Cyclic inhibitors of protein-tyrosine kinases

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide of the formula: and to its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition inhibiting activity of protein-tyrosine kinases and comprising the indicated compound, a method for treatment of disorders associated with protein-tyrosine kinases, such as an immune disorder, and oncology disease, and a method for cancer treatment.

EFFECT: valuable biochemical and medicinal properties of compounds and composition.

5 cl, 2 tbl, 581 ex

 

The area to which the invention relates.

This invention relates to cyclic compounds and their salts, to methods of using such compounds to treat disorders caused proteinkinase, such as immunological or oncological disorders, and to pharmaceutical compositions containing such compounds.

Background of invention.

Proteincontaining (RTC, HSS) are enzymes, which are in connection with ATP (ATP) as a substrate phosphorylate tyrosine residues in peptides and proteins. These enzymes are key elements in the regulation of signal transmission in cells, including proliferation and differentiation of cells. RTC include, among other things, the receptor tyrosine kinase (RPTK), including members of the family kinases epidermal growth factor (e.g., HER1 and R2), platelet-derived growth factor (PDGF) and kinases that play a role in angiogenesis (Tic-2 and KDR); in addition, preceptories tyrosine kinase, including members of their families Syk, JAK and Src (for example, Src, Fyn, Lyn, Lck, and Blk) (see Bolen, J.B., Rowley, R.B., Spana, C., and Tsygankov, A.Y., The src family of tyrosine protein kinases in hemopoietic signal transduction (Src-family proteincontaining in hemopoietic signal transduction), FASEB J., 6, 3403-3409 (1992); Ullrich, A. and Schlessinger, J., Signal transduction by receptors with tyrosine kinase activity (Signal transduction under the action of receptors with tyrosinekinase the second activity), Cell 61, 203-212 (1990); and Ihle, J.N., The Janus protein tyrosine kinases in hematopoietic cytokine signaling (Janus-proteincontaining in signaling in hematopoietic cytokines), Sem. Immunol., 7, 247-254 (1995).

Increased activity RTC entails a number of malignant and non-malignant proliferative diseases. In addition, RTC play a major role in the regulation of immune cells. The RTK inhibitors may therefore affect a large number of cancer and immunological disorders. Such disorders can be reduced (to weaken) by selective inhibition of a specific receptor or preceptory RTC, such as Lck, or, due to the homology between classes RTC, by inhibiting more than one RTC with inhibitor. RTC special interest, Lck is detected in T-cells, where it is part of fosfauriliruetsa key protein substrates. It is required for efficient antigen-receptor signal transduction and cell activation. In the absence of Lck activity Zeta(ξ)-chain T-cell receptor (TJC) not fosfauriliruetsa kinase ZAP-70 is not activated and does not occur immobilization of CA2+essential for activation of T cells (see Weiss, A. and Zittman, D. R., Signal transduction by lymphocyte antigen receptors (Signal transduction through receptor antigens of lymphocytes). Cell 76, 263-274 (1994); Iwashima, M., Irving, B. A., van Oers, N.S.C., Chan, A. C.,and Weiss, A., Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases (Sequential interaction of the TCR with two distinct cytoplasmic tyrosine kinases), Science, 263, 1136-1139 (1994), and Chan, A. C., Dalton, M., Johnson, R., Kong, G., Wang, T., Thoma, R., and Kurosaki, T., Activation of ZAP-70 kinase activity by phosphorilation of tyrosine 493 is required for lymphocyte antigen receptor function (For receptor function antigen lymphocyte activation ZAP-70 kinase activity by phosphorylation of tyrosine 493), EMBO J., 14, 2499-2508 (1995). Thus, inhibitors of Lck applicable for the treatment of disorders mediated by T-cells, such as chronic diseases with an important T-cell component, such as rheumatoid arthritis, multiple sclerosis and lupus, as well as acute diseases, in which T cells play a significant role, such as acute graft rejection and reaction of delayed hypersensitivity (DTN).

The essence of the invention.

This invention comprises a cyclic compound of the following formula I and their salts, useful as inhibitors proteincontaining

where Q represents:

(1) 5-membered heteroaryl cycle;

(2) 6-membered heteroaryl cycle or

(3) aryl cycle;

optionally substituted by one or more groups R1;

Z represents:

(1) simple connectivity;

(2) -R15C=CH - or

(3) -(CH2) m-where m is 1-2;

X1and X2each represents hydrogen or together form =O or =S;

R1means:

(1) hydrogen, or R6,

where R6denotes alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl, arylalkyl, heterocycle or heteroseksualci, each of which is unsubstituted or substituted Z1, Z2and one or more (preferably one or two) groups Z3;

(2) HE or OR6;

(3) -SH or-SR6;

(4) -C(O)2H, -C(O)qR6or-O-C(O)qR6where q denotes 1 or 2;

(5) -SO3N or-S(O)qR6;

(6) halogen (halogen);

(7) cyano;

(8) nitro;

(9) -Z4-NR7R8;

(10) -Z4-N(R9)-Z5-NR10R11;

(11) -Z4-N(R12)-Z5-R6;

(12) -P(O)(OR6)2;

R2and R3each independently represents

(1) hydrogen, or R6,

(2) -Z4-R6or

(3) -Z13-NR7R8;

R4and R5:

(1) each independently represents hydrogen or R6;

(2) -Z4-N(R9)-Z5-NR10R11;

(3) -N(R9Z4R6or

(4) together with the nitrogen atom to which they are bound, form a 3-8-membered saturated or unsaturated heterocycle, unsubstituted or zames the config with substituents Z 1, Z2and Z3, and the heterocycle may optionally be condensed with a benzene ring, which, in turn, is unsubstituted or has the substituents Z1, Z2and Z3;

R7, R8, R9, R10, R11and R12:

(1) each independently represents hydrogen or R6;

(2) R7and R8may together designate alkylen, albaniles or heteroalkyl forming a 3-8-membered saturated or unsaturated cycle with the nitrogen atom to which they relate, and the cycle is unsubstituted or substituted with substituents Z1, Z2and Z3or

(3) any two of R9, R10and R11may together designate alkylen or albaniles forming a 3-8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are linked, and this ring is unsubstituted or substituted with substituents Z1, Z2and Z3;

R13means:

(1) cyano;

(2) nitro;

(3) -NH2;

(4) -NH;

(5) HE;

(6) -NHO;

(7) -NHCOO;

(8) -NHCOO;

(9) -NHSO2alkyl;

(10) -NHSO2aryl;

(11) aryl;

(12) heteroaryl;

(13) -Alkyl or

(14) -Auril;

R14means:

(1) -NO2;

(2) -Coolkill or

(3) Sooory;

R15means:

(1) hydrogen;

(2) alkyl;

(3) aryl

(4) arylalkyl or

(5) cycloalkyl;

Z1, Z2and Z3each independently represents:

(1) hydrogen or Z6where Z6means (i) alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, aryl, aralkyl, alkylaryl, cycloalkyl, heterocycle or heterocyclyl; (ii) a group (i), which itself has as substituents or more identical or different groups (i); or (iii) a group (i) or (ii)which has as substituents one or more of the following groups, (2)to(16), denoting Z1, Z2and Z3;

(2) -Onli-OZ6;

(3) -SH or-SZ6;

(4) -C(O)qH, -C(O)qZ6or-O-C(O)qZ6;

(5) -SO3H, -S(O)qZ6; or-S(O)qN(Z9Z6;

(6) halogen (halogen);

(7) cyano;

(8) nitro;

(9) -Z4-NZ7Z8;

(10) -Z4-N(Z9)-Z5-NZ7Z8;

(11) -Z4-N(Z10)-Z5-Z6;

(12) -Z4-N(Z10)-Z5-H;

(13) oxo;

(14) -O-C(O)-Z6;

(15) any two of Z1, Z2and Z3may together designate alkylen or albaniles, forming together with the nitrogen atoms to which they are attached, a saturated or unsaturated cycle or

(16) any two of Z1, Z2and Z3may together denote-O-(CH2)r-O, where r denotes 1-5, forming acadeny or unsaturated 4-to 8-membered cycle together with the atoms with which they are associated;

Z4and Z5each independently represents:

(1) simple connectivity;

(2) -Z11-S(O)q-Z12-;

(3) -Z11-C(O)-Z12-;

(4) -Z11-C(S)-Z12-;

(5) -Z11-O-Z12-;

(6) -Z11-S-Z12-;

(7) -Z11-O-C(O)-Z12or

(8) -Z11-C(O)-O-Z12-;

Z7, Z8, Z9and Z10:

(1) each independently represents hydrogen or z6;

(2) Z7and Z8or Z6and Z10may together designate alkylen or albaniles forming a 3-8-membered saturated or unsaturated cycle together with the atoms to which they relate, and this cycle is unsubstituted or substituted with substituents Z1, Z2and Z3or

(3) Z7or Z8together with Z9can indicate alkylen or albaniles forming a 3-8-membered saturated or unsaturated cycle together with the nitrogen atoms to which they relate, and this cycle is unsubstituted or substituted with substituents Z1, Z2and Z3;

Z11and Z12each independently represents:

(1) simple connectivity;

(2) alkylene;

(3) albaniles or

(4) akinyan;and

Z13means:

(1) simple connectivity;

(2) -Z11-S(O)q-Z12-;

(3) -Z11-C(O)-Z12-;

(4) -Z11-C(S)-Z12-;

(5) -Z11-O-Z12-;

(6-Z 11-S-Z12-;

(7) -Z11-O-C(O)-Z12-;

(8) -Z11-C(O)-O-Z12-;

(9) -C(NR13)-;

(10) -C(CHR14)- or

(11) -C(C(Rl4)2)-.

Compounds corresponding to the formula I include compounds of the following formula II and their salts

where n denotes 1 or 2;

And are selected from carbon and nitrogen;

Choose from nitrogen, oxygen and sulfur;

X2denotes oxygen or sulfur, and

R1, R2, R3, R4and R5have the above values.

Detailed description of the invention.

In the present description uses the following definitions.

The initial group definition or term in this specification applies to that group or term throughout this description, separately or as part of another group, unless otherwise specified.

The term Ala or alkyl refers to hydrocarbon groups with linear or branched chain containing 1-12 carbon atoms, preferably 1-8 carbon atoms. The expression lower alkyl refers to alkyl groups with 1-4 carbon atoms.

The term alkenyl refers to linear or branched hydrocarbon groups of 2-10, preferably 2-4 carbon atoms, containing at least one double bond. If Alchemilla group linked to the nitrogen atom, it is preferable that the group does not b the La is connected directly via a carbon atom at the double bond.

The term quinil refers to linear or branched hydrocarbon groups of 2-10, preferably 2-4 carbon atoms, containing at least one triple bond. If Alchemilla group is associated with nitrogen, it is preferable that such a group was not linked directly via a carbon atom when a triple bond.

The term alkylen refers to a linear chain bridge of 1 to 5 carbon atoms connected by the ordinary ties (e.g.,- (CH2)x-where x denotes 1-5), which may have as substituents 1-3 lower alkyl groups.

The term albaniles refers to the line bridge from 2 to 5 carbon atoms containing one or two double bonds, which is connected by the ordinary ties and may have as substituents 1-3 lower alkyl groups. Examples alkenylamine groups are-CH=CH-CH=CH-, -CH2-CH=CH-, -CH2-CH=CH-CH2-, -C(CH3)2CH=CH-and-CH(C2H5)-CH=CH-.

The term akinyan refers to the line bridge from 2-5 carbon atoms containing a triple bond, linked by the ordinary ties which may have as substituents 1-3 lower alkyl groups. Examples alkenylamine groups are CH≡C-, -CH2-C≡C-, -CH(CH3)-C≡C-and-C≡-CH(C2H5)CH2-. The term ar (ar) or aryl refers to aroma the systematic cyclic groups (for example, 6-membered monocyclic, 10-membered bicyclic or 14-membered tricyclic systems)that contain 6-14 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl and anthracene.

The term cycloalkyl or cycloalkenyl refers to cyclic hydrocarbon groups of 3-12 carbon atoms.

The terms halogen and halogen (halo) are fluorine, chlorine, bromine or iodine. The term unsaturated cycle covers partially unsaturated and aromatic cycles.

The terms heterocycle, heterocyclic and heterocycle refer to fully saturated or unsaturated, including aromatic (i.e. heteroaryl) cyclic group, for example, 4-7-membered monocyclic, 7 to 10 membered bicyclic, or 10 to 15 membered tricyclic system containing at least one heteroatom having at least one carbon atom in the ring. Each cycle heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur, where the nitrogen and sulfur may optionally be oxidized, and the nitrogen may optionally be quaternity. Heterocyclic group may be associated with any heteroatom or carbon atom of the cycle or cyclic system. Examples of monocyclic heterocyclic groups include pyrrolidin is l, pyrrolyl, pyrazolyl, oxetanyl, pyrazolines, imidazoles, imidazolines, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, diazolidinyl, isothiazolin, isothiazolinones, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinil, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, 2-oxoazetidin, azepine, 4-piperidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiomorpholine, themorphological, themorphological, 1,3-dioxolane and tetrahydro-1,1-DIOXOLANYL, thiazolyl, triazinyl etc.

Examples of bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothiazyl, hinokitiol, chinoline, tetrahydroisoquinoline, ethenolysis, benzimidazolyl, benzopyranyl, indolizinyl, benzofuran, chromones, coumarinyl, benzopyranyl, cinnoline, honokalani, indazoles, pyrrolopyridine, properidine (such as furo [2,3-C] pyridinyl, furo[3,2-b]pyridinyl or furo[2,3-b]pyridinyl), dihydroisoquinolyl, dihydroquinazolines (such as 3,4-dihydro-4-oxothiazolidine), tetrahydroquinoline etc.

Examples of tricyclic heterocyclic groups include carbazolyl, bunzendahl, phenanthrolines, acridines, phenanthridines, xantener etc. the Term heteroaryl refers to aromatic the sky heterocyclic groups. Examples of heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolin, furyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, triazinyl etc.

If q denotes 1 or 2, -C(O)qH represents-C(O)-N or-C(O) -; - C(O)qR6 or -C(O)qZ6 denote, respectively, -C(O)-R6or-C(O)-OR6or-C(O)-Z6or-C(O)-OZ6; -O-C(O)qR6 or -O-C(O)qZ6 denote, respectively, -O-C(O)-R6or-O-C(O)-OR6or-O-C(O)-Z6or-O-C(O)-OZ6; - S(O)qR6 or -S(O)qZ6 denote, respectively, -SO-R6or-SO2-R6or-SO-Z6or-SO2-Z6.

The compounds of formula I may in some cases to form salts, which are also included in the scope of this invention. It is clear that the reference to the compound of formula I in the present description includes a reference to salts thereof, unless otherwise specified. The term Sol(s), as it is used herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. Zwitterion (internal salt) are included in the term Sol(s) in this description, and may be formed, for example, when the substituent R contains the remainder of the acid, such as carboxylic the group). Also in this description included Quaternary ammonium salts such as salts of alkylamine. Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although used and other salts, for example, in the stages of separation and purification, which can be used upon receipt. Salts of compounds of formula I can be formed, for example, by the reaction of compound I with a certain amount of acid or base, such as an equivalent amount, in a medium such as the medium in which the salt precipitates or in an aqueous medium followed by lyophilization.

Examples of salts of joining acids include acetates (such as salts formed with acetic acid or trihalomethanes acid, for example with triperoxonane acid), adipinate, alginates, ascorbates, aspartate, benzoate, bansilalpet, bisulfate, borates, butyrate, citrates, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, econsultancy, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, lactates, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrates, oxalates, pectinate, persulfates, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylates, succinate, sulphates (that is s as sulfate, formed with sulfuric acid), sulfonates (such as mentioned in this description), tartratami, thiocyanates, toluensulfonate, undecanoate etc.

Examples of basic salts (formed, for example, if the substituents contain the remainder of the acid, such as carboxyl group) include ammonium salts, alkali metal salts, such as salts of sodium, lithium and potassium, salts of alkaline earth metals such as calcium salts and magnesium salts of organic bases (for example, organic amines)such as benzathine, dicyclohexylamine, geranamine, N-methyl-D-glucamine, N-methyl-D-glucamine, tert-butylamine and salts with amino acids such as arginine, lysine and tposnova nitrogen-containing groups can quaternization under the action of such agents as lower alkylhalogenide (for example, methyl-, ethyl-, propyl - and butylchloride, bromides and iodides), diallylsulfide (for example, dimethyl-, diethyl-, dibutil and dimycolate), long chain halides (e.g. decyl-, lauryl-, myristyl and sterilgarda, bromides and iodides), aralkylated (for example, benzyl and phenylboronic) and others.

This paper also discusses the prodrugs and the solvate of the compounds according to the invention. The term prodrugas used herein, denotes a compound that with the introduction of his subject, undergoes chemical PR is rotation by metabolic or chemical processes, giving the compound of formula I or its salt and/or MES. The solvate of the compounds of formula I preferably are hydrates.

All stereoisomers of these compounds, such as stereoisomers that may exist due to the presence of asymmetric carbon atoms in the substituent R of the compounds of formula I, including enantiomeric and diastereomeric forms, are considered in the scope of this invention. Individual stereoisomers of the compounds according to the invention can, for example, be substantially free of other isomers, or may be mixed, for example, in the form of racemates or mixed with all other, or other selected stereoisomers. Chiral centers present invention can have the S - or R-configuration, defined according to the recommendations of the IUPAC 1974.

Throughout the description of the group and the substituents in them are chosen so that formed stable fragments and connections.

The preferred connection.

Preferred compounds according to this invention are the compounds of formula I and their salts, in which Q denotes the thiazole and in which one or more, and especially all of the Z, X1, X2, R1, R2, r3, R4and R5choose from the following values:

Z denotes the ordinary (simple) correlation;

R1selected from hydrogen, halogen, alkyl, aryl, alkoxy,alkoxycarbonyl or aryloxyalkyl, and more preferred is hydrogen;

X1and X2together form =O or =S, and more preferably form =O;

R2denotes hydrogen;

R3choose from a-Z4-R6or-Z13-NR7R8and more preferred is-Z4-R6where Z4represents a simple bond, and R6denotes aryl or heteroaryl, unsubstituted or substituted with substituents Z1, Z2and with one or more (preferably one or two) groups Z3;

R4denotes hydrogen and

R5selected from aryl groups or heteroaryl groups, which have substituents Z1, Z2and one or more (e.g. one or two) of Z3.

Methods of obtaining.

The compounds of formula I can be obtained by such methods, which are illustrated in the following schemes a-E and I-XI. Solvents, temperatures, pressures and other reaction conditions can easily choose an ordinary specialist in the field of technology. All cited references are introduced in this description as references in its entirety. The original substances are produced by the industry or can easily obtain an ordinary specialist in the field of technology. The composition of the compounds is given either in the description or specifically listed in the schema.

The methods described in this description, it is possible the OS is out, conducting the reaction of starting compounds and/or reagents in solution or, where appropriate, one or more of the original substances or reagents may be on a solid substrate (see (1) Thompson, L. A., Ellman, J. A., Chemical Reviews, 96, 555-600 (1996); (2) Terrett, N. K., Gardner, M., Gordon, D. W., Kobylecki, R. J., Steele, J., Tetrahedron, 51, 8135-8173 (1995); (3) Gallop, M. A., Barrett, R. W., Dower, W. J., Fodor, S. P. A., Gordon, M. E., Journal of Medicinal Chemistry, 37, 1233-1251 (1994); (4) Gordon, M. E., Barrett, R. W., Dower, W. J., Fodor, S. P. A., Gallop, M. A., Journal of Medicinal Chemistry, 37, 1385-1401 (1994); (5) Balkenhohl, F., von demLansky, A., Zechel, C., Angewandte Chemie-International Edition in English, 35, 2288-2337 (1996); (6) Balkenhohl, F., von demLansky, A., Zechel, C., Angewandte Chemie, 108, 2436-2487 (1996), and (7) Sofia, M. J., Drugs Discovery Today, 1,27-34 (1996)).

Scheme a illustrates a General method for obtaining compounds Ia, which is a compound of formula I, where X1and X2together form =O. As shown in Scheme A, compound Ia, where R2and R3denote hydrogen, can be formed by saponification of i (R* denotes carboxyl-protective group, such as alkyl or arylalkyl) followed by reaction with the amine iii is known from the prior art methods. Or i can respond with R2L, where L denotes a leaving group such as halogen (for example, in equimolar ratios), optionally followed by reaction with R3L (for example, in equimolar ratios) form ii. Or i may be subject to recovery aminating using the appropriate aldehyde or ketone with education ii. Compound ii can then omelets and react with the amine iii in conditions known to experts in the art, forming Ia, where R2and/or R3mean is other than hydrogen.

Methods of obtaining the preferred substituents in the compounds of the first data illustrated in the following Schemes I-XI

The scheme illustrates the General method for obtaining compounds Ib, which is a compound of formula I, where Z represents-CH=CH-, and X1and X2together form =o As shown in the Diagram, 2-galoisienne vi can be obtained by reaction of the corresponding substituted 2-amino compounds ia with a halide of copper (ii) and alkylnitrates, such as tert-butylnitrite, in an aprotic solvent such as acetonitrile, forming 2-galoisienne iv (see J. Het. Chem. 22, 1621 (1985)). Compound iv can be recovered by using a reducing agent such as detribalized in ethanol or aqueous tetrahydrofuran, with the formation of alcohol, which can oxidize so oxidant, as chlorproma pyridinium or pyridinium dichromate, with the formation of aldehyde v. Compound v can react with alkyl(triphenylphosphonium)acetate with education vi. Compound vi can omelets and then react with the amine iii is known to experts in the art ways with education vii. Compound vii may react with the amine R2R3NH education Ib where Z represents-CH=CH-, a X1and X2together form =o Or the compounds of formula Ib, where R1and R2denote N, can be obtained by the reaction of compound vii with an appropriate substituted benzylamino, such as 4-methoxybenzylamine, with the formation of compound ix, which can be subjected to hydrogenolysis or treated with acid, such as triftoratsetata and triperoxonane acid, in the presence of anisole with the formation of Ib, where R1and R2denote hydrogen.

Methods of obtaining the preferred substituents in the compounds I are illustrated in the following Schemes I-XI.

The diagram illustrates a General method for obtaining compounds of IC, which is a compound of formula I, where Z denotes-R15C=CH-and X1and X2together form =o As shown in the Diagram, 2-aminosidine ia may react with CHLOROFORMATES or dicarbonate, forming an x, which can be omelet and process organolithium reagent with the formation of compound xi. Compound xi can react with alkyl(triphenylphosphine)acetato the subsequent removal of the urethane protective group education xii. Or the connection of Ic, where R2and R3denote hydrogen, can be obtained by saponification xii and subsequent reaction with the amine R4R5NH carried out by well-known specialists in the field of engineering methods. Or compound xii may react with R2L, where L denotes a leaving group such as halogen (for example, in equimolar ratios), optionally followed by reaction with R3L (for example, in equimolar proportions) with the formation of xiii, which can omelets and react with the amine R4R5NH-known to experts in the art methods with the formation of Ia, where a value of R2and/or R3is other than hydrogen.

Methods of obtaining the preferred substituents in the compounds I are illustrated in the following Schemes I-XI.

Scheme D illustrates a General method to obtain the connection Id, which is a compound of formula I, where X1and X2together form =S. the compounds of formula Ia obtained according to Scheme A, can be transformed into the corresponding thioamide Id with the use of such a reagent as the reagent Lawesson (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide (see Bull. Soc. Chim. Belg.,87, 223 (1978)).

Methods of obtaining the preferred substituents of the compounds I is illustrated in predstavleniya Schemes I-XI.

Scheme E illustrates a General method for obtaining compounds of S, which is a compound of formula I, where X1and X2each denotes hydrogen. As shown in Scheme E, the compound of formula Id, obtained according to Scheme D, can be converted into the corresponding amine Ie restore, for example, Raney Nickel. Methods of obtaining the preferred substituents in the compounds of the first data illustrated in the following Schemes I-XI.

As shown in Scheme I, the carboxylate i can respond with CHLOROFORMATES or dicarbonate with the formation of 1. Compound 1 can be treated with a base such as sodium hydride, sodium/potassium hexamethyldisilazide or diisopropylamide lithium (LDA), and an alkylating agent R2X, where X denotes a halogen, a R2preferably represents alkyl, arylalkyl or cycloalkyl, and then omelet wodnym base, such as potassium hydroxide, with the formation of 2. Or 1 may be subjected to reductive aminating, using the appropriate aldehyde or ketone, and the saponification aqueous base, such as potassium hydroxide, with the formation of 2. Or connection 1 can easily omelet such water base as potassium hydroxide, to form a 3, where R2denotes hydrogen.

Acid 2 may easyroute with the amine iii in the conditions, well known from the prior art for the synthesis of the peptide bond (see, for example, Bodanszky and Bodanszky, The Practice of Peptide Chemistry, Springer-Verlag, 1984; Bodanszky, Principles of Peptide Synthesis, Springer-Verlag, 1984) with the formation of the connection Id, which is a compound of formula I, where X1and X2together form =O, R3means COOR6and since 2 is a source connection, R2denotes alkyl, arylalkyl or cycloalkyl. For example, reagents that activate the carboxyl group of 2 to reaction with the amine iv, include bis(2-oxo-3-oxazolidinyl)fatfingered) (THIEF chloride), benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium hexaflurophosphate (THIEF reagent), [O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium] hexaflurophosphate (HTAU) and carbodiimide, such as dicyclohexylcarbodiimide (DCC) or 3-ethyl-3'-(dimethylamino)propellerpowered (EDCI), alone or in combination with hydroxybenzotriazole. Or activated intermediate ester can be selected, and then treated with the appropriate amine iv in aprotonin a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF) in the presence of a base, for example an organic base, such as hexamethyldisilazide sodium/potassium, triethylamine, diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or inorganic bases such as carbonate intothree is, potassium or cesium or sodium hydride or potassium. Or the acid chloride acid 2 can be obtained for example by reaction with thionyl chloride or oxalylamino with subsequent reaction with the amine iii, which leads to the connection If that is a compound of formula I, where R3means COOR6X1and X2together form =O and R2denotes alkyl, arylalkyl or cycloalkyl.

Reactions similar to reactions used above for the conversion of 2 in the If, can be used to convert 3 in If, where R3means COOR6X1and X2together form =O and R2denotes hydrogen.

As shown in Scheme II, acid 4, where R2and R3not represent hydrogen, and are chosen so that the nitrogen to which they relate, is not the main, is reduced to aldehyde 5 methods well izvestnimi from the prior art (see March, Advanced Organic Chemistry, Wiley, 1985). For example, the acid 4 can be converted into the corresponding ester followed by reduction with diisobutylaluminium. Or acid 4 can be restored to the corresponding alcohol, for example, by treatment with borane/THF, LiAlH4or restoration of the mixed anhydride with subsequent oxidation to the aldehyde 5 with the use of Cr(VI) (for example, pyridineboronic, RCC) or in terms of enjoyment of the Nations Swarna or Moffat (for example, with (COCl)2/dimethylsulfoxide). The original acid 4 can be obtained, for example, by saponification ii.

Reductive amination (see Hudlicky, Reduction in Organic Chemistry, Wiley, 1984) of aldehyde 5 with the amine iii in the presence of a reducing agent such as NaBH3CN, NaBH3(SLA)3(AC=acetyl), or with hydrogen on palladium catalyst gives Amin Ig, which is a compound of formula I, where X1and X2each denotes hydrogen and R2and R3every one is not a hydrogen atom.

As shown in Scheme III, restoration of acid 4 in the primary alcohol (for example, by treatment with a reagent is borane/tetrahydrofuran, LiAlH4recovery or mixed anhydride) with subsequent transformation by methods well known in the prior art (see March, Advanced Organic Chemistry, Wiley, 1985), gives 6, which contains a leaving group such as halogen, tosylate (OTs), mesilate (OMs) or triphala (OTf). Group R2and R3are chosen so that the resulting nitrogen to which they relate, is not the main. Compound 6 can then be converted into the compound Ih, is a compound of formula I, where X1and X2each represents hydrogen, and R2and R3every one is not a hydrogen atom, a substitution reaction with the amine iii, preferably, when does the excess amine iii.

Scheme IV illustrates the methods that can be used to obtain compounds Ij, Ik, Il, Im and In. Ij, ik, Il, Im and In are the compounds of formula I, where R2refers to any group, by definition, R3denotes acyl or toallow group, X1and X2are not hydrogen atoms, and R1not a primary or secondary amine. Ij, Ik, Il, Im and In are other specific substituents as defined in the Diagram below. The original compound Ii can be obtained by the relevant methods described in Schemes a and D.

Amide Ij can be obtained by treatment of amine Ii carboxylic acid 7 in the presence of reagents which activate carboxyl group in the above reactions, for example the THIEF reagent HATU and carbodiimide, such as DCC or EDCI, alone or in combination with hydroxybenzotriazole. Or the acid chloride of the acid 8 can react with the amine Ii in the presence of catcher acid, such as diisopropylethylamine. Appropriate thioamide Ik can be obtained by treatment of the amide Ii (where X1X2not equal to 0) reagent Lawesson, as described above.

Carbamate II can be obtained by treatment of amine Ii chloroformiate 9 or dicarbonate 10 in the presence of islamologists (Converter), such as diisopropylethylamine. Urea Im can be obtained by treatment of amine Ii or 1) x is orformula 9, such as phenylcarbamate, followed by reaction with amine 11;

2) carbamoylation 12 in the presence of islamologists, such as diisopropylethylamine; or 3) by reaction with isocyanate 13A (where Rcin Im=N). The corresponding thiourea In can be obtained by treatment of amine Ii thioisocyanate 13b.

Rachoose from the groups included in the definition of R6so the group-C(=A)-Rarepresents acyl or toallow group falling under the definition of (designation) R3. Rbor Rcchoose from the groups covered by the definition of R7and R8so the group-C(=A)-N(Rb)(Rc) is amylou or toallow group falling under the definition of R3.

Scheme V illustrates a method that you can use to get the IP, which is a compound of formula I, where R2refers to any group, by definition, other than acyl, and which is chosen so that the nitrogen with which it is associated, is the principal, R3denotes alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl, aralkyl or rich heterocycle, a X1and X2do not denote hydrogen. The original connection Io and Iq can be obtained by the relevant methods described in Schemes a and D.

As shown in Scheme V, Amin Io reacts with al what digicam or ketone 14 in the conditions of reductive amination, as described above, gives the amine Ip. Ip connection can also be obtained by treating amine Iq, where R2and R3denote hydrogen, tert-butylnitrite or sodium nitrite in the presence of a halide of copper(II) with the formation of Alojamientos connection 15 with the subsequent substitution on the amine 16 in the presence of a base such as sodium hydride or potassium and the like(see Lee et al., J. Heterocyclic Chemistry, 22,1621 (1985)).

Rdand Reindependently selected from hydrogen, alkyl, aryl, cycloalkyl or cycloalkenyl, or together they represent alkylene or albaniles forming a 3-8-membered saturated or unsaturated cycle, so -(CH)(Rd)(Re) refers to a group falling under the definition of R3.

As shown in Scheme VI, when R2refers to any group, by definition, other than acyl, and is selected so that the nitrogen from cotrim it is associated, is the principal, R3denotes aryl or heteroaryl, a X1and X2not denote hydrogen, amine Ir, can react with helodrilinae or halogetonglomeratus group 17 in the presence of palladium (0) catalyst (see J. Am. Chem. Soc., 118, 7215 (1996)), giving Amin Is, which is a compound of formula I having the particular substituents described in this scheme. The original connection Ir can be obtained using appropriate methods, is written in the diagrams a and D.

As shown in Scheme VII, when R2refers to any group definition, and R3refers to heteroaromatic group, Amin It can respond, if necessary, in the presence of a base with 2-galoidzamyescyennykh heteroaromatic compound 17 where Q together with the atoms to which it is linked, forms a 5 - or 6-membered monocyclic or 10-12-membered bicyclic heteroaromatic group (for example, forms a 2-chloropyridine or 2-chloropyrimidine), giving Amin Iu, where Iu is a compound of formula I having the particular substituents described in this scheme. The original connection It is possible to obtain the corresponding methods described in schemes a and D.

As shown in Scheme VIII, thiourea In (where X1and X2do not represent hydrogen) can react with an appropriate amine in the presence of bis(2-oxo-3-oxazolidinyl)fatfingered (THIEF-chloride), benzotriazol-1 yloxy-Tris(dimethylamino)phosphodiesterase (THIEF-reagent), [O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium]hexaflurophosphate (HATU) and carbodiimide, such as dicyclohexylcarbodiimide (DCC), or 3-ethyl-3'-(dimethylamino)propellerpowered (EDCI), or diisopropylcarbodiimide (DIC)in the presence of organic base, such as triethylamine, diisopropylethylamine or dim delamination in solvents, such as dimethylformamide, dichloromethane or tetrahydrofuran, with the formation of compound Iv, which is a compound of formula I having the particular substituents described in this Scheme. Or a connection In may react with an appropriate amine in the presence of mercury salts (II), such as mercury chloride (II), or other known literature methods, form Iv.

As shown in Scheme IX, Ir Amin (where X1and X2do not represent hydrogen) can react with diphenylcarbonate, either alone or in the presence of a base such as sodium hydride, hexamethyldisilazide sodium or dimethylaminopyridine, acetonitrile, tetrahydrofuran or dimethylformamide at room or elevated temperatures with the formation of compound Iw. Connection Iw can react with the amine R7R8NH education with Iv, which is a compound of formula I having the particular substituents described in this Scheme.

As shown in Scheme X, the Ir connection (where X1and X2do not represent hydrogen) can react with 18 or 19 either by itself, or in the presence of a base such as sodium hydride, hexamethyldisilazide sodium or dimethylaminopyridine in dimethylformamide or tetrahydrofuran at room or increase the military temperature to form compounds Ix or Iy, respectively, which react with the amine R7R8NH at room or elevated temperatures to form compounds Iz or Iz*, respectively. Connection Iz is a compound of formula I having the particular substituents described in this Scheme. Connection Iz* is a compound of formula I having the particular substituents described in this Scheme.

As shown in Scheme XI, the compounds of formula I can also be obtained from 15 processing certain amine in the presence of an acid catalyst (see, for example, Gunzenhauser et al., Helv. Chim. Acta, 71, 33 (1988)).

Application.

The compounds of this invention inhibit proteincontaining, in particular kinases of the Src family, such as Lck, Fyn, Lyn, Src, Yes, Hck, Fgr and Bik, and therefore applicable for the treatment, including prevention and therapy, due to proteinkinase disorders such as immunologic and oncologic disorders. The compounds also inhibit receptor tyrosine kinase, including HER1 and HER2 and therefore applicable for the treatment of proliferative disorders such as psoriasis and cancer. The ability of these compounds to inhibit HER1 and other receptor kinases also enable their use as antiangiogenic agents for the treatment of disorders such as cancer and diabetes being patia. Disorders (disorder)caused proteinkinase, represent such disorders that arise due to aberration tyrosinekinase activity and/or which are attenuated when the inhibition of one or more of these enzymes. For example, Lck inhibitors are important for the treatment of a number of such violations (for example, in the treatment of autoimmune diseases), as inhibition of Lck blocks the activation of T cells. Treatment mediated T-cell diseases, including inhibition of the activation and proliferation of T cells, is a particularly preferred variant of the present invention. Compounds that selectively inhibit T-cell activation and proliferation, are preferred. Compounds according to this invention, which block the activation of RTK endothelial cells due to oxidative stress, thereby limiting the surface expression or adhesion molecules, which induce the binding of neutrophils and which inhibit RTK required for the activation of neutrophils, applicable, for example, for the treatment of ischemic and reperfusion injury.

The invention therefore encompasses methods of treatment of disorders caused proteinkinase, including the stage of introduction to a subject in need this, at least one of the compounds of formula I in an amount effective for this purpose. Other therapeutic agents, such as described below may be used with the compounds according to the invention by the present methods. In the methods according to this invention such(s) other(s) therapeutic(s) agent(s) can be entered before the introduction of the compound(s) according to this invention, simultaneously with or after him.

The use of compounds according to this invention in the treatment of disorders caused by proteincontaining, is illustrated as an example, without limitation, the treatment of a number of disorders such as transplant rejection (e.g. organ transplant, urgent transplant, hetero - or homotransplantation (which is used for burns)); protection from ischemic or reperfusion injury such as ischemic or reperfusion injury during organ transplantation, myocardial infarction, stroke, or other factors; and the induction of tolerance to the graft; arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis; chronic obstruction pulmonary (chronic obstructive pulmonary disease (COPD)such as emphysema, inflammatory bowel disease, including ulcerative colitis and Crohn's disease (Crohn); lupus (systemic lupus erythematosus); disease graft-versus-host; allergic reactions, mediated by T-cells, vkluchaetsia allergic reaction, allergic reaction of the delayed type and gluten enteropathy (coeliac disease coeliac); psoriasis; contact dermatitis (including dermatitis after contact with poison ivy is taking root, poison ivy); Hashimoto's thyroiditis; Sjogren syndrome; autoimmune hyperthyroidism, such as graves ' disease (Graves); Addison disease (autoimmune disease of the adrenal glands); autoimmune pluriglandular disease (also known as autoimmune pluriglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; hypopituitarism; Guillain-Barre syndrome; other autoimmune diseases; cancers, including malignant tumors, where Lck or other Src kinase-family, such as Src are activated and sverkhekspressiya, such as colon carcinoma and thymoma, and cancers where the activity of Src family kinases facilitates the growth or viability of the tumor; glomerulonephritis; serum sickness; urticaria; allergic diseases such as respiratory allergies (asthma, hay fever, allergic rhinitis) or skin allergies; scleroderma (scleracierma); mushroom mycosis fungoides; acute inflammatory responses (such as acute respiratory distress syndrome and ischemic/reperfusion injury); dermatomyositis; alopecia areata; HRO is practical radiation dermatitis; eczema; Behcet's disease; pustular atrophicans; pyoderma gangrenosum; syndrome Cesari; diffuse atopic dermatitis; systemic sclerosis and annular scleroderma. The invention also includes a method of treating the above disorders such as diffuse neurodermatitis (atopic dermatitis), the introduction of any compound capable to inhibit proteincontaining.

The Src kinase family, other than Lck, such as Hck and Fgr, important for FC-gamma receptor responses of monocytes and macrophages. The compounds of this invention inhibit Fc gamma-dependent production of TNF-alpha in cell lines monocytes TNR-1, which expresses not Lck. The ability to inhibit Fc gamma receptor-dependent macrophage and macrophage responses reported in the additional anti-inflammatory activity of these compounds in addition to their actions on T-cells. This activity is particularly important, for example, for the treatment of inflammatory diseases such as arthritis or inflammatory bowel disease. In particular, these compounds are important for the treatment of autoimmune glomerulonephritis and other cases of glomerulonephritis caused by deposition of immune complexes in the kidney, which run Fc gamma receptor response, leading to the defeat of kidneys.

In addition, the Src kinase family, other than Lck, such as Lyn Src, important for the called Fc Epsilon receptor degranulation of mast cells and basophils, which play a role in asthma, allergic rhinitis and other allergic diseases. Fc Epsilon receptors are stimulated by IgE-antigen complexes. The compounds of this invention inhibit induced Fc Epsilon the degranulation, including cell line basophils RBL, which expresses not Lck. The ability to inhibit Fc Epsilon receptor-dependent response of mast cells and basophils leads to additional anti-inflammatory activity of these compounds, in addition to their actions on T-cells. In particular, these compounds are important for the treatment of asthma, allergic rhinitis and other allergic diseases.

The combined activity of these compounds against monocytes, macrophages, T-cells, etc. may be important for the treatment of any of the above disorders. In a specific embodiment of the invention the compounds of this invention are used to treat the above as examples of disorders irrespective of their etiology, for example for the treatment of transplant rejection, rheumatoid arthritis, multiple sclerosis, chronic obstruction of the lungs, inflammation of the intestine, lupus, disease / graft versus host, mediated T-cell hypersensitivity, psoriasis, Tyr is the go Hashimoto, of Guillain-Barre syndrome, malignant tumors, contact dermatitis, allergic diseases such as allergic rhinitis, asthma, ischemic and reperfusion injury, atopic dermatitis, due or not due to RTC.

Due to their ability to inhibit kinase HER1 and HER2 compounds according to this invention can also be used to treat proliferative diseases, including psoriasis and cancer. It has been shown that the receptor kinase HER1 expresses and is activated in many solid tumors including non-small cell lung cancer, colon cancer and breast cancer. Similarly, HER2 receptor kinase has been shown to be sverkhekspressiya in breast cancer, ovarian, lung, and stomach. Monoclonal antibodies, which negatively modulate the proliferation of HER2-receptor or inhibit signaling by HER2 receptor, as demonstrated preclinical and clinical studies, have antitumor activity. Therefore, it is expected that inhibitors of kinases HER1 and HER2 will be effective in the treatment of tumors that depend on the signal transmission from any of the two receptors. It is expected that these compounds are effective either as a single agent, or in combination with other chemotherapeutic agents, such as paclitaxel (Taxol, Taxol, doxorubicin hydroch Oric (adriamycin) and cisplatin (Platinol, platinol). Cm. the following materials and references cited in this description: Cobleigh, M. A., Vogel, C. L., Tripathy, D., Robert, N. J., Scholl, S., Fehrenbacher, L., Wolter, J. M., Paton, V., Shak, S., Lieberman, G., and Slamon, D. J., Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease (International study of the effectiveness and security gumanitarnogo anti-R2 monoclonal antibodies in women with R2-sverkhekspressiya metastatic breast cancer that progressed after chemotherapy in disease with metastasis), J. of Clin. OncoL, 17(9), R. 2639-2648 (1999); Baselga, J., Pfister, D., Cooper, M. R., Cohen, R., Burtness, B., Bos, M., D'andrea, G., Seidman, A., Norton, L., Gunnett, K., Falcey, J., Anderson, V., Waksal, H., and Mendelsohn, J., Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and combination with cisplatin (Research phase I receptor antiepidermal factor growth of the chimeric antibody C225, single and in combination with cisplatin), J. Clin. OncoL, 18(4), R. 904-914 (2000).

This invention also encompasses pharmaceutical compositions containing at least one of the compounds of formula I, is able to treat due to proteincontaining disorder in amounts effective for this purpose, and a pharmaceutically acceptable carrier or diluent. The compositions of this invention may contain other therapeutic agents as described below, and can be prepared, nab is emer, with conventional solid or liquid carriers or diluents, as well as pharmaceutical additives that match the route of administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) by methods well known in the prior art for pharmaceutical preparations.

The compounds of formula I can be entered in any appropriate manner, for example orally in the form of tablets, capsules, granules or powders; sublingual; transbuild; parenteral, such as subcutaneous, intravenous, intramuscular or gluteal injection or infusion (e.g., in the form of a sterile aqueous or nonaqueous solutions or suspensions for injection); intranasally, for example in the form of a spray for inhalation; topically, such as in the form of a cream or ointment; rectally, for example in the form of suppositories; in standard doses containing non-toxic pharmaceutically acceptable carriers or diluents. These compounds can, for example, to enter in a form suitable for instantaneous or prolonged action. Instant or prolonged action is achieved by the use of suitable pharmaceutical compositions containing this compound, or, in particular, in the case of prolonged action, the use of devices such as subcutaneous implants or osmotic pumps. Data connection mo is but also be entered using liposomes.

Examples of compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting volume, alginic acid or sodium alginate as a suspending agent, methylcellulose to increase viscosity and sweeteners or flavoring additives known from the prior art; tablets instant action, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, fillers, substances that contribute to the grinding, diluents and lubricants, for example, known from the prior art. These compounds can be delivered through the oral cavity using the sublingual and/or translocating (hominids) introduction. Molten tablets, compressed tablets or freeze-dried tablets are examples of forms that can be used. Examples of compositions include compositions comprising this(s) compound(I) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. In such formulations may include high molecular weight excipients such as cellulose (avicel) or polyethylene glycol (PEG, PEG). Such formulations may also contain excipient promoting adhesion to the mucous Obolo is e, such as hydroxypropylcellulose (GOC, LDCs), hypromellose (receiver array), sodium carboxymethyl cellulose (SCMC), a copolymer of maleic anhydride (e.g., Gantrez), and agents for the regulation of allocation (action), such as polyacrylic copolymer (e.g., Carbopol 934). Lubrication, substances that promote ingestion, flavorings, colorants and stabilizers can also be added for ease of manufacture and application.

Examples of compositions for administration via nasal aerosol or inhalation include solutions in saline which can contain, for example, benzyl alcohol or other suitable preservatives, promoters suction to increase the bioavailability and/or other solubilizing or dispersing agents such as, for example, known from the prior art.

Examples of compositions for parenteral administration include solutions or suspensions for injection, which may contain, for example, suitable non-toxic parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, ringer's solution, isotonic sodium chloride or other suitable dispersing or moisturizing and suspendresume agents, including synthetic mono - or diglycerides, and fatty acids, including oleic acid. Examples of compositions for rect the high injection include suppositories, which may contain, for example, suitable not annoying excipient, such as cocoa butter, synthetic glycerides or polyethylene glycol that is solid at ordinary temperatures, but origaudio and/or dissolve in the rectal cavity with the release of medicinal substance.

Examples of compositions for the local introduction include local media, such as Plastibase (mineral oil, forming a gel with polyethylene).

An effective amount of the compounds of this invention can determine an ordinary specialist in the field of technology, it includes exemplary dosage for an adult is about 0.1-100 mg/kg of body weight of active compound per day, which can be entered as a single dose or in the form of individual small (separate) doses, for example, 1-4 times a day. It is clear that a particular level of dose and frequency of dosing for each particular subject may vary and depends on several factors, including the specific activity of the applied compound, the metabolic stability and length of action of that compound, the species, age, body weight, General health, sex, diet of the patient, method and time of administration, rate of excretion, combination of drugs and the severity of the particular condition. Preferred subjects for treatment include animals, most the e preferred mammals, such as people and Pets, such as dogs, cats, etc. are prone to disorders caused proteinkinase.

Compounds according to this invention can be applied separately or in combination with each other and/ or with other suitable therapeutic agents suitable for the treatment of disorders caused by proteinkinase such agents, as inhibitors of RTK, other than the RTK inhibitors according to this invention, anti-inflammatory, antiproliferative and chemotherapeutic agents, immunosuppressants, anticancer agents and cytotoxic agents.

Examples of such other therapeutic agents include the following: cyclosporine (e.g., cyclosporin A), CTLA4-Ig, antibodies such as anti-ICAM-3 receptor, anti-IL-2 (Anti-TAC), anti-D45R, anti-CD2, anti-D3 (OCT-3), anti-CD4, anti-CD80, anti-D86, monoclonal antibody OKT, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e CD154), slit proteins, designed from CD40 and gp39 (CD40Ig and CD8gp39)inhibitors, such as inhibitors of nuclear (nuclear) translocation, NF-Kappa b function, such as desoxypeganine (DSG), non-steroidal anti-inflammatory drug substance (NSAID)such as ibuprofen, steroids, such as prednisone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs, such as azathiprine and cyclophosphamide, inhibitors of TNF-αsuch as tenidap, antibodies against TNF or soluble TNF receptor such as etanercept (Enbrel), rapamycin (sirolimus or Rapamune), Leflunomide (Arava), and inhibitors of cyclooxygenase-2 (MOR-2), such as celecoxib (Celebrex) and refexes (Vioxx), or derivatives thereof, and RTK inhibitors, are described in the following patent applications U.S. entered links this description in its entirety: Serial No. 60/056770 filed 25.08.97; Serial No. 60/069159 filed 09.12.97; Serial No. 09/097338 filed 15.06.98; Serial No. 60/056797 filed 25.08.97; Serial No. 09/094797 filed 15.06.98; Serial No. 60/065042 filed 10.11.97; Serial No. 09/173413 filed 15.10.98; Serial No. 60 076 789, filed 04.03.98, and Serial No. 09 262 525, filed 04.03.99 (Applications for the same patent attorney for rooms QA202*, QA202a*, QA202b, QA205*, QA205a, QA207*, QA202a, QA208* and QA208a. Cm. the following materials and references cited hereinafter: Hollenbauch, D., Douthwright, J., McDonald, V., and Aruffo, A., Cleavable CD40Ig fusion proteins and the binding to sgp39 (Split CD40Ig proteins and binding sgp39), J. Immunol. Methods (Netherlands), 188(1), p. 1-7 (Dec. 15 of 1995); Hollenbauch, D., Grosmaire, L. S., Kullas, C. D., Chalupny, N. J., Braesch-Andersen, S., Noelle, R. J., Stamenkovic, I., Ledbetter, J. A., and Aruffo, A., The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with cell costimulatory actinity (Human T-cell antigen gp39, a member of the CE is ASTA TNF gene, represents a ligand of CD40 receptor: expression of a soluble form of gp39 with b-cell co-stimulatory activity); EMBO J (England), 11(12), R. 4313-4321 (Dec 1992); and Moreland, L. W., et al., Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein (Treatment of rheumatoid arthritis fused protein: receptor recombinant human necrosis factor tumor cells (p75)-Fc.

Examples of classes of anti-cancer and cytotoxic agents include, but are not limited to alkylating agents such as nitrogen mustard oil, alkyl sulphonates, nitrosamine, ethylenimine and triazine; antimetabolites such as folate antagonists, purine analogues, and pyrimidine; antibiotics such as anthracyclines, bleomycin, mitomycin, dactinomycin, and plicamycin; enzymes such as L-asparaginase; inhibitors farnesylation-transferase; hormonal agents such as glucocorticoids, estrogens (antiestrogens, androgens/antiandrogens, progestins, and antagonists of luteinizing hormone - releasing hormone, octreotide; agents that destroy microtubules, such as ecteinascidins or their analogs and derivatives; agents, stabilizing microtubules, such as paclitaxel (Taxol®), docetaxel (Taxotere®), and epothilones A-F or their analogues, or derivatives, herbal products, such as Vinca alkaloids, peptopro is oxine, taxanes; and topoisomerase inhibitors; inhibitors Plenipotentiaries; and mixed agents, such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, coordination complexes of platinum, such as cisplatin and carboplatin; and other agents used as anti-tumor and cytotoxic agents, such as biomodulatory, growth factors; immune modulators and monoclonal antibodies. Compounds according to the invention can also be used in combination with radiation therapy. Representative examples of these classes of antineoplastic (anti-cancer and cytotoxic agents include, without limitation, mechlorethamine hydrochloride, cyclophosphamide, chlorambucil, melphalan, ifosfamide, busulfan, carmustin, lomustin, semustine, streptozocin, thiotepa, dacarbazine, methotrexate, tioguanin, mercaptopurine, fludarabine, pentostatin, cladribine, cytarabine, fluorouracil, doxorubicin hydrochloride, daunorubicin, idarubitsin, bleomycin sulfate, mitomycin C, actinomycin D, saracini, saframycin, chinacartimes, discodermolide, vincristine, vinblastine, vinorelbine, tartrate, etoposide, teniposide, paclitaxel, tamoxifen, estramustine, estramustine, flutamide, buserelin, leuprolide, pteridine, dainty, levamisole, flacon, interferon, interleukins, aldeslakin, filgrastim, sargramostim, rituximab (rituximab), BG, tretinoin, irinotecan hydrochloride, betamethasone, gemcitabine hydrochloride, altretamine and topotecan and any analogues and derivatives.

Preferred representatives of these classes include, without limitation, paclitaxel, cisplatin, carboplatin, doxorubicin, karminomitsin, daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C, ecteinascidin 743, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or derivatives podofillotoksina, such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, laurasian, vindesine and Laursen (leurosine).

Examples of antineoplastic (anticancer and other cytotoxic agents include the following: derivative epothilone, as shown in the patent application U.S. Serial No. 09/506481, filed February 17, 2000 (No LD186 the patent attorney); the patent Germany 4138042.8; International applications WO 97/19086, WO 98/22461, WO 98/25929, WO 98/38192, WO 99/01124, WO 99/02224, WO 99/02514, WO 99/03848, WO 99/07692, WO 99/27890, WO 99/28324, WO 99/43653, WO 99/54330, WO 99/54318, WO 99/54319, WO 99/65913, WO 99/67252, WO 99/67253 and WO 00/00485; inhibitors of cyclin-dependent kinases, as found in the International application WO 99/24416, and inhibitors prenyl-proteincenter, as found in International applications WO 97/30992 and WO 98/54966.

Other therapeutic agents, when used in combination with the compounds according to this invention can use is taken, for example, in the quantities listed in the Directory of the doctor (Physicians' Desk Reference (PDR)or in some other way, opredelyaem an ordinary person skilled in the technical field.

The following tests can be used to determine the activity of compounds (test connection) as an inhibitor of RTK.

Compounds described in the examples below, were tested by one or more of these analytical methods and proved to be active.

Enzyme analysis using Lck, Fyn, Lyn, Hck, Fgr, Src. Bek or Yes.

The following analysis is performed using proteincontaining Lck, Fyn, Lyn, Hck, Fgr, Src, Bek and Yes.

Need proteincontaining incubated in the buffer for kinase (20 mm MOPS, pH 7, 10 mm MgCl2in the presence of the test compound. The reaction is initiated by adding the substrate to a final concentration of 1 μm ATP, 3,3 µci/ml [R] gamma-ATP, and 0.1 mg/ml denatured acid enolase (prepared as described in Cooper, J. A., Esch, F. S., Taylor, S. S., and Hunter, T., Phosphorylation sites in enolase and lactate dehydrogenase utilized by tyrosine protein kinases in vivo and in vitro (Sites of phosphorylation in enolase and lactate-dehydrogenase used proteinkinase in vivo and in vitro), J. Biol. Chem., 259, 7835-7841 (1984)). The reaction is stopped after 10 minutes by adding 10% trichloroacetic acid, 100 mm sodium pyrophosphate, and then 2 mg/ml bovine serum albumin. Protein labeled substrate enolase besieging the I at 4 degrees, going for tablets Packard Unifilter and is on Topcount scintillation counter in order to ensure inhibitory proteinkinase activity of the test compounds (activity is inversely proportional to the amount of protein labeled with enolate). The exact concentration of the reactants and the amount of radioactive label if necessary may vary.

This analysis is preferable, as it makes use of an exogenous substrate (enolase) for a more accurate study of the kinetics of the enzyme, and it can be performed in 96-well format, which is easily automated. In addition, labeled His proteincontaining (described below) provide a much higher the yields and purity compared with the fused protein GST-proteinkinase.

Proteincontaining can be obtained from industrial sources described below or recombinant methods. To obtain recombinant human Lck Lck get labeled His fused protein using the baculovirus vector (Life Technologies, Gibco) pFastBac Hta (manufacturing industry) in insect cells. cDNA encoding human Lck, highlighted by PCR (polymerase chain reaction)is inserted into the vector and the protein Express, using the methods described by the manufacturer. Lck purified by affinity chromatography. About producera the years of Lck in insect cells using baculovirus, see Spana, C., O'rourke, E. C., Bolen, J. C., and Fargnoli, J., an Analysis of tyrosine kinase p561ck, as expressing the protein of glutathione S-transferase in the cells of Spodoptera frugiperda, Protein expression and purification, Vol.4, p. 390-397 (1993). Similar methods can be used for other recombinant kinases of the Src family.

Enzyme analysis with the use of HER1 or HER2.

The desired compounds analyzed in the buffer for kinase, which contains 20 mm Tris-HCl, pH 7.5, 10 mm MnCl2, 0.5 mm dithiothreitol, bovine serum albumin 0.1 mg/ml poly(glu/tyr, 4:1) with 0.1 mg/ml, 1 μm ATP, and 4 µci/ml of [gamma33P]ATP. Poly(glu/tyr, 4:1) is a synthetic polymer that serves as the phosphoryl acceptor and comes Sigma Chemicals. The kinase reaction initiated by adding the enzyme, and the reaction mixture incubated at 26°C for 1 hour. The reaction is stopped by adding EDTA to 50 mm, and the protein precipitated by adding trichloroacetic acid to 5%. Precipitated proteins extracted by filtering through a tablet Packard Unifilter and using a Topcount scintillation counter to determine the radioactivity quantified.

To obtain recombinant HER1 cytoplasmic sequence to Express a receptor in insect cells in the form of a fused protein with GST, which is purified by affinity chromatography as described above for Lck. The cytoplasmic sequence of HER2 subcloning in expressing the vector of the tank is of lovirus pBlueBac4 (Invitrogen) and Express in the form of unlabeled protein in insect cells. Recombinant protein partially purified by ion exchange chromatography.

Cellular analyses.

(1) Cellular tyrosine phosphorylation.

T-Jurkat cells incubated with the test compound and then stimulated by adding antibody to CD3 (monoclonal antibody G19-4). Cells are lysed after 4 minutes, or through another period of time, adding a buffer to lysine containing the detergent NP-40. Phosphorylation of protein detect by Western blot turns anti-phosphotyrosine. Detection of phosphorylation of specific proteins of interest, such as ZAP-70, spend immunoprecipitate with antibody against ZAP-70, followed by immunoblotting with anti-phosphotyrosine. Such techniques are described in Schieven, G. L., Mittler, R. S., Nadler, S. G., Kirihara, J. M., Bolen, J. C., Kanner, S. C., and Ledbetter, J. A., ZAP-70 tyrosine kinase, CD45 and T cell receptor involvement in UV and H2O2induced T cell signal transolution (Part ZAP-70 tyrosine kinase, CD45 and T-cell receptor induced in the UV and H2About2signal transduction of T cells), J. BioL Chem., 269, 20718-20726 (1994) and presented in this article and the links. Lck inhibitors inhibit the tyrosine phosphorylation of cellular proteins induced by antibodies against CD3.

About getting G19-4, see Hansen, J. A., Martin, P. J., Beatty, P. G., dark, E. A., and Ledbetter, J. A., Human T lymphocyte cell surface molecules defined by the workshop monoclonal antibodies (surface Molecules in human T lymphocytes, defined shop MES the clonal antibodies) in Leukocyte Typing I, A. Bernard, J. Boumsell, J. Dausett, C. Milstein, and S. Schlossman, eds. (New York: Springer Verlag), p. 195-212 (1984); and Ledbetter, J. A., June, C. H., Rabinovitch, P. S., Grossman, A., Tsu, T. T., and Imboden, J. C., Signal transduction through CD4 receptors: stimulatory vs. inhibitory activity is regulated by CD4 proximity to the CD3/T cell receptor (Signal transduction through receptors CD4: the ratio of stimulatory/inhibitory activity is regulated by proximity to CD4 CD3/T-cell receptor), Eur. J. ImmunoL, 18, 525 (1988).

(2) Analysis of calcium.

The Lck inhibitors block the mobilization of calcium in T cells stimulated with antibodies against CD3. The load cell calcium indicator dye Indo-1, treated with antibody against CD3, such as monoclonal antibody G19-4. and mobilizing the measured flow cytometry by detecting changes in the ratio of blue/purple for Indo-1 as described in Schieven, G. L., Mittler, R. S., Nadler, G. S., Kirihara, J. M., Bolen, J. C., Kanner, S. C., and Ledbetter, J. A., ZAP-70 tyrosine kinase, CD45 and t cell receptor involvement in UV and H2O2induced T cell signal transolution (Part ZAP-70 tyrosine kinase, CD45 and T-cell receptor in the induction of UV and H2O2signal transduction of T cells), J. Biol. Chem., 269, 20718-20726 (1994) and presented in this article and the references.

(3) Determination of cell proliferation.

The Lck inhibitors inhibit the proliferation of normal human T cells in the peripheral blood, the growth of which is stimulated by antibodies against CD3 plus antibodies against CD28. 96-well plate pokr is provide a monoclonal antibody to CD3 (G19-4), give the antibody is able to communicate, and then washed tablet. The antibody associated with the tablet, serves to stimulate the cells. In wells add normal human T-cells peripheral blood together with the test compound plus antibodies against CD28 to ensure costimulation. After a preset period of time (e.g. 3 days) to cells add [3H]-thymidine and after further incubation for embedding tags in the newly synthesized DNA of cells collect and consider using a scintillation counter to determine cell proliferation.

The following examples illustrate variants of the present invention and does not purport to limit the scope of the invention.

Abbreviations used in the examples are explained below. Connection examples are represented by the numbers of the example and the stage at which they are derived (for example, 1A means: the title compound of stage a of example 1), or only the number of example, if the compound is the title compound of the example (for example, 2 denotes the title compound of example 2).

Abbreviations.

q.=water.=water

conc.=concentrated

DMSO=dimethyl sulfoxide

EtOAc=ethyl acetate

Et2O=diethyl ether

h, h=hours

HATU=N-[dimethylamino-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-

methylmethanamine hexaphosphate N-oxide

Meon=the ethanol

MOPS=4-morpholinepropanesulfonic

MS=mass spectrometry

Ret Time=retention time

rt=room temperature (˜ 20°)

us.=rich

TFA=triperoxonane acid

THF=tetrahydrofuran

DMF=N,N-dimethylformamide

Example 1.

Obtaining 1,1-dimethylethylene ester [5-[[(2,4,6-trimetilfenil)amino]carbonyl]-4-methyl-2-thiazolyl] carbamino acid.

A. Ethyl-2-tert-butoxycarbonyloxyimino-4-methyl-thiazole-5-carboxylate.

A suspension of ethyl-2-amino-4-methylthiazole-5-carboxylate (18.6 g, 100 mmol), di-tert-BUTYLCARBAMATE (26,2 g, 120 mmol) and 4-dimethylaminopyridine (800 mg, 6,55 mmol) in dry tetrahydrofuran (300 ml) is stirred under nitrogen for 18 hours. The solvent is evaporated in vacuum. The residue is suspended in methylene chloride (1 l) and filtered through a layer of celite. The filtrate was washed with 1N aqueous HCl (300 ml, 2x), water and brine, dried (MgSO4) and evaporated in vacuo. The residue is triturated with hexane. The solid is filtered and dried in vacuum, to obtain the title compound (20 g, 72%) as a reddish brown solid.

C. 2-tert-Butoxycarbonyloxyimino-4-methylthiazole-5-carboxylic acid.

Mix a solution of ethyl-2-tert-butoxycarbonyloxyimino-4-methylthiazole-5-carboxylate (10 g, 34,95 mmol) in a mixture of tetrahydrofuran/ethanol (250 ml, 2:3) treated with 6N KOH (250 ml). CME is ü warm at 55° With during the night. The solution is cooled to 0°and acidified with conc. HCl to pH 1. The solvent is evaporated in vacuum. The residue is washed with water, ditylum ether, dried in vacuum over anhydrous Fosforit anhydride, get the title compound (6 g, 89%) as a white solid.

C. 2-tert-Butoxycarbonyloxyimino-4-methylthiazole-5-carboxylic acid chlorine dioxide.

2 M solution of oxalicacid in methylene chloride (22.5 ml, 45 mmol) is added dropwise to a stirred suspension of 2-tert-butoxycarbonyloxyimino-4-methylthiazole-5-carboxylic acid (10 g, 38,72 mmol) in methylene chloride (150 ml) and N,N-dimethylformamide (150 ml) at 0°C. Suspension gradually becomes homogeneous after the end of addition. The solution was heated to room temperature and stirred at rt for 1.5 hours. The solvent is evaporated in vacuo and the residue evaporated with toluene (300 ml, 2x), and dried in vacuum, obtaining the title acid chloride of acid (10.7 g, 99%) as a reddish brown solid.

D. 1,1-Dimethylethylene ester [5-[[(2,4,6-trimetilfenil)amino]carbonyl]-4-methyl-2-thiazolyl]carbamino acid.

2,4,6-Trimethylaniline (6.3 ml, amounted to 38.66 mmol) is added dropwise to a stirred solution of the acid chloride of 2-tert-butoxycarbonyloxyimino-4-methylthiazole-5-carboxylic acid (10.7 g, amounted to 38.66 mmol) in methylene chloride (150 ml) at 0°C. Ceres minutes added dropwise diisopropylethylamine (8,8 ml, 44,88 mmol). The solution is brought to a ˜20°C and stirred for further 2 hours. The solvent is evaporated in vacuum. The residue is suspended in EtOAc (700 ml), washed with 1 N aq. HCl (300 ml, 2x), water and brine; dried (MgSO4), filtered and evaporated. The remainder RUB clean air, get the title compound (12.5 g, 86%) as a reddish brown solid.

Example 2.

Obtaining 2-amino-N-(2,4,6-trimetilfenil)-4-methyl-5-thiazolecarboxamide.

A solution of 1,1-dimethyl ester [5-[[(2,4,6-trimetilfenil)amino]carbonyl]-4-methyl-2-thiazolyl]carbamino acid (10 g, 26,63 mmol) in triperoxonane acid (100 ml) was stirred at rt for 3 hours. The solution is evaporated in vacuum and the residue diluted with EtOAc (700 ml), washed with 5% aq. Knso3(400 ml, 2x), water and brine; dried (MgSO4), filtered and evaporated. The residue is washed with ether (200 ml) and acetonitrile (100 ml), get the title compound (6.7 g, 91%) as a white solid.

Example 3.

Obtaining 1,1-dimethylethylene ester [5-[[(2,4,6-trimetilfenil)amino]carbonyl]-4-trifluoromethyl-2-thiazolyl] carbamino acid.

A. Ethyl-2-tert-butoxycarbonyloxyimino-4-cryptomaterial-5-carboxylate.

A suspension of ethyl-2-amino-4-cryptomaterial-5-carboxylate (of 5.05 g, 21,02 mmol), di-tert-BUTYLCARBAMATE (4,82 g, 22,07 mmol) and 4-dimethylamino the Dean (260 mg, 2.1 mmol) in methylene chloride (209 ml) is stirred under nitrogen for 1.5 hours. The solvent is evaporated in vacuum. The remainder chromatographic on a column of silica gel. Elute with 5% EtOAc in a mixture of hexanol, then 15% EtOAc in a mixture of hexanol receive the title compound (6,57 g, 92%) as a white solid.

C. 2-tert-Butoxycarbonyloxyimino-4-cryptomaterial-5-carboxylic acid.

Mix a solution of ethyl-2-tert-butoxycarbonyloxyimino-4-Cryptor-methylthiazole-5-carboxylate (6.5 g, 19,1 mmol) in methanol (100 ml) is treated with 1 N aq. NaOH (573 ml). The mixture was stirred at ˜20°With during the night. The solution is cooled to 0°and acidified with 1 M HCl (aq.) to pH 1 and extracted with chloroform (150 ml, 6x). The chloroform extracts are combined, dried (Na2SO4), filtered and evaporated in vacuum, receives a given acid (5.75 g, 96%) as a white solid.

C. 1,1-Dimethylethylene ester [5-[[(2,4,6-trimetilfenil)amino]carbonyl]-4-trifluoromethyl-2-thiazolyl]carbamino acid.

4 Methylmorpholine (40 μl, 0,39 mmol) are added to a mixture of 2-tert-butoxycarbonyloxyimino-4-cryptomaterial-5-carboxylic acid (100 mg, 0.32 mmol), 2,4,6-trimethylaniline (45 μl, 0.32 mmol) and benzotriazol-1 yloxy-Tris-(dimethylamino)phosphodiesterase (THIEF-reagent, 380 mg, 0.4 mmol) in DMF (2 ml). The solution was stirred at ˜20°C for 72 h, diluted with chlorite is th methylene and washed with 0.25 M aq. KHSO4and then Nason. Knso3. Separate the organic (CH2Cl2) layer, dried (Na2SO4), filtered and evaporated. The remainder chromatographic on a column of silica gel and elute with 5% EtOAc in a mixture of hexanol, and then 10% EtOAc in a mixture of hexanol, receiving the title compound (90 mg, 65%) as a white solid.

Example 4.

Obtaining 2-amino-N-(2,4,6-trimetilfenil)-4-trifluoromethyl-5-thiazolecarboxamide of triptoreline (1:1).

Rstor 1,1-dimethylethylene ester [5-[[(2,4,6-trimetilfenil)amino]carbonyl]-4-trifluoromethyl-2-thiazolyl]carbamino acid (120 mg, 0.28 mmol) in triperoxonane acid (5 ml) stirred at 0°With 1 hour. The solution is evaporated in vacuo and the residue evaporated with ether, receiving a yellow solid, which was triturated with a mixture of hexanol receive the title compound (96 mg, 76%) as a pale yellow solid.

Example 5.

Obtaining 1,1-dimethylethylene ester [5-[[(2,4,6-trimetilfenil)amino]carbonyl]-4-phenyl-2-thiazolyl] carbamino acid.

A. Ethyl-2-tert-butoxycarbonyloxyimino-4-phenylthiazol-5-carboxylate.

Compound 5A receive similar to 3A, but using ethyl-2-amino-4-phenylthiazol-5-carboxylate and receive the title compound 5A as a white solid (90,5%).

C. 2-tert-Butok is carbonylcyanide-4-phenylthiazol-5-carboxylic acid.

Connection 5V receive similarly 3V, but using 5A, and receive the title compound 5B as a white solid (99%).

C. the acid chloride of 2-tert-butoxycarbonyloxyimino-4-phenylthiazol-5-carboxylic acid.

Compound 5C get similarly 1C, but using 5V, and receive the title compound 5C as a white solid (90%).

D. 1,1-Dimethylethylene ester [5-[[(2,4,6-trimetilfenil)amino]carbonyl]-4-phenyl-2-thiazolyl]carbamino acid.

Compound 5D get similar to 1D, but using 5S, and receive the title compound 5D in the form of a light yellow solid (93%).

Example 6.

Obtaining 2-amino-N-(2,4,6-trimetilfenil)-4-phenyl-5-thiazolecarboxamide, triptoreline (1:1).

Connection 6 get 4 similarly, but take 5D, receiving the title compound 6 as a white solid (68%).

Example 7.

Obtaining 1,1-dimethylethylene ester [5-[[phenylamino]carbonyl]-4-methyl-2-thiazolyl]carbamino acid.

Connection get similar to 1D, but take aniline instead of 2,4,6-trimethylaniline and triethylamine instead of diisopropylethylamine, receiving the title compound 7 as off-white solid (76%).

Example 8.

Obtaining 2-amino-N-(phenyl)-4-methyl-5-thiazolecarboxamide, triptoreline (1:1).

Compound 8 get 4 similarly, but take 7, receiving the title compound 8 as a white solid (68%).

Example 9.

Obtaining 1,1-dimethylethylene ester [5-[[(2,4-dichlorophenyl]amino]carbonyl]-4-methyl-2-thiazolyl]carbamino acid.

Connection 9 get similar to 1D, but take 2,4-dichloraniline, receiving the title compound 9 as a white solid (28%).

Example 10.

Obtaining 2-amino-N-(2,4-dichlorophenyl)-4-methyl-5-thiazolecarboxamide, triptoreline (1:1).

Connection 10 get 4 similarly, except that they take 9 to give 10 as a white solid connections (100%).

Example 11.

Obtaining 1,1-dimethylethylene ester [5-[[(2,4,6-trimetilfenil]amino]-carbonyl]-2-thiazolyl]carbamino acid.

A. Ethyl-2-tert-butoxycarbonyloxyimino-5-carboxylate.

Compound 11A receive similarly 3A, but take ethyl-2-aminothiazol-5-carboxylate, receiving the title compound 11A as a white solid (79,5%).

C. 2-tert-Butoxycarbonyloxyimino-5-carboxylic acid.

Compound 11B get similarly 3V, but take 11A, receiving the title compound 11B as a white solid (95,5%).

C. the acid chloride of 2-tert-butoxycarbonyloxyimino-5-Carbo the OIC acid.

Compound 11C get similarly 1C, but take 11V, receiving the title compound 11C.

D. 1,1-Dimethylethylene ester [5-[[(2,4,6-trimetilfenil)amino]carbonyl]-2-thiazolyl]carbamino acid.

Compound 11D get similar to 1D, but take 11C, receiving the title compound 11D in the form of an off-white solid (70%).

Example 12.

Obtaining 2-amino-N-(2,4,6-trimetilfenil)-4-phenyl-5-thiazolecarboxamide, triptoreline (1:1).

Connection 12 get 4 similarly, but take 11D, receiving the title compound 12 as a pale yellow solid (88%).

Examples 13-53.

A General method.

Connection 13-53 receive the following method. The appropriate amine (0.40 mmol) and diisopropylethylamine (79 μl, 0.40 mmol) are added to the suspension 1C (100 mg, 0.36 mmol) in methylene chloride (3 ml). The solution is mechanically stirred in a sealed tube at ˜20°C for 16 hours. The reaction mixture is diluted with methanol (200 ml) and loaded onto a Varian SCX-ionoobmennye column (2 g/6 cm), pre-treated with methanol - methylene chloride (8 ml, 1:1)and then methylene chloride (8 ml). Filtered through SCX-column is carried out using automatic unit (robot) Gilson (Gilson). The column is washed sequentially methylene chloride (9 ml), methylene chloride - methanol (9 ml, 4:1), methylene chloride is nom - methanol (9 ml, 1:1), methanol (9 ml), 0.01 M ammonium hydroxide in methanol (9 ml), 0.05 M ammonium hydroxide in methanol (9 ml). Eluate collected separately using a machine (robot) and then evaporated on a rotary evaporator (speed vac.). The fractions containing the products unite.

HPLC time hold. indicates the retention time of HPLC under the following conditions: ballast column YMC S5 ODS 4,6·50 mm, 4 min gradient starting from 100% solvent A (10% Meon, 90% H2O, 0.2% of N3PO4) to 100% solvent B (90% Meon, 10% H2O, 0.2% of N3PO4), flow rate 4 ml/min, λ=220 nm.

Examples 54-129.

A General method.

Connection 54-129 receive the following method. Diisopropylethylamine (60 μl, 0.34 mmol) are added to a mixture of amine 2 (30 mg, 0.11 mmol), the corresponding carboxylic acid (0.13 mmol), 1-hydroxy-7-isobenzofuranone (19.5 mg, 0.14 mmol) and ethyl-3-(3-dimethylamino)-propylbromide hydrochloride (26,8 mg, 0.14 mmol) in THF (0.4 ml). The mixture is heated in a sealed tube under argon at 45°C for 14 hours. The reaction mixture was diluted chloride m is tylenol (4 ml) and washed with 2 N aq. HCl solution (2 ml, 3x). Solution in methylene chloride is passed through a Varian SCX-cation exchange column (2 g, 6 cm3) on the machine (robot) Gilson. Column elute sequentially acetonitrile-methanol (10 ml, 4:1), methanol - 2M ammonia in methanol (3 ml, 4:1) and 2 M solution of ammonia in methanol (3 ml, 4x). Fractions collected separately, using the robot Gilson. The fractions containing the product, evaporated and dried in vacuum. HPLC time beats. denotes the HPLC retention time under the following conditions: YMS S5 OD 4,6×50 mm ballast column, 4 min gradient starting from 100% solvent A (10% Meon, 90% H2O, 0.2% of N3PO4) to 100% solvent B (90% Meon, 10% N2O, 0.2% of N3PO4), flow rate 4 ml/min, λ=220 nm for compounds 54-127. For connections 128-129 conditions HPLC following: short column Bond S8-C18 4.5 mm × 7.5 cm, gradient 8 minutes, starting with 100% solvent A (10% Meon, 90% H2Oh, 0,2% H3PO4) to 100% solvent B (90% Meon, 10% N2O, 0.2% of N3PO4), flow rate 2.5 ml/min, λ=217 nm.

Example 130.

Obtaining 1,1-dimethylethylene ester [4-methyl-5-[[(2-nitrophenyl)amino]carbonyl]-2-thiazolyl]carbamino acid

To a solution of acid chloride of 2-tert-butoxycarbonyloxyimino-4-methylthiazole-5-carboxylic acid 1C (100 mg, 0.36 mmol) in methylene chloride (3 ml) with stirring, added dropwise 2-nitroaniline (55 mg, 0.4 mmol) and diisopropylethylamine (70 μl, 0.4 mmol). After 16 hours when ˜20°add 4,N,N-dimethylaminopyridine (22 mg, 0.18 mmol) and the mixture is stirred for another 3.5 hours. The solvent is evaporated in vacuum. The remainder chromatographic on a column of silica gel. Elution with 5% EtOAc in a mixture of hexanol followed by elution with 20% EtOAc in a mixture of hexanol gives the specified compound (15 mg, 11%) as a yellow solid

Example 131.

Getting phenylmethylene ester [4-methyl-5-[[(2,4,6-trimetilfenil)amino]-carbonyl]-2-thiazolyl]carbamino acid.

A. Ethyl-2-benzyloxycarbonylamino-4-methylthiazole-5-carboxylate.

To a solution of ethyl-2-amino-4-methylthiazole-5-carboxylate (372 mg, 2 mmol) in THF (20 ml) at 0-5°with stirring, add 3 M aq. NaHCO3(10 ml, 30 m is ol). Add benzoylchloride (500 μl). After 2 hours, add another 500 ál of benzoylformate and a two-phase system is stirred for further 2 hours at 0-5°C. the Mixture is diluted with claritim a methylene (50 ml) and water (30 ml). The organic layer is separated, dried (MgSO4), filtered and evaporated. The remainder chromatographic on a column of silica gel. Elute with 10% EtOAc in a mixture of hexanol, and then 20% and 30% EtOAc in a mixture of hexanol receive the title compound (310 mg, 48%) as a white solid.

Century 2-Benzyloxycarbonylamino-4-methylthiazole-5-carboxylic acid.

Connection U get similarly 3V, but take A and get B in the form of a white powder (77%).

C. Phenethyl ester [4-methyl-5-[[(2,4,6-trimetilfenil)amino]carbonyl]-2-thiazolyl]carbamino acid.

To a solution of W (100 mg, 0.34 mmol), 2,4,6-trimethylaniline (60 μl, 0.41 mmol) and [O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium]hexaflurophosphate (HATU, 160 mg, 0.41 mmol) added diisopropylethylamine (70 μl, 041 mmol). The mixture was stirred at rt for 24 hours, diluted with EtOAc (20 ml) and washed with 2N aq. HCl (3x), brine, dried (Na2SO4), filtered and evaporated. The residue is triturated with ether (40 ml), to obtain the title compound (100 mg, 77%) as off-white solid.

Example 132.

Obtaining 1,1-dimethylethylene ether methyl-[4-methyl-5-[[(2,4,6-trimetilfenil)amino]carbonyl] -2-thiazolyl] carbamino the th acid.

Connection 132 receive the same as 1, but take ethyl-2-tert-butoxycarbonyloxyimino-4-methylthiazole-5-carboxylate and receive the title compound 132 in the form of a reddish-brown solid.

Example 133.

Getting 4-methyl-2-(methylamino)-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide, triptoreline (1:1).

Connection 133 receive 4 similarly, but take 132, receiving the title compound 133 as a white solid (91%).

Example 134.

Obtaining 1,1-dimethylethylene ester [4-methyl-(2,4,6-trimetilfenil)amino]carbonyl]-2-thiazolyl]carbamino acid.

Connection 134 receive the same as 1, but use N-methyl-2,4,6-trimethylaniline, receiving the title compound 134 as a white solid (60%).

Example 135.

Obtaining 2-amino-N,4-dimethyl-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide, triptorelin (1:1).

Connection 135 receive 4 similarly, but take 134, receiving the title compound 135 as a white solid (97%).

Example 136.

Obtaining methyl ester [4-methyl-5-[[(2,4,6-trimetilfenil)amino]carbonyl]-2-thiazolyl]carbamino acid.

A mixture of 2 (100 mg, 0.36 mmol), pyridine (87 μl, of 1.08 mmol), methylcarbamate (111 is CL, 1.44 mmol) in methylene chloride (3 ml) was stirred at rt for 1.5 hours. The solution was diluted with methylene chloride and washed with aq. NaHCO3(20 ml, 2x), brine; dried (MgSO4), filtered and evaporated. The residue is triturated with ether and receive the title compound (88 mg, 82%) as a white solid.

Example 137.

Obtaining 1,1-dimethylethylene ester [4-ethyl-5-[[(2,4,6-trimetilfenil)amino]carbonyl]-2-thiazolyl]carbamino acid.

Connection 137 receive the same as 1, but take methyl-2-amino-4-utiltity-5-carboxylate, receiving the title compound 137 as a white solid (70%).

Example 138.

Obtaining 2-amino-4-ethyl-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide, triptoreline.

Connection 138 receive 4 similarly, but take 137, receiving the title compound 138 as a white solid (89%).

Example 139.

Obtaining 1,1-dimethylethylene ester [5-[[(2,6-dichlorophenyl)amino]carbonyl]-4-methyl-2-thiazolyl]carbamino acid.

1 M solution of sodium bis-trimethylsilane (290 μl, 0.29 mmol) is added to a stirred solution of 2,6-dichloraniline (13,4 mg, 0.08 mmol) in THF (1 ml). After 30 minutes the mixture is cooled to 0°add all at once the number (30 mg, 0.11 mmol) of compound 1C. The mixture is heated to room temperature the market and stirred for 16 hours. The solution was diluted with methylene chloride and washed with 2N HCl aq. (2 ml × 3), dried (MgSO4), filtered and evaporated. The remainder chromatographic on a column of silica gel and elute 30% EtOAc in a mixture of hexanol, receiving the title compound (20 mg, 45%) as a pale yellow solid.

Example 140.

Obtaining 2-amino-N-(2,6-dimetilfenil)-4-methyl-5-thiazolecarboxamide, triptorelin (1:1).

The connection 140 receive 4 similarly, but take 53, receiving the title compound 140 in the form of a light reddish-brown solid (100%).

Example 141.

Obtaining 2-amino-N-(2-methoxy-6-were)-4-methyl-5-thiazolecarboxamide, triptoreline (1:1).

Connection 141 receive by analogy with the 4, but take 13, when receiving the connection 141 in the form of an off-white solid (100%).

Example 142.

Obtaining 2-amino-N-(2-were)-4-methyl-5-thiazolecarboxamide, triptoreline (1:1).

Connection 142 receive by analogy to 4, except for the fact that but take 18, receiving the title compound 142 as a light tan solid (90%).

Example 143.

Obtaining 2-amino-N-(2,6-dimethyl-4-bromophenyl)-4-methyl-5-thiazolecarboxamide, triptoreline (1:1).

Connection 143 get similar to 4, n is used 15, receiving the title compound 143 in the form of light reddish-brown solid (70%).

Example 144.

Obtaining 2-amino-N-(2-chloro-6-were)-4-methyl-5-thiazolecarboxamide, triptoreline (1:1).

Connection 144 receive 4 similarly, but take 19, receiving the title compound 144 in the form of light reddish-brown solid (81%).

Example 145.

Obtaining 2-amino-N-(2,4-dimetilfenil)-4-methyl-5-thiazolecarboxamide, triptoreline (1:1).

Connection 145 receive 4 similarly, but take 17, receiving the title compound 145 in the form of light reddish-brown solid (68%).

Example 146.

Obtaining 2-amino-N-(2-methyl-6-isopropylphenyl)-4-methyl-5-thiazolecarboxamide, triptoreline (1:1).

Connection 146 receive 4 similarly, but take 16 and receive the title compound 146 in the form of light reddish-brown solid (100%).

Example 147.

Getting 2-(acetylamino)-4-methyl-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide.

A mixture of 2 (54 mg, 0.2 mmol), acetic anhydride (22 μl, 0.23 mmol), dimethylaminopyridine (3 mg) in methylene chloride (4.5 ml) was stirred at rt for 4.5 hours. The mixture is diluted with methylene chloride (65 ml) and washed with 1 N HCl aq. (20 ml), water, dried (MgSO4), introit and evaporated the Residue chromatographic on a column of silica gel and elute 35% EtOAc, receiving the title compound (43 mg, 69%) as a white solid.

Example 148. Getting 2-(benzoylamine)-4-methyl-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide.

A solution of 2 (100 mg, 0.36 mmol) and benzoic anhydride (226 mg, 1 mmol) in methylene chloride (10 ml) and pyridine (2 ml) was stirred at rt over night. The mixture is diluted with claritim a methylene (50 ml) and washed with 2 N HCl aq. (15 ml, 2x), 10% NaHCO3aq. (20 ml, 2); dried (MgSO4), filtered and evaporated the Residue chromatographic on a column of silica gel and elute 30% EtOAc in a mixture of hexanol, and then 50% EtOAc in a mixture of hexanol receive a specific connection with the admixture of benzoic acid. The solid compound was dissolved in EtOAc (40 ml) and washed us. solution of knso3(15 ml, 4x), dried (MgSO4), filtered and evaporated, to obtain the title compound (110 mg, 80%) as a white solid.

Example 149.

Getting 4-methyl-2-[(1-oxopropyl)amino] -N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide.

A mixture of 2 (100 mg, 0.36 mmol), propionic anhydride (332 μl, 2.58 mmol) in methylene chloride (10 ml) and pyridine (4 ml) was stirred at rt for 3 hours. Add dimethylaminopyridine (122 mg, 1 mmol) and the mixture is stirred for another 1.5 hours. The mixture is diluted with methylene chloride and washed with 1 N aq. HCl (25 ml, 3x), NaHCO3aq. (20 ml, 2x), water (20 ml), brine; sushi is t (MgSO 4), filtered and evaporated. The remainder chromatographic on a column of silica gel and elute with 20% EtOAc in a mixture of hexanol receive the title compound (81 mg, 68%) as a white solid.

Example 150.

Getting 4-methyl-2-[(1-oxobutyl)amino]-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide.

Connection 150 receive similar connection 149, but take butyric anhydride and receive the title compound 150 in the form of a white solid (76%).

Example 151.

Getting 4-methyl-2-[(oxobutyl)amino]-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide.

Connection 151 receive similar connection 149, but take valeric anhydride, receiving the title compound 151 as a white solid (77%).

Example 152.

Getting 4-methyl-2-[(1-oxohexyl)amino]-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide.

Connection 152 receive similar connection 149, but take hexanoic acid, and receive the title compound 152 as a white solid.

Example 153.

Getting 4-methyl-2-[(phenylacetyl)amino]-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide.

A solution of amine 2 (50 mg, 0.18 mmol), diisopropylethylamine (101 μl, of 0.58 mmol), phenylacetic acid (to 27.2 mg, 0.20 mmol), 1-hydroxy-7-azabenzo is Isola (of 29.4 mg, 0.22 mmol) and ethyl-3-(3-dimethylamino)propylbromide hydrochloride (42.2 mg, 0.22 mmol) in methylene chloride (0,62 ml) was mechanically stirred in a sealed vial for 16 hours. The reaction mixture is passed through an ion exchange column Varian SCX (2 g/6 cm3) and elute with a mixture of acetonitrile - methanol (10 ml, 4:1), then 2 M solution of ammonia in methanol (9 ml). The fractions containing the product are combined and then evaporated. The residue is dissolved in methylene chloride and washed with 2 N aq. HCl (3x), dried (Na2SO4), filtered and evaporated, obtaining the title compound (39 mg, 55%) as a reddish brown solid.

Example 154.

Getting 2-[[(acetylamino)acetyl]amino]-4-methyl-N-(2,4,6-trimetilfenil)-6-thiazolecarboxamide.

A solution of amine 2 (50 mg, 0.18 mmol), diisopropylethylamine (400 μl, 2.3 mmol), N-acetylglycine (42 mg, 0.36 mmol), 1-hydroxy-7-isobenzofuranone (49 mg, 0.36 mmol) and ethyl-3-(3-dimethylamino)propylbromide hydrochloride (72 mg, 0.36 mmol) in THF (5 ml) is heated at 50°With during the night. The mixture is cooled, diluted with methylene chloride (60 ml) and washed with 2N HCl aq. (20 ml), saturated aq. solution of knso3(20 ml), dried (MgSO4), filtered and evaporated. The crude solid product triturated with ether (10 ml), filtered and washed with ether (5 ml, 3x)to give the title compound as off-white solid prophetic is TBA.

Example 155.

Obtaining 2-amino-4-methyl-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide.

A suspension of 2 (50 mg, 0.18 mmol) and reagent Lawesson (44 mg, 0.11 mmol) in toluene (0,23 ml) is heated for 4 hours at 100°C. Add the reagent Lawesson (44 mg, 0.11 mmol) and the mixture is heated for an additional 3.5 hours. The crude mixture chromatographic on a column of silica gel and elute with 50% EtOAc in a mixture of hexanol, and then 70% EtOAc in a mixture of hexanol, receiving a yellow solid, which is triturated in a mixture of hexanol (6 ml)to give the title compound (11 mg, 21%), yellow solid.

Examples 156-170.

A General method.

Connection 156-170 receive the following method. Diisopropylethylamine (60 μl, 0.34 mmol) are added to a mixture of amine 2 (30 mg, 0.11 mmol), the corresponding carboxylic acid (0.13 mmol), 1-hydroxy-7-isobenzofuranone (19.5 mg, 0.14 mmol) and ethyl-3 -(3-dimethylamino)propylbromide hydrochloride (26,8 mg, 0.14 mmol) in THF (1 ml). The mixture is heated in a sealed tube under argon at 45°C for 24 hours. The reaction mixture is diluted with methylene chloride (4 ml) and washed with 2N aq. HCl (2 ml, 3x), dried (Na2SO4) and evaporated on the rotor (speedvac.). Raw foods or rubbed with a mixture of methylene chloride - ether (5 ml, 1:1), or clean by chromatography on silica gel (eluent: 50% EtOAc in a mixture of hexanol and EtOAc). HPLC time hold. is EMA retention under the following conditions: ballast column YMC S5 ODS 4,6× 50 mm, 4 min gradient starting from 100% solvent A (10% Meon, 90% H2O, 0.2% of N3PO4) to 100% solvent B (90% Meon, 10% H2O, 0.2% of N3PO4), flow rate 4 ml/min, λ=220 nm.

Examples 171-180.

A General method.

Connection 171-180 receive the following method. A mixture of 2 (80 mg, 0.29 mmol), the appropriate isocyanate (0.87 mmol) and pyridine (2 ml) in THF (3.5 ml) was stirred at room temperature overnight. In some cases, the reaction mixture is heated at 60-70°C for 5 hours. Some of these reactions are conducted at room temperature overnight in the presence of the catalyst N,N-dimethylaminopyridine (catalytic amounts). The reaction mixture is diluted with methylene chloride and washed with 1N HCl aq. (3x), water, brine; dried (MgSO4), filtered and evaporated. The crude product is purified or triturating with ether or with a mixture of ether - hexane, or by chromatography on a column of silica gel (eluent: 20-40% EtOAc in a mixture of hexanol) with subsequent grinding or passing through the cation exchange Varian SCX cartridge and sequential elution with methanol (5 ml), methylene chloride (5 ml), a mixture of acetonitrile - methanol (10 ml, 4:1) and a mixture of methanol -2 M solution of ammonia in methanol (10 ml, 4:1) to the floor of the treatment of the title compound. HPLC time hold. indicates the retention time of HPLC under the following conditions: for connections 171-172, 175 and 177 conditions HPLC essence Bond S8-C18 4.5 mm × 7.5cm short column, 30-min gradient starting from 100% solvent A (10% Meon, 90% H2Oh, 0,2% H3PO4) to 100% solvent B (90% Meon, 10% N2O, 0.2% of N3PO4), flow rate 2.5 ml/min, λ=217 nm. For other connection conditions HPLC essence: short column Bond S8-C18 4.5 mm × 7.5 cm, 8 min gradient starting from 100% solvent A (10% Meon, 90% H2O, 0.2% of N3PO4) to 100% solvent B (90% Meon, 10% N2O, 0.2% of N3PO4), flow rate 2.5 ml/min, λ=217 nm.

Example 181.

Getting phenyl ester [5-[[(2,4,6-trimetilfenil)amino]carbonyl]-4-methyl-2-thiazolyl]carbamino acid.

10% aqueous solution of knso3add with stirring to a solution of 2 (1,02 g, 3.7 mmol) in THF (130 ml). Phenylcarbamate (1.39 ml, 11.1 mmol) is added dropwise. A two-phase mixture is stirred at room temperature overnight, diluted with methylene chloride (200 ml) and washed with water and brine. The organic layer is separated, dried (MgSO4), filtered and evaporated. The remainder chromatographic on a column of silica gel with 10% EtOAc in a mixture of hexanol order to obtain the title compound (980 mg, 69%) in the de solid.

Examples 182-236.

A General method.

Connection 182-236 receive the following method.

The solution phenylcarbamate 181 (20 mg, 0,054 mmol) and the appropriate amine (0.08 mmol) in a mixture of THF - acetonitrile (3 ml, 1:1) was stirred at ˜20°With during the night. In some of these reactions require heat at 60°from 4 hours to a period during the night. The mixture is diluted with methylene chloride (4 ml) and washed with 1 N HCl aq. (1.5 ml, 2x), 1 N NaOH aq. (1.5 ml, 2x). The in dichloromethane layer is separated, dried (MgSO4), filtered and evaporated to obtain the title product. HPLC time beats. denotes the retention time of HPLC under the following conditions: for connections 182-192 conditions of HPLC are as follows: short column Bond SB-C18 4.5 mm × 7.5 cm, gradient 8 minutes, starting from 100% solvent A (10% Meon, 90% H2O, 0.2% of N3PO4) to 100% solvent B (90% Meon, 10% N2Oh, 0,2% H3PO4), flow rate 2.5 ml/min, λ=217 nm. For connections 193-236 HPLC conditions are as follows: ballast column YMC S5 ODS 4.6 mm × 50 mm, gradient 4 minutes, starting from 100% solvent A (10% Meon, 90% H2O, 0.2% of N3PO4) to 100% solvent B (90% Meon, 10% H2O, 0.2% of N3PO4), flow rate 4 ml/min, λ=220 nm.

Examples 237-285.

A General method.

Connection 237-285 receive the following method. The solution phenylcarbamate 181 (20 mg, 0,054 mmol) and the appropriate amine (0.08 mmol) in THF-acetonitrile (3 ml, 1:1) was stirred at room temperature. The mixture is diluted with methylene chloride (4 ml) and washed with 1 N HCl aq. (1.5 ml, 2x), 1 N NaOH aq. (1.5 ml, 2x). Separate the organic (methylene chloride) layer, dried (MgSO4), filtered and evaporated and get the title product. HPLC time beats. denotes the HPLC retention time under the following conditions: for connections 237-278 conditions HPLC essence: ballast column YMC S5 ODS 4,6×50 mm, gradient 4 minutes, starting from 100% solvent A (10% Meon, 90% H2Oh, 0,2% H3PO4) to 100% solvent B (90% Meon, 10% H2O, 0.2% of N3PO4), flow rate 4 ml/min, λ=220 nm. For connections 279-285 conditions HPLC essence: short column Bond S8-C18 4.5 mm × 7.5 cm, gradient 8 minutes, starting with 100% solvent A (10% Meon, 90% H2Oh, 0,2% H3PO4) to 100% solvent B (90% Meon, 10% N2O, 0.2% of N3PO4), the flow rate of 2-5 ml/min, λ=217 nm.

Examples 286-311.

A General method.

Connection 286-311, except for the connection 307, receive the following method.

The solution of acid chloride of 2-[[(butylamino)carbonyl]amino]-4-methyl-5-thiazolecarboxamide acid (30 mg, 0.11 mmol), the appropriate aniline (0.12 mmol) in THF (1 ml) is treated with diisopropylethylamine (22,6 μl, 0.13 mmol). The mixture is blown with argon and stirred mechanically in the ampoule for 22 hours, diluted with methylene chloride (4 ml) and washed with 2N HCl aq. (3). The organic layer is separated, dried(Na2SO4), filtered and evaporated. The crude product is purified or rubbed with a mixture of methylene chloride - ether (1:1), or by chromatography on silica gel (eluent: 80% EtOAc in a mixture of hexanol, then EtOAc), or automated preparative HPLC (conditions: column YMC S5 ODS 20×100 mm; 10 min gradient ranging from 30% solvent B (90% Meon, 10% N2O with 0.1% TFA) and 70% solvent A (10% Meon, 90% H2O with 0.1% TFA) to 100% solvent b, flow rate 20 ml/min, λ=220 nm.

Connection 307 receive the following method. A suspension of 2-[[(butyl-amino)carbonyl]amino]-4-methyl-5-thiazolecarboxamide acid is (100 mg, 0.36 mmol) and HATU (170 mg, 0.44 mmol) in DMF (3 ml) is treated with diisopropylethylamine (62 ml, 0.44 mmol). The mixture is heated at 60°2 hours, cooled, diluted with methylene chloride (12 ml), washed with 8 M urea solution in water in 2N HCl aq. (6 ml, 3x), 5% knso3aq. (6 ml, 3x), dried (Na2SO4), filtered and evaporated. The residue is triturated with a mixture of EtOAc - ether, receiving the intermediate mixed anhydride (102 mg, 74%) as a white substance. To a stirred solution of 2,6-dichloraniline (19.6 mg, 0.12 mmol) in THF (1 ml) was added dropwise 1M solution of sodium bis-(trimethylsilyl)in THF (170 μl, 0,17 mmol). After 15 minutes, a mixed anhydride intermediate (41.3 mg, 0.11 mmol) are added at once (in one piece). Add a few drops of DMF and the solution is stirred for 16 hours. Add a 1M solution of sodium bis-(trimethylsilyl)and (110 μl) and the mixture is stirred for another 2 hours. The mixture is diluted with methylene chloride (4 ml) and washed with 2N HCl aq. (2 ml, 3x), feast upon. Knso3aq. (3x), dried (Na2SO4), filtered and evaporated. The solid is washed with a mixture of hexanol (2) and the remainder chromatographic on a column of silica gel. Elution of 80% EtOAc in a mixture of hexanol, and then EtOAc gives 307 (12 mg, 27%) as a light tan solid. HPLC time beats. denotes the retention time under the following conditions: ballast column YMC S5 ODS 4,6×50 mm; gradient 4 minutes, from 100% R is storytale And (10% Meon, 90% N2Oh, 0,2% H3PO4) to 100% solvent B (90% Meon, 10% N2O, 0.2% of N3PO4), flow rate 4 ml/min, λ=220 nm.

Example 312.

Getting 4-methyl-2-[(methylsulphonyl)amino]-N-2,4,6-trimetilfenil)-5-thiazolecarboxamide.

A. Ethyl-2-[(methylsulphonyl)amino]-4-methylthiazole-5-carboxylate.

A solution of ethyl-2-amino-4-methylthiazole-5-carboxylate (558 mg, 3 mmol) in methylene chloride (15 ml) and pyridine (5 ml) with stirring, treated with methanesulfonamide (687 mg, 6 mmol) at ˜20°With during the night. The solution was diluted with methylene chloride (50 ml) and washed with 2N HCl aq. (15 ml, 3x), dried (MgSO4), filtered and evaporated. The crude residue was diluted with ether (25 ml) and filtered off the solid product is washed with a mixture (1:1) ether - hexane (10 ml, 3x) and dried in vacuum, to obtain the title compound (687 mg, 87%) as a white solid.

C. 2-[(Methylsulphonyl)amino]-4-methylthiazole-5-carboxylic acid.

A solution of ethyl-2-[(methylsulphonyl)amino]-4-methylthiazole-5-carboxylate (300 mg, to 1.14 mmol) in methanol (9 ml) is treated with stirring, 1N NaOH solution (28.4 ml, 28.4 mmol). The mixture is stirred at room temperature. The solution is Hledat to 0° With and acidified with 6N HCl aq. to pH 1. The solution is extracted with a mixture of methylene chloride - chloroform. The organic extracts are dried (MgSO4), filtered and evaporated in vacuum to get the title compound (148 mg, 55%).

C. 4-Methyl-2-[(methylsulphonyl)amino]-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide.

Diisopropylethylamine (87 μl, 0.5 mmol) are added to a solution V (99 mg, 0.42 mmol), 2,4,6-trimethylaniline (68 μl, 0.5 mmol) and [O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium]hexaflurophosphate (HATU, 191 mg, 0.5 mmol) in DMF (3 ml). The mixture is stirred at room temperature overnight, diluted with EtOAc and washed with 0,5N aq. HCl solution (15 ml), 10% aq LiCl. (25 ml, 3x), water (930 ml, 2x), brine, dried (MgSO4), filtered and evaporated. The remainder chromatographic on a column of silica gel and elute with 50% EtOAc in a mixture of hexanol, and then 75% EtOAc in a mixture of hexanol and 2% Meon in EtOAc, get the title compound (19 mg, 13%) as a white solid.

Example 313.

Getting 4-methyl-2-[[(phenylamino)thiocarbonyl]amino]-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide.

Solution 2 (45 mg, 0.16 mmol) and phenylisothiocyanate (43 mg, 0.32 mmol) in pyridine (2 ml) is heated to 80°C for 20 hours. The mixture is cooled, diluted with a mixture of methylene chloride - THF (80 ml, 3:1) and washed with 2N HCl aq. (15 ml, 2x). The organic extracts are dried (MgSO4), filtered and evaporated. the STATCOM is diluted with EtOAc (20 ml) and filtered the solid, washed with ether (10 ml, 3x) and dried in vacuum, to obtain the title compound (35 mg, 52%) as off-white solid.

Example 314.

Getting 2-[[(ethylamino)carbonyl]amino]-4-methyl-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide.

Connection 314 receive similar compounds 171-180, using utilitzant, receiving the title compound 314 in the form of a white solid (65%).

Example 315.

Obtaining N-(2-chloro-6-were)-2-[(cyclopropanecarbonyl)amino]-5-thiazolecarboxamide.

A. Ethyl-2-tert-butoxycarbonyloxyimino-4-methylthiazole-5-carboxylate.

A suspension of ethyl-2-aminothiazol-5-carboxylate (972 mg, 6 mmol, Century Plouver, C. Bailly, R. Houssin, j-P. Henlchart Heterocycles 32(4), 693-701, 1991, and H.J. Becker, J.de Jonge Rec. Trav. Chim., 61, 463, 1942), di-tert-BUTYLCARBAMATE (1,94 g, 9 mmol) and 4-dimethylaminopyridine (73 mg, 0.6 mmol) in dry tetrahydrofuran (75 ml) is stirred under nitrogen for 24 hours. The solvent is evaporated in vacuum. The residue is suspended in ether (50 ml). The solid is washed with ether (10 ml, 3x) and dried in vacuum, obtaining the title compound (1.1 g, 70%).

C. 2-tert-Butoxycarbonyloxyimino-5-carboxylic acid.

A solution of ethyl-2-tert-butoxycarbonyloxyimino-4-methylthiazole-5-carboxylate (1.1 g, 4.2 mmol) in a mixture of tetrahydrofuran - methanol (80 ml, 1:1) treated with 6N NaOH aq. (20 ml, 120 mmol). See the camping stirred at room temperature for 24 hours. A large part of THF and methanol is distilled off in vacuum and the aqueous solution acidified with 6N HCl aq. (22 ml). The precipitation is filtered off, washed with water and ether, dried in air and then in vacuum, obtaining the title acid (940 mg, 96%) as off-white solid.

C. 1,1-Dimethylethylene ester [5-[[(2-chloro-6-were)amino]carbonyl]-2-thiazolyl]carbamino acid.

To a solution of 2-tert-butoxycarbonyloxyimino-5-carboxylic acid (234 mg, 1 mmol) in THF (10 ml) and N,N-dimethylformamide (few drops) are added dropwise 2M solution oxalicacid in methylene chloride (1 ml, 2 mmol). The solution is stirred at room temperature for 4 hours. The solvent is evaporated in vacuum, obtaining the crude chloranhydride acid.

To a solution of crude acid chloride of 2-tert-butoxycarbonyloxyimino-5-carboxylic acid (1 mmol) in methylene chloride (10 ml) at 0°With added dropwise 2-chloro-6-methylaniline (212 mg, 1.5 mmol). Add diisopropylethylamine (516 mg, 4 mmol). The solution is brought to room temperature and stirred for 24 hours, diluted with methylene chloride (60 ml) and washed with 2N HCl aq. (15 ml). The organic extracts are dried (MgSO4), filtered and evaporated. The residue was diluted with EtOAc - ether (25 ml, 1:4) and the solid is filtered and washed with ether (5 ml, 4x) and dried in vacuum, obtaining the title compound (175 mg, 48%) as a reddish-measles is newago solids.

D. 2-Amino-N-(2-chloro-6-were)-5-thiazolecarboxamide.

Connection 315D get similar to compound 2, but take the connection S, receiving the title compound 315D in the form of a reddish-brown solid.

E. 2-[(Cyclopropanecarbonyl)amino]-N-(2-chloro-6-were)-5-thiazolecarboxamide.

The solution 315D (50,6 mg, 0,19 mmol) and anhydride cyclopropanecarbonyl acid (302 mg, a 1.96 mmol) in dioxane (2 ml) is heated to 93°With during the night. The mixture is evaporated in vacuo, diluted with EtOAc and washed with a saturated solution of knso3(2). The organic layer is dried (Na2SO4), filtered and evaporated. The residue is triturated with ether and receive the title compound (11 mg, 17%) as a white solid.

Example 316.

Getting 2-[[[(1,1 - dimethylethyl)amino]carbonyl]amino]-N-(2-chloro-6-were)-5-thiazolecarboxamide.

Sodium hydride (19.2 mg, 0.8 mmol) are added to a solution 315D (48,3 mg, 0.18 mmol) and tert-utilizationof (41 μl, 0.36 mmol) in THF (5 ml) at 0°C. After 1 hour the mixture is diluted with EtOAc and washed with a cold saturated solution of ammonium chloride. The aqueous layer was separated and extracted with EtOAc. The EtOAc extracts are combined, dried (Na2SO4), filtered and evaporated. The residue is purified automatic preparative HPLC (conditions: YMC S5 ODS 20×100 mm column; 10 min gradient starting from 10% solvent B (90% IU The N., 10% H2O with 0.1% TFA) and 90% solvent A (10% Meon, 90% H2O with 0.1% TFA) to 100% solvent b, flow rate 20 ml/min, λ=220 nm, receive the title compound (18 mg, 28%) as off-white liquid.

Example 317.

Getting 2-[[(1,1-dimethylmethoxy)carbonyl]amino]-4-methyl-N-(2,4,6-trimetilfenil)-5-thiazoleacetic.

Connection 317 receive similar connection 1, but take methyl-2-amino-4-methylthiazole-5-acetate, receiving the title compound 317 in the form of an off-white solid.

Example 318.

Obtaining 2-amino-4-methyl-N-(2,4,6-trimetilfenil)-5-thiazoleacetic.

Connection 318 receive 2 similarly, but take 317, giving the title compound 318 in the form of light solid brown color.

Example 319.

Obtaining N-(2-chloro-6-were)-2-[(4,6-dimethyl-2-pyridinyl)amino]-5-thiazolecarboxamide.

A. 2-Bromo-N-(2-chloro-6-were)-5-thiazolecarboxamide.

A solution of copper bromide (II) (2,68 g, 12 mmol) in acetonitrile (50 ml), rinsed with nitrogen and cooled to 0°C. Add tert-butyl (2 ml, 15 mmol), and then a solution of compound 315D (of 2.68 g, 10 mmol) in acetonitrile (50 ml). The mixture is stirred at room temperature overnight and evaporated in vacuum. The residue is dissolved in EtOAc, washed feast upon. a solution of NaHCO3and the precipitate is separated by the filtration. The organic layer is dried (Na2SO4), filtered and evaporated. The residue is recrystallized from a mixture of EtOAc/ether/mixture hexanol, receiving the title compound (1.68 g, 51%) as a yellow solid.

C. N-(2-Chloro-6-were)-2-[(4,6-dimethyl-2-pyridinyl)amino]-5-thiazolecarboxamide.

To the mixture A (25 mg, of 0.075 mmol) and 4,6-dimethyl-2-aminopyridine (37 mg, 0,302 mmol) in THF (1 ml) was added 95% sodium hydride (15 mg). The mixture is heated at 60°C overnight, cooled to room temperature and diluted with saturated aqueous ammonium chloride. The mixture is extracted with EtOAc (2x). The organic extracts are combined, washed with water and dried (Na2SO4), filtered and evaporated. The residue is triturated with ether, to obtain the title compound (17.5 mg, 63%) as a solid reddish-brown color.

Example 320.

Obtaining N-(2-chloro-6-were)-2-[(4-ethyl-2-pyridinyl)amino]-5-thiazolecarboxamide.

Connection 320 receive similar connection V, but take 4-ethyl-2-aminopyridine, leading to the title compound 320.

Example 321.

Obtaining N-(2-chloro-6-were)-2-[(2,6-dimethyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide.

Connection 321 receive similar connection V, but take 2,6-dimethyl-4-aminopyrimidine, leading to the title soedinenii.

Example 322.

Obtaining N-(2-chloro-6-were)-2-(3-pyridinylamino)-5-thiazolecarboxamide.

Connection 322 receive similar connection V, but take 3-aminopyridazine, giving the title compound 322.

Examples 323-335.

A General method.

Connection 323-335 receive the following method. To a mixture of amine 144 (31 mg, 0.11 mmol), the corresponding carboxylic acid (0.13 mmol), 1-hydroxy-7-isobenzofuranone (19.5 mg, 0.14 mmol) and ethyl-3-(3-dimethylamino)propylbromide hydrochloride (26,8 mg, 0.14 mmol) in THF (0.4 ml) was added diisopropylethylamine (60 μl, 0.34 mmol). The mixture is heated in a sealed tube under argon at 50°With 24 hours. The reaction mixture is diluted with methylene chloride (4 ml) and washed with 1N HCl aq. Solution in methylene chloride is passed through cation exchange column Varian Meda Bond Elut SCX, pre-washed with methanol and equilibrated with a mixture of acetonitrile - methanol (4:1). Column elute successively with a mixture of acetonitrile - methanol (4:1), methanol - 2M ammonia solution in methanol (4:1). The fractions containing the product are combined and evaporated in vacuum. VIEH - time beats. denotes the HPLC retention time under the following conditions: ballast column YMC S5 ODS 4,6×50 mm, 4 min gradient starting from 100% solvent A (10% Meon, 90% H2Oh, 0,2% H3PO4) to 100% solvent B (90% Meon, 10% N23RHO4), flow rate 4 ml/min, λ=220 nm.

Examples 336-362.

A General method.

Connection 336-362 get similar compounds 323-335, but take 315D instead of 144. Raw food cleanse automated preparative HPLC (conditions:column YMC S5 ODS And h mm; 10 min gradient starting from 10% solvent B (90% Meon, 10% H2O with 0.1% TFA) and 90% solvent A (10% Meon, 90% H2O with 0.1% TFA) to 100% solvent b, flow rate 20 ml/min, λ=220 nm) and receive the title compound 336-362. VIEH - time beats. denotes the HPLC retention time under the following conditions: ballast column YMC S5 ODS 4,6×50 mm, 4 min gradient starting from 100% solvent A (10% Meon, 90% H2Oh, 0,2% H3PO4) to 100% solvent B (90% Meon, 10% H2Oh, 0,2% H3PO4), flow rate 4 ml/min, λ=220 nm.

Example 363.

Getting 2-[(cyclopropanecarbonyl)amino]-N-(2,6-dimetilfenil)-5-thiazolecarboxamide.

Compound 363 receive similar connection 315, but take 2,6-dimethylaniline, leading to the title compound 363.

Example 364.

Getting 2-[(cyclopropanecarbonyl)the Mino]-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide.

Connection 364 receive similar connection 315, but take 2,4,6-trimethylaniline, giving the title compound 364.

Example 365.

Obtaining N-(2-chloro-4,6-dimetilfenil)-2-[(cyclopropanecarbonyl)amino]-5-thiazolecarboxamide.

Connection 365 receive similar connection 315, but to obtain the title compound 365 take 2-chloro-4,6-dimethylaniline.

Example 366.

Obtaining 1,1-dimethylethylene ether (4-[2-oxo-2-[(2,4,6-trimetilfenil)amino]ethyl]-2-thiazolyl]carbamino acid.

Connection 366 receive similarly to compound 1, but take 2-tert-butoxycarbonylamino-4-acetic acid, receiving the title compound 366 in the form of a white solid.

Example 367.

Obtaining 2-amino-N-(2,4,6-trimetilfenil)-4-thiazoleacetate.

Connection 367 get similar to compound 4, but take 365, receiving the title compound 367 in the form of a white solid.

Example 368.

Obtaining 2-methyl-5-nitro-N-(2,4,6-trimetilfenil)benzamide.

Connection 368 receive similar connection 3, but take 2-methyl-5-nitrobenzoic acid, receiving the title compound 368 in the form of a white solid.

Example 369.

Obtaining 5-amino-2-methyl-N-(2,4,6-t is iletiler)benzamide.

To a solution of 368 (149 mg, 0.5 mmol) in EtOAc (50 ml) with stirring, add 10% palladium on coal (30 mg). The reaction flask is connected with a hydrogen balloon through a three-way valve. The air from the bulb pumped in a vacuum and fill it with hydrogen from a balloon. After 4 hours, the catalyst was filtered, washed with EtOAc (5 ml, 5x). The filtrate is evaporated, obtaining the title compound (133 mg, 99%) as a white solid.

Example 370.

Obtaining 2-amino-5-chloro-N-(2,4,6-trimetilfenil)-4-pyrimidinecarboxylic.

Connection 370 receive similar connection 3, but take 2-amino-5-chloropyrimidine-4-carboxylic acid, receiving the title compound 370 in the form of a white solid.

Example 371.

Obtaining 1,1-dimethylethylene ester [4-methyl-5-[[(2,4,6-trimetilfenil)amino]carbonyl] -2-oxazolyl]carbamino acid.

Connection 371 receive analogously to compound 1, but take 2-tert-butoxycarbonyloxyimino-4-methyl-5-oxazolidinone acid, receiving the title compound 371 in the form of a light white foam.

Example 372.

Obtaining 2-amino-4-(methyl)-N-(2,4,6-trimetilfenil)-5-oxazolinone, triptoreline (1:1).

Connection 372 receive is similar to compound 4, but take the connection 369, receiving

Sagl the main connection 372 in the form of a white solid.

Example 373.

Obtaining 2-amino-N-(2,4,6-trimetilfenil)-5-pyridinecarboxamide.

Connection 373 receive similar connection 3, but using 6-aminonicotinic acid, receiving the title compound 373 in the form of a white solid.

Example 374.

Obtain 3-amino-N-(2,4,6-trimetilfenil)-4-pyridinecarboxamide.

Connection 374 receive similar connection 3, but using 3-amino-4-pyridylcarbonyl acid, receiving the title compound 374 in the form of a white solid.

Example 375.

Obtaining 2-amino-4-methyl-N-(2,4,6-trimetilfenil)-5-pyrimidinecarboxylic.

Connection 375 receive similar connection 3, but using 2-amino-4-methyl-5-pyrimidinecarbonitrile acid, receive the title compound 375 in the form of a white solid.

Example 376.

Obtaining N-(2-chloro-6-were)-2-[(4-methyl-2-pyridinyl)amino]-5-thiazolecarboxamide.

Connection 376 receive similar connection V, but using 2-amino-4-methylpyridin, and receive the title compound 376 in the form of an off-white solid.

Example 377.

Getting 2-[(6-amino-2-pyridinyl)amino]-N-(2-chloro-6-were)-5-thiazolecarboxamide.

Compound 377 recip who have similar connection V, but using 2,6-diaminopyridine, and receive the title compound 377 in the form of a light brown solid.

Example 378.

Obtaining N-(2-chloro-6-were)-2-[(6-propyl-2-pyridinyl)amino]-5-thiazolecarboxamide.

Connection 378 receive similar connection V, but using 2-amino-6-propylpyridine, receiving the title compound 378 in a solid off-white color.

Example 379.

Obtaining N-(2-chloro-6-were)-2-[(6-ethyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide.

Connection 379 receive by analogy with the connection V, but using 2-amino-6-ethylpyrimidine receive the title compound 379 in a solid white color.

Examples 380-409.

A General method.

Connection 380-409 get similar connection W. For the following examples 380-527 VIEH-time beats. denotes the retention time of HPLC under the following conditions: ballast column YMC S5 ODS 4,6×50 mm, 4 min gradient from 100% solvent A (10% Meon, 90% H2Oh, 0,2% H3PO4) to 100% solvent B (90% Meon, 10% N2O, 0.2% of N3PO4), flow rate 4 ml/min, λ=220 nm. If used VIEH - time beats per, this means HPLC retention time under the following conditions: column YMC S5 ODS 4,6×33 mm Turbo; 2-min gradient from 100% solvent A (10% Meon, 90% of the 2O with 0.1% TFA) to 100% solvent B (90% Meon, 10% H2O with 0.1% TFA) for 1 minute at 100% solvent b, flow rate 4 ml/min, λ=220 nm.

Example 410.

Obtaining N'-(2,6-dimetilfenil)-2-(phenylamino)-5-thiazolecarboxamide.

A. 1,1-Dimethylethylene ester [5-[[(2,6-dimetilfenil)amino]carbonyl]-2-thiazolyl]carbamino acid.

Connection I get similar connection S, but using 2,6-dimethylaniline.

C. 2-Amino-N-(2,6-dimetilfenil)-5-thiazolecarboxamide.

Connection V get similar connection 315D, but use the connection A.

C. the Title compound.

The title compound get similar connection V, but use the connection V and aniline. HPLC - retention time of 3.69 min

Examples 411-427.

A General method.

Connection 411-427 get similar connection W.

Example 428. Obtaining 2'-(2-pyridinylamino)-N-(2,4,6-trimetilfenil)-5-thiazolecarboxamide.

A. 1,1-Dimethylethylene ester [5-[[(2,4,6-trimetilfenil)amino]carbonyl-2-thiazolyl]carbamino acid.

Connection I receive by analogy with the connection C, but use the form 2,4,6-trimethylaniline.

C. 2-Amino-N-(2,6-dimetilfenil)-5-thiazolecarboxamide.

Connection V get similar connection 315D, but use the connection A and 2-aminopyridine. Retention time in HPLC 3,66 minutes

Examples 429-443.

A General method.

Connection 429-443 get similar connection W.

Example 444.

Obtaining N'-(2-chloro-6-were)-2-[[2-methyl-6-[[2-(4-morpholinyl)ethyl]amino]-4-pyrimidinyl]amino]-5-thiazolecarboxamide.

To a suspension of NaH (148 mg, of 6.17 mmol) in THF (20 ml) add a solution of compound 315D (551 mg, of 2.06 mmol) in THF (10 ml) and stirred at room temperature for 0.5 hour.

A solution of 4,6-dichloro-2-methylpyrimidine (671,6 mg, 4,12 mmol) in THF (10 ml) was stirred at room temperature overnight. To the reaction mixture of acetic acid and the solvent is removed in vacuum. To the residue water is added and the us. the solution of NaHCO3and extracted with CH2Cl2. The organic layer is removed in vacuo and the crude material purified by chromatography on a column of receiving A (494 mg).

C. the Title compound.

To connect A (30 mg) is added N-(2-amino-ethyl)morpholine (300 μl) and the mixture is heated at 80°C for 2 hours. Water added to the reaction mixture and the product collected by filtration. HPLC retention time 2,357 minutes

An example is 445-461.

A General method.

Connection 445-461 get similar W replacement to the corresponding amine.

Example 462.

Obtaining N'-(2-chloro-6-were)-2-[[6-[[2-(4-morpholinyl)ethyl]amino]-4-pyrimidinyl] amino] -5-thiazolecarboxamide.

Connection I get similar A, but take 4,6-dichloropyrimidine.

C. the Title compound.

The title compound get similar V, but instead of connecting A take

connection A. Retention time in HPLC 2,553 minutes

Examples 463-472.

A General method.

Connection 463-472 get similar V, substituting the corresponding amine. VIEH - time beats per, denotes the HPLC retention time under the following conditions: column YMC S5 ODS 4,6×33 mm Turbo; 2-min gradient starting from 100% solvent A (10% Meon, 90% H2O with 0.1% TFA) to 100% solvent B (90% Meon, 10% N2O with 0.1% TFA) for 1 minute at 100% solvent b, flow rate 4 ml/min, λ=220 nm.

Example 473.

Obtaining N'-(2-chloro-6-were)-2-[[6-[[2-(4-morpholinyl)ethyl]amino]-2-pyridinyl]amino]-5-thiazolecarboxamide.

To suspen the AI NaH (2.83 g, 118 mmol) in DMF (350 ml), cooled to 0°add connection A (31 g of 93.5 mmol). The mixture is stirred for 45 minutes at 0°With, then add Bu4NJ (6,9 g, 18.4 mmol) and then add 4-methoxybenzylamine (18 g, 115 mmol). The reaction mixture is brought to room temperature. After stirring overnight at room temperature to the reaction mixture is slowly added acetic acid, then the solvent is removed in vacuum. To the residue add water and neutralized with a saturated aqueous solution of NaHCO3. The mixture is extracted 3 times with EtOAc and the combined extract (organic layer) was washed with water and then saturated NaCl solution. The EtOAc extracts evaporated in vacuo and the residue purified column chromatography, obtaining A (35 g).

To connect A (0.5 g, 1.1 mmol)dissolved in THF (50 ml), slowly added NaH (0,13 g, 5.5 mmol)and then 2-bromo-6-aminopyridine (0,76 g, 4.4 mmol). The reaction mixture is heated at boiling for 2 hours, then cooled to room temperature and damp acetic acid. The solvent is removed in vacuum, then add water and hexane and stirred at room temperature. The solid precipitate is collected by filtration and washed with water and Et2O, get V (0,48 g).

To connect V (0,48 g)dissolved in TFA (5 ml), add anise is (2 ml), and then triftormetilfullerenov (triflic acid) (1 ml). The reaction mixture was stirred at room temperature for 3 hours, then gradually add to the rapidly stirred mixture of ice, feast upon. NaHCO3Et2O and CH2Cl2. The mixture is stirred in the cold for 1 hour, then filtered (solid) precipitate and washed with water and a mixture of Et2O/CH2Cl2getting S (0,344 g). Time beats. HPLC of 3.85 min

D. the Title compound.

The title compound get similar V, but instead of connecting A take

connection S. HPLC time beats. 2,80 minutes

Examples 474-480.

A General method.

Connection 474-480 get similar 443D, substituting the corresponding amine.

Example 481.

Obtaining N'-(2-chloro-6-were)-2-[[6-[[2-(4-morpholinyl)ethyl]amino]-2-pyrazinyl]amino]-5-thiazolecarboxamide.

Connection I get similar V, but instead of 2-bromo-6-aminopyridine using 2-chloro-6-aminopyrazine.

Century Alternative synthesis of compound 406.

Connection 406 receive similar S, but instead of connecting V use connection A.

C. the Title compound.

The title compound get similar V, but instead of connecting A

use connection 406. HPLC - time what I beats. 2,69 minutes

Examples 482-486.

A General method.

Connection 482-486 get similar S, substituting the corresponding amine.

Example 487.

Obtaining N'-(2-chloro-6-were)-2-[[6-(3-hydroxy-1-pyrrolidinyl)-3-pyridazinyl]amino]-5-thiazolecarboxamide.

Connection I get similar V, but instead of 2-bromo-6-aminopyridine using 2-bromo-6-aminopyrazine.

Connection V get similar S, but instead of connecting V use connection A.

C. the Title compound.

The title compound get similar V, but instead of connecting A use connection B and 3-hydroxypyrrolidine instead of N-(2-amino-ethyl)research. HPLC - time beats. 2,493 minutes

Example 488.

Obtaining N'-(2-chloro-6-were)-2-[[6-(1H-imidazol-1-yl)-3-pyridazinyl] amino] -5-thiazolecarboxamide.

Connection 488 receive similar S, but instead of 3-hydroxypyrrolidine using imidazole. HPLC - time beats. 2,61 minutes

Example 489.

Obtaining N'-(2-chloro-6-were)-2-[[3-(methylamino)-2-pyrazinyl]amino]-5-thiazolecarboxamide.

A. Connection I get similar V, but instead of 2-bromo-6-aminopyridine take 2-chloro-3-aminopyrazine.

Connection V get similar S, but instead of connecting V use

connection A.

C. the Title compound.

The title compound get similar V, but instead of connecting A use connection V and instead of N-(2-aminoethyl)research using methylamine. HPLC - time beats. 2,81 minutes

Examples 490-494.

A General method.

Connection 490-494 get similar S, but take the appropriate amine.

Example 495.

Obtaining N'-(2-chloro-6-were)-2-(cyclohexylamino)-5-thiazolecarboxamide.

Connection 495 receive similar V, but instead of connecting A use connection A and instead of N-(2-amino-ethyl)research take cyclohexylamin. HPLC - time beats. 3,547 minutes

Examples 496-500.

A General method.

Connection 496-500 get similar 495, but take the appropriate amine.

Table 17A

Example 501.

Obtaining N'-(2-chloro-6-were)-2-[[6-(methoxymethyl)-4-pyrimidinyl]amino]-5-thiazolecarboxamide.

To a mixture of methyl-4-methoxyacetanilide (methyl ester 4-methoxyacetophenone acid) (14.6 g,0,1 mol) and muriate of formamidine (16,1 g, 0.2 mol) is 70 ml of dry Meon portions add 25% solution of sodium methoxide (70 ml, of 0.3 mol) in Meon. Immediately a white precipitate is formed. The reaction mixture was stirred at room temperature for 1.0 hour. Add acetic acid (28,6 ml of 0.5 mol) and the reaction mixture is evaporated in vacuum. To the residue water is added and the mixture (above) perenasyschay NaCl and extracted with EtOAc (X5). The combined extracts dried over bezvadnym Na2SO4and evaporated in vacuum, obtaining the connection A in the form of a yellow solid.

The mixture of compounds A (5,3 g, 37.8 mmol) and POCl3(40 ml) is heated at boiling for 2 hours. Evaporated in vacuo and the residue poured into a mixture of ice-CH2Cl2. Bring the pH to 6.5-7 with concentrated NH4OH. The mixture is extracted with CH2Cl2(×3) and the combined extracts dried over Na2SO4. Evaporation in vacuum with subsequent flash chromatography (CH2Cl2- EtOAc 9:1) on silica gel gives 5,33 g of compound B in the form of a light yellow oil.

The mixture of compounds V (3.2 g, 20 mmol) and NH4OH (50 ml) is heated at 85°in the tube under pressure of 3.0 hours. Upon cooling to room temperature the reaction mixture is evaporated in vacuo and the residue triturated with ether, receiving of 2.81 g of compound C in the form of a light yellow solid.

Connection 501D produced from compound S analogtechnologies W.

E. the Title compound.

The title compound is obtained from the connection 501D similar connection S.

Time beats. when HPLC of 3.25 minutes

Example 502.

Obtaining N'-(2-chloro-6-were)-2-[[6-(hydroxymethyl)-4-pyrimidinyl]amino]-5-thiazolecarboxamide.

To a solution of compound 501 (56 mg, 0.144 mmol) in dry CH2Cl2(3.0 ml), cooled to 0°add clean BBr3(0,054 ml, 0,574 mmol). The mixture is stirred for 1 hour at room temperature. Slowly and carefully at 0°add Meon and the resulting mixture is evaporated in vacuum. To the residue add water and bring the pH to 7 .NaHCO3. White precipitate is filtered off, washed with water/ether and dried in high vacuum, obtain 52 mg of compound 502 in the form of an off-white solid. HPLC retention time 2,84 minutes

Example 503.

Obtaining N'-(2-chloro-6-were)-2-[[6-(4-morpholinylmethyl)-4-pyrimidinyl] amino] -5-thiazolecarboxamide.

To a suspension of compound 502 (a 44.2 mg, the amount of 0.118 mmol) in 0.5. ml dry. CH2Cl2add thionyl chloride (0,086 ml, 1.18 mmol). The reaction mixture was stirred at 5.0 hours. Evaporated in vacuo and the residue after azeotropic evaporation with CH2Cl2give 56 mg of compound 503 in the form of a yellow solid.

C. the Title compound.

The mixture of compounds A (20 mg),research (of 0.014 ml) and diisopropylethylamine (0,09 ml) in 0.5 ml of dry dioxane is heated at 85° C for 4 hours. Evaporation in vacuum with subsequent flash chromatography (CH2Cl2-MeOH-NH4OH 95:5:0.5 to) on silica gel gives 15 mg of the title compound as off-white solid. Retention time HPLC 2,52 minutes

Examples 504-513.

A General method.

Connection 504-513 produced from compound A similar connection 503. These compounds have the following structure.

Example 514.

Obtaining N'-(2-chloro-6-were)-2-(2-naphthalenamine)-5-thiazolecarboxamide.

Connection A produced from compound A similarly V, but instead of 2-bromo-aminopyridine take 2-aminonaphthalene.

C. the Title compound.

The title compound get similar connection S, but instead of connecting W take the connection A. Retention time in HPLC 4,11 minutes

Example 515.

Obtaining N'-(2-chloro-6-were)-2-(2-hyalinella)-5-thiazolecarboxamide.

Connection A produced from compound A similar connection V, but instead of 2-bromopyrimidine take 2-aminoquinoline.

C. the Title compound.

The title compound get similar connection S, but instead of connecting W take the connection A. HPLC - retention time of 3.94 min

Example 516.

Receiving '-(2-chloro-6-were)-2-(3-ethanolamine)-5-thiazolecarboxamide.

Connection A produced from compound A similar connection V, but instead of 2-bromo-6-aminopyridine take 3-aminoisoquinoline.

C. the Title compound.

The title compound get similar connection S, but instead of connecting W take the connection A. Retention time in HPLC 3,94 minutes

Example 517.

Obtaining N'-(2-chloro-6-were)-2-(2-khinoksalinona)-5-thiazolecarboxamide.

Connection A produced from compound A similar connection V, but instead of 2-bromo-6-aminopyridine take 2-aminopenicillin.

C. the Title compound.

The title compound get similar connection S, but instead of connecting W take the connection A. Retention time in HPLC 3,927 minutes

Example 518.

Obtaining N'-(2-chloro-6-were)-4-methyl-2-[[2-methyl-6-(4-morpholinyl)-4-pyrimidinyl] amino] -5-thiazolecarboxamide.

Connection A produced from compound 144 similar to the connection A.

Connection V get similar connection A, but instead of connecting A take the connection A.

Connection S get similar connection V, but instead of connecting A take the connection V and instead of 2-amino-6-bromopyridine take 4 am the but-6-chloro-2-methylpyridin.

Connection 518D get similar connection S, but instead of connecting W take the connection S.

E. the Title compound.

The title compound get similar connection V, but instead of connecting A take the connection 518D and instead of N-(2-amino-ethyl)-the research take morpholine. HPLC retention time 3,397 minutes

Example 519.

Obtaining N'-(2-chloro-6-were)-4-methyl-2-[[2-methyl-6-[[2-(4-morpholinyl)ethyl]amino]-4-pyrimidinyl]amino]-5-thiazolecarboxamide.

Connection 519 receive similar connection A, but instead the research take N-2-aminoethylphosphonic. Retention time in HPLC 2,493 minutes

Example 520.

An alternative method of obtaining compounds of 321.

Connection A obtained from 2-aminothiazole according to the method described in the patent application great Britain GB 2323595 A.

To a solution of compound A (480 mg, 4.0 mmol) in dry THF (10 ml), cooled to -78°add 2.5m solution of n-BuLi (1,68 ml, 4.2 mmol) in hexane dropwise from a syringe when the inside temperature of the flask below -75°C. Upon completion of addition, receive a suspension of the color beige. The reaction mixture was stirred 15 minutes at -78°C. Add a solution of 2-chloro-6-methylphenothiazine (0.6 ml, 4.4 mmol) in 5 ml dry THF and the reaction see what camping is stirred for further 2 hours at -78° C. Add a saturated solution of NH4Cl (10 ml), the mixture is distributed in the system EtOAc-water and extracted with EtOAc (x2). The combined extracts dried over Na2SO4and evaporated in vacuum, obtaining, after recrystallization from EtOAc-hexane 0,99 g of the title compound as a pale yellow crystalline substance.

Connection S get similar connection A, but instead of connecting A take the connection W.

Connection 520D is produced from compound S similar connection W.

E. the Title compound.

Connection 321 receive similar connection S.

Example 521.

Obtaining 2'-[[2,6-dimethyl-4-pyrimidinyl]amino]-N-phenyl-5-thiazolecarboxamide.

Connection I get similar connection V, but instead of 2-chloro-6-methylphenothiazine use phenylisocyanate.

Connection V get similar connection A using the connection A instead of connecting A.

Connection IS produced from compound V similar connection W.

D. the Title compound.

The title compound get similar connection S. HPLC - retention time of 1.3 min, method C.

Example 522.

Obtaining 2'-[(2,6-dimethyl-4-pyrimidine is l)methylamino]-N-(2-were)-5-thiazolecarboxamide.

Connection I get similar connection V, but instead of 2-chloro-6-methylphenothiazine use 2-methylphenylsulfonyl.

Connection V get similar connection A, but instead of connecting A take the connection A.

Connection IS produced from compound V similar connection W.

To a solution of compound C (280 mg, 0.61 mmol) in 2 ml DMF at room temperature is added sodium hydride (60% in oil, 40 mg, 1 mmol). After 30 minutes stirring itmean (0.2 ml, 3 mmol) and the reaction mixture is stirred for 4 hours. After distribution of the reaction mixture in the system ethyl acetate (50 ml) and water (50 ml) the organic layer washed with water (2×50 ml) and brine (50 ml). Drying (MgSO4) and evaporation gives an oil which chromatographic on a column of 2.5×15 cm silica gel, using 50-75% ethyl acetate/hexane. Pure fractions evaporated and the residue recrystallized from ethyl acetate/hexane, receiving 100 mg 522D in the form of light yellow solid

E. the Title compound.

The title compound get similar connection S. HPLC - time

retention of 1.21 min, method C.

Example 523.

Obtaining 2'-[(2,6-di is ethyl-4-pyrimidinyl)amino]-N-(2-were)-5-thiazolecarboxamide.

Connection 523 receive similar connection S, but instead of connecting W take the connection S. HPLC - retention time of 1.24 min, method C.

Example 524.

Obtaining N'-(3,5-acid)-2-[(2,6-dimethyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide.

Connection I get similar connection V, but instead of 2-chloro-6-methylphenothiazine take 3,5-dimethoxyphenylacetic.

Connection V get similar connection A using the connection A instead of connecting A.

Connection IS produced from compound V similar connection W.

D. the Title compound.

The title compound get similar connection S, but instead of connecting

V take S. Retention time HPLC 1,28 min, method C.

Example 525.

Obtaining N'-[2,6-bis(1-methylethyl)phenyl]-2-[(2,6-dimethyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide.

Connection I get similar connection V, but instead of 2-chloro-6-methylphenothiazine take 2,2-diisopropylaniline.

Connection 525V get similar connection A, applying instead the soedineniya A connection A.

Connection IS produced from compound 525V similar connection W.

D. the Title compound.

The title compound get similar connection S, but instead of connecting W take the connection S. HPLC - retention time of 1.6 minutes, method C.

Example 526.

Obtaining N'-(2-chloro-6-were)-2-[(2,6-dimethyl-4-pyrimidinyl)methylamino]-5-thiazolecarboxamide.

A mixture of compound 321 (110 mg, 0.29 mmol), potassium carbonate (138 mg, 1 mmol) and iodomethane (0.06 ml, 1 mmol) in DMF is stirred for 2 hours at room temperature. After distribution of the reaction mixture between ethyl acetate (25 ml) and water (25 ml) the organic layer washed with water (2×25 ml) and brine (25 ml). Drying (MgSO4) and evaporation receive oil, which chromatographic on a column of 2.5×15 cm silica gel, elwira 1-4% Meon/CHCl3and collect the fractions containing 526; receive 20 mg of product. HPLC - retention time of 1.3 min, method C.

Example 527.

Obtaining N'-(2-chloro-6-were)-2-[(2,6-dimethyl-4-pyrimidinyl)amino] -N-methyl-5-thiazolecarboxamide.

Connection 527 receive similar connection 526, but collect the fractions containing the compound 527, receiving 60 mg of product. HPLC - retention time of 1.23 min, method C.

Example 528.

Obtain 2-bromo-N,N-(2-chloro-6-ethylphenyl)-(4-methoxybenzyl)-5-thiazolecarboxamide.

To a cooled (0° (C) to a solution of 2-chloro-6-methylaniline (2,86 ml, with 23.3 mmol, 1,10 EQ.) in THF are added dropwise 1.0 M solution of lithium bis(trimethylsilyl)- amide (42.2 ml, 42.2 per mmol, 2.00 EQ.) with a syringe. The homogeneous solution is stirred for 5 minutes and then add through a needle of a solution of ethyl-2-bromo-5-thiazolecarboxamide (of 5.00 g, 21.1 mmol, 1.00 equiv., obtained similarly to the compound of A) in THF. The solution is stirred for 15 minutes, until TLC shows the absence of the source. Then to the reaction mixture was added 4-methoxybenzylamine (7,15 ml, and 52.7 mmol, 2.5 equiv.) then a catalytic amount of tetrabutylammonium (1.56 g, 4,22 mmol, 0,20 EQ.). The homogeneous mixture was stirred at room temperature overnight and then evaporated in vacuum. The residue is distributed between ethyl acetate and water, the extract washed with brine and dried with Na2SO4. After filtration and removal of solvent the product was then purified on a flash chromatography (10-20% ethyl acetate in a mixture of hexanol)to give the title compound as a reddish brown solid (47%).

Example 529.

Obtaining N,N-(2-chloro-6-were)-(4-methoxybenzyl)-2-[(6-bromo-2-pyridinyl)amino]-5-thiazolecarboxamide.

Connection 529 receive similar connection V, but take as reagents connection 528 and 6-bromo-2-aminopyridine.

the example 530.

Obtaining N-(2-chloro-6-were)-2-[(6-bromo-2-pyridinyl)amino] -5-thiazolecarboxamide.

Connection 529 (0,500 g, 0,919 mmol, 1.00 equiv.) dissolve in 5 ml triperoxonane acid and thereto at room temperature, add 2 ml of anisole, and then 1 ml triftormetilfullerenov acid. Dark red homogeneous solution is stirred overnight and then gently damp, pouring the solution into a mixture of ice/sodium bicarbonate. White precipitate is filtered off and successively washed with water, a mixture of 1:1 hexane/ether and ether, receiving the title compound (41%).

Examples 531-538.

A General method.

Connection 531-538 get for the following General method. In vials 1 dram (60 or 28 grams) put the connection 530 and the excess amine and heated at 90°With during the night. The residue is then purified by reversed-phase HPLC, getting net connection. For the following compounds 531-555 VIEH - time beats. represents the retention time in HPLC under the following conditions: YMC ODS And 18 S7 3,0×50 mm; 2-min gradient starting from 100% solvent A (10% Meon, 90% H2O with 0.1% TFA) to 100% solvent B (90% Meon, 10% H2O with 0.1% TFA), flow rate 5 ml/min, λ=220 nm.

Example 539.

Getting ethyl-2-[(6-bromo-2-pyridinyl)amino]-5-thiazolecarboxamide.

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Connection 539 receive similar V, but are used as reagents ethyl-2-bromo-5-thiazolecarboxamide and 6-bromo-2-aminopyridine.

Examples 540-550.

A General method.

Connection 540-550 receive the following General method. Connection 539 is condensed with the appropriate aniline by the method described in example 528, thus obtain the corresponding N-(4-methoxybenzyl)amide. Intermediate bromopyridin then reacts with N-(3-aminopropyl)imidazole by the method proposed for examples 531-538, with the formation of the corresponding diaminopyridine. Removing the 4-methoxybenzophenone groups according to the method described in Example 530, followed by purification by reversed-phase preparative HPLC gives connection 540-550.

Example 551.

Getting ethyl-2-[(6-bromo-2-pyridinyl)amino]-4-methyl-5-thiazolecarboxamide.

Connection 551 receive similar V, but as reagents using 2-bromo-4-methyl-5-thiazolecarboxamide and 6-bromo-2-aminopyridine.

Examples 552 and 553.

Connection 552 and 553 receive according to the method similar to the method of producing compounds 540-550, but as the source is used as a compound 551.

Example 554.

Obtaining N'-(2-chloro-6-were)-2-[3-[[3-(1H-imidazol-1-yl)propyl]-amino]phenyl]amino]-5-thiazolecarboxamide.

A solution of 528 (to 0.127 g, 0,281 mmol, 1.00 equiv.) and 3-[N,N-(tert-butoxycarbonyl)-(3-aminopropyl)-imidazolyl]-1,3-phenylenediamine (0,178 g, 0,563 mmol, 2.00 EQ.) in 0,200 ml of DMSO is heated at 120°C in a sealed vial overnight. Purification by reversed-phase preparative HPLC with a subsequent removal of the protection according to the method described for compound 530, gives the title compound.

Example 555.

Obtaining N'-(2-chloro-6-were)-2-[[5-[[3-(1H-imidazol-1-yl)propyl]-amino]-2-nitrophenyl]amino]-5-thiazolecarboxamide.

In a solution of 2,4-deformirovannoe (0,400 ml, 3.65 mmol, 1.00 equiv.) in acetonitrile To put2CO3(0,605 g of 4.38 mmol, 1.20 equiv.) and then ethyl-2-amino-5-thiazolecarboxamide (0,628 g, 3.65 mmol, 1.00 equiv.) in the form of solids. The heterogeneous mixture was sealed and heated at 120°With during the night. The solution is filtered and then evaporated in vacuum. Clean flash-chromatography gives ethyl-2-[(3-fluoro-6-nitro-1-phenyl)amino]-5-thiazolecarboxamide in the form of a yellow solid (9%). This intermediate compound is reacted with 2-chloro-6-methyl-aniline production according to the method described for compound 528, giving N'-(2-chloro-6-were)-2-[3-(fluoro-6-nitro-1-phenyl)amino]-5-thiazolecarboxamide (21%). The title compound is synthesized by reaction of the intermediate with an excess of N-(3-aminopropyl)-imidazole in 80°followed about what estcoy reverse-phase preparative HPLC.

Examples 556-566.

A General method.

Connection 556-566 receive the following General method. A mixture of 2-bromo-N-[2-chloro-6-were]-5-thiazolecarboxamide A, aniline (1 equiv.) of 1.0 N HCl aq. (0.5 EQ.) in n-BuOH heated overnight at 120°C in sealed vials, diluted with methanol and the product emit preparative HPLC (YMC S5 ODS 30×100 mm column; elution in a gradient mixture of two solvents (a mixture of: 10% Meon, 90% water and 0.1% TFA, the mixture: 90% Meon, 10% water and 0.1% TFA). In the case of anilines, substituted carboxylic acid group, the reaction mixture was treated with 1N aq. NaOH (5 EQ.) during the night before the final purification of the product by HPLC. VIEH - time beats. represents the retention time in HPLC under the following conditions: YMC S5 ODS 4,6×30 mm (556-560) or YMC ODS S7 3×50 mm column (561-566); 2-min gradient starting from 100% solvent A (10% Meon, 90% H2O with 0.1% TFA) to 100% solvent B (90% Meon, 10% H2O with 0.1% TFA), flow rate 5 ml/min, λ=220 nm.

Example 567.

N-(2-Chloro-6-were)-2-[[1-[3-(1H-imidazol-1-yl)propyl] -1H-benzimidazole-4-yl] amino] -5-thiazolecarboxamide.

A mixture of 1-bromo-3-chloropropane (10 ml, 0.10 mmol), imidazole (for 6.81 g, 0.10 mmol) in ethanol NaOEt (41,3 ml, 21 wt.%, to 1.1 mol) is heated at boiling for 1 hour. Upon cooling to room the second temperature, filtered and the filter cake washed with EtOH. The solvent is evaporated from the filtrate and obtain crude 3-chloro-1-(imidazo-1-yl)-propane in the form of oil. Part of the crude chloride (1.07 g, 7.40 mmol) are added to a mixture of 4-nitro-benzimidazole (1,09 g of 6.66 mmol) and NaH (293 mg, 60% in oil, to 8.14 mmol) in DMF (15 ml). After heating overnight at 60°and then 3 hours at 75°the solvent is removed. The residue is partitioned between water and a mixture of 10% Meon in DSM. The organic phase is separated, dried (Na2SO4) and the solvent is distilled off. Radial chromatography (4 mm plate with silica gel, which elute in a stepwise gradient DSM containing 2, 3, 4,...10% Meon) gives the main product 1-[3-imidazo-1-ylpropyl]-4-nitrobenzimidazole in the form of a solid (518 mg, 28%). A mixture of this material (250 mg) and 10% palladium on coal (200 mg) in EtOH (10 ml) in an atmosphere of hydrogen (balloon) vigorously stirred for 1 hour. The catalyst is filtered off and the solvent evaporated under pressure, to the residue receive crude 4-amino-1-[3-imidazo-1-ylpropyl]-benzimidazole in the form of solids. Part of this substance (46 mg, 0,191 mmol) is added to the mixture A (63 mg, 1.0 EQ.), aqueous HCl (to 0.24 ml, 1.0 M, 1.25 EQ.) and n-BuOH (1 ml). Heated in a sealed vial at 120°C for 44 hours. Upon cooling to room temperature preparative HPLC allocate connection 567 (retention time HPLC (YMC S5 ODS 4,6×30 mm) 1,20 min).

Example 568.

N-(2-Chloro-6-methylpheni is)-2-[[1-[2-(1H-imidazol-1-yl)ethyl]-1H-indazol-6-yl]amino]-5-thiazolecarboxamide.

A mixture of 1-bromo-2-chlorethane (4.6 ml, by 0.055 mol), imidazole (3,40 g 0,050 mol) NaOEt in ethanol (19 ml, 21 wt.%, 1 mol) are heated at boiling for 2 hours. Upon cooling to room temperature the reaction mixture is filtered and the filter cake washed with EtOH. The solvent is distilled off from the filtrate and obtain crude 2-chloro-1-(imidazo-1-yl)-ethane. Part of the crude chloride (2.24 g of 17.2 mmol) was added to a mixture of 6-nitroindazole (1.63 g, 10.0 mmol), K2CO3(1.50 mg, 1.1 EQ.) and KJ (1.70 g,1.1 EQ.) in DMF (15 ml). After heating at 70°during the night, and then at 90°C for 4 hours the solvent is removed. The residue is partitioned between water and a mixture of 5% Meon in DSM. The organic phase is separated, dried (Na2SO4) and the solvents removed. Radial chromatography (4 mm plate with silica gel, which elute in a stepwise gradient DSM containing 0, 1, 2% Meon) gives 659 mg of 1-[2-imidazo-1-ileti]-6-nitroindazole and 450 mg of the isomeric 2-[2-imidazo-1-ileti]-6-nitroindazole. A mixture of 1-[2-imidazo-1-ileti]-6-nitroindazole (650 mg) and 10% palladium on coal (600 mg) in EtOH (10 ml) in an atmosphere of hydrogen (balloon) vigorously stirred over night. The catalyst is filtered off, the solvent is removed in vacuum, remains the crude 6-amino-1-[2-imidazo-1-ileti]-indazole in the form of solids. Part of this substance (68,1 mg, 1.5 EQ.) add to the mixture 556 (99,3 mg, 0,300 what they say), aqueous HCl (0.45 ml, 1.0 M, 1.5 EQ.) and n-BuOH (1.5 ml). Heated in a sealed vial at 120°C for 44 hours. Upon cooling to room temperature preparative chromatography allocate connection 568 (HPLC retention time (YMC ODS S7 3×50 mm) 1,31 min).

Example 569.

N-(2-Chloro-6-were)-2-[[2-[2-(1H-imidazol-1-yl)ethyl]-2H-indazol-6-yl]amino]-5-thiazolecarboxamide.

On the basis of the isomeric 2-[2-imidazo-1-ileti]-6-nitroindazole, the connection 569 (HPLC retention time (YMC ODS S7 3×50 mm) of 1.28 min) are obtained similarly to the compound of 568.

Example 570 and 571.

N-(2-Chloro-6-were)-2-[(1-methyl-1H-benzimidazole-6-yl)amino]-5-thiazolecarboxamide.

N-(2-Chloro-6-were)-2-[(1-methyl-1H-benzimidazole-5-yl)amino] -5-thiazolecarboxamide.

Based on 5-nitrobenzimidazole and iodotope bromide compound 570 (HPLC retention time (YMC ODS S7 3×50 mm) of 1.23 min) and the connection 571 (HPLC retention time (YMC ODS S7 3×50 mm) of 1.23 min) get similar compounds 557 and 558.

Example 572.

N-(2-Chloro-6-were)-2-[[2-[3-(1H-imidazol-1-yl)propyl]amino-1H-benzimidazole-5-yl]amino]-5-thiazolecarboxamide.

A mixture of 2-chloro-5-nitrobenzimidazole (985 mg, 5.0 mmol) and 1-(3-aminopropyl)-imidazole (1.8 ml, 3 EQ.) in toluene (15 ml) is heated under a pile is AI 5 hours. The reaction mixture was partitioned between EtOAc and brine, receive the precipitate, which is filtered off. Flash chromatography (silica gel; elution in a stepwise gradient mixtures containing DSM and 1, 2, 3...10% Meon) gives 2-[3-[imidazo-1-yl]propylamino]-5-nitrobenzimidazole (550 mg) as a solid. This compound is combined with 10% Pd on coal (500 mg)suspended in EtOH and stirred in hydrogen atmosphere (balloon) overnight. The catalyst is filtered off, the solvent is distilled off in vacuum, remains the crude 5-amino-2-[3-imidazo-1 iproplatin]-5-benzimidazole in the form of solids. Part of it (77 mg, 0.30 mmol) was added to a mixture of compound A (99 mg, 1.0 EQ.), aqueous HCl (0,60 ml, 1.0 M, 2 EQ.) and n-BuOH (1.5 ml). Heated in a sealed vial at 120°20 hours. Upon cooling to room temperature emit preparative chromatography connection 572. (HPLC retention time (YMC ODS S7 3×50 mm) 1,20 min).

Example 573.

N-(2-Chloro-6-were)-2-[[2-(4-morpholinylmethyl)-1H-benzimidazole-5-yl]amino]-5-thiazolecarboxamide.

A mixture of 3,4-diaminoanisole of 15.3 g of 0.10 mol) and Chloroacetic acid (14,18 g, 1.5 EQ.) 5.0 N aqueous HCl (80 ml) is boiled for 1 hour. Upon cooling to room temperature the reaction mixture was filtered through celite and the filtrate was kept at 0°With 2 days. The resulting crystals are collected and paracrystals who agree from a mixture of EtOH and water, obtain 7.2 g of hydrochloric acid salt of 2-chloromethyl-5-nitrobenzimidazole. Part of this salt (528 mg, 2,13 mmol) and morpholine (1.31 ml, 7 EQ.) boiled in toluene (15 ml) for 4 hours. Upon cooling to room temperature the reaction mixture is filtered and the filter cake washed with toluene. The solvent is removed from the filtrate and obtain crude 2-[N-morpholinylmethyl]-5-nitrobenzimidazole in the form of oil. Part of it (657 mg) and 10% palladium on coal (650 mg) in EtOH (10 ml) is stirred overnight in a hydrogen atmosphere (balloon). The catalyst is filtered off, remove the solvent, remains the crude 5-amino-2-[N-morpholinylmethyl]-benzimidazole in the form of oil. Part of it condenses with 556 as described for 570, get the connection 573 (HPLC retention time (YMC ODS S7 3×50 mm) to 0.92 min).

Example 574.

N-(2-Chloro-6-were)-2-[[2-(1H-imidazol-1-ylmethyl)-1H-benzimidazole-5-yl]amino]-5-thiazolecarboxamide.

Based on imidazole and 2-chloromethyl-5-nitrobenzimidazole connection 574 (HPLC retention time (YMC ODS S7 3×50 mm) at 1.17 min) are obtained similarly to the compound of 570.

Example 575.

N-(2-Chloro-6-were)-2-[[3-[[5-(1H-imidazol-1-yl)-2-pyridinyl]amino]phenyl]amino]-5-thiazolecarboxamide.

A mixture of 3-nitroaniline (2.91 in g, 21.1 mmol) and 2,5-dibromopyridine (5.0 g, 1 EQ.) heated at 185°With 1 hour. After cooling to room temperature, the solid is first substance is pulverized and treated with a mixture feast upon. NaOH aq. and 10% Meon in DSM. The suspended solid is filtered off and washed with a small amount of 10% of the Meon in the DSM, and then with water, after drying receive and 3.72 g of crude N-[5-bromopyridin-2-yl]-5-nitroaniline. Part of it (500 mg, 1.70 mmol) is mixed with imidazole (116 mg, 1 EQ.), CuJ (81 mg, 0.25 EQ.) and K2CO3(235 mg, 1 EQ.) in DMF (2 ml) and the mixture for 2 days is heated at 130°C. Upon cooling to room temperature the solvent is removed and the residue partitioned between water and a mixture of 20% Meon in DSM. The organic layer is separated, dried (Na2SO4) and remove the solvents, remains solid N-[5-imidazo-1-yl]-pyridine-2-yl]-5-nitroaniline. It is treated with 10% palladium on coal (650 mg) in EtOH in an atmosphere of hydrogen for 1.5 hours. After removal of the catalyst and then the solvent remains crude N-[5-imidazo-1-yl]-pyridine-2-yl]-5-aminoaniline. It purify by radial chromatography (plate with 4 mm silica gel elute in a stepwise gradient DSM containing 1, 2, 3...6% Meon). Then aniline condense with A as described for 570, receiving the connection 575 (HPLC retention time (YMC ODS S5 4,6×30 mm) of 1.42 min).

Example 576 and 577.

N-(2-Chloro-6-were)-2-[[3-[3-(1H-imidazol-1-yl)propoxy]phenyl]amino]-5-thiazolecarboxamide.

N-(2-Chloro-6-were)-2-[[4-[3-(1H-imidazol-1-yl)propoxy]phenyl]amino]-5-thiazolecarboxamide.

A suspension of 3-NITROPHENOL (837 mg, of 6.02 mmol), 1-chloro-3-[imidazo-1-yl]-propane (811 mg, 1 EQ.), To2CO3(3,3 g, 4 EQ.) and NaJ (1.0 g, 1.1 EQ.) in DMF is heated at 120°C for 6 hours. Upon cooling to room temperature the reaction mixture is filtered and the precipitate washed with DMF. The solvent is removed and the residue chromatographic (radial chromatography; plate with 4 mm silica gel elute in a stepwise gradient DSM containing 0; 1; 2,5; 5; 7,5% Meon), receive 400 mg of 3-[3-imidazo-1 ylpropionic]] -nitrobenzene. It is treated with 10% palladium on coal (400 mg) in EtOH in an atmosphere of hydrogen for 4 hours. After removal of catalyst and solvent is 3-[3-imidazo-1 ylpropionic]]-aniline, which condense with A as described for 570, get the connection 576 (HPLC retention time (YMC ODS S5 4,6×30 mm) of 1.33 min). On the basis of 4-NITROPHENOL and 1-chloro-3-[imidazo-1-yl]-propane receive connection 577 (HPLC retention time (YMC ODS S5 4,6×30 mm): 1,42 min) similar to the connection 576.

Example 578.

N-(2-Chloro-6-were)-2-[[4-[2-(1H-imidazol-1-yl)ethoxy]-3-methoxyphenyl]amino]-5-thiazolecarboxamide.

On the basis of 2-methoxy-4-NITROPHENOL and 1-chloro-3-[imidazo-1-yl]-ethane, the compound 578 (HPLC retention time (YMC ODS S5 4,6×30 mm) min 1,35) are obtained similarly to the compound of 576.

Example 579 and 580.

N-(2-Chloro-6-were)-2-[[3-[[[3-(1H-imidazol-1-yl)who ropyl]amino]sulfonyl]phenyl]amino]-5-thiazolecarboxamide.

N-(2-Chloro-6-were)-2-[[4-[[[3-(1H-imidazol-1-yl)propyl]amino]sulfonyl]phenyl]amino]-5-thiazolecarboxamide.

3 Imidazo-1-ylpropionic (2,04 ml, 2.5 EQ.) added to a solution of 3-nitrobenzenesulfonamide (1.5 g, 6,77 mmol) in THF (20 ml) at room temperature. After 1 hour the solvent is removed and the residue partitioned between water and a mixture of 10% Meon in DSM. The organic layer is separated, washed with water and dried (Na2SO4). The crude product N-[3-imidazo-1-yl]-propyl]-3-nitrobenzenesulfonamide treated with 10% palladium on coal (2 g) in THF (60 ml) in an atmosphere of hydrogen overnight. After removal of catalyst and solvent to obtain crude 3-amino-N-[3-[imidazo-1-yl]-propyl]-benzosulfimide, which then reacts with A as described for 570, giving connection 579 (HPLC retention time (YMC ODS S7 3×50 mm) 1,22 min). On the basis of 4-nitrobenzenesulfonamide and 3-[imidazo-1-yl]-Propylamine get a connection 580 (HPLC retention time (YMC ODS S7 3×50 mm) to 1.21 min) similar to the connection 579.

Example 581

Of the above compounds, N-(2-chloro-6-were)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinil]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide appearing in the examples under No. 455 (hereinafter for brevity connection 455) was identified as an inhibitor Srs/Abl kinase to eliminate Inoi antiproliferative activity against hematological cell lines and cell lines and solid tumors. Compound 1 was active when administered orally on a model C the xenograft chronic myelogenous leukemia (CML), showing complete regression of tumors and low toxicity at the level of multiple doses.

Targeted therapy really is carried out when conducting preclinical and clinical cancer research. The use of imatinib (Gleevec™) for the treatment of chronic myelogenous leukemia (CML) is proof of the concept that therapeutic agents aimed at specific cancer pathways (cascades of reactions can lead to significant improvements compared to conventional chemotherapeutic agents. CML is a myeloproliferative disorder that is characterized by hyperproliferative stem cells and subsequent differentiation into cells of peripheral white blood cells (leukocytes). The presence of the Philadelphia chromosome, resulting from the translocation domain of Abl kinase on chromosome 9 with a specific area of the break point (bcr) on chromosome 22, is characteristic of CML. The gene product of this translocation is a constitutively-activated tyrosinekinase, known as Bcr-Abl, which stimulates the proliferation of stem cells in the bone marrow and as a result causes the pathology of the disease. Focusing tyrosinekinase actively the th Bcr-Abl, imatinib normalizes the number of cells of peripheral white blood cells (lymphocytes) and significantly reduces the positive against the Philadelphia chromosome clone stem cells in the bone marrow, causing the clinic effective hematologic and cytogenetic response.

Protooncogene C-Src plays a major role in the development, growth and metastasis in the case of a wide range of human cancers. Activation of Src in the form of elevated kinase activity and/or expression of the protein demonstrated at several major types of cancer, including cancer of the colon, breast, pancreas and brain. Src kinase modulates signal transduction through multiple oncogenic pathways, including EGFR, Her2/neu-DERIVED, FGFR and VEGFR. Thus, it can be expected that the blocking signal transmission through inhibition of kinase activity of Src will provide an effective way of modulating aberrant ways that stimulate cancer cells transformation.

Connection 455 was obtained with a total yield of 61% from chlorothiazole optimized synthetic sequence shown in detail in Scheme XII. Condensation of the lithium anion of compound 1 with 2-chloro-6-methylprenisolone in THF proceeds smoothly, it is appropriate carboxamide, which protects a 4 methoxybenzylthio derived . Replacement 2-chlorine substituted for the sodium salt of 4-amino-6-chloro-2-methylpyrimidine boiling, followed by removing the protective 4-methoxybenzyloxy group in TfOH/TFA to give chloropyrimidine 3. Finally, the reaction of 3 with 1-(2-hydroxyethyl)piperazine in dioxane boiling gives compound 455, which is then under the action of HCl in ether is converted into the corresponding hydrochloride. It was found that the extent of this reaction can be increased and all stages can be performed in quantities of 50 g or more with comparable outputs.

(a) n-BuLi, THF, 2-chloro-6-methylphenylsulfonyl, -78°C, 86%; (b) NaH, boiling, 4-methoxybenzylidene, THF, 95:; (c)NaH, THF, 4-amino-6-chloro-2-methylpyrimidin, boiling, 83%; (d) TfOH, TFA/CH2Cl2(1:1), 99%; (e) 1-(2-hydroxyethyl)piperazine, 1,4-dioxane, boiling; (f) HCl, Et2O, MeOH, 91% (two stages).

For a better understanding of enzyme-inhibitory properties of the compounds 455, this compound was studied on the inner panel of kinase selectivity and defined valuesias for Src and Bcr-Abl kinase. It was confirmed that the compound is highly active inhibitor for Src and Bcr-Abl, the measured values Forimake up 16±1.0 PM and 30±22 PM, respectively. Data on the selectivity of the compounds are summarized in table 1. It was found that the compound inhibits one is x representatives of the Src-family. The connection also shows appreciable activity against C-kit and DERIVEDβ. For all other kinase targets on the panel was observed by more than 1000-fold selectivity.

Table 1

The selectivity profile of compound 455 against kinases.
KinaseEnzyme

IC50, nM
KinaseEnzyme

IC50, nM
Bcr-Abl<1.0MEK1700
src9.50VEGFR-2>2000
lck0.40DK2>5000
ycs0,50IKK>10000
c-kit5.0ACT>50000
DERIVEDβ28FAK>50000
p38100IGF-1R>50000
Hcrl180IR>50000
Hcr2710MK2>50000
TCFR-I880RKSα,δ,τ,ε>50000

In pharmacokinetic studies in rats connection 455 was described is how the connection to the high volume of distribution (V ss) systemic clearance (Cl) of about 40% of hepatic blood flow. Oral dose of 10 mg/kg, administered in the form of a solution in a mixture of 1:1 propylene glycol : water, quickly absorbed and demonstrated a suitable half-life (t1/2) and the mean resident time (MRT). Found oral bioavailability (Fpo) in this study was 27%. Together with the data of the 4-hour oral exposure obtained in mice, these data allow us to conclude that has a pharmacokinetic profile suitable for a successful transition to study in vivo effectiveness. The parameters RK obtained in studies in rats are summarized in table 2.

Table 2

The pharmacokinetic properties of the compounds obtained in rats Sprague-Dawley
UnitCenturies doseP.O. dose
Dosemg/kg1010
CmaxuM132 (-)0.5(0.2)
Tmaxhr-2,2(3.2)
AUCintulvf*hr13.9 (4,6)3,8(2,1)
t1/2hr3.3 (0.9)3.1 (0.3)
hr4.1 (1.2)6.7 (0.6)
ClmL/min/mg26.4 (7.8)-
VssL/kg6.3 (2.2)-
Fpo%-27

In vivo activity of the compounds 455 studied by analysis K xenograft models naked mice. Tumor cells are implanted subcutaneously and grow to about 300 mg and spend 2 cycles of oral treatment according to the scheme: 5 days take a break for 2 days. When once-daily dosing of compound 13 or 5, or 50 mg/kg decrease was observed (regression) after one cycle of treatment and the complete disappearance of the tumor mass by the end of the treatment drug. In one group of animals was not observed no toxicity (death of animals, lack of weight gain). Thus, it was found that the compound 455 has a high in vivo activity and a high border of security in this animal model of CML.

Connection 455 was tested for toxicity in several tests. It was negative in the Ames test for mutagenicity. It was also negative in the analysis of human hepatocytes in immortalized (>40 μm) and premirovany cell lines (up to 16 µm). It showed a minimum of cardiotech what was mentioned.

1. N-(2-Chloro-6-were)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinil]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide

and its pharmaceutically acceptable salts.

2. A method of treating cancer, comprising the administration to a patient an effective amount of the compounds under item 1.

3. The pharmaceutical composition inhibiting proteincontaining containing compound under item 1 and a pharmaceutically acceptable carrier or diluent.

4. The method of treatment due to proteinkinase violations, including the introduction to the patient an effective amount of the compounds under item 1 or the pharmaceutical composition according to p. 3.

5. The method according to p. 4, wherein the patient is administered at least one additional therapeutic agent selected from cyclosporine A; CTLA4-Ig, antibodies selected from anti-ICAM-3 receptor, anti-IL-2 (Anti-Tac), anti-D45R, anti-CD2, anti-D3 (OCT-3), anti-CD4, anti-CD80, anti-D86 and monoclonal antibodies ACT; agents blocking the interaction between CD40 and gp39; fused proteins created from CD40 and gp39; inhibitors of NF-Kappa b function; non-steroidal anti-inflammatory drugs (NSAIDs); steroids; gold compounds; antiproliferative agents; FK506, mycophenolate mofetil; cytotoxic drugs; inhibitors of TNF-α; antibodies against TNF or soluble TNF receptor; rapamycin; Leflunomide; inhibitors of cyclooxygenase-2; paclitaxel; cisplatin, carboplatin, doxorubicin, karminomitsin, daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C, ecteinascidin 743, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podofillotoksina, etoposide, etoposide phosphate, teniposide, melphalan, vinblastine, vincristine, laronidase, epothilone, vindesine or lareina.



 

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SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

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EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

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SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

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EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

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10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of aminomethylpyrrolidine of the formula (I) , their salts or hydrates wherein R1 represents aryl with from 6 to 10 carbon atoms or heteroaryl wherein heteroaryl is a five-membered ring or a six-membered ring and comprises from 1 to 2 heteroatoms taken among nitrogen, oxygen and sulfur atom; aryl and heteroaryl can comprise one or more substitutes taken among the group consisting of halogen atom or (C1-C6)-alkoxyl; each radical among R2, R3, R4, R5, R6, R7 and R8 represents hydrogen atom (H) independently; Q represents incomplete structure representing by the following formula: wherein R9 means (C3-C6)-cyclic alkyl that can be substituted with halogen atom; R10 means hydrogen atom (H); R11 means hydrogen atom (H), NH2; X1 means halogen atom; A1 represents incomplete structure representing by the formula (II): wherein X2 means hydrogen atom (H), halogen atom, halogenmethoxyl group, (C1-C6)-alkyl or (C1-C6)-alkoxyl group; X2 and above indicated R9 can be combined to form the ring structure and inclusion part of the main skeleton and such formed ring comprises oxygen, nitrogen or sulfur atom as a component atom of the ring and the ring can comprise (C1-C6)-alkyl as a substitute; Y means hydrogen atom (H). Compounds of the formula (I) elicit an antibacterial effect and can be used for preparing a therapeutic agent.

EFFECT: valuable medicinal properties of compounds.

2 tbl, 61 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

10 cl, 2 sch, 4 tbl, 9 ex

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

FIELD: medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to agents used in treatment of ulcerous-erosion injures in gastroduodenal region. Method involves diluting 100 mcg of dry lyophilized powder of immunomodulating agent "Superlimf" in 3-5 ml of 0.9% isotonic solution and irrigation of ulcer or erosion with this solution 1 time per a day by the endoscopy method. The treatment course is 3-4 procedures with break for 4-5 days. Method provides alteration of cytokine pattern of tissues, induction of influx of mononuclear phagocytes to the injure focus that results to localization of inflammation and the complete epithelization of ulcers and erosions.

EFFECT: improved and effective method for treatment.

1 ex

FIELD: biotechnology, medicine.

SUBSTANCE: invention relates to method for isolation of bioactive fraction (BAF) containing essentially S-lipopolysaccharides (S-LPS) from endotoxic S-LPS producing gram-negative bacteria, useful in prophylaxis and therapy. From endotoxic S-LPS producing gram-negative bacteria BAF is isolated that has in lipid A S-LPS molar ratio of D-glucoseamine and β-hydroxy acids selected from β-hydroxydecanic, β-hydroxydodecanic, β-hydroxytetradecanic and β-hydroxyhexadecanic acids of about 2:1-4, and molar ration of D-glucoseamine and high fatty acids connected via either amide or ester bond in lipid A S-LPS of about 2:3-7. Isolated BAF ins used in pharmaceutical composition to increase of patient immune status.

EFFECT: method for isolation from gram-negative bacteria bioactive fraction of S-LPS with high immunogenic properties, being capable to induce cytokine production with low pyrogenic and endotoxic properties.

41 cl, 4 dwg, 14 tbl, 24 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new heterocyclic derivatives having calpain inhibition activity or oxygen reactive form recovering entrapping activity of formula I

1, wherein Het represent monocyclic 5-6-membered hetericyclic radical containing 1-2 heteroatoms selected from O or N; A represents A1

2, A'1 3, A2 4, A3 5 and A4 6; X represent -(CH2)n-, -(CH2)n-CO-, -N(R45)-CO-(CH2)n-CO, -CO-N(R45)-D-CO-, -N(R45)-(CH2)n-CO-, -N(R45)-CO-C(R46R47)-CO-, -O-(CH2)n-CO-, -N(R45)-CO-NH-C(R46R47)-CO-, -CO-N(R45)-C(R46R47)-CO- or -Z-CO Y represents -(CH2)p-, C(R53R54)-(CH2)p-, C(R53R54)-CO-; R1 represents hydrogen, group CR3 or oxo; R3 represents hydrogen, monocyclic saturated 6-membered heterocycloalkylcarbonyl, wherein heterocycle contains two heteroatoms selected from nitrogen or oxygen, C1-C6-alkylcarbonyl, phenylcarbonyl or phenyl(C1-C6)-alkylcarbonyl optionally substituted with NR4R5, or R4 and R5 independently represent C1-C6-alkyl; R2 represents hydrogen, and pharmaceutical compositions containing the same.

EFFECT: new heterocyclic drugs.

18 cl, 37 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for preparing an anti-inflammatory, wound-healing, capillary-strengthening, immunomodulating agent. Method for preparing an anti-inflammatory, wound-healing, capillary-strengthening, immunomodulating agent is carried out for four stages. At the first stage violet tricolor and/or field milled herb is extracted with fluidized carbon dioxide under the definite condition followed by separation of grist from lipophilic fraction of extract; at the second stage defatted grist is subjected for three-fold extraction by remaceration method under the definite condition followed by treatment and purification of combined extract, treatment, condensation and preparing liquid alcoholic extract; at the third stage liquid alcoholic extract is used for preparing polysaccharide and flavonoid complexes by precipitation of polysaccharide with three-fold volume of 96% ethyl alcohol and the following drying at the definite temperature; at the forth stage grist after isolation of polysaccharide and flavonoid complexes is used for preparing pectins by treatment with three-fold volume of ammonium oxalate solution at the definite temperature, evaporation and drying. Liquid alcoholic is evaporated to 1/5 of the parent volume, dried by spraying drying or lyophilic drying at definite temperatures. Each end product prepared at each stage can be used as both independent medicinal formulation and can be used for preparing other medicinal formulations (tablets, capsules, suppositories, films). Also, invention relates to a method for preparing an anti-inflammatory, wound-healing, capillary-strengthening, immunomodulating agent that involves extraction of violet tricolor and/or field milled herb with 70% ethyl alcohol by infusion for a definite time followed by purification of the end product, settling at the definite temperature and filtration. Method provides preparing agent with broad pharmacological pattern of action and provides the maximal using the medicinal vegetable raw.

EFFECT: improved preparing method, valuable medicinal properties of agent.

5 cl, 5 tbl, 17 ex

FIELD: veterinary medicine.

SUBSTANCE: preparation has riboxin, glycolysis activator, vitamin B12, ascorbic acid, citric acid and glucose. The preparation calcium glycerophosphate as the glycolysis activator and additionally has succinic and folic acid and fructose taken in the following ingredient proportions in % by mass: riboxin -10,0-40, calcium glycerophosphate - 30,0-40,0, vitamin B12 - 0.02-0.04, ascorbic acid - 2-4, citric acid - 2-4, succinic acid - 2-4, folic acid - 1-2, fructose 5-10, glucose to 100.

EFFECT: increased laying ability of hens; reduced fodder consumption.

FIELD: medicine.

SUBSTANCE: means has lipid fraction obtained from Berryteuthis Magister Comandor squid liver containing 10% of polyunsaturated fatty acids and 50% of alkyl-diacylglycerides showing marked lipid-correcting and immunomodulating properties.

EFFECT: enhanced effectiveness in treating lipid metabolism disorders and immunity system disorders.

4 tbl

FIELD: medicine.

SUBSTANCE: method involves applying tetradecylthioacetic acid as fatty acid analog for treating inflammatory disorders. Method for stimulating endogenous interleukine-10 production is suggested. Fatty acid analogs are applied for suppressing stimulated mononuclear cells proliferation in peripheral blood.

EFFECT: enhanced effectiveness of anti-inflammatory action.

17 cl, 5 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: medicine.

SUBSTANCE: method involves administering inmmunotherapy with recombinant interferon-α2b in daily dose of 3x106 MU. It is incubated in thermostat during 1 h at 37°C with 100 ml of autoblood and then it is intravenously introduced to a patient during 1-1.5h daily under blood formula control to reach leukocyte content of>4*109 /l, granulocytes >2*109 /l.

EFFECT: eliminated leukopenia and dose-limiting toxicity risk; accelerated treatment course; reduced risk of infectious complications.

FIELD: organic chemistry, microbiology.

SUBSTANCE: invention relates to new synthetic biologically active derivatives of pyrimidine, namely to 2,4-dioxo-5-(2-hydroxy-3,5-dichlorobenzylidene)imino-1,3-pyrimidine potassium, sodium or ammonium salt of the general formula: wherein X is taken among the group: Na+, K+, NH+4. The claimed substance shows expressed antibacterial activity directed mainly against different fungi, bacteria, protozoan and viruses.

EFFECT: valuable biological properties of compounds.

13 tbl, 13 ex

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