture was stirred in a microwave synthesizer at 140°C for 15 minutes the mixture is Then extinguished 1H. NaOH, the precipitate was filtered with suction and then washed with water, ether and dichloromethane. The crude residue was then dissolved in DMF and concentrated until dry. This product is triturated with hot dioxane and filtered. The mother liquid was concentrated under reduced pressure, obtaining 5-(2-amino-4-ethoxyquinoline-6-ylmethylene)-2-[2-(3-forfinal)ethylamino]thiazole-4-one in the form of a powder (23 mg, 28%). LC-MS m/e 437 (MN+).

Example 3

2-Amino-5-(2-amino-4-ethoxyquinoline-6-ylmethylene)thiazole-4-one

A solution of N-(4-ethoxy-6-formylindole-2-yl)ndimethylacetamide (example 2E, 50 mg, 0,19 mmol) in acetic acid (1.5 ml) was treated with pseudothiohydantoin (34 mg, 0.29 mmol) and sodium acetate (63 mg, 0.77 mmol) in a microwave synthesizer at 180°C for 45 minutes the Mixture was divided between 1H. NaOH and dichloromethane. The aqueous layer containing the desired product were concentrated until dry, and the crude residue was purified of obrashennih the Oh HPLC, receiving the product as a salt with TFU (5 mg, 8%). LC-MS m/e 315 (MN+).

Example 4

N-(4-Ethoxy-6-{4-oxo-2-[(tetrahydropyran-4-ylmethylamino)-4H-thiazol-5-ylidenemethyl}quinoline-2-yl]ndimethylacetamide

Getting acetate-(tetrahydropyran-4-yl)methylamine

Chilled in an ice bath, a solution of tetrahydro-4H-Piran-4-it (7.5 g, 75 mmol) and toiletrieschoice (of 16.05 g, and 82.4 mmol) in DME (125 ml) was treated with a suspension of tert-butoxide potassium (16,8 g, 150 mmol) in tert-butyl alcohol (250 ml). The reaction mixture was stirred for 3.5 h at room temperature and then was diluted with ether (250 ml). The mixture is then washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by rapid distillation of short-fridge, getting the nitrile as a colorless oil (2,98 g). This substance was dissolved in 1M borane/tetrahydrofuran (THF) (134 ml, 134 mmol) and was stirred over night. The excess borane "extinguished" by methanol (room temperature, 1 h) and then the mixture was concentrated to a dry residue. The residue was dissolved in 4n. HCl/dioxane was stirred 1 h at room temperature and then concentrated under reduced pressure. The solid is triturated with ether and was filtered by suction. The suspension of the substance (1,81 g, to 11.9 mmol) in THF (30 ml) was treated with 1H. NaOH (11.9 ml, with 11.9 mmol) in half an hour at room temperature. Was removed by distillation of THF, the aqueous solution was saturated with NaCl and was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was treated with acetic acid (0.68 ml, with 11.9 mmol)to give after drying in a vacuum Cabinet acetate-(tetrahydropyran-4-yl)methylamine (1,71 g).

Obtaining N-(4-ethoxy-6-{4-oxo-2-[(tetrahydropyran-4-ylmethylamino)-4H-thiazol-5-ylidenemethyl}quinoline-2-yl]ndimethylacetamide

A suspension of N-[4-ethoxy-6-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)quinoline-2-yl]ndimethylacetamide (example 6A, 50 mg, 0.12 mmol) in acetonitrile (2 ml) was injected into the reaction with diisopropylethylamine (0,20 ml, 1.2 mmol) and iodine stands (0.15 ml, 2.3 mmol) at room temperature for 45 minutes the Mixture was concentrated to a dry residue, the residue suspended in acetonitrile (2 ml). Sequentially added at room temperature diisopropylethylamine (0,20 ml, 1.2 mmol) and acetate-(tetrahydropyran-4-yl)methylamine (100 mg, of 0.58 mmol) and the mixture was stirred at room temperature overnight. The residue was collected by filtration with suction, adsorbing on SiO2and was purified on a column of silica gel in a mixture of methanol-ethyl acetate, gradient 0-10%, getting a solid product (29 mg, 56%). LC-MS m/e 455 (MN+/sup> ).

Example 5

N-[6-(2-Cyclopropylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-4-ethoxyquinoline-2-yl]ndimethylacetamide

Getting 2-cyclopropylamino-4-it

The solution ethylchloride (20 g, 0.16 mol) and potassium thiocyanate (12.7 g, 0.13 mol) in ethanol (100 ml) was boiled for 3 hours Then the solution was filtered and concentrated under reduced pressure, getting to 18.7 g of ethyl ether tizianalucarini acid (97%). A mixture of acetate of cyclopropylamine (0.50 g, 4,27 mmol) and ethyl ether tizianalucarini acid (0,62 g, 4,27 mmol) was heated to 90°C for 3 h and left overnight at room temperature. Then the reaction mixture was distributed between 6N. HCl and dichloromethane. The layers were separated. The aqueous layer was podslushivaet adding 6N. the ammonium hydroxide and then concentrated until dry. The crude product is triturated with dichloromethane and the precipitate was filtered. The filtrate was dried over sodium sulfate and concentrated until dry. The crude product was cleaned by passing through a column of silica gel with 100% ethyl acetate, receiving 2-cyclopropylamino-4-one (244 mg, 37%).

Obtaining N-[6-(2-cyclopropylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-4-ethoxyquinoline-2-yl] ndimethylacetamide

A solution of N-(4-ethoxy-6-formylindole-2-yl)ndimethylacetamide (100 mg, 0,39 mmol) in acetic Ki the lot (2 ml) was treated with 2-cyclopropylamino-4-one (61 mg, 0,39 mmol) and sodium acetate (127 mg, 1.55 mmol) in a microwave synthesizer at 180°C for 90 minutes the Precipitate was collected by filtration with suction, then washed with water and ether, receiving after drying in a vacuum drying Cabinet product N-[6-(2-cyclopropylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-4-ethoxyquinoline-2-yl]ndimethylacetamide in the form of a solid (32 mg, 21%). LC-MS m/e 397 (MN+).

Example 6

N-(4-Ethoxy-6-{4-oxo-2-[2-tetrahydropyran-4-yl)ethylamino]-4H-thiazol-5-ylidenemethyl}quinoline-2-yl)ndimethylacetamide:

Obtaining N-[4-ethoxy-6-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)quinoline-2-yl]ndimethylacetamide

A solution of N-(4-ethoxy-6-formylindole-2-yl)ndimethylacetamide (400 mg, 1.55 mmol) in acetic acid (6 ml) was treated with Rodnina (320 mg, 0.29 mmol) and sodium acetate (530 mg, 6.5 mmol) in a microwave synthesizer at 160°C for 25 minutes the Precipitate was collected by filtration with suction, washed with acetic acid, water and ether, then dried in a vacuum Cabinet, receiving the intermediate N-[4-ethoxy-6-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)quinoline-2-yl]ndimethylacetamide in the form of a brown solid substance (396 mg, 68%).

Obtaining N-(4-ethoxy-6-{4-oxo-2-[2-tetrahydropyran-4-yl)ethylamino]-4H-thiazol-5-ylidenemethyl} quinoline-2-yl)ndimethylacetamide

Suspensio N-[4-ethoxy-6-(4-OK, what about the-2-thioxothiazolidin-5-ylidenemethyl)quinoline-2-yl]ndimethylacetamide (example 6A, 50 mg, 0.11 mmol) in acetonitrile (1.5 ml) were treated for 30 min at room temperature diisopropylethylamine (0,200 ml, 1.15 mmol) and iodine stands (0.15 ml, 2.3 mmol), the mixture is then concentrated until dry and the residue suspended in acetonitrile (1.5 ml). To him successively added at room temperature diisopropylethylamine (of 0.20 ml, 1.15 mmol) and 4-(2-amino-ethyl)tetrahydropyran (0.075 ml, of 0.58 mmol) and the mixture was stirred over night at room temperature. The precipitate was collected by filtration with suction and washed with acetonitrile. Then it was adsorbing on SiO2and was purified column chromatography on silica gel with a gradient of methanol/ethyl acetate 0-10%, getting the product N-(4-ethoxy-6-{4-oxo-2-[2-tetrahydropyran-4-yl)ethylamino]-4H-thiazol-5-ylidenemethyl}quinoline-2-yl)ndimethylacetamide in the form of a pale yellow solid (22 mg, 50%). LC-MS m/e 469 (MH+).

Example 7

N-(6-{2-Amino-4-oxo-4H-thiazol-5-ylidenemethyl}-4-ethoxyquinoline-2-yl)ndimethylacetamide

A suspension of N-[4-ethoxy-6-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)quinoline-2-yl]ndimethylacetamide (example 6A, 80 mg, 0.21 mmol) in acetonitrile (3 ml) was injected into the reaction with diisopropylethylamine (and 0.40 ml, 2.2 mmol) and iodine stands (0,30 ml, 4.6 mmol) for 30 min at room temperature. The mixture was concentrated until dry and the residue suspended in the MT (0.5 ml). Was added at room temperature a solution of ammonia in methanol (7n., 5 ml, 35 mmol) and the mixture was stirred at room temperature for 24 h Then the mixture was concentrated until dry and the solid residue triturated with water. The precipitate was collected by filtration with suction, then washed with water and ether and then dried in the air, getting the product as light brown solid (50 mg, 63%). LC-MS m/e 357 (MN+).

Example 8

N-[6-(2-Cyclopropylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-4-ethoxyquinoline-2-yl]ndimethylacetamide

Getting 2-cyclopropanemethylamine-4-it

A mixture of acetate of cyclopropanemethylamine (0.45 g, 3,44 mmol) and ethyl ether tizianalucarini acid (0.5 g, 3,44 mmol) was heated for 2 h at 90°C. the Reaction mixture was divided between 6N. HCl and dichloromethane. The layers were separated. The aqueous layer was podslushivaet 6N. the ammonium hydroxide and then extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The water layer is concentrated to a dry residue, which is triturated with DMF. Solution in DMF) was filtered and concentrated until dry. The residues were combined and purified on a column of silica gel with 100% ethyl acetate, receiving 2-cyclopropanemethylamine-4-one (275 mg, 47%).

Obtaining N-[6-(2-cycloprop is ylmethylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-4-ethoxyquinoline-2-yl]ndimethylacetamide

A solution of N-(4-ethoxy-6-formylindole-2-yl)ndimethylacetamide (100 mg, 0,39 mmol) in acetic acid (2 ml) was treated with 2-cyclopropanemethylamine-4-one (66 mg, 0,39 mmol) and sodium acetate (127 mg, 1.55 mmol) in a microwave synthesizer at 180°C for 2 h, the Reaction mixture is then distributed between 1N. NaOH and the mixture of ethyl acetate/dichloromethane (1:1). The organic layer was dried over sodium sulfate, filtered and concentrated until dry. The crude residue was purified column chromatography on silica gel with a gradient of methanol/ethyl acetate 0-7%, getting the product N-[6-(2-cyclopropylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-4-ethoxyquinoline-2-yl]ndimethylacetamide in the form of a solid (10 mg, 7%). LC-MS m/e 411(MH+).

Example 9

N-(6-{2-[([1,4]Dioxin-2-ylmethyl)amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-4-ethoxyquinoline-2-yl)ndimethylacetamide

A suspension of N-[4-ethoxy-6-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)quinoline-2-yl]ndimethylacetamide (example 6A, 50 mg, 0.12 mmol) in acetonitrile (1.5 ml) was injected into the reaction with diisopropylethylamine (0,20 ml, 1.2 mmol) and iodine stands (0.15 ml, 2.3 mmol) at room temperature for 30 minutes the Mixture was concentrated until dry and the residue suspended in acetonitrile (1.5 ml). Sequentially at room temperature was added diisopropylethylamine (0,20 ml, 1.2 mmol) and[1,]dioxin-2-ylmethylamino (68 mg, of 0.58 mmol) and the mixture was allowed to mix at room temperature over night. The precipitate was collected by filtration with suction, adsorbing on SiO2and was purified on a column of silica gel with 100% ethyl acetate, getting the product N-(6-{2-[([1,4]dioxin-2-ylmethyl)amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-4-ethoxyquinoline-2-yl)ndimethylacetamide in the form of a solid (34 mg, 63%). LC-MS m/e 457 (MN+).

Example 10

Pharmacological tests

Pharmacological properties of the compounds of the present invention can be confirmed by a number of pharmacological experiments. Below are examples of pharmacological experiments, which were carried out with the compounds of the invention and their salts. Compounds of the invention are CDKl/cyclin In activity with values of Kiless of 5.0 μm. This means that all these compounds are active in the inhibition of CDK-1/cyclin Century

To determine the inhibitory CDK1 activity were carried out analyses or FlashPlateTM(NENTM-Life Science Products) or HTRF (homogeneous method allowed time fluorescence). Both types of analyses kinase was performed using recombinant human CDK1/cyclin In the complex. GST (glutathione-3-transferase)-cyclin b and CDK1 cDNA clones in baculovirus vectors were provided by Dr. W. Harper from Baylor College of Medicine, Houston, TX. Proteins were coexpress iravani in High Five TMbased on insect cells, and the complex was purified on glutathione Sepharose resin (Pharmacia, Piscataway, NJ)as described previously (Harper J.W., and others, Cell, 75, 1993, s-816). BH-Histidine labeled truncated form of the protein retinoblastoma (RB) (amino acid 386-928) was used as the substrate in the analysis of CDKl/cyclin B (plastid expression was provided by Dr. Veronica Sullivan, Department of Molecular Virology, Roche Research Center, Welwyn Garden City, UK). The RB protein is a natural substrate for phosphorylation by the kinase CDK1 (see Herwig and Strauss Eur. J. Biochem., 246, 1997, s-60 and are there links). The expression 62Kd protein controlled induced by IPTG (isopropyl-beta-D-thiogalactopyranoside) promoter in strain 5 Ml of E.coli. Cells were literally ultrasound and conducted clearing through linking lysates at pH 8.0 Ni-chelated agarose column pre-treated with a 1 mm imidazole. The resin is then washed several times with buffer, gradually lowering the pH to 6.0 and was suirable 500 mm imidazole. Suirvey protein were dialyzed against 20 mm HEPES with pH 7.5, 30% glycerol, 200 mm NaCl and 1 mm DTT (dithiotreitol, the reagent Cleland). In spare peeled plums RB protein was determined by the concentration of protein was brought to the aliquots and stored at -70°C.

When conducting FlashPlate analysis kinases, 96-well plate FlashPlate covered RB protein with a concentration of 10 μg/ml using 100 µl of the cell. Plates were incubated at 4°C during the night the Lee 3 h on a shaker at room temperature. To control for nonspecific phosphorylation of a single row of cells covered by a protective buffer 100 μl/cell (20 mm HEPES, 0.2 M NaCl). Die then washed twice with washing buffer (0.01% tween-20 in phosphate-buffered saline). The test compound (test compound) was added to the cells at 5x final concentration. The reaction was initiated by the immediate addition of 40 μl of reaction mixture (25 mm HEPES, 20 mm MgCl2, 0,002% tween-20, 2 mm DTT, 1 μm ATP, 4 nm R-ATP) and a sufficient amount of enzyme, so that the signals exceeded the zero level at least ten times. Plates were incubated at room temperature on a shaker for 30 minutes, the Plates were washed four times with wash buffer, closed it, and took the readings TopCount scintillation counter (Packard Instrument Co., Downers Grove, IL). The percentage of inhibition of the phosphorylation of the RB protein, which is a measure of the inhibition of CDK activity was determined by the following formula:

100 × (1-test-connection-respecof.)/(total-respecof.)

where "test connection" refers to the average values of pulses per min test connection in the double repetition, "respecof." refers to the average values of pulses per min in the absence of CDKl/cyclina In and "total" refers to the average values of pulses per min in the absence of connection. The value of the IC50means the concentration of the tested soybean is inane, which reduces by 50% caused by protein kinase incorporation of radioactive label in the described test conditions. The amount of inhibitor constants Kiis calculated by the following equation: Ki=IC50/(1+[S]/Km), where [S] denotes the concentration of ATP and Kmmeans the Michaelis constant.

Analysis of the kinase by the method of homogeneous allowed time fluorescence (HTRF) was performed in 96-well polypropylene plates (BD Biosciences, Bedford, MA). The test compounds were first dissolved in DMSO, and then diluted with buffer 1 for analysis of kinase (25 mm HEPES, pH 7.0, 8 mm MgCl21.5 mm DTT and 162 μm ATP) concentration of DMSO 15%. CDKl/cyclin In the enzyme was diluted in buffer 2 for analysis of kinase (25 mm HEPES, pH 7.0, 8 mm MgCl2, 0,003% tween-20, 0,045% BSA, 1.5 mm DTT and 0,338 μm RB protein). To initiate the kinase reaction, 20 μl of a solution of the compound was mixed with 40 μl of a solution of CDK1/cyclin In analytical dies with a final concentration of CDK1/cyclin b and RB 0.1 ág/ml and 0,113 μm, respectively, and incubated for 30 min at 37°C. was Added 15 μl antifactor antibody (Ser 780) (Cell Signaling Technology, Beverly, MA) with antibody dilution 1:7692. Continued to incubate at 37°C for 25 min, after which cells were added labeled LANCE Eu-W1024 anti-LgG rabbit and anti-His antibody conjugated with the reagent for fluorescence SureLightAllophucocyanin (20 nm PerkinElmer, Wellesley, MA). Incubation prodoljalas 40 min at 37°C. At the end of incubation, 35 μl of the reaction mixture was placed in a fresh black polystyrene Board with 384 wells (Corning incorporated. Corning, NY) and read on a fluorescence tablet reader readings at a wavelength of excitation of 340 nm and the emission wavelength 665/615 nm.

Values of Kishowing the activity of CDK1/cyclin b, which belong to the compounds of the invention are in the range of about 0,001 microns to about 5,000 microns. Specific data for some of the following examples:

ExampleKi(µm)
10,023
30,030
50,085
70,097
93,241

1. The compound of the formula

where R1means hydrogen or R2(X)n-;
X means lower alkylene or sallisbury lower alkylene;
R2means
;
wheremeans phenyl; cycloalkyl containing 3-6 carbon atoms; 4-6-membered geteroseksualnoe ring containing 3-5 atom is in carbon and 1-2 oxygen atom;
R5, R6and R7independently selected from the group comprising hydrogen or halogen;
R4means hydrogen or -(O)k(CH2CH2O)y-R10;
R19means hydrogen;
R20means hydrogen or-C(O)-R11;
R10and R11mean lower alkyl;
n and k denote an integer from 0 to 1;
I means an integer from 0 to 3;
or their pharmaceutically acceptable salts.

2. The compound according to claim 1 of formula I-A

where R1' signifies hydrogen; and
R4, R19and R20have the meanings indicated in claim 1;
or their pharmaceutically acceptable salts.

3. The compound according to claim 2, where
R1' signifies hydrogen;
R4means -(O)k(CH2CH2O)y-R10;
R10, k and y have the meanings indicated in claim 1.

4. The compound according to claim 3, where the specified connection selected from the group including
N-(6-{2-amino-4-oxo-4H-thiazol-5-ylidenemethyl}-4-ethoxyquinoline-2-yl)ndimethylacetamide, and
2-amino-5-(2-amino-4-ethoxyquinoline-6-ylmethylene)thiazole-4-one.

5. The compound according to claim 1 of formula I-B

where R1means R2'-(X')n-;
n, R4, R19and R20have the meanings indicated in claim 1, and
X' means the lowest alkylen or sallisbury lower alkylene;
R2' means

where means phenyl; cycloalkyl ring containing 3-6 carbon atoms; 4-6-membered geteroseksualnoe ring containing 3-5 carbon atoms and 1-2 oxygen atom;
R5' and R6' are independently selected from the group comprising hydrogen or halogen;
or their pharmaceutically acceptable salts.

6. The compound according to claim 5, where
X' means the lowest alkylen;
R2' means phenyl, optionally substituted by halogen;
R4means-O-CH2-CH3;
n is 1.

7. The connection according to claim 6, where the specified connection is a 5-(2-amino-4-ethoxyquinoline-6-ylmethylene)-2-[2-(3-forfinal)ethylamino]thiazole-4-one.

8. The compound according to claim 5, where
X' means the lowest alkylen;
R2' means a heterocyclic ring containing 3-5 carbon atoms and 1-2 oxygen atom;
R4means-O-CH2-CH3;
n is 1.

9. The connection of claim 8, where the specified connection selected from the group including
N-(4-ethoxy-6-{4-oxo-2-[2-(tetrahydropyran-4-yl)ethylamino]-4H-thiazol-5-ylidenemethyl}quinoline-2-yl)ndimethylacetamide;
N-(4-ethoxy-6-{4-oxo-2-[(tetrahydropyran-4-ylmethylamino)-4H-thiazol-5-ylidenemethyl}quinoline-2-yl]ndimethylacetamide; and
N-(6-{2-[([1,4]dioxin-2-ylmethyl)amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-4-ethoxyquinoline-2-yl]ndimethylacetamide.

10. The compound according to claim 5, where
X' means the lowest alkylen;
R2' means cyclopropyl;
R4means bodoro the or-O-CH 2-CH3;
n is 0 or 1.

11. The connection of claim 10, where the specified connection selected from the group including
N-[6-(2-cyclopropylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-4-ethoxyquinoline-2-yl]ndimethylacetamide;
N-[6-(2-cyclopropylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-4-ethoxyquinoline-2-yl]ndimethylacetamide; and
5-[1-(2-aminoquinoline-6-yl)meth-(Z)-ilidene]-2-((1R,2S)-2-phenylcyclopropane)thiazole-4-one.

12. The compound of formula I according to claim 1, having inhibitory activity against CDK1 kinase.

13. Pharmaceutical composition having inhibitory activity against CDK1 kinase, comprising one or more compounds of the formula I according to claim 1 together with pharmaceutically acceptable excipients.

14. The compound of formula I according to claim 1 to obtain drugs having inhibitory activity against CDK1 kinase.

15. The compound of formula I according to claim 1 for obtaining a medicinal product intended for the treatment of cancer, particularly solid tumors.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (XXI) where values of R1, Y, Ra and Rb are given in subparagraphs 1 and 2 of the formula of invention, as phosphatidylinositol-3-kinase inhibitors, a pharmaceutical composition based on said compounds and their use.

EFFECT: compounds can be used for treating and preventing diseases mediated by phosphatidylinositol-3-kinase.

5 cl, 5 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I)

Values of radicals R1-R6 are given in the formula of invention. The compounds inhibit protein kinase MEK1/2. Also described is a pharmaceutical composition for administration in diseases mediated by MEK1/2.

EFFECT: compounds are highly efficient.

16 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to cyclic derivatives of aminobenzoic acid and to their pharmaceutically acceptable salts of general formula , in which ring Ar is a phenyl group, a 5-member aromatic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, sulphur and oxygen, or a benzothiazolyl group; where the said groups can have 1-2 substitutes selected from a group comprising lower alkyl; a phenyl group; a phenyl group substituted with 1-2 halogens; a phenyl group substituted with a lower alkoxy group; a phenyl group substituted with a halogen-substituted lower alkyl group; a phenoxy group substituted with a halogen; a halogen; Z is an oxygen atom or -(CH2)-n (where n equals 0, 1 or 2); Y is C1-C4 alkylene, C2-C4 alkenylene or general formula (2) -T-A-U- (2) in which T is a single bond, C1-C4 alkylene or C2-C4 alkenylene; U is single bond, C1-C4 alkylene; values of the rest of radicals are given in the formula of invention.

EFFECT: obtaining a PPARα, agonist which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid, and an agent which reduces the level of lipids which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid.

12 cl, 16 tbl, 184 ex

FIELD: chemistry.

SUBSTANCE: agent is a 6-bromo-5-methoxy-indole-3-carboxylic acid derivative of general formula (I) , where B is a N(R)2 group, where both R groups together with the nitrogen atom to which they are bonded form a 5-6-member heterocyclic ring containing 1-2 heteroatoms selected from nitrogen, such as pyrrolidine, piperidine, piperazine or morpholine, where each of the said heterocyclic rings can be substituted with C1-4alkyl, phenyl, benzyl, phenethyl, carbonylamino, -COOC1-4alkyl group or -COOC1-4alkyl group and phenyl, which can also be substituted or have substitutes selected from halogen, C1-4alkyl, C1-4alkoxy, and alkyl in the said groups can be linear or branched; R1 is C1-4alkyl, phenyl, possibly substituted with C1-4alkyl or C1-4alkoxy, halogen atoms; R2 is -S-phenyl, -S-benzyl, -O-phenyl, where in each of the said groups, the phenyl ring is possibly substituted with C1-4alkyl, C1-4alkoxy, halogen atoms, or R2 denotes a -N(R)2 group, or pharmaceutically acceptable salts thereof.

EFFECT: agent has antiviral activity towards influenza A virus.

3 dwg, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[1-(methylsulfonyl) piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[4- (methylsufonyl)phenyl]acetamide or its pharmaceutically acceptable salts. The invention also relates to a method for synthesis of the compound in paragraph 1, as well as to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with activity towards CCR5 (chemokine receptor 5).

6 cl, 6 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention concerns derivatives of thiazolidine-4-one of general formula (I) and general formula (II), to their isomers and pharmaceutically acceptable salts which can be used as a medical product with immunosuppressive activity. In formulae (I) and (II), R1 and R14 independently represent lower alkyl, lower alkenyl; cycloalkyl; 5,6,7,8-tetrahydronaphth-1-yl; phenyl group or phenyl group independently mono- or disubstituted with lower alkyl, halogen, lower alkoxy or group -CF3; R2 and R15 independently represent lower alkyl; allyl; cyclopropyl; or di- lower alkylamino; R3 represents -NR5R6 or -O-CR7R8-CR9R10-(CR11R12)n-O-R13; R23 represents hydrogen; hydroxycarbonyl-lower alkyl or 1-glyceryl. Values of the other radicals are specified in the patent claim. The invention also concerns application of one or more compounds of general formula (I) or (II) for preparation of a medical product with immunosuppressive activity.

EFFECT: agent exhibits improved efficiency.

24 cl, 1 tbl, 157 ex

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

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of common formula IC1: , where A represents cyano; B represents hydrogen; R1, R2, R3 and R4 independently represent hydrogen; alkyl; halogen or nitro; R5 and R6 independently represent hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heteroarylalkyl; alkenyl; carboxyalkyl; cyanoalkyl; diphenylalkyl; aryl, arylalkoxyaryl, arylalkyl, arylalkylaryl, arylcarbonylaryl or aryloxyaryl, or R5 and R6, together with atom of nitrogen, to which they are connected, create heterocyclic ring system; or to salts of such compound; at the same time "heteroaryl" used separately or in combination, is related to mono-, bi- or tricyclic aromatic ring system, which contains up to 14 atoms included in ring, in which at least one ring contains at least one heteroatom, independently chosen from nitrogen, oxygen or sulfur, besides specified heteroaryl group may be unsubstituted or substituted with one to three substituents, independently selected from alkyl and alkoxy; "diphenylalkyl" is related to alkyl group, where each of two atoms of hydrogen is substituted with unsubstituted phenyl group; "aryl" is related to carbocyclic group, selected from group, which consists of phenyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, antryl, phenantryl, fluorenyl, indanyl, 2,3-dihydrobenzo[1,4]dioxynyl and benzo[1,3]dioxolyl group, besides specified aryl group may be unnecessarily substituted with functional groups in number from one to three, which are separately and independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, cyano, halogen, halogenlkoxy, halogenalkyl and nitro groups, where in certain specific cases, if aryl group represents condensed system from several rings, in which not all the rings are aromatic, one of carbon atoms of which is not included into aromatic ring may be in oxidised condition, and according fragment of ring -CH2- will be substituted by fragment-C(O); "arylalkoxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkoxygroup, where aryl group is unsubstituted; "arylalkyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkyl group, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "aryloxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via oxygen bridge, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "arylcarbonyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via carbonyl group, where aryl group is unsubstituted; "heterocyclic ring system", used separately or in combination, is related to monocyclic, bicyclic or polycyclic ring system, which contains up to 15 atoms included into ring, at least one of which represents heteroatom, independently selected from nitrogen, oxygen or sulfur, besides specified ring system may be saturated, partially unsaturated, unsaturated or aromatic, where specified heterocyclic fragment may be unnecessarily substituted with one or more substituents, every of which separately and independently is selected from group made of halogen and halogenalkyl, excluding the following compounds: {3-[(E)-2-cyano-2-(4-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-m-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(3-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-phenylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-benzylcarbamoyl-2-cyanovinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-o-tolylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-t-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(4-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-ethylphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2~cyano-2-(4- ethoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-isopropylcarbamoylvinyl)indole-1-yl]acetic acid; {3-[(E)-2-cyano-2-(3-etoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-[[2-(1H-indole-3-yl)ethyl]amino]-3-oxo-1-propenyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-chlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-(4-methyl-piperidine-1-yl)-3-oxopropenyl]indole-1-yl}acetic acid; {3-[(E)-2-(3-chloro-4-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(3-phenylpropylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2,3-dichlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-(5-chloro-2-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxybenzylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; and {3-[(E)-2-cyano-3-oxo-3-(4-phenyl-piperazine-1-yl)propenyl]indole-1-yl}acetic acid. Invention is also related to pharmaceutical composition, and also to application of compounds of clause 1.

EFFECT: production of biologically active compounds, which have activity of antagonist coupled with G-protein of chemoattractant receptor of molecules homologue released by Th2-cells.

11 cl, 156 ex, 8 tbl

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I) compounds and to their use in treating diseases related to lipid storage disorders, such as atherosclerosis and diabetes. In R1 represents hydrogen, alkyl, halogen, formyl, hydroxyalkyl or trifluoromethyl, R2 represents hydrogen, alkyl or halogen, R3 represents hydrogen or alkyl, R4 represents hydrogen, alkyl, hydroxy or alkoxy, R5 and R6 are chosen from hydrogen, alkyl, phenylalkyl, hydroxyalkyl, alkoxycarbonyl and phenyl, A represents aryl or heterocyclyl, m equals 0-3, n equals 0-1, p equals 0-3, sum of m, n and p equals 1-4, the bond between carbon atoms Ca and Cb is a single or double carbon-carbon bond.

EFFECT: obtaining new biologically active compounds.

27 cl, 147 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: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts and esters. The disclosed compounds have inhibitory effect on cyclin-dependant kinase. In formula I R1 denotes , R3 is selected from a group consisting of H, CO2R6, C(O)R6, SO2R6 and SO2NR5R6, R5 and R6 are each independently selected from a group which includes H and (lower)alkyl, R2 is phenyl which contains one, two or three substitutes independently selected from a group which includes halogen or -O-(lower)alkyl.

EFFECT: preparation of a pharmaceutical composition which contains an effective amount of a formula I compound as an active ingredient.

6 cl, 1 tbl, 22 ex

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