Novel chemical compounds - 2,4-diamino-1,3,5-triazine derivatives for preventing and treating human and animal diseases

FIELD: chemistry.

SUBSTANCE: invention relates to a 2,4-diamino-1,3,5-triazine derivative of general formula I, having protein kinase inhibitor properties, use thereof and a pharmaceutical composition based thereon. In general formula I Y is CH2, CHR', O, S, S(O) or S(O)2; X1, X2, X3 are independently selected from a CH groups or N; R1 is a C1-8 aliphatic group, C3-8 cycloalkyl, C6-10 aryl, ethylene-dioxyphenyl, methylene dioxyphenyl, pyridyl, each of which is optimally substituted with one or more identical or different groups R"; R' is hydrogen, OH, halogen, such as F, Cl, Br, I, or carboxyl or carboxamide, optimally N-substituted with (C1-6)alkyl, or cyano or halo(C1-8)alkyl, (C1-8)alkoxy, piperidinyl, optimally substituted with methyl; R" is R' or RD; R21, R22, R23, R24 are independently selected from groups F, Cl, Br, I, CN, (C1-16)alkyl; furthermore, R21 and R22 and/or R23 and R24 can be combined and represent one oxo (=O) group or together with a carbon atom can form a spirocycle containing 3 to 7 carbon atoms; furthermore, R21 and R24 together with two carbon atoms can form an aliphatic or aromatic ring containing 4 to 8 atoms, optionally substituted with one or more groups R'; RD is an oxo group =O or =S.

EFFECT: invention can be used to treat autoimmune or cancerous diseases, rheumatoid arthritis and non-Hodgkin lymphoma.

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This invention relates to the treatment of allergic, autoimmune, cancer and other diseases using the new collections of chemical compounds with improved efficacy in the inhibition of SYK-kinase and its mutant forms, and other therapeutically relevant kinases, increased selectivity, and bioavailability.

The level of technology

Protein kinases are an important family of proteins involved in the regulation of key cellular processes, disturbance activity which can lead to cancer, autoimmune diseases, chronic inflammatory diseases, diseases associated with tissue destruction, etc. the List of kinases, therapeutic significance of which to date has preclinical or clinical validation includes: ABL1, ALK, ACT, ACT2, AURKA, skin disease, BCR-ABL, BLK, BRK, C-KIT, C-MET, C-SRC, SAMC, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CRAF1, SNACK, SNACK, CLK1, CLK3, CSF1R, CSK, CSNK1G2, CSNK1G3, CSNK2A1, DAPK1, DAPK2, DAPK3, EGFR, ERNA, ERNA, ERNA, ERBB2, ERBB3, ERBB4, ERK, ERK2, ERK3, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, FGR, FLT-1, FYN, GSK3B, NSC, IGF1R, INSR, ITK, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KIT, LCK, LOK, MARK, MARKERS, MARK1, MAC, MAC, MET, MKNK2, MST1, NEK2, 38α, 38δ, 38γ, RAC, RAC, RAC, RAC, PDPK1, DERIVED, PIK3CG, PIM1, PIM2, CSWs, PLK1, PLK4, PRKCQ, PRKR, RTC, RTCW, RET, ROCK1, ROS, RPS6KA1, SLK, SRC, SRPK1, STK16, SYK, TAK1, TGFBR1, TIE, TIE2, TNK2, TRK, VEGFR2, WEE1, ZAP70 (Vieth, M. et. al., Drug Discov Today 2005, 10, 839-46; Fedorov, O. et. al., Nat Chem Biol, 2010, 6, 166-169; Gaestel, M. et. al., Nat Rev Drg Discov, 2009, 8, 480-99; Karaman, M. W. et. al., Nat Biotechnol, 2008, 26, 127-32; Fabian, M.A. et. al., Nat Biotechnol, 2005, 23, 329-36; Bhagwat, S. S., Purinergic Signal, 2009, 5, 107-15; Grimminger, F. et. al., Nat Rev Drug Discov, 2010, 9, 956-70). With the advent of new experimental data, this list is constantly growing.

A promising approach for the treatment of diseases associated with abnormal activity of protein kinases, is the use of low molecular weight chemical compounds for inhibition of their activity. Examples of such inhibitors approved for use in clinical practice are: Imatinib (Imatinib), Nilotinib (Nilotinib), Dasatinib (Dasatinib), Sunitinib (Sunitinib), Sorafenib (Sorafenib), Lapatinib (Lapatinib), Gefitinib (Gefitinib), Erlotinib (Erlotinib), Cristini (Crizotinib). A large number of drug candidates, kinase inhibitors are currently in clinical trials and preclinical development.

SYK-kinase (Spleen tyrosine kinase) - preceptory cytoplasmic tyrosinekinase involved in the signal transmission antigen and Fc receptor, BCR and other receptors. The most intensively SYK kinase is expressed in hematopoietic cells (such as macrophages, mast cells, leukocytes, platelets and erythrocytes), to a lesser extent in epithelial cells, fibroblasts, neuronal cells, hepatocytes, etc. (Yanagi, S., et al., Biochem BiophysRes Commun, 2001, 288, 495-8).

Activation of SYK-kinase starts cleocin the th cascade, leading to the synthesis and release of a large number of modulators of inflammation, which can cause severe allergic reactions (Valent et al., Intl J Hematol, 2002, 75, 257-362). In addition, SYK-kinase plays a key role in the immune response, autoimmune (Lee, DM. et al., Lancet, 2001, 358, 903-11) and cancers, such as lymphomas (Young, RM., et al., Blood, 2009, 113, 2508-16).

Inhibition of SYK-kinase is a promising strategy for coping with a variety of allergic, autoimmune, cancer, the cause of which is Abbasanta activity of cells expressing SYK-kinase. Establishing the function of SYK kinase in the development of autoimmune diseases and lymphomas has led to an active search for its selective inhibitors. Today we know of more than a hundred low molecular weight substances capable of inhibiting SYK (Xie, H.Z., et al., Bioorg Med Chem Lett, 2009, 19, 1944-9). The greatest interest of the existing inhibitors of SYK-kinase are substances R112, R343 (developed on the basis of R112 as convenient for inhalation form), R406 and R788, in various stages of clinical trials. These structurally similar derivatives of 2,4-diaminopirimidina were developed by Rigel Pharmaceuticals, Inc. The first representative of this family, R112, binds to SYK Ki=96 nm (WO0306379). R788 developed on the basis of R406 to improve oral biodot is Prosti (Bajpai, M, IDrugs, 2009, 12, 174-85). It should be noted that R788 in the body disintegrates, and the active substance, in fact, is R406. Currently R788 is undergoing clinical trials in rheumatoid arthritis (phase II) (Weinblatt, M.E. Ter-Minassian, et al., N Engl J Med 2010, 363, 1303-12) and non-Hodgkin's lymphoma (phase II) (Friedberg, J.W., et al., Blood, 2010, 115, 2578-85).

The use of low molecular weight inhibitors of SYK in therapeutic practice identified several serious problems related to their bioavailability and efficiency. For example, clinical trials R112 against allergic rhinitis were discontinued because the second phase did not show efficacy of the drug compared to placebo, but not satisfactory pharmacokinetic parameters R406 forced to apply it in the form of prodrugs. Thus, the creation of new compounds able to inhibit kinase, and with good pharmacokinetic parameters is practically important task.

As the closest analogue may be indicated in the international application WO 2009143389 describing new inhibitors of kinases, which represents a phosphate derivative, a number of alternatives containing diamino-triazine group. The compounds have activity against a whole group of kinases.

This invention relates to new chemical compounds inhibitors of kinases with enhanced efficiency in which Euromoney SYK-kinase and its mutant forms, and promising for the treatment of cancer, autoimmune, inflammatory and other diseases.

The object of the present invention are inhibitors of protein kinases, characterized by the fact that represents compounds of General formula I, their pharmaceutically acceptable salt, solvate or hydrate, as well as prodrugs in the form of esters, amides, carbamates, N-hydroxymethyl derivatives, O-hydroxymethylpropane, esters of sulfuric or phosphoric acids, methylphosphonates or their salts:

Where:

Y represents CH2, CHR', CRDC(R')2, NR', O, S, S(O) or S(O)2.

X1X2X3are selected independently from the groups CH, CR' or n

R1represents an aliphatic group, aryl group, atlanticcity, methylenedioxyphenyl, optionally substituted by one or more identical or different groups R"

R' represents hydrogen, OH, halogen, such as F, Cl, Br, I, or carboxyl or carboxamido or cyano, or halo(C1-8)alkyl, (C1-8) alkyl, (C1-8) alkoxy, (C1-8) haloalkoxy

R" is R' or RD

R21, R22, R23, R24are selected independently from the group F, Cl, Br, I, CN, (C1-16) alkyl, additionally, R21and R22or/and R23and R24can be combined and before the by one oxo (=O) group or, together with the carbon atom to form spirits containing from 3 to 7 carbon atoms, additionally, R21and R24can work together with the two carbon atom to form an aliphatic or aromatic cycle containing 4 to 8 atoms optionally substituted by one or more groups R'.

RDrepresents an oxo group, =O, =S

2. Preferred variants of the embodiment of the invention

2.1. A separate class of compounds of interest include compounds according to formula I, in which R1represent aliphatic, optionally substituted by one or more identical or different groups R". Illustrative examples of this class are the following compounds:

2.2. A separate class of compounds of interest include compounds according to formula I, in which R1represent aryl, ethylenevinyl group, optionally substituted by one or more identical or different groups R". Illustrative examples of this class are the following compounds:

2.3. One of the preferred variants of the embodiments of the invention are compounds according to the formula

IA-1, in which R1represents a phenyl group,optionally substituted by one or more identical or different groups R".

Where n- 0, 1, 2, 3, 4 or 5

2.4. Particularly preferred embodiments of the invention are compounds according to formula IA-1, in which R represents an alkoxy group. Illustrative examples of this class are the following compounds:

2.5. Separate preferred embodiments of the invention are compounds according to formula IA-1, where R' is a halogen or-CF3. Illustrative examples of this class are the following compounds:

2.6. One of the preferred variants of the embodiments of the invention are compounds according to the formula

IA-2, in which R1represents a 3,4-ethylenedioxythiophene group, optionally substituted by one or more identical or different groups R".

Where n is 0, 1, 2, 3 or 4; m is 1, 2 or 3

2.7. Particularly preferred embodiments of the invention are compounds according to formula IA-2, in which R' represents an alkoxy group or a halogen or haloalkyl. Illustrative examples of this class are the following compounds:

2.8. One of the preferred variants of the embodiments of the invention are compounds according to the formula

IA-3 in which R1represents a 3,4-methylenedioxyphenyl group, optionally substituted by one or more identical or different groups R".

Where n is 0,1 or 2; m -1,2 or 3

2.9. Particularly preferred embodiments of the invention are compounds according to formula IA-3, where R" is an alkoxy group or a halogen or haloalkyl.

Illustrative examples of this class are the following compounds:

2.10. A separate class of compounds of interest include compounds according to formula I, in which X2or X3is an atom N. Illustrative examples of this class are the following compounds:

2.11. A separate class of compounds of interest include compounds according to formula I, in which X2and X3represents CH or CR' group. Illustrative examples of this class is vlahuta the following connections:

2.12. A separate class of compounds of interest include compounds according to formula I in which Y represents CIS, CHR', CRDC(R')2group. Illustrative examples of this class are the following compounds:

2.13. A separate class of compounds of interest include compounds according to formula I in which Y represents NR', S, S(O) or S(O)2group. Illustrative examples of this class are the following compounds:

2.14. One of the preferred variants of the embodiments of the invention are compounds according to the formula

IB-1, in which in which X2and X3represents a CH group, X1represents the N group, Y represents an atom O R23and R24United and are one oxo (=O) group.

2.15. Particularly preferred embodiments of the invention are compounds according to formula IB-1, in which R21and R22is the th alkyl (usually metal) group. Illustrative examples of this class are the following compounds:

2.16. One of the preferred variants of the embodiments of the invention are compounds according to the formula

IB-2, in which in which X1X2and X3represents a CH group, Y represents oxygen On the group R23and R24United and are one oxo (=O) group.

2.17. Particularly preferred embodiments of the invention are compounds according to formula IB-2, in which R21and R22represents a halogen (usually fluorine). Illustrative examples of this class are the following compounds:

Compounds of the present invention, of particular interest, possess one or more of the following characteristics:

molecular weight less than 1000, preferably less than 750, and most preferably less than 500 g/mol (not including the weight of any relative exchange constants or co-crystallizing substances, as well as the counterions in the case of salts); or

- inhibitory activity relative to the native or Mutan the figures (especially clinically relevant mutant) kinase, especially the kinases SYK, ZAP-70, JAK1 JAK2, JAK3, CPD, TYK1 and LYN, or other kinases of interest, with the value of the IC505 μm or less (obtained using any scientific experiment for determining the inhibition of kinases), preferably with an IC50 of 1 μm or less, and optimally with IC50500 nm or below; or

- inhibitory activity against SYK-kinase with IC50at least 100 times smaller than the corresponding values IC50for other kinases of interest; or

- inhibitoren activity against signaling pathway Fc or BCR receptors (particularly preferably Fes and Fey receptor), responsible for the development postlicensure response defined in expiremented in vitro, or in animal studies using a scientifically acceptable model (the preferred connection, ingibiruet-ing abberant activity of cells of the immune system (e.g., fat, hematopoi-ethical cells and compounds that inhibit abberant proliferation and growth of culture of Daudi cells, LYMPHOBLASTOID, P3H3, P3H3-1, Raji).

In addition, the invention provides compositions containing at least one connection which is the subject of the invention or a salt, hydrate or other MES thereof, and at least one pharmacologically acceptable excipient or additive. Such compositions can be administered to the object that needs the of usemouse in suppressing abberant activity and/or aberrant proliferation of cells of the immune system.

The pharmaceutical compositions may be useful for treatment of allergic, autoimmune and oncological diseases according to the present invention, which includes the introduction (as monotherapy or in combination with one or more immunodepressants or anticancer agents, one or more agents to mitigate the side effects, irradiation, etc.) a therapeutically effective amount of the compound which is the subject of the invention, in a human or animal in need of inhibition abberant activity or abberant proliferation of cells of the immune system. This introduction is a method of treatment or prevention of diseases caused by one or more kinases, inhibiting one of the disclosed compounds or their pharmacologically acceptable derivatives. "Introduction" in the body of the compounds of the present invention includes delivery to the recipient of the compounds described in the present invention, prodrugs, or other pharmacologically acceptable derivative of such compounds, using any valid drugs or routes of administration in the body, as described herein. Typically, the compound is injected into the patient one or more times per week, for example, daily, every other day, 5 days per week, etc. Peroral the second and intravenous administration is of particular interest.

The term "pharmaceutically acceptable derivative" herein refers to any pharmacologically acceptable salt, ester, or salt of ester compounds, or any other adduct or derivative which, upon administration to a patient, capable of providing (directly or indirectly) the delivery of the substance, its metabolite or the product of its decay (having a molecular weight of greater than 300). Pharmacologically acceptable derivatives, thus, include, in particular, prodrug. The prodrug - derived compounds, usually with greatly reduced pharmacological activity, which contains additional chemical group capable of removal in vivo, with the formation of the source of pharmacologically active molecules connection. For example, the prodrug may be an ester or amide, which is decomposed in vivo with the formation of the desired compounds. Prodrugs of various compounds, materials and methods of deriving the initial compounds are well known and can be adapted for the present invention.

Particularly favorable derivatives and prodrugs of the parent compounds are derivatives and prodrugs, which increase the bioavailability of the compounds when introduced into the body of a mammal (for example, an increase in absorption in the blood when oral intake is), or those that enhance the delivery in any part of the body relative to the original connection. Preferred prodrugs include derivatives of compounds that are the subject of the invention, with increased solubility in water, or more actively penetrating through the membrane of the intestine compared to the original connection.

An important aspect of the invention is a method for the prevention and treatment of diseases of man and animals, based on the inhibition of one or several protein kinases including but not limited to SYK, ZAP-70, JAK1 JAK2, JAK3, CPD, TYK1 and LYN kinases therapeutically effective amount of a composition comprising a compound of the invention. The treatment may be conducted in combination with one or more other drugs and non-drug therapy, including surgery, radiation therapy (e.g., gamma radiation, neutron, electron, proton beam therapy, brigite-therapy, etc), hormonal therapy, biological modifiers of response, hyperthermia, cryotherapy, agents to mitigate any adverse effects (e.g., antiemetics), and other anti-cancer chemotherapeutic drugs. Other agent(s) can be introduced into the patient using similar or different from those used for the dinani of the present invention, technologies prepare drugs, routes of administration and dosing schemes.

The invention also includes obtaining compounds of any of formulas I, IA-1, IA-2, IA-3, IB-1, IB-2, or any other compounds of the present invention.

The invention also includes the use of compounds of the invention or its pharmacologically acceptable derivative in the manufacture of drugs for the treatment of allergic, autoimmune, cancer, and diseases associated with the destruction or vospaleniyam tissues. The compounds which constitute the essence of the present invention can be used in the manufacture of medicaments for the prevention and treatment of diseases associated with abberant activity of cells of the immune system. The compounds which constitute the essence of the present invention can be used in the production of anti-cancer drugs. Compounds of the present invention can also be used in the manufacture of drugs to reduce or prevent various disorders by inhibiting one or more kinases such as SYK, ZAP-70, JAK1 JAK2, JAK3, CPD, TYK1 and LYN etc.

The invention also encompasses compositions containing the compounds of the present invention, including compounds of any of the above classes or subclasses, including any of the formulae described above, besides what about the other things, preferably in a therapeutically effective amount, in combination with at least one therapeutically acceptable carrier, adjuvant or diluent.

Compounds of the present invention can also be used as standards and reagents for characterization of various kinases, especially, but not limited to kinases SYK, ZAP-70, JAK1 JAK2, JAK3, CPD, TYK1 and LYN, as well as to study the role of these kinases in biological and pathological phenomena; the study of signaling pathways, carried out with the help of such kinases, for the comparative evaluation of new kinase inhibitors; and to study various types of cancer models, cell lines and animals.

The following definitions apply in this document unless otherwise noted. In addition, unless otherwise specified, all occurrences of the functional groups are selected independently.

The term "aliphatic" herein means both saturated and unsaturated (but not aromatic) straight (i.e. unbranched), branched, cyclic or polycyclic non-aromatic hydrocarbon chain residue, which can optionally be substituted one or more functional group. Unless otherwise specified, alkyl, other aliphatic, alkoxy and acyl groups contain 1-8 (i.e. C1-8), and in most cases 1-6 (C16 adjacent aliphatic carbon atoms. As an example, such an aliphatic group include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methylene cyclopropyl allyl,n-butyl, sec-Bootle, cyclobutyl, cyclobutylmethyl, n-pentyl, 2-cyclopentenyl, cyclopentyl, tert-pentyl, isopentyl, cyclopentylmethyl, n-hexyl, sec-Texel, cyclohexyl, cyclohexylmethyl, propargyl, allyl, Gamaliel, Homo-propargyl, substituted derivatives and the like, which may contain one or more substituents. The term "aliphatic", therefore, implies the inclusion of alkyl, alkenyl, quinil, cycloalkyl and cycloalkenyl fragments.

The term "alkyl" herein means both unbranched and branched, cyclic or polycyclic alkyl group. Similar conventions apply to other General terms such as "alkenyl", "quinil", etc. in Addition, the "alkyl", "alkenyl", "quinil" and similar groups can be substituted, or unsubstituted.

The term "alkyl" herein refers to groups typically having from one to eight, preferably one to six carbon atoms. For example, "alkyl" means methyl, ethyl, n-propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, cyclobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, tert-pentyl, isopentyl, hexyl, from the hexyl, cyclohexyl, etc. To illustrate, substituted alkyl groups include, but are not limited to, the following groups: vermeil, deformity, trifluoromethyl, 2-foretel, 3-forproper, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, substituted benzyl, 2-phenylethyl, substituted 2-phenylethyl, etc. the Term C1-6alkyl means alkyl containing from 1 to 6 carbon atoms, and includes the C1With2With3With4C5and C6is an alkyl group.

The term "alkoxy" refers to alkyl groups corresponding to the definition given above, and which are connected to the molecule via a bridging oxygen atom. For example, the term "alkoxy" means-O-alkyl, where the alkyl group contains from 1 to 8 carbon atoms in a linear (unbranched) or branched chain or cycle. As an illustration of alkoxy groups include, but are not limited to, the following groups: methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, allyloxy, CYCLOBUTANE etc.

The term "haloalkyl" includes branched and linear saturated hydrocarbon chain, in which one or more hydrogen atoms are replaced by halogen. Examples of ha-alkiline groups include, but are not limited to, the following groups: deformity, trifluoromethyl, trichloromethyl, pentafluoroethyl, 1,1,1,3,3,3-hexamer-2-methylpr the pan-2-yl, etc.

The term "alkenyl" refers to the groups typically having from two to eight, usually from two to six carbon atoms. For example, "alkenyl" can mean prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, Gex-5-enyl, 2,3-dimethylbutan-2-enyl, etc. the Term "quinil" also applies to groups, typically with from two to eight, usually from two to six carbon atoms, including, but not limited to, the following groups: prop-2-inyl, but-2-inyl, but-3-inyl, Penta-2-inyl, 3-methylpent-4-inyl, Gex-2-inyl, Gex-5-inyl etc.

The term "cycloalkyl" refers to groups having from three to 12, usually from three to ten carbon atoms in the mono-, di - or polycyclic (i.e. ring) structure. As an illustration, cycloalkyl include, but are not limited to, the following radicals: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, etc. that, as in the case of other aliphatic or heteroalicyclic or heterocyclic substituents can be substituted. The terms "cycloalkyl and carbocycle are equivalent.

The term "aryl"used alone or as part of a larger fragment, such as "arylalkyl", "araxi" or "aryloxyalkyl", means a group containing an aromatic cycle, and having six to fourteen carbon atoms in such a cycle, such as phenyl, 1-naphthyl, 2-naphthyl, 1-EN is Razil and 2-antracol. "Aryl" cycles can contain one or more substituents. The term "aryl" may be used interchangeably with the term "aryl ring". "Aryl" also includes polycyclic aromatic system in which the aromatic cycle combines one or more cycles. Examples of cyclic aryl groups include, but are not limited to, phenyl, hydroxyphenyl, gargantini, alkoxyphenyl, dialkoxybenzene, tralkoxydim, alkylenedioxy, naphthyl, tenantry, Anthranilic, phenanthrolines, etc. as well as 1-naphthyl, 2-naphthyl, 1-antracol and 2-antracol. In addition, the term "aryl", as used here, includes groups in which the aromatic cycle is connected with one or more non-aromatic cycles or heterocycles, such as indanyl, phenanthridine or tetrahydronaphthyl, 3,4-atlanticcity that radical an atom or a link belongs to the aromatic cycle.

This invention contains only such combinations of substituents and derivatives, which form a stable or chemically possible connection. Stable or chemically feasible compound is compound, jiski which is enough for its synthesis and analytical detection. Preferred compounds of this invention awsomesauce stable and do not decompose at temperatures up to 40°C in the absence of moisture or other chemically reactive conditions, for at least one week.

Some compounds of this invention may exist in tautomeric forms and the invention includes all such tautomeric forms of such compounds, unless otherwise noted.

Unless otherwise specified, pictured here patterns also include all stereochemical forms, that is, R - and S-isomers for each asymmetric center. In addition, single stereochemical isomers as well as enantiomers and diastereomers mixtures of these compounds are also the subject of this invention. Thus, the invention encompasses each diastereoisomer or enantiomer, free substantially from the other isomers (>90%, and preferably >95% molar purity), as well as a mixture of such isomers.

Specific optical isomer can be obtained by separation of the racemic mixture in accordance with standard procedure, for example by obtaining diastereoisomeric salts by treatment with an optically active acid or base, followed by separation of the mixture of diastereoisomers by crystallization followed by separation of the optically active bases or acids from the salts. Examples of appropriate acids are tartaric, diatsetilvinny, dibenzoyltartaric, dItalia and camphorsulfonic acid. Another method is the division of optical isomers involves the use of chiral chromatographic columns. In addition, another method of separation involves synthesis of covalent diastereoisomeric molecules by reaction of compounds of the invention with an optically pure acid in an activated form or an optically pure base. The resulting diastereomers can be divided in the usual ways, for example, chromatography, distillation, crystallization or sublimation, and then hydrolyze to obtain enantiomerically pure compounds.

Optically active compounds of this invention can be obtained by using optically active starting materials. Such isomers can be in the form of a free acid, free base, ester or salt.

The compounds that make up the essence of this invention may be labelled with a radioisotope in the form, i.e. these compounds may contain one or more atoms whose atomic mass or mass number different from the atomic mass or mass number most widespread in nature. For example, radioisotopes of hydrogen, carbon, phosphorus, chlorine include3H,14C,32R35S, and36Cl, respectively. The compounds of this invention which contain such radioisotopes and/or other isotopes of other atoms are within the scope of the present invention. Detarieae, ie2H, tritium, i.emnand carbon, i.e14/sup> With radioisotopes are particularly preferred because of the ease of preparation and detection.

Radioisotope labeled compounds of the present invention can be obtained using methods well known to specialists in this field. Labeled compound can be obtained by using the procedures described here, a simple replacement of unlabeled reagents appropriate labeled reagents.

Methods for obtaining compounds of the invention

Compounds that are the subject of the present invention, can be obtained using various known synthetic methods, including using the following synthetic methods. The synthesis of chemical compounds that are the subject of the present invention, may be made from commercially available starting reagents or reagents, which can be obtained according to the methods described in the works (Weigand-Hilgetag. Methods experiment in organic chemistry. Edited by Prof. Nov. M, Chemistry, 1968, "the Syntheses of heterocyclic compounds" issue 1-16 Yerevan 1956-1987; "Syntheses of organic products" 4.1-12 M 1949-1964; "Syntheses of organic compounds with the hydrogen isotope" Merry A., William DL Moscow, Publishing house IL, 1961; "preparative organic chemistry" Ed. of Wolfson NS, M 1959; "Selected methods for synthesis of org is practical connections" Repin IB, Schwartzberg MS, Novosibirsk, Publishing house of Novosibirsk University, 2000; "Reactions and methods of the study of organic compounds" TT-26, 1951-1986; "Organic Syntheses Based on Name Reactions and Unnamed reactions)) Hassner, A., C. Stumer Pergamon, Oxford, 1994), the full disclosure of which is incorporated into this description by reference. These methods are not exhaustive and allow the introduction of reasonable modifications. These reactions should be carried out using suitable solvents and materials. With the implementation of these General methods for the synthesis of specific substances you should consider the substances present in the functional groups and their influence on the course of the reaction. For some substances it is necessary to change the order of the stages or to give preference to one of several alternative schemes of synthesis.

The synthesis of compounds that are the subject of this invention may be carried out in accordance with schemes I-IV by standard methods.

Where XX represents halogen.

Where XX and YY represents a halogen.

Where XX and YY represents a halogen

Where XX and YY represents a halogen

All connections that are the subject of this invention can be obtained is based on the above synthetic approaches examples of experimental techniques and well-known techniques and materials.

The use of chemical compounds of the invention

The use of compounds according to medical indications

Compounds described in this invention can be used for the treatment of diseases, the pathogenesis of which involves protein kinase. In particular, the compounds described in this invention is able to inhibit tyrosine kinase SYK, ZAP-70, JAK1 JAK2, JAK3, CPD, TYK1 and LYN. In addition it is shown that the number of connections that comprise the present invention, inhibit abberant activity of cells of the immune system in vitro experiments and possess antiproliferative activity in vitro against cancer cell lines, such as Daudi, NAMALVA, P3H3, P3HR-1, Raji. Such compounds are of interest for the treatment of autoimmune, allergic diseases and cancer, and in particular for the treatment of diseases that are resistant to other therapies. Diseases for which treatment can be applied to the compounds of this invention include allergic diseases (e.g., conjunctivitis, rhinitis, asthma, atopic dermatitis, food Allergy, etc.), autoimmune diseases (e.g., Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis, pernicious anemia, autoimmune encephaloma is it autoimmune orchitis syndrome?, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, graves ' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis, membrane glomerulopathy, systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome, Reiter syndrome, polymyositis, dermatomyositis, sistemnaya scleroderma, polyarteritis arthritis, multiple sclerosis etc), and cancers (for example, non-Hodgkin's lymphoma and other forms of cancer, the pathogenesis of which is associated with the activity of SYK, ZAP-70, JAK1 JAK2, JAK3, CPD, TYK1 and LYN kinases).

SYK-kinase (Spleen tyrosine kinase) - preceptory cytoplasmic tyrosinekinase involved in the signal transmission antigen and Fc receptor, BCR and other receptors. The most intensively SYK kinase is expressed in hematopoietic cells (such as macrophages, mast cells, leukocytes, platelets and erythrocytes), to a lesser extent in epithelial cells, fibroblasts, neuronal cells, hepatocytes, etc. (Yanagi, S., et al., Biochem BiophysRes Commun, 2001, 288, 495-8). Activation of SYK-kinase triggers cellular cascade leading to the synthesis and release of a large number of modulators of inflammation, which can cause severe allergic reactions (Valent et al., Intl J Hematol, 2002, 75, 257-362). In addition, SYK-kinase plays a key who's role in the immune response, the development of autoimmune (Lee, DM. et al., Lancet, 2001, 358, 903-11) and cancers, such as lymphomas (Young, RM., et al., Blood, 2009, 113, 2508-16). Inhibition of SYK-kinase is a promising strategy for coping with a variety of allergic, autoimmune, cancer, the cause of which is Abbasanta activity of cells expressing SYK-kinase.

Thus, we assume that the use of an inhibitor of SYK as a drug for monotherapy or in combination with the current means of chemotherapy against cancer, autoimmune and allergic diseases, will allow to achieve significant and long-term remission, or SYK inhibitor can be used as a means of maintenance therapy designed to prevent possible relapse in patients in need of such treatment.

therapeutic method of using compounds

The subject of this invention includes an introduction to the subject in need of appropriate treatment, a therapeutically effective amount of the compounds of this invention.

"Therapeutically effective amount" is an amount of compound that is necessary for program kill cancer cells or inhibiting their growth or propagation velocity on the body, size, or number of tumors, or a friend of the x characteristics of cancer. The exact quantity required may vary from subject to subject, depending on the species, age and General condition of the patient, the severity of the disease, the characteristics of the anti-cancer agent, methods of administration, combined treatment with other drugs, etc.

Substance or pharmaceutical composition containing a substance can be introduced into the patient in any amount and any route of administration, effective for suppressing abberant activity or/and suppression abberant proliferation of cells of the immune system.

Single doses of drug compounds, castelnaui object of the present invention preferably are formulated in a form suitable for introduction into the patient. The expression "single dose"in terms of the present invention means a portion of the drug suitable for treatment of the patient. According to current practice, the total daily dose of the compounds and compositions described in this invention, is assigned by the attending physician based on a thorough medical assessment. The specific therapeutically effective dose level for each particular patient or organism will depend on several factors, including the type of disorder, severity of illness, the specific activity of the preparation used, particularly the pharmaceutical composition, age, mA the su body, General health, sex and diet of the patient, the manner and schedule of administration, rate of metabolism and/or excretion of the compound, the duration of treatment, drugs used in combination or in conjunction with the introduction of the compound of the invention, and similar factors well known in medicine.

After mixing the drug with a particular suitable pharmaceutically acceptable carrier in a desired dosage, the composition constituting the essence of the invention may be introduced into the body of man or other animals orally, rectally, parenterally, intracisternally, intrawaginalno intraperitoneally, locally (using skin patches, powders, ointments or drops), sublingual, buccal, in the form of a spray for the mouth or nose, etc.

Effective systemic dosage connections, enter one-off or in the form of several individual doses, typically lies in the range from 0.05 to 500 mg of compound per kg of body weight of the patient, preferably from 0.1 to 150 mg/kg Usually compound is administered to a patient in need of such treatment, a daily dosage of approximately 50 to 2000 mg per patient. The introduction can be carried out once or several times per day, week or any other time interval), or from time to time. For example, the connection may be introduced into the patient one who does several times a day on a weekly basis (for example, every Monday) for an indefinite time or for several weeks (e.g., 4-10 weeks). In addition, the connection may be injected into the patient daily for a certain period of days (e.g., 2-10 days), followed by a period without treatment (e.g., 1-30 days). This cycle can be repeated indefinitely or for a specified number of cycles, for example 4-10 cycles. As an example, the compound of the present invention can be administered to the patient daily for 5 days, followed by a break for 2 days, and so on, repeating the cycle indefinite number of times, or within 4-10 cycles.

The number of connections that will be effective in the treatment or prevention of a particular disorder or condition depends, in particular, from the well-known factors affecting the effective dosage of the drugs. In addition, optional can be used to measure in vitro or in vivo to determine the optimal dose range. Rough by determining the effective doses may be extrapolated curves dose - response, which will depend on model testing in vitro or on animals. The exact dose level determined by the attending physician, depends on well-known factors, including route of administration of the drug, as well as age, weight, sex and General state who their patient's health; the nature, severity and clinical status of the disease; the use (or disuse) of concomitant medications; and the nature and extent of genetic changes in the cells of the patient.

When administered for the treatment or suppression of a particular disease state or disorder, an effective dosage of the compounds of this invention may vary depending on the specific applied compound, the route of administration of the drug in the body, conditions and severity of this introduction; the state of illness, and number of physical factors associated with the patient undergoing treatment. In most cases, a satisfactory result can be achieved with the introduction of the patient connections in the daily dosage of from about 0.05 mg/kg to 500 mg/kg, usually between 0.1 and 150 mg/kg Estimated daily dose, as expected, it can vary depending on the method of introduction into the patient. Thus, the level of dosage parenteral often ranges from 10 to 20% level oral dosage.

In cases when the connection of the present invention is used as part of the mode of combination therapy, the dose of each component of the combination therapy is introduced within the required period of treatment. The connection components of the combination therapy, may be introduced into the organism PA the rate lump sum in the form of dosage, containing all components, and in the form of individual dosages of the components; in addition, the compounds of the combination may be introduced into the patient at various times during the treatment period, or one of them may be introduced as a pre-treatment for another.

Pharmaceutically acceptable derivatives of compounds

The compounds of this invention can exist in free form in the process, or, if required, in the form of a pharmaceutically acceptable salt or other derivative. Used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the framework of the conducted medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic reactions, etc. and meet a reasonable balance between benefits and risks. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of connections are well known in medicine. Detailed description of the properties of these salts is given S.M. Berge, et al., in "Pharmaceutical Salts" J. Pharmaceutical Science, 66: 1-19 (1977), cited here as reference. Salts can be obtained in situ in the process of separation or purification of the compounds of the invention and can be obtained separately by reacting the free acid or free base compounds of the image is to be placed with a suitable base or acid, respectively. Examples of pharmaceutically acceptable, non-toxic salts of the acids can serve as a salt of an amino group formed with inorganic acids such as hydrochloric, Hydrobromic, phosphoric, sulfuric acid, or organic acids such as acetic, oxalic, maleic, tartaric, succinic, methansulfonate or malonic acid or by other methods used in this field, for example, by using ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, bansilalpet, benzoate, bisulfate, borate, butyrate, comfort, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, formate, fumarate, glucoheptonate, glycerol, gluconate, hemisulfate, heptanal, hexanal, hydroiodide, 2-hydroxyethanesulfonic, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, Pro-piont, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluensulfonate, undecanal, Valais-RIAT and the like. Typical salts of alkali and alkaline earth metals include sodium, lithium, potassium, calcium, magnesium and others. In addition, pharmaceutically acceptable salts can sod is neigh, if required, non-toxic cations ammonium, Quaternary ammonium and amine obtained with the use of such counterions as the halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and the aryl sulfonates.

In addition, the term "pharmaceutically acceptable ester"as used here, denotes hydrolisis in vivo ester, which is easily decomposed in the human body, to the parent compounds or their salts. Suitable ether group includes, for example, pharmaceutically acceptable derivatives of aliphatic carboxylic acids, in particular alkanovykh, alkenovich, cycloalkanes and alkadienes acid in which each alkyl or alkanniny component usually has not more than 8 carbon atoms.

Specific examples of the esters can serve as derived formate, acetate, propionate, butyrate, acrylates and ethylsuccinate. Obviously, the esters can also be formed by a hydroxyl group or carboxylic acid group of compounds of the invention.

The term "pharmaceutically acceptable proletarienne form", in the context of this invention means those prodrugs of the compounds that make up the essence of this invention, which is suitable for use by humans and animals without excessive toxicity, irritation, allergiesallergies etc., meet a reasonable balance between benefits and risks. The term "prodrug" means compounds that are transformed in vivo with the formation of the parent compound of the above formula, for example, hydrolysis in the blood (See. work .Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987).

The pharmaceutical composition

Claimed also to pharmaceutical compositions that contain one of the compounds described herein (or Palekastro form, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers or excipients. These compositions can also contain one or more additional therapeutic agents. On the other hand, the compound of this invention can be administered to the patient in need of appropriate therapy, in combination with one or more other therapeutic regimens (e.g., in conjunction with other inhibitors of kinases, antibodies that block binding with TNF TNFR, methotrexate etc).

Pharmaceutical compositions claimed in this invention contain compounds of the present invention together with pharmaceutically acceptable carriers, which may include any and all solvents, diluents, di is Persia or suspension, surface-active agents, isotonic agents, thickening agents and emulsifiers, preservatives, binding agents, lubricants, etc. that are appropriate for specific forms of dosing. Remington''s Pharmaceutical sciences (15thedition, E.W. Martin, Mack Publishing Co., Easton, Pa., 1975) discloses various carriers used in the development of pharmaceutical compositions and known techniques for their preparation. Except in such cases when the normal environment of the media is incompatible with the compound of the invention, for example, in case of occurrence of any undesirable biological effects or other undesirable interactions with any other component (components) of the pharmaceutical composition, the use of such compositions is within the scope of this invention. Materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, mono-and oligosaccharides and their derivatives; malt, gelatin; talc; excipients such as cocoa butter and wax for suppositories; oils such as peanut, cottonseed, Safronova, sesame, olive, corn and soybean oil; glycols, such as propylene glycol; esters, such as etiloleat and tillaart; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic, the solution Ri is Gera; ethyl alcohol and phosphate buffer solutions. Also in the composition may be other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and colouring agents, the separation of a liquid, film-forming agents, sweeteners, flavorings and fragrances, preservatives and antioxidants.

Dosage forms

The subject of this invention are also pharmaceutical form is a class of pharmaceutical compositions, the composition of which is optimized for a particular route of administration into the body in a therapeutically effective dose. Pharmaceutical compositions of this invention can be introduced into the body orally, topically, rectally, intraocular way, pulmonal, for example, in the form of an inhalation spray, or intravascular way, intranasal, intraperitoneal, subcutaneously, intramuscularly, intrasternally, as well as the infusion method, recommended dosages.

Pharmacologically active compounds that make up the essence of this invention can be processed in accordance with the standard methods of pharmaceutical production to obtain the appropriate dosage forms for administration to a patient, including humans and other mammals.

When administered orally, the dosage form can be, for example, in the form of a tablet and, capsule, suspension or liquid. Dosage form preferably made in the form of a unit dose containing a certain amount of the active ingredient.

An example of such a single dose are tablets or capsules, which can contain from 1 to 2000 mg of active ingredient, preferably from 1 to 500 mg, usually from 5 to 200 mg. a Suitable daily dose for a human or other mammal depends on the patient's condition and other factors.

For therapeutic purposes, the active compounds which constitute the essence of the invention is usually combined with one or more adjuvant, excipient or carrier suitable for the chosen route of administration into the body. For oral administration, the compound may be mixed with lactose, sucrose, starch powder, cellulose ethers and alkanovykh acids, alkyl esters of cellulose, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum Arabic, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol, and then tabletroute or encapsulated for convenient introduction into the patient. Such capsules or tablets may have the property of controlled selection active compounds, provided the dispersion of active compound in hydrox propeller-cellulose.

In case of skin diseases predpochitala topical application of the compounds of the present invention to the affected area one to four times per day.

Dosage forms suitable for local administration include liquid or semi-liquid preparations suitable for penetration through the skin (e.g., ointments, lotions, ointment, cream or paste), and drops suitable for insertion through the eyes, nose or ear. A typical dosage of the active compounds of this invention lies in the range from 0.1 to 150 mg, administered daily from one to four times, preferably once or twice a day. For local injection into the patient, the concentration of active ingredient in the dosage form can be from 0.001 to 10 wt.%, for example, from 1% to 2% by weight of the preparation. Mass fraction of active ingredient may also comprise up to 10 wt.%, preferably not more than 5 wt.%, and even more preferably from 0.1 to 1% by weight of the drug.

In the preparation of ointments, the active ingredient can be used with any paraffinic or a water-soluble basis. In addition, when combining the active ingredient with the emulsion of the type oil-in-water can be cooked cream. Optionally, the aqueous phase of the cream base may include, for example, from 30 wt.% polyhydric alcohols, such as propylene glycol, butyl-1,3-diol, mannitol, sorbitol, glyceri is, the polyethylene glycol or mixtures thereof. Local drug can also include compounds that facilitate the absorption or penetration of the active ingredient through the skin or other areas. Examples of such compounds to enhance penetration through the skin are dimethyl sulfoxide and similar compounds.

The compounds that make up the essence of this invention, can also be introduced into the patient using the device for transdermal input. Preferably, the transdermal injection is carried out using a sticker or patch with the reservoir and porous membrane, or a solid-phase carrier. In any case, the active ingredient is delivered continuously from the reservoir or microcapsules through a membrane permeable to the active agent layer which is in contact with the skin or mucosa of the patient. If the active agent is absorbed by the skin, the patient introduces a controlled and predetermined amount of the active agent. In the case of microcapsules encapsulating material may serve as a membrane.

The oil phase of the emulsion, a part of this invention, can be constructed from known ingredients in a known manner. The oil phase may consist only of emulsifier, or may contain a mixture of at least one emulsifier with a fat or oil, or with both at once is. Preferably, the hydrophilic emulsifier is used in conjunction with a lipophilic emulsifier, which acts as a stabilizer. It is also desirable use simultaneously and grease, and oil. Together, the emulsifier(s) with or without stabilizer(s) form the so-called emulsion wax, and the wax together with the fat and oil forms a so-called emulsifying ointment base, which is an oil phase of the cream. Emulsifiers and emulsion stabilizers suitable for use in pharmacological composition based on compounds of the present invention include tween 60, span 80, cetosteatil alcohol, ministerului alcohol, glycerylmonostearate, sodium lauryl sulfate, glycerin distearate, by themselves or together with wax or other materials known in pharmacology.

The choice of suitable oils or fats for optimal composition based on the desired cosmetic properties. The cream should preferably be non-greasy, does not leave stains and easily washable in consistency to avoid leakage from tubes or other containers. You can use mono - or dienone alkyl esters of straight or branched chain, such as digitariat, isocetyl stearate, diesters of propylene glycol and coconut fatty acids, isopropylmyristate, decillia, isopropyl, butyls the Arat, 2-ethylhexylamine or mixture of esters with branched chain. These substances can be used separately or in combination, depending on the desired properties. In addition, you can use lipids with high melting temperature, as well as white soft paraffin and/or liquid paraffin or other mineral oils.

Formulations suitable for local ophthalmic use, also include eye drops, in which the active ingredients are dissolved or suspended in a suitable carrier, especially an aqueous solvent. Usually in such compositions; select ~ concentration of active ingredient is from 0.5 to 20%, mostly from 0.5 to 10%, in particular about 1.5 wt.%.

Preparations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. Such solutions or suspensions may be prepared from sterile powders or granules, using one or more carriers or solvents listed for use in compositions for oral administration, or by using other suitable dispersing or wetting or suspendida substances. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn, cottonseed, peanut, sesame oil, benzyl alcohol, chloride is the atrium, and other buffer solutions.

The active ingredient may also be introduced into the patient by injection of the composition with suitable carriers including saline, dextrose, solubilizers solvent (e.g. propylene glycol), or micellar a solubilizer (e.g., tween 80). In addition, as solvents or suspendida funds often use sterile oil. For these purposes, any non-volatile oil, including synthetic mono - and diglycerides. In addition, in the preparation of injections you can use fatty acids such as oleic acid.

For intra-lungs injection dosage form can be an aerosol (including powder) and be entered using the inhaler.

Suppositories for rectal administration of medication can be made by mixing the drug with a suitable non-irritating excipient, such as cocoa butter and polyethylene glycol that is solid at ordinary temperature but liquid at rectal temperature, so that the filler is melted in the rectum and release the drug.

Dosage form can be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional additives such as preservatives, stabilizers, moisturizers, emulsifiers, uferi etc. Tablets and pills can additionally be intersolubility floor. Such compositions may also contain auxiliary substances, such as humectants, sweeteners, flavoring agents, deodorizing agents.

Dosage form of the present invention may contain a compound described herein of the formula or its pharmaceutically acceptable salt, and an additive, for example, selected from among the following: a kinase inhibitor, an antidepressant, anticancer drug, an antiviral drug, an anti-inflammatory drug, an antifungal drug or compound against vascular hyperproliferative, and any pharmaceutically acceptable carrier, adjuvant or diluent.

The term "pharmaceutically acceptable carrier or adjuvant" means a carrier or adjuvant that may be introduced into the patient together with the compound constituting the essence of this invention, and which does not destroy the pharmacological activity of this compound, and is non-toxic at the doses sufficient to deliver a therapeutic amount of the compounds.

Pharmaceutically acceptable carriers, adjuvants and solvents that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, CTE is Rath aluminum, lecithin, self emulsifiable system drug delivery (SEDDS)such as polietilenglikolsuktsinata d-alpha-tocopherol, surface-active substances in pharmaceutical forms, such as Twins, or other similar polymeric matrix delivery, serum proteins such as human serum albumin, buffers, such as phosphonates, glycine, sorbic acid, potassium sorbate, partial mixture of glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as preteenslut, sodium phosphate, potassium phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium silicate, polyvinylpyrrolidone, substances based on cellulose, polyethylene glycol, sodium carboxy-methyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, polyethylene glycol and lanolin. The cycle of dextrins, such as u-, P - and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkyl-cyclodextrins, including 2 - and 3-hydroxypropyl-cyclodextrins, or other soluble derivatives, can also be successfully used to enhance delivery of compounds of formulas described here.

The pharmaceutical compositions of the present invention can be introduced into the patient through the mouth in any of the available dosage form, including, n is not limited to, capsules, tablets, emulsions, aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. In addition, it is usual to add lubricating agents such as magnesium stearate. For oral administration in capsule form, used diluents include lactose and dried corn starch. In the case of aqueous suspensions and/or emulsions for oral administration, the active ingredient may suspendibility or dissolved in the oil phase in combination with emulsifying or aspergilosis agent.

Dosage forms of this invention may contain sweeteners and/or flavorings and/or colorings.

Dosage forms of this invention may contain the compounds obtained by the use of liposomes or microcapsulation methods, methods of cooking nanoform drug, and other examples known in the pharmaceutical industry.

The use of the compounds in combination therapy

Despite the fact that the compounds of this invention can be administered as the sole active pharmaceutical agents, they can also be used in combination with one or more compounds of the invention, or one or more other agents. When combined ingestion of therapeutic Agay is you can be a different dosage forms, entered simultaneously or sequentially at different times, or therapeutic agents can be combined in a single dosage form.

The phrase "combination therapy" in relation to the compounds of this invention in combination with other pharmaceutical agents, means of simultaneous or successive reception of all agents that will provide beneficial effects of the combination of drugs. Joint introduction implies, in particular, joint delivery, for example, in one tablet, capsule, injection or other form, having a fixed ratio of active substances, as well as the simultaneous delivery of multiple, separate dosage forms for each connection, respectively.

Thus, the introduction of the compounds of this invention can be carried out in conjunction with additional therapies known to experts in the field of prevention and treatment of allergic, autoimmune, cancer and other diseases, including radiation therapy, the use of immunodepressants, cytostatic and cytotoxic drugs and drugs to suppress symptoms or side effects of one drug.

If the dosage form is a fixed dose, such combination uses the connections of izobreteniya acceptable dose range. Substances of this invention can also be introduced into the patient sequentially with other antineoplastic, cytotoxic or suppress immunity agents, in the case when the combination of these drugs is impossible. The invention is not limited to the sequence of administration; compounds of this invention can be introduced into the patient together, before or after administration of other anticancer or cytotoxic drug.

Therapeutic kits

The object of the present invention are also pharmaceutical kits for easy and effective therapy. In General, the pharmaceutical kit or the kit includes one or more containers filled with one or more of the pharmaceutical composition described in the invention. Such kits are particularly useful for delivery of solid dosage forms for oral administration such as tablets or capsules. This set usually contains a certain number of unit doses and may also include cards with doses arranged in the order of their intended use. Optionally, can also optionally be provided memo, for example in the form of numbers, letters, or other markings, or calendar, indicating the schedule of treatment with marked days for the dose. In addition, for everyday applications to the tion, to provide a pharmaceutical kit may be included doses of placebo, calcium supplements, in the same or another form. Optionally, together with such container(s)may be accompanied by a notice in the form prescribed by a governmental Agency regulating the manufacture, use or sale of pharmaceutical products, which reflects the resolution of this institution to manufacture, use or sale of the drug for use in humans.

The possibility of carrying out the invention can be illustrated by the following examples.

Examples

Synthesis of dichloro-1,3,5-triazine.

In accordance with scheme I from commercially available starting compounds are synthesized

2,4-dichloro-1,3,5-triazine

Synthesis of N-cyanocarbonimidate

6.40 g (71 mmol) of Dicyanamide sodium is dissolved in water and rapidly added to 50 ml of concentrated hydrochloric acid, cooled to -30°C. the Reaction mixture is stirred at this temperature for 15 minutes, then heated to 35°C and after 5 minutes, again cooled to 4°C and then stirred at the specified temperature for another 45 minutes. The formed precipitate is filtered off, washed with a small amount of water and dried in vacuum for 20 hours. Obtain 2.90 g (39%) N-cyanocarbonimidate.

Synthesis of 2,4-dichloro-1,3,5-triazine

To a solution of 2.5 ml (34.0 mmol) of dimethylformamide in 50 ml of anhydrous dichloromethane at room temperature was added 2.8 ml (30.0 mmol) POCl3the reaction mixture is stirred for 10 minutes, added 2.9 g (29.0 mmol) of N-cyanocarbonimidate and left under stirring overnight, then, to the reaction mixture was added 100 ml of dichloromethane and the organic phase is washed with water (4×15 ml), dried over Na2SO4the solvent is removed. Obtain 1.7 g (40%) of 2,4-dichloro-1,3,5-triazine.

Synthesis of 6-amino-2,2-debtor-2H-benzo[8][1,4]-oxazin-3(4H)-it

In accordance with scheme V from commercially available starting compounds are synthesized

6-amino-2,2-debtor-2H-benzo[8][1,4]-oxazin-3(4H)-it.

Synthesis of 2-bromo-2,2-debtor-N-(2-hydroxy-5-NITROPHENOL)ndimethylacetamide

To a solution of 25.0 g (162 mmol) of 2-amino-4-NITROPHENOL and 21.9 g (170 mmol) of the Foundation of Kuninga in 250 ml of anhydrous acetonitrile are added dropwise 29.7 g (170 mmol) of the acid chloride bradypterus acid, maintaining the temperature of the reaction mixture at 0°C. After addition, the reaction mixture is stirred for 4 h to maintain the right temperature and left overnight. The solvent is removed in vacuo, to the residue was added 500 ml of ethyl acetate and the resulting solution washed with saturated NaCl solution (3×70 ml), the organic f the zu dried over MgSO 4the solvent is removed in vacuum. Obtain 41.8 g (83%) of product as a dark brown oil, which is used in the next stage without additional purification.

Synthesis of 2,2-debtor-6-nitro-2H-benzo[8][1,4]-oxazin-3(4H)-it

41.8 g (134 mmol) of deverbalization obtained at the preceding stage, dissolved in 200 ml of anhydrous degassed DMF and added 20.5 g (148 mmol) of calcined in vacuum To2CO3the reaction mixture is heated to 85°C and maintained at this temperature and vigorous stirring for 40 hours, the Solvent is removed in vacuum, the residue is extracted with ethyl acetate (3×800 ml), the extracts combined, the solvent is removed in a vacuum rotary evaporator. The remainder is shared by chromatography using pentane-ether of increasing polarity. Obtain 19.1 g (62%) of product as brown crystals.

Synthesis of 6-amino-2,2-debtor-2H-benzo[8][1,4]-oxazin-3(4H)-it

To a solution of 19.1 g (83 mmol) of nitro-derivatives of 2,2-debtor-6-nitro-2H-benzo[8][1,4]-oxazin-3(4H)-she's in 200 ml of methanol add 840 mg of 10% palladium on coal and hydronaut at 1 ATM. hydrogen for 20 hours. After absorption of the calculated amount of hydrogen the catalyst is filtered off, the solvent is removed in vacuum. The residue is separated using chromatographic system PI is roform-methanol of increasing polarity Gain: 14.5 g (87%) of product 6-amino-2,2-debtor-2H-benzo[8][1,4]-oxazin-3(4H)-it.

Synthesis of 6-amino-2,2-dimethyl-2H-pyrid[3,2-b][1,4]oxazin-3(4H)-it

According to scheme VI from commercially available starting compounds are synthesized

6-amino-2,2-dimethyl-2H-pyrid[3,2-b][1,4]oxazin-3(4H)-it.

Synthesis of methyl ester of 2-methyl-2-[(2-nitropyridine-3-yl)oxy]propanoic acid

To a solution of 0.31 g (2.2 mmol) of 2-nitro-3-hydroxypyridine in 5 ml of anhydrous DMF was added 1.10 g (8 mmol) of K2CO3and 0.52 g (2.5 mmol) of methyl dimethylfumarate, the reaction mixture was stirred at 50°C to 80 hours, then the solvent is removed in vacuum, the residue is extracted with ethyl acetate (3×30 ml), washed on the filter with water (3×10 ml), dried and recrystallized from benzene. Get: 0.46 g (87%) of product.

Synthesis of methyl ester of 2-methyl-2-[(2,6-dinitropyridine-3-yl)oxy]propanoic acid

0.46 g (1.8 mmol) of nitro-derivatives dissolved in 5 ml of concentrated sulfuric acid and added 0.36 g (3.5 mmol) of dry potassium nitrate. The reaction mixture is stirred for 4 hours at 20°C, poured into water, the resulting precipitate is filtered off, repeatedly washed on the filter with cold water until neutral wash water and dried. Get: 0.39 g (71%) of the product methyl ester of 2-methyl-2-[(2,6-dinitropyridine-3-yl)oxy]propanoic acid.

Sin is ez 6-amino-2,2-dimethyl-2H-pyrid[3,2-b][1,4]oxazin-3(4H)-it

A solution of 0.39 g (1.37 mmol) dinitropropanol methyl ester of 2-methyl-2-[(2,6-dinitropyridine-3-yl)oxy]propanoic acid in 20 ml of DMF hydronaut 80 mg of 5% palladium on coal at 1 ATM. hydrogen for 6 hours. After absorption of the calculated amount of hydrogen the catalyst is filtered off, the solvent is removed in vacuum at 70°Poluchenii the residue is transferred to a filter, washed with water (2x10 ml), dried and paracrystal-lizovyvatj out in ethanol. Get: 0.22 g (84%) of product 6-amino-2,2-dimethyl-2H-pyrid [3,2-b][1,4] oxazin-3 (4H)-it.

Synthesis of 7-amino-3,3-dimethyl-3,4-dihydro-1,8-naftalin-2(1H)-it

According to scheme VII from commercially available starting compounds are synthesized

7-amino-3,3-dimethyl-3,4-dihydro-1,8-naftalin-2(1H)-it.

Synthesis of 2,6-definitately acid

To a solution of 337 ml (0.54 mol) of 1.6M solution of n-utility in hexane in 600 ml of THF in an argon atmosphere was added a solution of 67.5 g (0.54 mol) of Diisopropylamine in 150 ml of THF. The reaction mixture was stirred 40 min at 10°C, followed by vigorously stirring and cooled to -78°C was added a solution of 57.5 g (0.5 mol) of 2,6-diphereline in 150 ml of THF maintaining the temperature of about -78°C. the Reaction mixture is stirred for 2.5 hours and add ~80 g of crushed dry ice, after which peremeci is up for another 45 minutes, then slowly allowed to warm to 5°C and poured into a mixture of 5 l of ice water. The resulting solution was extracted three times with ethyl acetate (3×200 ml), the aqueous layer was acidified with 6M hydrochloric acid to pH ~4 and extracted with chloroform (4×500 ml). Combined organic extracts washed with brine (3×200 ml) and dried over MgSO4. The solvent is removed in vacuum, the residue is recrystallized from a mixture of firescan 1:1. Get: 66.0 g (83%) of product as colorless crystals.

Synthesis of 2,6-debtor-3-hydroxymethylpropane

To a cooled to 0°C solution 55.65 g (0.35 mol) of 2,6-definitately acid in 400 ml of anhydrous THF in an argon atmosphere, was added to 1500 ml (1.2 mol) 0.8M solution of borane in THF. The resulting mixture was stirred for 4 hours at room temperature, then boiled for 140 hours, cooled to -10°C and gently, drop by drop, without increasing the temperature above 5°C add 920 ml of 4M NaOH solution in water. The aqueous layer was additionally saturated NaCl, the organic phase is separated, the aqueous extracted with ether (3×500 ml). The organic fractions combined, washed with brine (2x200 ml) and dried over MgSO4, filtered through a layer of silica gel, the solvent is removed. Get: 34.0 g (67%) 2,6-debtor-3-hydroxymethylbilane, which is used in the next stage without additional purification.

Synthesis of 2,6-debtor-3-chloromethylpyridine

14.5 g (0.1 mol) Obtained in the previous phase 2,6-debtor-3-hydroxymethylpropane dissolved in 200 ml of dry chloroform and added, keeping the temperature around 0°C, 8.8 ml (~0.12 mol) of thionyl chloride. Reactional the mixture is stirred for 4.5 hours, then remove the solvents in vacuo, and ostatok washed with ether (3×100 ml). Get: 16.0 g(98%) 2,6-debtor-3-chloromethylpyridine.

Synthesis of ethyl 3-(2,6-differencein-3-yl)-2,2-dimethylpropanoate

To a solution of 50 ml (0.08 mol) of 1.6M solution of n-utility in hexane in 100 ml of anhydrous THF in an argon atmosphere was added a solution of 13.9 ml (0.08 mol) of Diisopropylamine in 150 ml of anhydrous THF. The reaction mixture is stirred for 1 hour at 10°C, followed by vigorously stirring and cooled to -78°C was added a solution of 11.6 g (0.1 mol) of ethyl isobutyrate in 100 ml of THF. The reaction mixture is stirred for one hour at -78°C, then for another hour at -50°C and maintain the temperature was added 9.8 g (0.06 mol) of 2,6-debtor-3-chloromethylpyridine, the reaction mixture is stirred for another 2 hours at -50--40°C, and then left overnight, poured into 1 l of cold water and acidified to pH~4, extracted with ethyl acetate (3×300 ml). The combined organic phases are washed with water until neutral, then with brine and dried over MgSO4the solvent is removed and the residue is dried and share chromatography the Eski (fergenson). Get 3.5 g (24%) of ethyl 3-(2,6-differencein-3-yl)-2,2-dimethylpropanoate.

Synthesis of 7-amino-3,3-dimethyl-3,4-dihydro-1,8-naftalin-2(1H)-it

To a solution of 4.87 g (0.02 mol) of ethyl 3-(2,6-differencein-3-yl)-2,2-dimethylpropanoate in 20 ml of anhydrous ethanol was added 15 ml of a 6M solution of ammonia in anhydrous ethanol. The reaction mixture is heated in an autoclave for 6 hours at 60°C, then add another 10 ml of a 6M solution of ammonia in anhydrous ethanol and heated in an autoclave for another 6 hours at 120°C, cooled, the solvent is removed, the remainder is shared by chromatography (dichloromethane:methanol 9:1->4:1). Get: 0.61 g (16%) of product.

Synthesis of 6-amino-2,2-dimethyl-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-it

According to scheme VIII from commercially available starting compounds are synthesized

6-amino-2,2-dimethyl-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-it.

Synthesis of N-(6-herperidin-2-yl)Pihlajamaa

A solution of 13.8 g (0.11 mol) of trimethylacetylchloride in 150 ml of dichloromethane was added cooled to 0°C a solution of 11.2 g (0.1 mol) 2-amino-6-herperidin in and 15.3 ml (0.11 mol) of triethylamine in 200 ml of dichloromethane. The resulting mixture was stirred for 2 hours at 0°C and left overnight, then poured into water. The organic layer was washed with a saturated solution of NaHCO3(4×70 ml) and dried over MgSO4RA the solvent is removed, the remainder of Perekrest-lizovyvatj from hexane. Obtain 17.2 g (88%) of product.

Synthesis of isopropyl 2-((2-fluoro-6-evaluieren-3-yl)thio)-2-methylpropanoate

A solution of 14.7 g (0.075 mol) of N-(6-herperidin-2-yl)Pihlajamaa in 400 ml of ether is cooled to -78°C and added ml (0.19 mol) of a 1.7M solution of tert-utility in pentane, and then stirred the reaction mixture for 4 hours to maintain the right temperature, then add 51.6 g (0.16 mol) disulfide, give the reaction mixture sodium to -35°C and stirred at this temperature for 4 hours, then allow to slowly warm to room temperature at which maintain the reaction mixture for another 4 hours. Then poured into 300 ml of 10% solution of ammonium chloride in water, the organic phase is separated, the aqueous extracted with ether (2×200 ml) the combined organic extracts washed with saturated solution of NaHCO3(3×100 ml), then water and dried over MgSO4. The solvent is removed, the remainder is shared by chromatography (hexane:ether 9.1->ether). Get: 15.3 g (57%) of product as a Golden yellow oil.

Synthesis of isopropyl 2-((2-amino-6-evaluieren-3-yl)thio)-2-methylpropanoate

10.7 g (0.03 mol) of isopropyl 2-((2-fluoro-6-evaluieren-3-yl)thio)-2-methylpropanoate dissolved in 100 ml of a 4M solution of ammonia in methanol is heated to the reaction mixture in an autoclave at 90°C for 70 hours, cool, the solvent is removed, the remainder is shared by chromatography (dichloromethane->dichloromethane:methanol 4:1). Get: 3.08 g (29%) of product.

Synthesis of isopropyl 2-((2-amino-6-evaluieren-3-yl)thio)-2-methylpropanoate

To 1.77 g (0.005 mol) of isopropyl 2-((2-amino-6-evaluieren-3-yl)thio)-2-methylpropanoate add 15 ml of acetic acid and 2 ml of hydrochloric acid, the mixture is boiled for 4 hours, the solvents are removed in vacuo, to the residue was added 8 ml of 6M NaOH solution in water and incubated the mixture for 8 hours at 80°C, cooled, acidified to neutral reaction, the precipitate is filtered off, washed on the filter with cold water (3×2 ml) and dried. Obtain 0.42 g (37%) of product.

Synthesis of 6-amino-2,2-dimethyl-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-it

To a solution of 1.14 g (0.005 mol) of 2-((2,6-diaminopyridine-3-yl)thio)-2-methylpropionic acid in 30 ml of DMF was added 1.30 g (0.008 mol) of carbonyldiimidazole, the reaction mixture was stirred at room temperature for 4 hours, the solvent is removed in vacuum, the residue is shared by chromatography (dichloromethane:methanol 19:1->4:1. Obtain 0.71 g (68%) of 6-amino-2,2-dimethyl-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-it.

Synthesis of 7-amino-3a,9a-dimethyl-1,2,3,3a,9,9a-hexahydrobenzo[b]cyclopent[e][1,4]oxazin-1-ol

In accordance with the scheme IX of commercially available recognize the different substances are synthesized

7-amino-3a,9a-dimethyl-1,2,3,3a,9,9a-hexahydrobenzo[b]cyclopent[e][1,4]oxazin-1-ol.

Synthesis of diethyl(3-[(1)-3-methylpentan-2-he-4-yl] phosphate

To a suspension of 18.0 g (0.45 mol) of sodium hydride (60% suspension in mineral oil) in 180 ml of diethyl ether in an argon atmosphere, is added dropwise, maintaining the temperature around 0°C was added 46.8 ml (0.40 mol) of 3-methyl-2,4-pentanedione in 200 ml of ether. The reaction mixture was stirred at 18°C for 30 minutes until gas evolution stops and add a solution of 77.6 g (0.45 mol) of diethylphosphate in 200 ml of ether, maintaining the temperature around 0°C, after which the reaction mixture was stirred for another 4 hours at 18°C, followed by dropwise, keeping the temperature around 0°C, was added 15 ml of a saturated aqueous solution of ammonium chloride and stirred for maintaining a given temperature until the gas evolution stops (about 20 minutes), the organic layer is separated, washed with saturated aqueous NaHCO3(1×100 ml), then with ice water (2×100 ml) and dried over MgSO4. The solvent is removed in vacuum at a temperature not exceeding 10°C. Receive: 92.1 g (92%) of product, which was immediately used in the next stage.

Synthesis of (Z)-3,4-dimethylpentan-3--2

To a suspension of 19.0 g (0.1 mol) of dry potassium iodide copper (I) in 450 ml of diethyl ether, in an atmosphere of argon is, add 420 ml (0.21 mol) of a 0.5M solution metallice in the air, keeping the temperature around -10°C. the Reaction mixture is stirred until complete dissolution of the precipitate and education slightly yellow clear solution which is cooled to -78°C was added a solution of 9.4 g (0.04 mol) of a previously received phosphonate in 120 ml of diethyl ether. The reaction mixture is stirred at a predetermined temperature for 8 hours, allowed to warm to room temperature and added to 100 ml of a saturated aqueous solution of ammonium chloride and stirred for maintaining the temperature until the gas evolution stops. The precipitate is filtered off, washed with ether (3×100 ml), the filtrate is washed with 20% aqueous ammonia solution (3×100 ml)and then water (3×200 ml), dried over Na2SO4the ether was removed and the residue is distilled in vacuum (76-79°C./50 Torr). Get: 4.0 g (89%) of product.

Synthesis of (Z)-3,4-dimethylpentan-3-ol-2

To a solution of 2.3 g (~0.06 mol) of lithium aluminum hydride in 220 ml of ether, in an argon atmosphere, at 0°C, was added 6.7 g (0.06 mol) of (Z)-3,4-dimethylpentan-3-it-2 in 80 ml of diethyl ether, the reaction mixture is stirred for 4 hours, cooled to -5°C. and add dropwise water, until the addition of a new portion will not cause the evolution of gas, after which the reaction mixture is stirred for another 20 minutes, the precipitate filtered off, washed with ether (4×100 ml), the organic phase is separated, washed with water(3×50 ml), dried over Na2SO4the ether was removed and the residue is distilled (65-69°C/25 Torr). Get: 5.34 g (78%) of product.

Synthesis of 3,4-Dimethylpent-3-EN-2-yl(3-nitrophenyl)carbamate. NEt3, MeCN

To a solution of 2.28 g (0.02 mol) (g)-3,4-dimethylpentan-3-ol-2 in acetonitrile was added 3.04 g (0.02 mol) of 3-nitrophenylacetate and 1 drop of triethylamine. The reaction mixture is stirred for 5 hours at 50°C, the solvent is removed, the remainder is shared by chromatography (hexane:ethyl acetate 9:1->1:1). Get: 6.91 g (88%) of product.

Synthesis of 2A1,4A-dimethyl-8-nitro-2A,3,4,4A-tetrahydro-2,5-dioxo-9b-isopentene[1,6-ab]naphthalene-1(2A1N)-it

To a solution of 5.57 g (0.02 mol) obtained at the previous stage of the carbamate in 200 ml of benzene was added 17.00 g (~0.04 mol) periodinane dess-Martin and boil the resulting solution for 1.5 hours, cooled, add 300 ml of ethyl acetate, washed with saturated aqueous NaHCO3(4×150 ml), then brine (2×100 ml) and dried over Na2S04. The solvent is removed under vacuum the residue is the residue divided chromatography (hexane:ethyl acetate 9:1->1:1). Get: 2.49 g (43%) of product.

Synthesis of 8-amino-214A-dimethyl-2A,3,4,4A-tetrahydro-2,5-dioxo-9b-isopentene[1,6-ab]naphthalene-1 (2A1N)-it

To a solution of 2.90 g (0.01 mol) 2A',4A-dimethyl-8-nitro-2A,3,4,4A-tetrahydro,5-dioxo-9b-isopentene[1,6-ab]naphthalene-1(2a 1H)is it in 200 ml of ethanol was added 300 mg of 5% palladium on coal and hydronaut at 1 ATM. of hydrogen and a temperature of 20°C for 12 hours. After the standard procedure of processing of the reaction mixture get: 2.44 g (94%) of product.

Synthesis of 7-amino-3a,9a-dimethyl-1,2)3,3a,9,9a-hexahydrobenzo[b]cyclopent[e][1,4]oxa-Zin-1-ol

To a solution of 5.0 g of potassium hydroxide in 30 ml of a mixture of methanol-water (4:1 v/v) was added 1.30 g (0.005 mol) 2A1,4A-dimethyl-8-amino-2A,3,4,4A-tetrahydro-2,5-dioxo-9b-isopentene[1,6-ab] naphthalene-1(2a1H)-she and boil for 60 hours in an argon atmosphere. The solvent is removed, to the residue was added 600 ml of ether and 200 ml of water, the organic phase is separated, washed with brine (4×100 ml), dried over MgSO4the solvent is removed, the remainder is shared by chromatography-Cesky (dichloromethane->dichloromethane:methanol 4:1). Get: 0.90 g (77%) of 7-amino-3a,9a-dimethyl-1,2,3,3a,9,9a-hexahydrobenzo[b]cyclopent[e][1,4]oxazin-1-ol.

Synthesis of 7'-aminosterol[cyclopropane-1,3'-pyrido[3,4-b][1,4]oxazin]-2'(1'H)-it

In accordance with the scheme X from commercially available starting compounds are synthesized

7'-aminosterol [cyclopropane-1,3'-Piri to [3,4-b] [1,4]oxazin]-2'(1 ' H)-she.

Synthesis of 5-((4-benzylcarbamoyl-1-methoxy-1-oxobutyl-2-yl)oxy)-2-chloropyridine

To a solution of 23.3 g (0.18 mo is b) 3-hydroxy-5-chloropyridine in 300 ml of DMF was added 4.8 g (0.20 mol) of sodium hydride (60% suspension in mineral oil). The reaction mixture is stirred for 2 hours and added, keeping the temperature around 30°C, 66.2 ml (0.2 mol) of methyl-4-(benzyloxycarbonyloxy)-2-bromobutyronitrile the mixture is stirred at room temperature for 6 hours and left overnight. Poured into 1.5 l of ice water and extracted the product with dichloromethane (3×300 ml). Combined extracts washed with water (3×100 ml) and dried over Na2SO4. Get: 58.0 g (79%) of 5-((4-benzylcarbamoyl-1-methoxy-1-oxobutyl-2-yl)oxy)-2-chloropyridine.

Synthesis of 5-((4-benzylcarbamoyl-1-methoxy-1-oxobutyl-2-yl)oxy)-2-chloropyridine-1-oxide

To a solution of 56.4 g (0.14 mol) of methyl 2-(6-chloropyridin-3-yloxy)propionate 500 ml of pyridine was added 35 ml (-0.3 mol) of 30% aqueous hydrogen peroxide solution and 35 mg of methyl tri-oxirane. The mixture is stirred for 4 hours at room temeprature, cooled to 0°C and added dropwise 100 ml of a saturated aqueous solution of NaHCO3, the organic layer is separated, washed with saturated aqueous NaHCCh (2×160 ml)and then water (2×100 ml). The organic phase is dried over MgSO4the solvent is removed. Get: 57.55 g (97%) of 5-((4-benzylcarbamoyl-1-methoxy-1-oxobutyl-2-yl)oxy)-2-chloropyridine-1-oxide.

Synthesis of 5-((4-benzylcarbamoyl-1-methoxy-1-oxobutyl-2-yl)oxy)-2-chloro-4-nitropyridine 1-oxide

8.48 g (0.02 mol) of N-OK the IDA dissolved in 40 ml of sulfuric acid, cooled to 0°C and add 2 ml of nitric acid. The reaction mixture largemouth to 60°C, maintained at this temperature for 8 hours and drink in a mixture of water and ice, neutralized by adding small portions of sodium bicarbonate to pH~5 and extracted with ethyl acetate (3×200 ml), the combined organic phases washed with water (3×100 ml), dried over Na2SO4and remove the solvent. Get: 7.31 g (78%) of 5-((4-benzylcarbamoyl-1-methoxy-1-oxobutyl-2-yl)oxy)-2-chloro-4-nitropyridine-1-oxide.

Synthesis of 5-((4-benzylcarbamoyl-1-methoxy-1-oxobutyl-2-yl)oxy)-2-chloro-4-nitropyridine 1-oxide

7.03 g (0.015 mol) of the nitro compounds are dissolved in 100 ml of methanol and hydronaut on skeletal Nickel at 1atm. hydrogen and 10°C for 1.5 hours. The catalyst is filtered off, the filtrate was added 50 ml of chloroform and filtered through a thin (~1 cm) layer of silica gel, the solvent removed, to the residue was added 200 ml of toluene and boiled for 4 hours, the toluene is removed, the residue is separated chromatographically. Get: 2.50 g (73%) of 6-chloro-2-(2-hydroxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-it.

Synthesis of the hydrochloride of 6-chloro-2-(2-chloroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-it

To a solution of 11.43 g (0.05 mol) of alcohol in 200 ml of dichloromethane was added 4.4 ml (0.06 mol) thionyl chloride. The resulting mixture is boiled for 4 hours, the solvent is removed, OST the current dry. Get: 13.75 g (97%) of the hydrochloride of 6-chloro-2-(2-chloroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-it.

Synthesis of 7'-chlorpro[cyclopropane-1,3'-pyrido[3,4-b][1,4]oxazin]-2'(1 N)-it

To a solution of 43.8 ml (0.07 mol) of 1.6M solution of m-utility in hexane in 120 ml of anhydrous THF in an argon atmosphere was added a solution of 16 ml (0.07 mol) of dicyclohexylamine in 150 ml of anhydrous THF. The reaction mixture is stirred 2 hours at 20°C, after cooled down to -50°C and add small portions of 8.51 g (0.03 mol) of the hydrochloride of 6-chloro-2-(2-chloroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-she. The reaction mixture is stirred for 1 hour at -50°C, and then left under stirring overnight, then poured into 800 ml of cold water and acidified to pH~6, extracted with ethyl acetate (3×200 ml). The combined organic phases are washed with water until neutral, then with brine and dried over MgS04, the solvent is removed and the residue is dried in vacuum and share chromatographically (ether:hexane). Obtain 1.28 g (20%) 7'-chlorpro[cyclopropane-1,3'-pyrido[3,4-b][1,4]oxazin]-2'(1'H)-it.

Synthesis of 7'-aminosterol[cyclopropane-1,3'-pyrido[3,4-b][1,4]oxazin]-2'(1 N)-it

A mixture of 2.17 g (0.012 mol) benzophenone, tert-butyl sodium 1.15 g (0.012 mol), 200 mg Pd2(dba)3and 2.11 (0.01 mol) of 7'-chlorpro[cyclopropane-1,3'-pyrido[3,4-b][1,4]oxazin]-2'(1'H)-she and 337 mg (0.6 mmol) of 2,2 is the bis(diphenylphosphino)-1,Binaphthyl (40 ml toluene was stirred at 80°C for 14 hours, cooled to room temperature, add 100 ml of 1M hydrochloric acid in a mixture of THF:water 1:1, stirred for 2 hours, extracted with ethyl acetate (3×200 ml), the extracts combined washed with saturated aqueous NaHCO3(2×150 ml), dried over MgSO4the solvent is removed, the residue is separated chromatographically. Get: 1.22 g (53%) 7'-aminosterol[cyclopropane-1,3'-pyrido[3,4-b][1,4]oxazin]-2'(1'H)-it.

Synthesis of 3'-amino-5 N-Spiro[icoprofen-1,7'-pyrido[2,3-b]pyrazin]-6' (8'H)-it

In accordance with the scheme XI from commercially available starting compounds are synthesized

3'-amino-5 N-[icoprofen-1,7'-pyrido[2,3-b]pyrazin]-6'(8'H)-it.

Synthesis of ethyl 1-((3,5-dichloropyrazine-2-yl)methyl)cyclopropanecarboxylate

To a suspension of 1.25 g (0.052 mol) of sodium hydride (60% suspension in mineral oil) in anhydrous DMF was added 11.44 g (0.052 mol) of iodide trimethylsilane and the resulting mixture was stirred for 40 minutes at room temperature, then added a solution of 5.74 g (0.022 mol) of ethyl 2-((3,5-dichloropyrazine-2)methyl)acrylate in 40 ml of DMF. The reaction mixture is stirred for 4 hours, poured into 200 ml ice water and exteriour with ethyl acetate (3×250 ml). The combined extracts washed with brine (3×100 ml) and dried over MgSO4. The residue is triturated in a mixture of hexameter the result is it is the crystallization of the product, which is filtered off, washed on the filter with semest hexane:ether (2×10 ml) and dried. Get: 4.90 g (81%) of ethyl 1-((3,5-dichloropyrazine-2-yl)methyl)cyclopropanecarboxylate.

Synthesis of 7'-aminosterol[cyclopropane-1,3'-pyrido[3,4-b][1,4]oxazin]-2'(1 N)-it

A mixture of 5.80 g (0.032 mol) benzophenone, tert-butyl sodium 3.07 g (0.032 mol), 356 mg Pd2(dba)3, 995 mg of 2,2'-bis(diphenylphosphino)-1,1 binaphtyl and 3.30 g (0.012 mol) obtained in the previous phase of ethyl 1-((3,5-dichloropyrazine-2-yl)methyl)cyclopropanecarboxylate in 40 ml of toluene was stirred at 90°C for 42 hours, cooled to room temperature, add 100 ml of 0.5M hydrochloric acid in a mixture of THF:water 1:1, stirred for 2 hours, add 20 g of solid NaHCO3, stirred for 20 minutes and extracted with ethyl acetate (3×200 ml), the extracts combined washed with saturated aqueous NaHCO3(2×150 ml), dried over MgSO4the solvent is removed, the remainder is shared by the HRO-metagraphics. Get: 1.11 g (49%) of 3'-amino-5'H-Spiro[icoprofen-1,7'-pyrido[2,3-b]pyrazin]-6'(8'H)-it.

1. Getting 2,2-debtor-6-({4-[(3,4,5-trimethoxyphenyl)amino]-1,3,5-triazine-2-yl} amino)-2H-benzo [8][1,4]-oxaze h-3(4H)-it.

Sites 2,2-debtor-6-({4-[(3,4,5-trimethoxyphenyl)amino]-1,3,5-triazine-2-yl}amino)-2H-benzo[8][1,4]-oxazin-3(4H)-it is carried out in accordance with scheme I. When this is used is commercially available 3,4,5-trimethoxyaniline, and 6-amino-[(4-chloro-1,3,5-triazine-2-yl)amino]-2,2-debtor-2H-benzo[8][1,4]-oxazin-3(4H)-he synthesized according to scheme V

Synthesis of 6-amino-[(4-chloro-1,3,5-triazine-2-yl)amino]-2,2-debtor-2H-benzo[8][1,4]-oxazin-3(4H)-it

0.17 g (1.15 mmol) of 2,4-dichloro-1,3,5-triazine are dissolved in 5 ml of anhydrous degassed DMF, was added 0.23 g (1.15 mmol) 6-amino-2,2-debtor-2H-benzo[8][1,4]-oxazin-3(4H)-it is stirred in an argon atmosphere at 60°C for 8 hours. The solvent is removed in vacuum (5 mm Hg), the residue is washed with cold water (2×5 ml), dried and share chromatography using as eluent system of chloroform:methanol of increasing polarity. Get: 0.29 g (81%) of product 6-amino-[(4-chloro-1,3,5-triazine-2-yl)amino]-2,2-debtor-2H-benzo[8][1,4]-oxazin-3(4H)-it.

Synthesis of 2,2-debtor-6-({4-[(3,4,5-trimethoxyphenyl)amino]-1,3,5-triazine-2-yl}amino)-2H-benzo[8][1,4]-oxazin-3(4H)-it

0.29 g (0.92 mmol) of compound 6-amino-[(4-chloro-1,3,5-triazine-2-yl)amino]-2,2-debtor-2H-benzo[8][1,4]-oxazin-3(4H)-she dissolved in 5 ml of anhydrous degassed DMF, was added 0.34 g (1.84 mmol) of 3,4,5-trimethoxyaniline and stirred in an argon atmosphere for 6 hours at 110°C. the Solvent is removed in vacuum (5 mm Hg), the residue is washed with cold water (2×5 ml), dried and share chromatography using as eluent system of chloroform:methanol of increasing polarity. Get: 0.29 g (67%) of 2,2-di-fluoro-6-({4-[(3,4,5-trimethoxyphenyl)amino]-1,3,5-triazine-2-yl}amino)-2H-benzo [8] [1,4]-oxazin-3 (4H)-it.

1H (500 MHz, DMSO-d6): 3.52 (c, mn, CH3), 3.70 (s, 6N, SN), 6.28 (s, 2H, 2HAr), 7.10 (doctor J=9.0Hz, 1H, HAr), 7.47 (doctor J=9.1Hz, 1H, HAr), 7.88 (USS, 1H, NH), 8.21 (USS, 1H, NH), 8.00 (s, 1H, HAr), 8.42 (c, 1H, HAG), 9.26 (c, 1H, C(O)NH).

2. Getting 2,2-debtor-6-({4-[(1,3-benzodioxol-5-yl)amino]-1,3,5-triazine-2-yl}amino)-2H-benzo[8][1,4]-oxazin-3(4H)-it.

Synthesis of 2,2-debtor-6-({4-[(1,3-benzodioxol-5-yl)amino]-1,3,5-triazine-2-yl}amino)-2H-benzo[8][1,4]-oxazin-3(4H)-it is carried out in accordance with scheme I. using commercially available 3,4-methylenedioxyaniline and 2,2-debtor-6-nitro-2H-benzo[8][1,4]-oxazin-3(4H)-he synthesized according to scheme V

Synthesis of 6-[(4-chloro-1,3,5-triazine-2-yl)amino]-2,2-debtor-2H-benzo[8][1,4]-oxazin-3(4H)-it

0.17 g (1.15 mmol) of 2,4-dichloro-1,3,5-triazine are dissolved in 5 ml of anhydrous degassed DMF, was added 0.20 g (1 mmol) 6-amino-2,2-debtor-2H-benzo[8][1,4]-oxazin-3(4H)-she and 0.2 ml (1.15 mmol) of the Foundation of Huningue and stirred in an argon atmosphere at 60°C for 8 hours. The solvent is removed in vacuum (5 mm Hg), the residue is washed with cold water (2×5 ml), dried and share chromatography using as eluent system of chloroform-methanol increasing polarity. Get: 0.29 g (81%) of product 6-[(4-chloro-1,3,5-Treaty the-2-yl)amino]-2,2-debtor-2H-benzo[8][1,4]-oxazin-3(4H)-it.

Synthesis of 2,2 - debtor-6-({4-[(1,3-benzodioxol-5-yl)amino]-1,3,5-triazine-2-yl}amino)-2H-benzo[8][1,4]-oxazin-3(4H)-it

0.29 g (0.92 mmol) of 6-[(4-chloro-1,3,5-triazine-2-yl)amino]-2,2-debtor-2H-benzo[8][1,4]-oxazin-3(4H)-she dissolved in 5 ml of anhydrous degassed DMF, was added 0.25 g (1.85 mmol) of 3,4-methylenedioxyaniline and stirred in an argon atmosphere at 110°C for 6 hours. The solvent is removed in vacuum (5 mm Hg), the residue is washed with cold water (2×5 ml), dried and share chromatography using as eluent system of chloroform: methanol of increasing polarity. Get: 0.22 g (59%) of 2,2 - debtor-6-({4-[(1,3-benzodioxol-5-yl)amino]-1,3,5-triazine-2-yl}amino)-2H-benzo[8][1,4]-oxazin-3(4H)-it.

1H (500 MHz, DMSO-d6): 6.01 (s, 2H, CH2), 6.55 (s, 1H, HAr), 6.58 (doctor J=8.2 Hz, 1H, HAr), 6.84 (doctor J=8.2Hz, 1H, HAr), 7.10 (doctor J=9.0Hz, 1H, HAr), 7.47 (doctor J=9.0Hz, 1H, HAr), 7.85 (USS, 1H, NH), 8.21 (USS, 1H, NH), 8.00 (s, 1H, HAG), 8.42 (s, 1H, HAr), 9.26 (s, 1H, C(O)NH).

3. Obtain 2,2-dimethyl-6-({4-[(3,4,5-trimethoxyphenyl)amino]-pyrimidine-4-yl}amino)-2H-pyrid[3,2-B][1,4]oxazin-3(4H)-it.

Sites 2,2-dimethyl-6-({4-[(3,4,5-trimethoxyphenyl)amino]-pyrimidine-4-yl}amino)-2H-pyrid[3,2-b][1,4]oxazin-3(4H)-it is carried out in accordance with scheme I. using commercially available 2,2-debtor-3,4-methylenedioxyaniline, and 6-amino-2,2-dimethyl-2H-pyrid[3,2-b][1,4]oxazin-3(4H)-is it synthesized according to the according to scheme VI

Synthesis of 6-[(4-chloro-1,3,5-triazine-2-yl)amino]-2,2-dimethyl-2H-pyrid[3,2-b][1,arszyn-3(4H)-it

0.17 g (1.15 mmol) of 2,4-dichloro-1,3,5-triazine are dissolved in 5 ml of anhydrous degassed DMF, was added 0.22 g (1.15 mmol) 6-amino-2,2-dimethyl-2H-pyrid[3,2-b][1,4]oxazin-3(4H)-she and 0.2 ml (1.15 mmol) of the Foundation of Huningue and stirred in an argon atmosphere at 60°C for 8 hours. The solvent is removed in vacuum (5 mm Hg), the residue is washed with cold water (2×5 ml), washed with ethanol (3×2 ml) and dried. Get: 0.28 g (80%) of the product 6-[(4-chloro-1,3,5-triazine-2-yl)amino]-2,2-dimethyl-2H-pyrid[3,2-b][1,4]oxazin-3(4H)-it.

Synthesis of 2,2-dimethyl-6-({4-[(3,4,5-trimethoxyphenyl)amino]-1,3,5-triazine-2-yl}amino)-2H-pyrid[3,2-b][1,4]oxazin-3(4H)-it.

0.28 g (0.92 mmol) obtained in the previous method 6-[(4-chloro-1,3,5-triazine-2-yl)amino]-2,2-dimethyl-2H-pyrid[3,2-b][1,4]oxazin-3(4H)-she dissolved in 5 ml of anhydrous degassed DMF, was added 0.32 g (1.84 mmol) of 2,2-debtor-5-amino-1,3-benzocaine and stirred in an argon atmosphere at 110°C for 6 hours. The solvent is removed in vacuum (5 mm Hg), the residue is washed with cold water (2×5 ml), dried and share chromatography using as eluent system of chloroform: methanol of increasing polarity. After the standard procedure of processing get: 0.28 g (65%) of target compound 2,2-dimethyl-6-({4-[(3,4,5-trimetho Setenil)amino]-1,3,5-triazine-2-yl }amino)-2H-pyrid[3,2-b] [1,4]oxazin-3(4H)-it.

1H (500 MHz, DMSO-d6): 1.47 (s, 6N, SNS), 6.81 (s, 1H, HAr), 7.03 (doctor J=8.2Hz, 1H, HAr), 7.09 (doctor J=8.2Hz, 1H, HAr), 7.31 (doctor J=8.6Hz, 1H, HAr), 7.43 (doctor J=8.6Hz, 1H, HAG), 7.84 (USS, 1H, NH), 8.42 (s, 1H, HAr), 8.39 (USS, 1H, NH), 9.28 (s, 1H, C(O)NH).

4. Obtain 7-((4-(cyclopropylamino)-1,3,5-triazine-2-yl)amino)-3,3-dimethyl-3,4-dihydro-1,8-naphthyridin-2(1H)-it.

Sites 7-((4-(cyclopropylamino)-1,3,5-triazine-2-yl)amino)-3,3-dimethyl-3,4-dihydro-1,8-naphthyridin-2(1H)-it is carried out in accordance with scheme I. using commercially available 7-amino-3,3-dimethyl-3,4-dihydro-1,8-naftalin-2(1H)-she was synthesized according to scheme VI

Synthesis of 7-((4-chloro-1,3,5-triazine-2-yl)amino)-3,3-dimethyl-3,4-dihydro-1,8-naphthyridin-2(1H)-it

12.0 g (8 mmol) of 2,4-dichloro-1,3,5-triazine are dissolved in 12 ml of anhydrous degassed DMF, cooled to -5°C and added 11.5 g (6 mmol) of 7-amino-3,3-dimethyl-3,4-dihydro-1,8-naftalin-2(1H)-she and stirred for 2 hours at 20°C, then cooled to -5°C and add 11.8 ml (6.8 mmol) of the Foundation of Huning, peremanivat 2 hours at room temperature, and then another 5 hours at 40°C. the Solvent removed in vacuum (5 mm Hg), the residue is washed with cold water (2×5 ml), isopropanol (2×5 ml), ether (2×10 ml) and dried. Get: 16.6 g (91%) of 7-((4-chloro-1,3,5-triazine-2-yl)amino)-3,3-dimethyl-3,4-dihydro-1,8-naphthyridin-2(1H)-it.

Synthesis of 7-((4-(cyclopropyl the Mino)-1,3,5-triazine-2-yl)amino)-3,3-dimethyl-3,4-dihydro-1,8-naphthyridin-2(1H)-it

3.66 g (1.2 mmol) obtained in the previous method monochloropropane dissolved in 5 ml of anhydrous degassed DMF, was added 1.71 g (3.0 mmol) of cyclopropylamine and heated in an autoclave at 90°C for 6 hours. The solvent is removed in vacuum (5 mm Hg), the residue is washed with cold water (2×5 ml), dried and share chromatography using as eluent system of chloroform: methanol of increasing polarity. After the standard procedure of processing get: 3.04 g (78%) of 7-((4-(cyclopropylamino)-1,3,5-triazine-2-yl)amino)-3,3-dimethyl-3,4-dihydro-1,8-naphthyridin-2(1H)-it.

1H (500 MHz, DMSO-d6): 0.91 (s, 6N, SNS), 1.11-1.19 (m, 4H, SN), 2.28 (s, 2H, CH2), 3.77-3.82 (m, 1H, CH), 7.14 (doctor J=5.6Hz, 1H, HAr), 7.45 (doctor J=5.7Hz, 1H, HAr), 7.58 (USS, 1H, NH), 8.26 (s, 1H, HAr), 8.50 (USS, 1H, NH), 9.47 (s, 1H, C(O)NH).

Elemental composition: C(58.93%), H(5.81%), N(30.22%).

5. Obtaining 3,3-dimethyl-7-((4-((2,2,3,3-titrator-2,3-Dihydrobenzo[b] [1,4]dioxin-6-yl)amino)-1,3,5-triazine-2-yl)amino)-3,4-dihydro,8-naphthyridin-2(1H)-it.

Sites 3,3-dimethyl-7-((4-((2,2,3,3-titrator-2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)amino)-1,3,5-triazine-2-yl)amino)-3,4-dihydro,8-naphthyridin-2(1H)-it is carried out in accordance with scheme I. using commercially available 7-amino-3,3-dimethyl-3,4-dihydro-1,8-naftalin-2(1H)-she was synthesized according to scheme VI

Synthesis of 7-((4-chloro-1,3,5-triazine-2-yl)am the but)-3,3-dimethyl-3,4-dihydro-1,8-naphthyridin-2(1H)-it

12.0 g (8 mmol) of 2,4-dichloro-1,3,5-triazine are dissolved in 12 ml of anhydrous degassed DMF, cooled to -5°C and added 11.5 g (6 mmol) of 7-amino-3,3-dimethyl-3,4-dihydro-1,8-naftalin-2(1H)-she and stirred for 2 hours at 20°C, then cooled to -5°C and add 11.8 ml (6.8 mmol) of the Foundation of Huning, peremanivat 2 hours at room temperature, and then another 5 hours at 40°C. the Solvent removed in vacuum (5 mm Hg), the residue is washed with cold water (2×5 ml), isopropanol (2×5 ml), ether (2×10 ml) and dried. Get: 16.6 g (91%) of 7-((4-chloro-1,3,5-triazine-2-yl)amino)-3,3-dimethyl-3,4-dihydro-1,8-naphthyridin-2(1H)-it.

Synthesis of 3,3-dimethyl-7-((4-((2,2,3,3-titrator-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-1,3,5-triazine-2-yl)amino)-3,4-dihydro,8-naphthyridin-2(1H)-it

2.59 g (0.85 mmol) obtained in the previous method monochloropropane dissolved in 5 ml of anhydrous degassed DMF, add 4.13 g (1.85 mmol) of 2,2,3,3-titrator-6-amino-1,4-benzodioxane and heated for 6 hours at 100°Systemical removed in vacuum (5 mm Hg), the residue is washed with cold water (2x5 ml), dried and share chromatography using as eluent system of chloroform: methanol of increasing polarity. After the standard procedure of processing get: 2.21 g (53%) of 3,3-dimethyl-7-((4-((2,2,3,3-titrator-2,3-digidrive the AOR[B][1,4]dioxin-6-yl)amino)-1,3,5-triazine-2-yl)amino)-3,4-dihydro 1,8-naphthyridin-2(1 H)-she.

W (500 MHz, DMSO-d6): 0.91 (s, 6N, SN), 2.27 (s, 2H, CH2), 7.02 (doctor J=8.1Hz, 1H, HAr, 7.30 (doctor J=5.7Hz, 1H, HAr, 7.38 (doctor J=8.2Hz, 1H, HAG), 7.45 (doctor J=5.7Hz, 1H, H^), 7.55 (s, 1H, HAG), 7.87 (USS, 1H, NH), 8.43 (s, 1H, HAr, 8.50 (USS, 1H, NH), 9.46 (s, 1H, C(O)NH).

Elemental composition: C(51.46%), N(3.63%), N(19.79%)

6. Getting 6-((4-((4-methoxyphenyl)amino)-1,3,5-triazine-2-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-it.

Sites 6-((4-((4-methoxyphenyl)amino)-1,3,5-triazine-2-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-it is carried out in accordance with scheme I. it uses a 76-amino-2,2-dimethyl-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-he synthesized according to scheme VII

Synthesis of 6-((4-chloro-1,3,5-triazine-2-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-it

675 mg (0.45 mmol) of 2,4-dichloro-1,3,5-triazine are dissolved in 12 ml of anhydrous degassed DMF, cooled to -5°C and add 627 g (0.3 mmol) 6-amino-2,2-dimethyl-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-she and stirred for 2 hours at 20°C, then cooled to -5°C and add 0.7 ml (~0.4 mmol) base Huning, peremanivat 2 hours at room temperature, and then 5 more hours at 45°C. the Solvent is removed in vacuum (5 mm Hg), the residue is washed with cold water (2x1 ml), isopropanol (2×1 ml), ether (2×2 ml) and soucat: 859 mg (89%) of 6-((4-chloro-1,3,5-triazine-2-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b] [1,4]thiazin-3(4H)-it.

Synthesis of 6-((4-((4-methoxybenzylamine)-1,3,5-triazine-2-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-it

260 g (0.08 mmol) obtained in the previous method monochloropropane dissolved in 3 ml of anhydrous degassed DMF, was added 220 g (0.18 mmol) of n-anisidine and heated for 6 hours at 100°C. the Solvent is removed in vacuum (5 mm Hg), the residue is washed with cold water (2×5 ml), dried and precrystallization from aqueous alcohol Get: 210 g (64%) of 6-((4-((4-methoxyphenyl)amino)-1,3,5-triazine-2-yl)amino)- 2,2-dimethyl-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-it.

1H (500 MHz, DMSO-d6): 1.43 (s, 6N, SNS), 3.73 (s, mn, OCNS), 6.93 (doctor J=8.6Hz, 2H, HAr, 7.14 (doctor J=9.2Hz, 1H, HAr, 7.41 (doctor J=8.7Hz, 2H, HAr, 7.43 (doctor J=9.2Hz, 1H, HAr, 7.84 (USS, 1H, NH), 8.16 (USS, 1H, NH), 8.42 (s, 1H, HAr, 9.19 (s, 1H, C(O)NH).

Elemental composition: C(55.47%), N(4.61%), N(23.74%)

7. Obtain 7-((4-((2,2-debtorrent[d]1,3]dioxol-5-yl)amino)-1,3,5-triazine-2-yl)amino)-3a,9a-dimethyl-1,2,3)3a,9,9a-hexahydrobenzo[b]cyclopent[e][1,4]oxazin-1-ol

Sites 7'-((4-((3,3-diversilobum)amino)-1,3,5-triazine-2-yl)amino)Spiro[cyclopropane-1,3'-pyrido[3,4-b][1,4]oxazin]-2'(1'H)-it is carried out in accordance with scheme I. this uses 7'-chlorpro[cyclopropane-1,3'-pyrido [3,4-b] [1,4]oxazin]-2'(1 'H)-she was synthesized according to scheme VIII

Synthesis of 7-((4-chloro-1,3,5-triazine-2-yl)amino)-3a,9a-dimethyl-1,2,3,3a,9,9a-hexahydrobenzo[b]cyclopent[e][1,4]oxazin-1-ol

1.20 g (8 mmol) of 2,4-dichloro-1,3,5-triazine dissolved in 2 ml of anhydrous degassed DMF, cooled to -5°C and added 1.40 g (6 mmol) of 7-amino-3,3-dimethyl-3,4-dihydro-1,8-naftalin-2(1H)-she and stirred for 2 hours at 20°C, then cooled to -5°C and add 1.2 ml (~6.8 mmol) base Huning, peremanivat 2 hours at room temperature, and then another 5 hours at 40°C. the Solvent is removed in vacuum (5 mm Hg), the residue is washed with cold water (2×5 ml), ether (2×5 ml) and dried dried and share chromatography using as eluent system of chloroform: methanol of increasing polarity. After standard processing procedures obtain 1.27 g (61%) of 7-((4-chloro-1,3,5-triazine-2-yl)amino)-3a,9a-dimethyl-1,2,3,3a,9,9a-hexahydrobenzo[b] cyclopent [e][1,4]oxazin-1-ol.

Synthesis of 7-((4-((2,2-debtorrent[d][1,3]dioxol-5-yl)amino)- 1,3,5-triazine-2-yl)amino)-3a,9a-dimethyl-1,2,3,3a,9,9a-hexahydrobenzo[b]cytopenia[e][1,4]oxazin-1-ol

A mixture of 1.55 g (9 mmol) of 2,2-debtor-5-amino-1,3-benzodioxole, tert-butyl sodium 864 mg (9 mmol), 280 mg of 2,2'-bis(diphenylphosphino)-1,1 binaphthyl (X mol, 1.2% mln.), 89 mg of Pd2(dba)3 and CH 2.43 g (0.007 mol) monochloropropane obtained at the previous step in 15 ml of toluene was stirred at 60°C for 38 hours, cooled to room temperature, add 100 ml of 1M hydrochloric acid in a mixture of THF:water 1:1, stirred for 2 hours, extracted with ethyl acetate (3×200 ml), the extracts combined, washed the feast upon the tion in an aqueous solution of NaHCO 3(2×150 ml), dried over MgSO4the solvent is removed, the residue is separated chromatographically. Get: 768 mg (31%) 7-((4-((2,2-debtorrent[(1][1,3]dioxol-5-yl)amino)- 1,3,5-triazine-2-yl)amino)-3a,9a-dimethyl-1,2,3,3a,9,9a-hexahydrobenzo[b]cyclopent[e][1,4]oxazin-1-ol.

1H (500 MHz, DMSO-d6): 1.30 (s, mn, CH3), 1.37 (s, mn, CH3), 1.85-2.43 (m, 4H, 2CH2), 4.24-4.29 (m, 1H, CH), 4.61 (ush. s, 1H, OH), 6.44 (d, J=8.7Hz, 1H, HAr), 6.68 (s, 1H, HAr), 6.81 (s, 1H, HAr), 7.03 (d, J=8.2Hz, 1H, HAr), 7.07 (d, J=8.7Hz, 1H, HAr), 7.09 (d, J=8.2Hz, 1H, HAr), 7.31 (USS, 1H, NH), 7.48 (USS, 1H, NH), 7.84 (USS, 1H, NH), 8.42 (c, 1H, HAr).

Elemental composition: C(57.13%), H(4.51%), N(17.26%)

8. Getting 7'-((4-((3,3-diversilobum)amino)-1,3,5-triazine-2-yl)amino)Spiro[cyclopropane-1,3'-pyrido[3,4-b][1,4]oxazin]-2'(1'H)-it

Sites 7'-((4-((3,3-diversilobum)amino)-1,3,5-triazine-2-yl)amino)Spiro[cyclopropane-1,3'-pyrido [3,4-b][1,4] oxazin]-2'(1'H)-it is carried out in accordance with scheme I. this uses 7'-chlorpro [cyclopropane-1,3'-pyrido [3,4-b] [1,4] oxazin]-2'(1'H)-she was synthesized according to scheme IX

Synthesis of 7'-((4-chloro-1,3,5-triazine-2-yl)amino)Spiro[cyclopropane-1,3'-pyrido[3,4-b][1,4]oxazin]-2'(1'H)-it

750 mg (5 mmol) of 2,4-dichloro-1,3,5-triazine are dissolved in 5 ml of anhydrous degassed DMF, cooled to -5°C and add 764 mg (4 mmol) of 7'-chlorpro[cyclopropane-1,3'-pyrido[3,4-b][1,4]oxazin]-2'(1'H)-she displaced the more 2 hours at 20°C, then again cooled to -5°C and add 0.9 ml (~5 mmol) of the Foundation of Huning, peremanivat 2 hours at room temperature, and then another 5 hours at 55°C. the Solvent is removed in vacuum (5 mm Hg), the residue is washed with cold water (3×5 ml), isopropanol (2×2 ml), ether (2×5 ml) and dried. Get: 938 mg (77%) of 7'-((4-chloro-1,3,5-triazine-2-yl)amino)Spiro[cyclopropane-1,3"-pyrido[3,4-b][1,4]oxazin]-2'(1'H)-it.

Synthesis of 7'-((4-((3,3-diversilobum)amino)-1,3,5-triazine-2-yl)amino)Spiro[cyclopropane-1,3'-pyrido[3,4-b][1,4]oxazin]-2'(1 N)-it

360 mg (0.12 mmol) obtained in the previous method monochloropropane dissolved in 5 ml of anhydrous degassed DMF, was added 230 mg (0.16 mmol) of the hydrochloride of 3,3-diverticulosisvitamin and 0.6 ml (~0.33 mmol) base Huning and heated in zapasnoy ampoule for 9 hours at 80°C. the Solvent is removed in vacuum (5 mm Hg), the residue is washed with cold water (2×5 ml), dried and share chromatography using as eluent system of chloroform: methanol of increasing polarity. After the standard procedure of processing get: 441 mg (59%) of 7'-((4-((3,3-diversilobum)amino)-1,3,5-triazine-2-yl)amino)Spiro[cyclopropane-1,3'-pyrido[3,4-b][1,4]oxazin]-2'(1'H)-it.

1H (500 MHz, DMSO-d6): 1.76-2.16 (m, 8H, 4CH2), 3.92-4.06 (m, 1H, CH), 7.17 (d, J=2.1Hz, 1H, Hat), 7.62 (USS, 1H, NH), 7.95 (D., J=2.1Hz, 1H, HAr), 8.34 (USS, 1H, NH), 8.5 (s, 1H, HAr).

Elemental composition: C(51.39%), H(4.22%), N(30.12%).

9. Getting 6'-((4-cyclopentylamine-1,3,5-triazine-2-yl)amino)Spiro[cyclopropane-1,2,-pyrazino[2,3-b][1,4]oxazin]-3'(4 M)-it.

Sites 6'-((4-cyclopentylamine-1,3,5-triazine-2-yl)amino)Spiro[cyclopropane-1,2'-pyrazino[2,3-b][1,4]oxazin]-3'(4'H)-it is carried out in accordance with scheme I. this uses 6'-chlorpro[cyclopropane-1,2,-pyrazino[2,3-b][1,4]oxazin]-3'(4'H)-she was synthesized according to scheme XI

Synthesis of 6'-((4-chloro-1,3,5-triazine-2-yl)amino)Spiro[cyclopropane-1,2'-pyrazino[2,3-b][1,4]oxazin]-3'(4 N)-it

660 mg (4.4 mmol) of 2,4-dichloro-1,3,5-triazine are dissolved in 3 ml of anhydrous degassed DMF, cooled to -5°C and add 769 mg (4 mmol) of 6'-chlorpro [cyclopropane-1,2'-pyrazino[2,3-b][1,4]oxazin]-3'(4'H)-she and stirred for 2 hours at 20°C, then cooled to -5°C and added 0.73 ml (4.2 mmol) of the Foundation of Huning, peremanivat 2 hours at room temperature, and then 5 hours at 40°C. the Solvent is removed in vacuum (5 mm Hg), the residue is washed with cold water (2×5 ml), isopropanol (2×5 ml), ether (2×10 ml) and dried. Get: 1.02 g (83%) of 6'-((4-chloro-1,3,5-triazine-2-yl)amino)Spiro[cyclopropane-1,2'-pyrazino[2,3-b][1,4]oxazin]-3'(4'H)-it.

Synthesis of 6'-((4-itapetininga-1,3,5-triazine-2-yl)amino)Spiro[cyclopropane-1,2'-pyrazino[23-b][1,4]oxazin]-3'(4 N)-it

367 mg (1.2 mmol) obtained in the previous method monochloropropane dissolved in 3 ml of anhydrous degassed DMF, add 255 mg (3.0 mmol) of cyclopentylamine and incubated for 8 hours at 90°C. Rastvoritelyami in vacuum (5 mm Hg), the residue is washed with cold water (4×5 ml), dried and share chromatography using as eluent system of chloroform: methanol of increasing polarity. After the standard procedure of processing get: 208 mg (49%) of 6'-((4-cyclopentylamine-1,3,5-triazine-2-yl)amino)Spiro[cyclopropane-1,2'-pyrazino[2,3-b][1,4]oxazin]-3'(4'H)-it.

1H (500 MHz, DMSO-d6): 1.32-1.68 (m, 8H, SN), 1.75-2.07 (m, 4H, SN), 3.75-3.83 (m,1H, CH), 7.78 (USS, 1H, NH), 8.13 (s, 1H, HAr), 8.33 (s, 1H, HAr), 8.37 (USS, 1H, NH), 9.46 (s, 1H, C(O)NH).

Elemental composition: C (54.46%), N (4.21%), N (31.48%)

10. Getting 6-((4-((4-methoxyphenyl)amino)-1,3,5-triazine-2-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-she sulfoxide

To a cooled to 0°C a solution of 409 mg (1 mmol) of starting compound in 50 ml of DMF is added dropwise with vigorous stirring was added a solution of 223 mg (1 mmol) of 77% m-chloroperbenzoic acid and stirred at 0°C for 4 hours. Then the reaction mixture is poured into 300 ml of 3% aqueous solution of NaHCO3. The precipitation is filtered off, washed on the filter with water (5×10 ml) and dried the vacuum. Get: 386 mg (67%) of product.

1H (500 MHz, DMSO-d6): 1.43 (s, 6N, 2CH3), 3.73 (s, 3H, och3), 6.93 (d, J=8.6 Hz, 2H, HAr), 7.14 (doctor J=9.2 Hz, 1H, HAr), 7.41 (doctor J=8.7 Hz, 2H, HAr), 7.43 (doctor J=9.2Hz, 1H, HAr), 7.84 (USS, 1H, NH), 8.16 (USS, 1H, NH), 8.42 (s, 1H, HAr), 9.19 (s, 1H, C(O)NH).

Elemental analysis: C, 53.75%; H, 4.48%; N, 22.83%; S, 6.99%

11. Getting 6-((4-((4-methoxyphenyl)amino)-1,3,5-triazine-2-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-she sulfone monohydrate

To a solution of 409 mg (1 mmol) of starting compound in 20 ml of DMF was added 470 mg (2.1 mmol) of 77% m-chloroperbenzoic acid. The reaction mixture was stirred at 40°C for 4 hours, then poured into 100 ml of 3% aqueous solution of NaHCO3. The precipitation is filtered off, washed on the filter with water (5×10 ml) and dried in vacuum. Get: 238 mg (53%) of product as a monohydrate.

1H (500 MHz, DMSO-d6): 1.7 (s, 6N, CH3), 3.81 (s, 3H, CH3), 6.78 (d, J=7.5 Hz, 1H, CH), 6.93 (d, J=7.5 Hz, 2H, CH), 7.44 (s, 1H, CH), 7.64 (d, J=7.5 Hz, 2H, CH), 8.3 (d, J=7.5 Hz, 1H, CH), 9.43 (USS, 1H, NH), 10.18 (USS, 1H, NH), 11.26 (USS, 1H, NH)

Elemental composition: C, 49.92%; N, 4.52%; N, 21.03%; S, 6.72%

12. Getting prodrugs of the active compounds in the form of esters, amides, N-hydroxymethyl derivatives, O-hydroxymethylpropane, esters of sulfuric or phosphoric acids, methylphosphonates

Synthesis of ethyl 3-((4-((2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxaze the-6-yl)amino)-1,3,5-triazinyl-2-)amino)propionate

A solution of 359 mg (1 mmol) of the original acid was dissolved in 5 ml of anhydrous N-methylpyrrolidone add 2 ml of anhydrous ethanol and 100 mg of ion-exchange resin KU-2-8 and stirred at 50°C for 8 hours. Ion-exchange resin is filtered off, the filtrate is separated, is removed in vacuum, the solvent, the residue is washed on the filter with water (2×5 ml), a saturated solution of NaHCO3(4×5 ml), with water until neutral reaction of the wash water dry. Obtain 221 mg (57%) of ethyl 3-((4-((2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)amino)-1,3,5-triazinyl-2-)amino)propionate.

1H (500 MHz, DMSO-d6): 1.07 (m, J=8.0 Hz, 1H, CH3), 2.62 (s, 6N, CH2), 3.56 (d, J=7.5 Hz, 1H, CH2), 4.01 (d, J=7.5 Hz, 1H, CH2), 7.01 (s, 2H, NH), 7.14 (s, 1H, CH), 7.44 (USS, 1H, CH), 10.18 (USS, 1H, NH), 11.26 (USS, 1H, NH).

Elemental analysis: From: 52.59%, H: 5.39%; N:25.06%.

Synthesis of 4-((4-((2,2-debtor-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)amino)-1,3,5-triazine-2-yl)amino)-2,6-acid of isobutyrate

To a solution of 447 mg (1 mmol) of starting compound in 4 ml of anhydrous N-methylpyrrolidone added 146 mg (1.2 mmol) of 4-dimethylaminopyridine and 125 μl (1.2 mmol) of the acid chloride somaclonal acid. Reaktsionnuyu the mixture was stirred at 25-30°C for 5 hours. The solvent is removed in vacuum, the residue is washed on the filter with water (2×5 ml), a saturated solution of NaHCO3(4×5 ml), water to Nate the social reaction of the wash water dried and separated chromatographically. Get: 403 mg (78%) of 4-((4-((2,2-debtor-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)amino)-1,3,5-triazine-2-yl)amino)-2,6-acid of isobutyrate.

1H (500 MHz, DMSO-d6): 1.19 (s, 6N, CH3), 2.53 (m, 1H, CH), 3.83 (s, 6N, CH3), 6.5 (s, 2H, CH), 6.58 (d, J=7.5 Hz, 1H, CH), 7.14 (d, J=7.5 Hz, 1H, CH), 7.44 (s, 1H, CH), 9.43 (USS, 1H, NH), 10.18 (USS, 1H, NH), 11.26 (USS, 1H, NH).

Elemental analysis: From: 49.98%, H: 4.02%; N: 19.03%.

Synthesis of 4-((4-((2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)amino)-1,3,5-triazinyl-2-yl)amino)-2,6-acid of ethylcarbonate.

To a solution of 439 mg (1 mmol) of starting compound in 4 ml of anhydrous N-methylpyrrolidone added 146 mg (1.2 mmol) of 4-dimethylaminopyridine and 115 μl (1.2 mmol) of ethyl chloroformiate. The reaction mixture was stirred at 25-30°C for 7 hours. The solvent is removed in vacuum, the residue is washed on the filter with water (2×5 ml), a saturated solution of NaHCO3(4×5 ml), water until neutral wash water, dried, dissolved in 25 ml of hot ethanol, the solution is decanted, the solvent is removed and the residue is dried. Get: 353 mg (69%) of 4-((4-((2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)amino)-1,3,5-triazinyl-2-yl)amino)-2,6-acid of ethylcarbonate.

1H (500 MHz, DMSO-d6): J=8 Hz 1.55 (s, 6N, CH3), 3.83 (s, J=7.5 Hz, 6N, CH3), 4.22 (q, J=7.5 Hz, 2H, CH2), 6.47 (s, 2H, CH), 7.14 (s, J=7.5 Hz, 1H, CH), 7.44 (s, 1H, THE N), 9.43 (USS, 1H, NH), 10.18 (USS, 1H, NH), 11.26 (USS, 1H, NH).

Elemental analysis: From: 54.11%, H: 4.89%; N: 21.77%.

Synthesis of 4-((4-((2,2-debtor-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)amino)-1,3,5-triazine-2-yl)amino)-2,6-acid of dimethylcarbamate.

To a solution of 446 mg (1 mmol) of starting compound in 4 ml of anhydrous N-methylpyrrolidone added 146 mg (1.2 mmol) of 4-dimethylaminopyridine and 110 μl (1.2 mmol) of ethyl chloroformiate. The reaction mixture was stirred at 25-30°C for 7 hours. The solvent is removed in vacuum, the residue is washed on the filter with water (2×5 ml), a saturated solution of NaHCO3(4×5 ml), water until neutral wash water, dried and separated chromatographically. Get: 419 mg (81%) of 4-((4-((2,2-debtor-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)amino)-1,3,5-triazine-2-yl)amino)-2,6-acid of dimethylcarbamate.

1H (500 MHz, DMSO-d6): 3.27 (s, 6N, CH3), 3.83 (s, 6N, CH3), 6.47 (s, 2H, CH), 7.02 (d, J=7.5 Hz, 1H, CH), 7.3 (s, 1H, CH), 7.39 (d, J=7.5 Hz, 1H, CH), 7.44 (s, 1H, CH), 9.43 (ush. s, 1H, NH), 9.43 (USS, 1H, NH), 10.66 (USS, 1H, NH)

Elemental analysis: From: 49.90%, N: 4.01%; N: 18.83%.

Synthesis of 2,2-debtor-4-(hydroxymethyl)-6-((4-((3-methoxy-4,5-methylendioxyphenyl-5)amino)-1,3,5-triazine-2-yl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-it

To a solution of 444 mg (1 mmol) of starting compound in 12 ml of anhydrous dioxane, was added 100 mg of potash and 92 μl (1.2 mmol) of 36% aqueous races is the thief of formaldehyde. The reaction mixture was stirred at room temperature for 6 hours, add 100 ml of ethyl acetate and the resulting solution washed with water (4×30 ml), the solvent is removed and the residue is dried. Get 346 mg (73%) of 2,2-debtor-4-(hydroxymethyl)-6-((4-((3-methoxy-4,5-methylendioxyphenyl-5)amino)-1,3,5-triazine-2-yl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-it contains according to HPLC ~6% of isomeric products.

1H (500 MHz, DMSO-d6): 3.83 (s, 3H, CH3), 4.12 (ush. s, 1H, OH), 5.62 (s, 2H, CH2), 6.07 (s, 2H, CH2), 6.5 (s, 2H, CH), 6.89 (s, 1H, CH), 6.97 (d, J=7.5 Hz, 1H, CH), 7.44 (s, 1H, CH), 7.53 (d, J=7.5 Hz, 1H, CH), 9.43 (ush. s, 1H, NH), 9.84 (ush. s, 1H, NH)

Elemental analysis: From: 50.69%, N: 3.42%; F: 7.97%, N: 17.83%.

Synthesis of 7-((4-((2,2-debtor-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)amino)-1,3,5-triazine-2-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl of hydrosulfate

To a solution of 890 mg (2 mmol) of starting compound in a mixture of 8 ml of a mixture of anhydrous pyridine and DMF (1:2 vol./about.) give 333 mg (2.2 mmol) of a complex of sulfur trioxide with DMF. The reaction mixture was stirred for 12 hours at room temperature, the solvents are removed in vacuo at a temperature not exceeding 30°C. the Residue is transferred to a filter and washed with diethyl ether (5×8 ml) and dried. Get:956 mg (91%) of 7-((4-((2,2-debtor-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)amino)-1,3,5-triazine-2-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl of hydrosulfate.

1H (500MHz, DMSO-d6): 4.28 (t, J=7.1 Hz, 2H, CH2), 4.32 (t, J=7.1 Hz, 2H, CH2), 6.35 (s, 1H, CH), 6.38 (s, 1H, CH), 7.44 (s, 1H, CH), 7.77 (d, J=7.5 Hz, 1H, CH), 8.47 (s, 1H, NH), 8.52 (d, J=7.5 Hz, 1H, CH), 9.43 (s, 1H, NH), 10.56 (s, 1H, NH)

Elemental analysis: From: 40.36%, H: 2.41%; F: 7.17%, N:17.06%.

Synthesis of 4-((4-((2,2-debtor-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)amino)-1,3,5-triazine-2-yl)amino)-2,6-acid phosphate in the form of MES

To a solution of 446 mg (1 mmol) of starting compound in 4 ml of anhydrous N-methylpyrrolidone added 146 mg (1.2 mmol) of 4-dimethylaminopyridine and 346 mg (1.2 mmol) of dibenzoylmorphine. The reaction mixture was stirred at 25-30°C for 7 hours. The solvent is removed in vacuum, the residue is dissolved in 100 ml ethyl acetate, washed with water (2×30 ml) and dried. The solvent is removed in vacuum, the residue is dissolved in ethanol. To the resulting solution was added 300 mg of 10% Pd/C and stirred under hydrogen atmosphere for 8 hours. The catalyst is filtered off, the filtrate is evaporated. Get: 353 mg (67%) of 4-((4-((2,2-debtor-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)amino)-1,3,5-triazine-2-yl)amino)-2,6-acid phosphate in the form of MES.

1H (500 MHz, DMSO-d6): 1.06 (t, J=7.2 Hz, 3H, CH3-EtOH), 3.44 (q, J=7.2 Hz, 2H, CH2-EtOH), 3.83 (s, 6N, CH3), 4.63 (s, 1H, HE-EtOH), 4.8 (USS, 1H, OH), 6.51 (s, 2H, CH), 7.44 (s, 1H, CH), 7.77 (d, J=7.5 Hz, 1H, CH), 8.47 (USS, 1H, NH), 8.52 (d, J=7.5 Hz, 1H, CH), 9.43 (USS, 1H, NH), 10.56 (USS, 1H, NH).

Elemental analysis: From: 41.1, H: 3.84; F: 6.67, N:17.01.

Synthesis of (4-((4-((2,2-debtor-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)amino)-1,3,5-triazine-2-yl)amino)-2,6-dimethoxyphenoxy)acetate

To a solution of 446 mg (1 mmol) of starting compound in 5 ml of anhydrous DMF was added 276 mg (2 mmol) of anhydrous svejeporublennogo potash and 184 mg (1.2 mmol) of Bromeliaceae. The reaction mixture was stirred at 0°C for 10 hours, then poured into 20 ml of water. Extracted with ethyl acetate (2×50 ml), the combined organic phases washed with water (3×50 ml), dried over Na2SO4the solvent is removed, the residue is dried in vacuum. Get: 454 mg (90%) (4-((4-((2,2-debtor-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)amino)-1,3,5-triazine-2-yl)amino)-2,6-dimethoxyphenoxy)acetate.

1H (500 MHz, DMSO-d6): 2.19 (s, 3H, CH3), 3.83 (s, 6H, CH3), 6.5 (s, 2H, CH), 6.73 (s, 2H, CH2), 7.02 (d, J=7.5 Hz, 1H, CH), 7.3 (c, 1H, CH), 7.39 (d, J=7.5 Hz, 1H, CH), 7.44 (c, 1H, CH), 9.43 (c, 1H, NH), 9.43 (c, 1H, NH), 10.66 (c, 1H, NH)

Elemental analysis: From: 51.06%, H: 3.91%; F: 7.28%, N: 16.07%.

Synthesis of N-(4-((2,2-diethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)amino)-1,3,5-triazine-2-yl)-N-(3,4,5-trimethoxyphenyl)ndimethylacetamide

To a solution of 481 mg (1 mmol) of starting compound in 5 ml of anhydrous degassed DMF in an argon atmosphere is added 122 mg (1 mmol) of N,N-dimethylaminopyridine and 0.7 ml (1.1 mmol) of acetylchloride. The reaction mixture is stirred is at 50°C in an inert atmosphere for 8 hours. The solvent is removed in vacuum, the residue is dissolved in 150 ml of chloroform, washed with a saturated solution of NaHCO3(2×25 ml), water (3×25 ml), dried, the solvent is removed, the residue is separated chromatographically. Get: 351 mg (67%) of N-(4-((2,2-diethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)amino)-1,3,5-triazine-2-yl)-N-(3,4,5-trimethoxyphenyl)ndimethylacetamide.

1H (500 MHz, DMSO-d6): 0.69 (t, J=8.0 Hz, 6N, CH3), 1.93 (q, J=8.0 Hz, 4H, CH2), 2.07 (s, J=7.8 Hz, 3H, CH3), 3.71 (s, 3H, CH3), 3.83 (s, 6N, CH3), 6.5 (s, 2H, CH), 7.61 (d, J=7.5 Hz, 1H, CH), 7.91 (s, 1H, CH), 8.2 (d, J=7.5 Hz, 1H, CH), 9.43 (USS, 1H, NH), 11.26 (USS, 1H, NH)

Elemental analysis: From: 57.30%, H: 5.54%; N: 18.62%.

Synthesis of 7-((4-((4-(1-acetylpiperidine-4-yl)phenyl)amino)-1,3,5-triazine-2-yl)amino)-3,3-dimethyl-3,4-dihydro-1,8-naphthiridine-2(1H)-it

To a solution of 444 mg (1 mmol) of starting compound in 10 ml of pyridine, cooled to 0°C, was added to 0.14 ml of acetic anhydride, and stirred at room temperature for 8 hours. The reaction mixture is poured into 200 ml of water, extracted with ethyl acetate (3×100 ml). The organic fractions combined, washed with saturated solution of NaHCO3(2×25 ml), water (2×25 ml), the solvent is removed, the residue is dried in vacuum. Get: 450 mg (93%) of 7-((4-((4-(1-acetylpiperidine-4-yl)phenyl)amino)-1,3,5-triazine-2-yl)amino)-3,3-dimethyl-3,4-dihydro-1,8-naphthiridine-2(1H)-it.

1H (500 MHz, DMSO-d6): 1.34 (s, 6N, CH3), 1.63-1.89 m, 4H, CH2), 2.1 (s, 3H, CH3), 2.65-2.72 (m, 1H, CH), 2.71 (s, 2H, CH2), 3.5-3.6 (m, 4H, CH2), 6.34 (d, J=7.5 Hz, 1H, CH), 7.06 (s, 2H, CH), 7.38 (s, 2H, CH), 7.42 (d, J=7.5 Hz, 1H, CH), 7.44 (s, 1H, CH), 9.43 (USS, 1H, NH), 10.18 (USS, 1H, NH), 11.26 (USS, 1H, NH)

Elemental analysis: From: 64.15%, H: 6.24%; N:22.89%.

13. Characterization of the biological activity of compounds

The biological activity of the compounds that are the subject of the present invention was studied by different methods. For example, it was investigated the inhibition of the kinase activity of these compounds. Some compounds showed significant inhibitory activity at nanomolar concentrations against the kinase SYK. Also some compound showed significant antiproliferative activity on cells of non-Hodgkin's lymphoma Daudi, NAMALVA, RN. P3HR-1. Raji (sensitive to inhibition of SYK kinase) in concentrations of 10-10000 nm. In addition, a number of soedinenii which is the subject of the present invention showed high activity in cell models of rheumatoid arthritis. The effectiveness of inhibitors of Syk kinase was investigated by determining the inhibition of cytokine production by differentiated monocytes and has been shown that chemical compounds that are the subject of the present invention, showed inhibitory ability in relation to the production of cytokines differentiated mo what acetami (cell line TNR-1) with values IS 0.1-100 microns.

Illustrative examples of compounds having a high inhibitory and antiproliferative activity below

13.1. Inhibition of kinases

For compounds that are the subject of this invention were studied for their ability to inhibit the kinase of interest for the treatment of allergic, autoimmune, cancer, and other chronic inflammatory diseases. The list of kinases, inhibition of which were studied in accordance with the described method include, (but is not limited in principle) ALK kinase, JAK2, skin disease, MET, TIE-2, FLT3, ABL, LCK, LYN, SRC, FYN, SYK, ZAP70, ITK, TEC, CPD, EGFR, ERB2, PDGFRa, PDGFRb, KFR, IGF-1R, FLT1, TECH, ACT, ROS, EPHA1, and their mutant forms, including giving resistance to existing therapies of autoimmune, inflammatory diseases and cancer.

Kinase, in the form of the kinase domain or the full-size protein coupled to glutathione-S-transferase (GST) or poly-his-tag fragments, expressibility in infected with a baculovirus cells n the Contracting out (for example, Sf21) or in E. coli cells. After separation from cells proteins were purified to almost complete homogeneity using affinity chromatography by known methods (Lehr, R.V. et. al., Gene, 1996, 169, 275-9; Gish, G. et. al., Protein Eng, 1995, 8, 609-14). In some cases kinase Ko expressibility or mixed with purified or partially purified regulatory polypeptides prior to activity measurement.

Activity and inhibition of kinases was determined in accordance with known protocols (Braunwaler, A.F. et. al., Anal Biochem, 1996, 234, 23-6). Measure the enzymatic activity was speed transfer labeled33PO4with ATF synthetic substrate poly(Glu, Tyr) 4:1, attached to the bioactive surface of the microtiter substrate. At the end of the incubation period (120 min) substrate was washed with 0.5% phosphoric acid, was added to the liquid scintillant, and on the basis of counting the number of scintillations in liquid scintillation detector was determined by the number of transferred phosphate. IC50corresponded to the concentration of the substance which reduces by 50% the number of33P transferred to the substrate associated with the substrate.

To determine the inhibition of kinases can be used and other methods based on measuring the degree of transfer of the phosphate to a peptide or polypeptide containing tyrosine, series or threonine present in rastvoreno is or immobilized form.

Compounds described in this invention have nanomolar or micromolar values IC50against various kinases, including SYK, ZAP-70, JAK1 JAK2, JAK3, CPD, TYK1 and LYN. Also the compounds described in this invention are selective, and in concentrations up to 1000 nm significantly inhibit these kinases, as ABL, ACT2, AURA, AURC, AXL, CDK2, STK, FAK, IGF1R, IR, IRR, ITK, mTOR, MUSK, RCA, θ, RON, SRC, TYRO3.

Below is a list of compounds inhibiting SYK kinase with values IC50less than 100 nm

The list of compounds inhibiting SYK kinase with values IC50less than 10 microns

The list of compounds inhibiting ZAP-70 with the values of the IC50less than 10 microns

The list of compounds inhibiting JAK3 and CPD kinase with values IC50less than 10 microns

img src="https://img.russianpatents.com/1163/11636233-s.jpg" height="21" width="145" />

The list of compounds inhibiting JAK1 and JAK2 kinase with the values IC50less than 10 microns

The list of compounds inhibiting TYK1 kinase with values IC50less than 10 microns

The list of compounds inhibiting LYN kinase with values IC50less than 10 microns

13.2. Experiments with cell cultures

Compounds that are the subject of the present invention to inhibit aberrant activity and proliferatio cells of the immune system and, thus, can be applied for the treatment of inflammatory, autoimmune, cancer and other diseases.

Cellular methods for determining the effectiveness of suppression abberant activity of cells of the immune system are well known and can be used for comparative characteristics of the compounds described in this invention. According to modern concepts the development of many autoimmune diseases is associated with activation of BP is in terms of the immune system by external agents of different nature with subsequent preservation of self-sustaining autoimmune reactions. Among the antigens that cause an autoimmune response, isolated Fc fragments of immunoglobulin G (IgG), which along with other antigens lead to the activation of immune cells and release of cytokines, leading in turn to the development of autoimmune diseases. Study of the mechanism of activation of cells of the immune system showed that the distribution of the signal goes through Fc receptors located on the surface of macrophages and neutrophils. The impact on these receptors leads to the production of cytokines that are important for the start and spread of the disease. Syk-kinase is preceptory receptor and is involved in the signal transmission antigen and Fc receptors. To evaluate the effectiveness of inhibitors of Syk kinase can be used in different in vitro models, in particular models based on the stimulation of the FcγR receptors located on the surface of macrophages.

Below is an example of determining the activity of compounds in cell models of autoimmune diseases. In this experiment, the methodology is based on the stimulation of macrophages immunoglobulin IgG, and subsequent determination of the intensity of the release of cytokines. The method of determining the inhibition of signaling pathways FcγR receptors of macrophages, obtained by differentiation of monocytes, as described in (Braselmann, S., et al., J Pharmacol Exp Ther, 2006. 319, 998-1008) and Pat is the (WO 2004/014382 A1). Cell line THP-1 are incubated in culture medium RPMI 1640 (5% CO2humidified atmosphere, at 37°C). For induction of differentiation TNR-1 in macrophages cells exposed to IFN-γ for 6 days. 96-well tablets are covered by the joint human IgG, and kept overnight at 4°C or for 1 hour at 37°C. to assess background stimulation of cells with a portion of the wells as a negative control cover fragments of antibodies, F(ab')2. Unbound antibodies are removed by using sodium phosphate buffer. Each hole is made and a solution of the compound to a final concentration of 0.01-50 μm and cells differentiated macrophages in culture medium. Each concentration of the drugs examined in 3 Parallels. Cells are incubated at 37°C, after which the supernatant determine the concentration of TNFα.

Illustrative examples of compounds with activity values (EC500.1-100 ám). in in vitro to suppress abberant activity of cells of the immune system, below

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In General, the experiments to determine cell proliferation and the number of viable cells provide the detected signal is proportional to the number of metabolically active cells. Antitumor activity of compounds can be determined using any of the features, reflecting a reduction in the metabolic activity of the cells after exposure to compounds. Traditionally used methods, in which a measure of viable cells perform the integrity of the membrane (for example, analysis of the elimination Trypanosoma blue) and DNA synthesis (e.g., determination of BrdU incorporation, or3H-thymidine).

In some methods for determination of cell proliferation are used reagents, which are in turn detected compounds during cell proliferation. The preferred reagents for this determination are the salt of tetrazole, including, for example, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy)-2-(4-sulfophenyl)-2H-tetrazole), XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazole-5-carboxanilide), INT (2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyl, tetrazolyl), NBT (2N-Tetrazole, 2,2'-(3,3'-dimethoxy[1,1'-biphenyl]-4,4'-diyl)bis[3-(4-nitrophen is)-5-phenyl, dichloride) (Bernas, T. et. al., Biochim Biophys Acta, 1999, 1451, 73-81). To determine cell proliferation carry out the measurement of the amount of the product of the enzymatic conversion of salts of tetrazole in blue derivative formazan, which can be easily detected by spectroscopic methods (Mosmann, T., J Immunol Methods 1983, 65, 55 to 63).

In General, the preferred methods for the determination of cell proliferation include incubation of the cells in the growth medium in the presence of a test substance or without him. Growth conditions for a variety of prokaryotic and eukaryotic cells is described (Ausubel et al. Current Protocols in Molecular Biology. Wiley and Sons. 1999; Bonifacio et al. Current Protocols in Cell Biology. Wiley and Sons. 1999). To determine cell proliferation after incubation they added salt tetrazole and then determined the amount of the formed formazan. The number of the resulting derivatives formazan is determined by the optical density of treated cells.

To determine the antiproliferative activity of the compounds can be used cancer cell lines, such as Daudi, NAMALVA, RN, P3HR-1, Raji (non-Hodgkin's lymphoma), COLO 205, DLD-1, HCT-15, NT (colon cancer); HEP G2 (hepatoma); K-562 (leukemia); A, NCI-N, NCI-H2228, NCI-H3122 (lung cancer); Karpas-299, SU-DHL-1 (lymphoma); MCF7, MDA-MB-231 (breast cancer); SAOS-2 (osteosarcoma); OVCAR-3 (ovarian cancer); PANC-1 (pancreatic cancer); DU-145, PC-3 (prostate cancer); ACHN CAKI-1 (kidney cancer); MG-63 (sarcoma).

Although to determine the antiproliferative activity of the compounds preferably are mammalian cells, for this purpose can also be used in cells of lower eukaryotes, such as yeast. Preferably the use of cell lines of human, rats, mice, rabbits, lower monkeys, hamsters and Guinea pigs, as cell lines of these organisms is the most well studied and fully characterized.

Below is an example of determining the activity of compounds in cell models of cancer. In this experiment, the methodology of measurement of cytotoxicity of compounds based on measuring the activity of cellular dehydrogenases optical densities repeatedly described in the scientific literature and is the standard definition of cytotoxicity. The biochemical process underlying the method is to restore yellow bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-tetrazole (MTT) into an insoluble purple-blue intracellular crystals of MTT-formazan (MTT-f) under the action of dehydrogenases, localized in the mitochondria. Nonviable dead cells, this ability does not possess. The intensity of the conversion of MTT to MTT-f reflects the overall level of dehydrogenase activity of the investigated cells and modulates the activity involves what's enzyme systems, for example, the respiratory chain electron transfer, etc. the Activity of dehydrogenases reduced on most late stages of cell death, so the method is suitable for screening of cytotoxicity and toxic, and toxic compounds.

The weighed sample was dissolved in dimethyl sulfoxide to a final concentration of 10 mm. From these solutions prepared by dilution of each drug in the medium for cultivation.

Cell non-Hodgkin lymphoma (cell line Raji, NAMALVA, Daudi, RN, RN-1) inoculated in 96-well plates. In wells add investigational drugs to target concentrations of 0.01-50 μm. In the control wells add culture medium. Each concentration of the drugs examined in three Parallels. Cells are incubated at 37°C, 5% CO2in moistened atmosphere, and then the wells contribute MTT solution, incubated in CO2-incubator, resulting formazan dissolved in dimethyl sulfoxide and measure the optical density at a wavelength of 540 nm. The optical density in the wells without test compound is taken as 100% survival. The optical density in the wells with the test compound characterized by the percentage inhibition of cell proliferation.

Illustrative examples of compounds with activity values (IC5010-10000 nm) in vitro to suppress abberant cell proliferation nehodgkinski l is mpoma.

14. Experiments in animal models

Compounds that are the subject of the present invention to inhibit aberrant activity and proliferatio cells of the immune system and, thus, can be applied for the treatment of inflammatory, autoimmune, cancer and other diseases.

In vivo models to determine the efficiency of chemical compounds in the treatment of various autoimmune diseases is well known and can be used for comparative characteristics of the compounds described in this invention. Below is an example of determining the activity of compounds in the in vivo model of adjuvant arthritis in rats (chronic immune inflammation).

Chronic immune inflammation in rats (preferably the Lewis rats aged 6-7 weeks) cause subplanetary the introduction of the right hind paw with 0.1 ml of complete adjuvant's adjuvant (PAF). Evaluate secondary immunological reaction (swelling of the left paw). The measurement of the volume of the paws and the introduction of the investigated substances nachinat 14 days (after involvement in especially process of the contralateral paw). The compounds administered intragastrically twice a day for 11 days at concentrations of 30, 60 and 100 milligrams per kilogram of weight of the animals. The first assessment of the effects of substances carried out 24 hours after the first intragastric administration, the last measurement volume feet spend on the 25th day of the experiment (24 hours after the last injection of substances) and on the 27th day (2 days after termination of the introduction). The effect of therapeutic effects of the compounds under study is assessed according to the degree of inhibition of the inflammatory response and prevention of bone destruction in comparison with the control group not receiving treatment. To assess the damage dice from each animal used the following scale: 1. Pathological setting of nail phalanges; 2. The presence of soft tissue swelling; 3. The presence of friendly defeat limb; 4. The presence of subchondral sclerosis; 5 deformation of the metatarsal bones; 6. The narrowing of the joint space of the proximal joints; 7. The narrowing of the joint space of the distal joints; 8. The presence of specific signs of rheumatoid polyarthritis (rheumatoid nodules). For analysis the data obtained were ranked depending on the significance of the sign in the pathogenesis.

Illustrative examples of compounds with activity in vivo therapeutic dose of 60 mg/kg or more to suppress the inflammatory reaction is the destruction of bone tissue in a model of adjuvant arthritis in rats are presented below. These connections allow to completely prevent friendly defeat limbs and other more serious joint damage. The average assessment of the damage dice for the group of 20 rats receiving treatment was less than 2.5, and for a group of 20 rats not treated with drugs was more than 7.

Compounds that are the subject of this invention, showed antiproliferative activity in cell experiments, then studied in vivo in mammals. Typically, in vivo experiments were conducted on rodents, such as mice and rats.

Cell line nakhodkinskoj lymphoma (Raji, NAMALVA, Daudi, RN, RN-1) in number 5*106cells in serum-free medium were injected subcutaneously into the right flank of the Nude Nude mice (NCr) by the age of 3-4 weeks. Upon reaching the tumor volume ~200 mm3the mice were divided into 2 groups: control and treatment. Mice of the control group with oral probe was injected with 0.3 ml of 0.5% solution of methylcellulose in water, mice therapeutic groups - 0.3 ml of 0.5% solution of methylcellulose in which was suspended a therapeutic substance. Tumor volume (mm3) was calculated on the trail of the soup to the formula: V=L×W2×0.5, and where L is the length of the tumor in mm, W - Sirina in mm To determine the effectiveness of inhibition of tumor growth after treatment (20 days) was calculated the ratio of medium volume to terapevticheskii/control groups (% T/C). For the obtained data was analyzed statistical significance using the Dunnet test. Examples of compounds with high activity (% T/C<40) in a therapeutic dose of 50 mg/kg, below

15. Examples of the pharmaceutical composition

Substances described in this invention can be used for the prevention and treatment of human diseases in the form of the following compositions (by "Substance" is understood as the active ingredient):

12.1. Tablet Img tablet
Substance50
Lactose Ph. Eur223.75
Croscarmellose sodium6.0
Corn starch15
Polivinilpirolidon (5% w/v paste)2.25
Magnesium stearate3.0
12.2. Tablet IImg tablet
Substance200
Lactose Ph. Eur182.75
Croscarmellose sodium12.0
Corn starch (5% w/v paste)2.25
Magnesium stearate3.0
12.3 Tablet IIImg tablet
Substance1.0
Lactose Ph. Eur93.25
Croscarmellose sodium4.0
Corn starch (5% w/v paste)0.75
Magnesium stearate1.0-76
12.4. Capsulemg/capsule
Substance10
Lactose Ph. EurMagnesia1.5
14.5. The composition for injection I(50 mg/ml)
Substance5.0% w/v
1M sodium hydroxide solution15.0% w/v

1M hydrochloric acid to pH 7.6

The polyethylene glycol 4004.5% w/v

Water for injection to 100%

12.6. The composition for injection II(10 mg/ml)
Substance1.0% w/v
Sodium phosphate BP3.6% w/v
M solution of sodium hydroxide15.0% w/v

Water for injection to 100%

12.7. The composition for injection III(1 mg/ml, buffered to pH 6)
Substance0.1% w/v
Sodium phosphate BP2.26% w/v
Citric acid 0.38% w/v
The polyethylene glycol 4003.5% w/v
12.8. Aerosol Img/ml
Substance10
Trioleate sorbitan13.5
Trichlorofluoromethane910.0
DICHLORODIFLUOROMETHANE490.0
12.9. Aerosol IImg/ml
Substance0.2
Trioleate sorbitan0.27
Trichlorofluoromethane70.0
DICHLORODIFLUOROMETHANE280.0
Dichlorotetrafluoroethane1094.0
12.10.Aerosol III mg/ml
Substance2.5
Trioleate sorbitan3.38
Trichlorofluoromethane67.5
DICHLORODIFLUOROMETHANE 1086.0
Dichlorotetrafluoroethane191.6
12.11.Aerosol IV mg/ml
Substance2.5
Soy lecithin2.7
Trichlorofluoromethane67.5
DICHLORODIFLUOROMETHANE1086.0
Dichlorotetrafluoroethane191.6
12.12.Ointment ml
Substance40 mg
Ethanol300 l
Water300 l
1-dodecylcyclobutanone50 l
Propylene glycolto 1 ml

Note: these compounds may be prepared in accordance with standard pharmaceutical techniques. Tablets (1)-(3) may be enteric-coated membrane using, for example, phthalate cellulose acetate. Aerosol formulations (8)-(11) can be used in acetoneiso standard dispensers; as a suspending agent instead of trioleate sorbitan and soya lecithin may be used monooleate sorbitan, polyolef sorbitan, Polysorbate 80, of the polyglycerol oleate or oleic acid.

1. A derivative of 2,4-diamino-1,3,5-triazine - General formula I, or its pharmaceutically acceptable salt, hydrate or pharmaceutically acceptable ester, hydrolisis in vivo ÷

where:
Y represents CH2, CHR', O, S, S(O) or S(O)2,
X1X2X3are selected independently from the groups CH or N,
R1represents a C1-8aliphatic group3-8cycloalkyl,6-10aryl, ethylene-dioksifenil, methylenedioxyphenyl, pyridyl, each of which is optimally substituted by one or more identical or different groups R”,
R' represents hydrogen, HE, halogen, such as F, Cl, Br, I, or carboxyl or carboxamide optimal N-substituted (C1-6)alkyl, or cyano, or halo(C1-8)alkyl, (C1-8)alkoxy, piperidinyl, timeline replaced by stands,
R” represents a
R' or RD
R21, R22, R23, R24are selected independently from the group F, Cl, Br, I, CN, (C1-16)alkyl, additionally, R21and R22or/and R23and R24can be combined to represent one oxo (=O) group or, together with at the IOM carbon to form spirits containing from 3 to 7 carbon atoms, additionally, R21and R24can work together with the two carbon atoms to form an aliphatic or aromatic cycle, containing from 4 to 8 atoms, optionally substituted by one or more groups R',
RDrepresents an oxo group =O or =s

2. The derivative according to claim 1, where X2and X3represent CH.

3. The derivative according to claim 1, where Y represents O.

4. The derivative according to claim 1, where R1represents phenyl, optimally substituted by one or more identical or different groups R'.

5. The derivative according to claim 4, where R1is a 3,4,5-trimetoksi phenyl.

6. The derivative according to claim 1, where X1represents N, R21, R22represents-CH3, R23, R24United and are one oxo (=O) group.

7. The derivative according to claim 1, where X1represents CH, R21, R22represents-F, R23, R24United and are one oxo (=O) group.

8. Derivative according to any one of claims 1 to 7, with efficiency in the inhibition of SYK, ZAP-70, JAK1 JAK2, JAK3, BTK, TYK1 and LYN kinases.

9. The use of derivatives according to any one of claims 1 to 7 for the treatment of diseases caused by aberrant activity of protein kinases SYK, ZAP-70, JAK1, JAK2, JAK3, CPD, TYK1 and LYN.

10. The use of derivatives according to any one of claims 1 to 7 in the treatment of autoimmune or cancer-related disease is evani.

11. The use of chemical compounds according to any one of claims 1 to 7 for the treatment of rheumatoid arthritis and non-Hodgkin's lymphoma.

12. Pharmaceutical composition for treating autoimmune diseases and cancer, characterized in that it contains an effective amount of a derivative according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to item 12, suitable for the treatment of rheumatoid arthritis and non-Hodgkin's lymphoma.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted 7,8-dicyanopyrimido[2,1-b][1,3]benzothiazoles of general formula (I)

where a R=CH3, R1=C6H5; b R=CH3, R1=4-CH3OC6H4; c R=CH3, R1=2-thienyl; d R=C6H5, R1=4-CH3OC6H4. The method is carried out by reacting 4-bromo-5-nitrophthalonitrile with esters of 2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acids in the presence of triethylamine, which is used as a deprotonating agent. The reaction takes place at temperature of 18…35°C and molar ratio of reactants (1):(2):(TEA)=1:1:2, for 12-30 hours in dimethylformamide solution. Further, the reaction mass is diluted with water, the water being in tenfold excess, at temperature T=0…25°C; the tarry residue released is decanted from the aqueous layer and recrystallised from alcohol; the precipitate of the end product is filtered and dried on air.

EFFECT: synthesis of compounds which are used as precursors for producing phthalocyanines.

1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I, including stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof: where Z1 is CR1; Z2 is CR2; Z3 is CR3 or N; Z4 is CR4 or N; where (i) X1 is N and X2 is S or (iv) X1 is S and X2 is CR7; R1, R2, R3, R4 and R7 are independently selected from H, F, Cl, Br, I, -CN, -CH2OR10, -(C1-C12 alkylene)NR10R11, -(C1-C12 alkylene)NR12C(=O)R10, -CO2R10, -C(=O)N(R10)OR11, -NR10R11, -C(=O)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10C(=O)OR11, -C(=O)NR10(C1-C12 alkylene)NR10C(=O)R11, -C(=O)NR10(C1-C12 alkylene)R11, -C(=O)NR10(C1-C12 alkylene)R10, -C(=NR10)NR10R11, -NR12C(=O)R10, -NR12C(=O)OR11, -NR12C(-O)NR10R11, -NR12C(=O)(C1-C12 alkylene)NR10R11, NR12(C=O)C1-C12 alkylene)NR11(C=O)R12, -C≡CR10, C1-C20 heteroaryl, said heteroaryl being an unsaturated carbocyclic residue containing 5-6 ring atoms, where 1-4 ring atoms are nitrogen atoms, and phenyl, where the heteroaryl and phenyl are optionally substituted with one or two groups selected from -CH2OH, -(CH2)2OH, -CH2CO2H, -CN, -CH2NH2, -(CH2)2N(CH3)2, -CH3, -CO2H, -CH2CO2CH3, -NH2 and -S(O)2CH3; A is selected from -C(=O)NR5R6, -C(=S)NR5R6, phenyl and C1-C20 heteroaryl, said heteroaryl being an unsaturated carbocyclic residue containing 5-10 ring atoms, 1-4 of which are heteroatoms selected from nitrogen, oxygen or sulphur, C1-C20 heteroaryl and phenyl are optionally substituted with one or three groups independently selected from C1-C12 alkyl, -(C1-C12 alkylene)NR10R11, -CH3, oxo, -CO2CH3, -NH2, 1-methylpiperid-4-yl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, benzoimidazolyl, benzyl and phenyl, where the alkyl, benzoimidazolyl and phenyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CF3, -CH2OH, -CH3, -C(=O)NHCH3, -NH2, -OH, -OCH3, -CH2OCH3, -C(=O)N(CH3)2, -N(CH3)2, -C(CH3)2OH, -CH(CH3)2, -CH2(1H-1,2,4-triazol-5-yl) and C(=O)4-methylpiperazin-1-yl; R5 is selected from C1-C12 alkyl, optionally substituted with one group independently selected -NH2, -NHCOCH3 and -OH; R6 is selected from pyridinyl and phenyl, each optionally substituted with one or two groups independently selected from F, Cl, Br, I, -CN, -CF3, -C(=O)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10R11 and -C(=O)NR10R11; R10, R11 and R12 are independently selected from H, C1-C12 alkyl, C1-C12 alkylene-phenyl, cyclopentyl, pyridinyl and imidazolyl, where C1-C12 alkyl, cyclopentyl are optionally substituted with one or two groups independently selected from -CH2OH, -N(CH3)2, -NHCOCH3, -OH and -S(O)2CH3; or R10 and R11 together with a nitrogen atom to which they are bonded form a C5-C6 heterocyclic ring containing one or two heteroatoms selected from nitrogen and oxygen, or pyrazolyl, optionally substituted with one or two groups independently selected -CH3, -NH2, -N(CH3)2; -OH and oxo. The invention also relates to a pharmaceutical composition having PI3K inhibiting activity based on said compounds.

EFFECT: obtaining novel compounds which can be used in medicine for treating cancer.

25 cl, 5 dwg, 2 tbl, 331 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to new compounds represented with common formula (I) to its pharmaceutically acceptable salts that have inhibiting activity in relation to products of amyloid β-protein (Aβ42) or decomposition with ferment of beta-site of amyloid-β (BACE1) precursor. In general formula , circle A represents aryl chosen from phenyl, which can be replaced with substitutes with number of 1 to 3, which have been chosen from a group of substitutes α, 5-6-membered heteroalkyl with sulphur atom as heteroatom that can have 1 to 3 substitutes chosen from a group of substitutes α, or 9-10-membered benzo-condensed heterocyclic group having 2 atoms of oxygen in heterocyclic part of the above group, which can be replaced with substitutes with number of 1 to 3, which have been chosen from the group of substitutes α, L means ordinary bond, -NRLCO- (in which RL means hydrogen atom) or -NRLCO-C1-6alkyl (in which RL means hydrogen atom). Circle B represents 5-6-membered heteroaryl or saturated heterocyclic group with 1-3 heteroatoms in a cycle, which have been chosen from a group of hydrogen, oxygen or sulphur atoms, each of which can have 1 to 3 substitutes chosen from the group of substitutes α, or 9-10-membered benzo-condensed group having 2 oxygen atoms in heterocyclic part of the above group, X means methylene that can have 1 to 2 substitutes chosen from the group of substitutes α, Y means methylene that can have 1 to 2 substitutes chosen from the group of substitutes α, and Z means oxygen atom. The rest substitutes are specified in the claim.

EFFECT: compounds can be used for treatment of neurodegenerative diseases caused with Aβ presented with Alzheimer disease as a typical case.

9 cl, 13 dwg, 12 tbl, 88 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzodiazepine compounds of general formula , wherein each R1, R2, R3 and R4 independently represent hydrogen or alkyl, or R2 and R3 together represent lower alkylene; A1 is lower alkylene optionally substituted by hydroxy; and R5 is a fragment of formula , wherein each R6 and R7 independently represents hydrogen, lower alkyl, cycloalkyl, phenyl, furyl, thienyl, pyrazolyl, etc.; each XA and XB independently represents a bond, lower alkylene, -CO-, -SO2- etc., a pharmaceutical composition containing them, and using the above compound as the pharmaceutical composition or for preparing the same.

EFFECT: new compounds may be used for preventing and treating cardiac arrhythmia.

8 cl, 1047 ex, 78 tbl

Iap inhibitors // 2491276

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula: U1-M-U2, where U1 and U2 have general formula (I), where: G stands for: IVb IVd ive, and values M, X1, X2, R2, R3, R3', R4, R4', R5, R5', R6, R6', R7, Z7, Z2, Z3, Z4, Q2 are given in item 1 of the formula.

EFFECT: compounds can be applied for induction of apoptosis in cell.

37 cl, 13 dwg, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and salts thereof wherein R1 represents -A11-A12-; R2 represents tetrahydrofurylmethyl, tetrahydropyranylmethyl or tetrahydropyranyl; A11 represents a single bond, methylene or 3,2-ethylene; A12 represents C1-6 alkyl, C3-6 cycloalkyl or C3-6 cycloalkyl containing methyl; R3 represents methoxy, cyano, cyclobutyloxymethyl, methoxymethyl or ethoxymethyl; and R4 represents methoxy or chlorine. Also, the invention also refers to a pharmaceutical composition possessing corticotrophin-releasing factor (CRF) receptor antagonist activity, containing a compound of formula (I), to a therapeutic/preventive agent, and a method of treating the diseases specified in the patent claim.

EFFECT: there are presented the compounds of formula (I) as corticotropin-releasing factor (CRF) receptor antagonists.

20 cl, 2 dwg, 2 tbl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 , where X and T are N or C, Q is a (3-7)-member aromatic ring which contains 0-3 nitrogen atoms as ring members, and which is optionally benzo-condensed and is substituted with oxo; C1-C6-alkyl; halogen- C1-C6-alkyl; hydroxy-C1-C6-alkyl; C1-C6-alkoxy; C6-C10-aryl; or a (3-7)-member heteroaryl containing 1-3 oxygen atoms, P is C1-C6-alkyl, optionally substituted with a halogen, and R is a group selected from: (i) -C1-C6-alkyl-R1, (ii) -NR2R3, (iii) -O-R4, (iv) -S-R5, (v) -C (=O))-R6, (vi) optionally substituted (3-7)-member heteroaryl containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (vi) optionally substituted (3-7)-member heteroatom containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (vii) optionally substituted, saturated or partially unsaturated, separate or condensed (3-10)-member heterocyclic ring containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (viii) azido; where each R1, R2, R3, R4, R3, R6, is as described in the claim. The invention also relates to a pharmaceutical composition for preventing and treating a vascular disease, which contains a compound of formula 1.

EFFECT: compounds of formula 1 with inhibitory activity with reference to aggregation of thrombocytes.

7 cl, 7 dwg, 2 tbl, 519 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2-aza-bicyclo[3.3.0]octane derivative of formula , with stereogenic centres in a (1S,3S,5S)-configuration, where A is a thiazolyl which is unsubstituted or monosubstituted, where the substitute is independently selected from a group comprising C1-4alkyl, C3-6cycloalkyl and NH2; B is phenyl which is unsubstituted or mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, trifluoromethyl, NHC(O)CH3 and halogen; and R1 is an imidazo[2,1·b]thiazolyl or benzoisoxazolyl group, where said groups are independently unsubstituted or monosubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl; or R1 is a 2,3-dihydrobenzofuranyl group; or a pharmaceutically acceptable salt. The 2-aza-bicyclo[3.3.0]octane derivative of formula (I) is as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: obtaining novel 2-aza-bicyclo[3,3,0]octane derivatives as orexin receptor antagonists.

8 cl, 1 tbl, 26 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a number of bicyclic nitroimidazole-replaced phenyloxazolydinones of the following structural formula (I):

,

containing nitroimidazole circle, or to its pharmaceutically acceptable salt; where R1 represents hydrogen, (C1-C6)alkyl or aryl; n is equal to 0, 1 or 2; X1 and X2 independently represent H, CF3, CI, OCF3 or F; G represents -OH, triazole or -NHCOR2; R2 represents (C1-C6)alkyl, cycloalkyl or aryl; and L represents a bond or a linker group chosen from any combination 2-3 of the following groups: 1) (C1-C6)alkylene, 2) (C3-C8)cycloalkylene, 3) arylene, arylene-replaced CN, ore arylene-replaced F, 4) group chosen from the group consisting of

,

where R10 represents H, CF3, hydroxyl, amino, alkyl, alkylamino, alkoxy or aryl, and R13 represents H, hydroxyl, amino, alkyl, alkyl amino, alkoxy or aryl, or R13 in combination with nitroimidazole circle can form spiral-shaped structure, 5) -C(=O)-, 6) -O-, 7) -S(O)n-, in which n is equal to 0.1 or 2, 8) -N(R3)-, 9) -C(R4)=C(R5)-, R3 represents hydrogen, (C1-C6) alkyl or aryl, and R4 and R5 represent hydrogen, (C1-C6) alkyl or aryl, or R4 and R5 can be combined together so that they can form a bond. Besides, the invention refers to pharmaceutical composition for treatment of bacterial infection based on compounds of formula I, as well as to a bacterial infection treatment method.

EFFECT: invention describes new compounds that have antibacterial activity against a line of wild type and stable lines of pathogenic microorganisms, and as a result, are suitable for prevention, control and treatment of a number of human and mammal bacterial infections caused by these pathogenic microorganisms such as bacillus Kochii.

15 cl, 93 ex, 1 tbl, 22 dwg

FIELD: biotechnologies.

SUBSTANCE: invention refers to derivatives of oxazolopyrimidine in any of their stereoisomeric forms, or in the form of a mixture of stereoisomeric forms specified in Claim 1.

EFFECT: oxazolopyrimidine derivatives having agonistic activity in relation to Edg-1 receptor.

5 tbl, 319 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic nitrogen- and oxygen-containing compounds having insecticidal activity. In formulae (A) (B) (C) (D) R1 is a 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/ or sulphur atom, a halogen-substituted 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/or sulphur atom, a substituted or unsubstituted phenyl, where the substitutes are one or more groups selected from a group consisting of halogen atoms, C1-4 halogen alkyl or C1-4 chloroalkoxyl; R5, R6, R7, R8 and R9 are H, saturated or unsaturated C1-4 alkyl, halogen atom, saturated or unsaturated C1-4 alkoxyl, saturated C1-4 halogenalkoxyl, C1-4 alkylcarbonyl, C1-8 alkyl ester, C1-4 alkylsulphonyl, phenyl, benzyl or trifluoromethane sulphonyl ether group; Y is nitro, cyano, trifluoromethyl, trifluoroacetyl or trifluoromethylsuphonyl. Values of radicals R, R2-R4 are given in the claim.

EFFECT: invention also relates to an agrochemical composition containing said compounds, use of the agrochemical composition in pest control and a method of producing said compounds.

12 cl, 7 tbl, 36 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described macrocyclic phenylcarbamates of formula (I), wherein A represents -C(=O)OR1 or -C(=O)-NH-SO2-R2, wherein R1 represents hydrogen or C1-C6alkyl; R2 represetns C3-7cycloalkyl, phenyl, thiazolyl or pyridyl each of which is optionally substituted by one or more substituted specified in C1-6alkyl, C1-6alkoxy, trifluoromethyl and halogen; X represents N or CH; E represents NR5; R5 represents hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl or C3-7cycloalkyl; n is equal to 4 or 5; wherein a dash line -----, adjoining the fragment -(CH2)n-, represents a double bond; and wherein the dash line in a five-merous cycle including X, represents a single bond, and R7 represents hydrogen; R8 is such as specified in the patent claim, or N-oxide thereof, a pharmaceutically acceptable additive salt or a pharmaceutically acceptable solvate possessing antiviral activity, and used as HCV inhibitors; as well as pharmaceutical compositions containing the above compounds as an active ingredient.

EFFECT: preparing the pharmaceutically acceptable additive salt or pharmaceutically acceptable solvate possessing antiviral activity.

10 cl, 23 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazo[4,5-b]pyrazine derivatives of general formula or to its pharmaceutically acceptable salt wherein: R1 represents either aryl unsubstituted or substituted by one of the groups: halogen, hydoxyl, C1-6alkyl, C1-6alkoxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC1-6alkylC1-6alkoxy, C1-6alkylhydroxy, -C(O)NH2, -C(O)OC1-6alkyl, -C(O)NH C1-6alkyl, cyano, carboxy, heteroaryl and heterocycloalkyl; or heteroaryl unsubstituted or substituted by one of the groups: C1-6alkoxy, hydroxy, -C1-6alkyl, NH2 and NHC1-6alkyl; heterocycloalkyl unsubstituted or substituted by one group =O; and R2 represents H; unsubstituted C3-4alkyl; C1-4alkyl substituted by C5-6cycloalkyl unsubstituted or substituted by one group specified in amino, hydroxyl, C1-6alkoxy, or heterocycloalkyl unsubstituted or substituted by 1-2 groups specified in =O, C1-6alkyl; or C5-6cycloalkyl substituted by one group specified in hydroxyl, C1-6alkoxyl, C1-6alkylC1-6alkoxy, C1-6alkylhydroxy, CONH2; or substituted ir unsubstituted heterocycloalkyl; wherein aryl represents an aromatic structure consisting of 6-10 carbon atoms containing one ring or two condensed rings; wherein heteroaryl represents a 5-10-member aryl ring system containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur; wherein heterocycloalkyl represents a 5-9-member nonaromatic cycloalkyl wherein 1-2 heteroatoms specified in nitrogen and oxygen; provided the compound does not represent 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-one. Also, the invention refers to the specific imidazo[4,5-b]pyrazine derivatives, to a based pharmaceutical composition, to a method of treating or preventing cancer, inflammatory conditions, immunological diseases, metabolic conditions, and to a method of kinase inhibition in a cell expressing said kinase.

EFFECT: there are produced new imidazo[4,5-b]pyrazine derivatives showing effective biological properties.

17 cl, 2 tbl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 2-substituted-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-ones and 2-substituted-2,3,5,6-tetrahydrooxazolo[3,2-a]pyrimidin-7-ones of formula (I): where p, n, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are described in the description. These compounds are modulators of metabotropic glutamate receptors (mGluR), particularly the mGluR2 receptor. Compounds in the present invention are therefore suitable for use as pharmaceutical agents, especially in treating and(or) preventing various disorders of the central nervous system (CNS), including, among others, acute and chronic neurodegenerative disorders, psychosis, convulsions, anxiety, depression, migraine, pain, sleep disorder and emesis.

EFFECT: improved method.

14 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a novel intermediate epoxy compound of general formula (2), where R1 represents hydrogen or a lower alkyl group; and R2 represents a piperidinyl group of general formula (A1), where R3 represents a phenoxy group, having a halogen-substituted lower alkoxy group, substituted with a phenyl group, and other similar groups; and n is an integer from 1 to 6, to obtain 2,3-dihydroimidazo[2,1-b]oxazole. The invention also relates to specific epoxy compounds, a method of producing epoxy compounds of formula (2) and a method of producing 2,3-dihydroimidazo[2,1-b]-oxazole using a novel intermediate epoxy compound.

EFFECT: obtaining 2,3-dihydroimidazo[2,1-b]oxazole with high output and high purity.

4 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to bicyclic heterocycles of formula I and formula II , in which radicals and symbols have values specified in the formula of the invention. These compounds have inhibiting activity in relation to MEK kinase. The invention also refers to a pharmaceutical composition for treatment of hyperproliferation disease or inflammatory disease, to a method for inhibition of abnormal growth of cells or treatment of hyperproliferation disorders and to a treatment method of inflammatory diseases of a mammal. Besides, the invention refers to use of a pharmaceutical composition for preparation of a medicinal agent for treatment of the above diseases of a mammal.

EFFECT: improving compound application efficiency.

19 cl, 29 ex

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