Pyrrolopyrimidine derivatives applicable in treating proliferative diseases

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I where R1 stands for phenyl; G stands for C1-C7-alkylene; Q stands for -NH-; and X stands for C1-C7- alkylene, or to its salts. In addition, the invention concerns a pharmaceutical composition, to application of compound of formula I as defined in claims 1-5 item, as well as the method for making the compound of formula I.

EFFECT: production of the new biologically active compounds inhibiting protein tyrosine kinase.

8 cl, 3 ex

 

The present invention relates to derivatives of 7H-pyrrolo[2,3-d]pyrimidine and method of production thereof, to pharmaceutical compositions containing such derivatives and to the use of such derivatives - individually or in combination with one or more other pharmaceutically active compounds - for the preparation of pharmaceutical compositions intended for the treatment preferably a proliferative disease such as a tumor.

The present invention relates to derivatives of 7H-pyrrolo[2,3-d]pyrimidine of the formula I

,

in which

R1denotes a heterocyclic radical, or an unsubstituted or substituted aromatic radical;

G denotes a1-C7-alkylene, -C(=O)- or1-C6-alkylen-C(=O)-in which the carbonyl group is attached to pieperazinove fragment;

Q represents-NH - or-O-, provided that Q represents-O-, when G represents-C(=O)- or1-C6-alkylen-C(=O)-; and

X or is absent, or represents C1-C7-alkylene, provided that the heterocyclic radical R1attached through a cyclic carbon atom when X is absent;

or salts of these compounds.

General terms used above and below in the present invention, in the context of the present disclosure predpochtitel what about have the following values, unless otherwise noted:

If for compounds, salts, etc. used the plural, it means also a single compound, salt, etc.

If the compounds of formula I, which can form tautomers, this means the inclusion and tautomers of such compounds of formula I. In particular, tautomerism is manifested, for example, compounds of formula I, which contain 2-hydroxypyridine radical. In such compounds 2-hydroxypyridine radical may also be in the form of pyrid-2(1H)-onila.

Asymmetric carbon atoms, which optionally contains in the compound of formula I, can be in (R), (S) or (R, S) - configuration, preferably in the (R) or (S) configuration. Deputy double bonds or rings can be in the CIS- (Z-) or TRANS (=E-) form. Thus, the compounds may contain in the form of mixtures of isomers or, preferably, in the form of pure isomers.

The prefix "ness." denotes a radical containing from 1 carbon atom and a maximum of 7 carbon atoms inclusive, preferably up to 4 carbon atoms, inclusive, these radicals are linear or branched and contain one or more branches.

Ness. alkyl means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,n-hexyl or n-heptyl.

Ness. alkoxygroup means, for example, ethoxy - or methoxy-, preferably a methoxy group.

Substituted ness. alkyl preferably represents ness. alkyl, as defined above, which may contain one or more, preferably one Deputy, such as, for example, amino group, N-ness. alkylamino, N,N-di-ness. alkylamino, N-ness. alkanolamine, N,N-di-ness. alkanolamine, the hydroxy-group, NISS. alkoxygroup, NISS. alkanoyl, NISS. alkanoyloxy, cyano, a nitro-group, carboxypropyl, NISS. alkoxycarbonyl, carbarnoyl, N-ness. allylcarbamate, N,N-di-ness. allylcarbamate, medinova, guanidine, uraidla group, mercaptopropyl, NISS. allylthiourea, halogen or heterocyclic radical.

Heterocyclic radical preferably contains up to 20 carbon atoms, and preferably represents a saturated or unsaturated monocyclic radical containing from 4 to 8 atoms in the cycle and from 1 to 3 heteroatoms, which are preferably selected from the group comprising nitrogen, oxygen and sulfur, or bi - or tricyclic radical, in which, for example, 1 or 2 carbocyclic radical, such as, for example, benzene radicals, annelirovaniya (condensed) with the specified monocyclic radical. If the heterocyclic radical contains undeservedly carbocyclic radical, the heterocyclic radical can also be attached to the rest of the molecule of formula I through a ring atom condensed carbocyclic radical. Heterocyclic radical (including a condensed carbocyclic radical(s), if it contains) optionally contains one or more, preferably one radical, such as, for example, unsubstituted or substituted ness. alkyl, amino group, N-ness. alkylamino, N,N-di-ness. alkylamino, N-ness. alkanolamine, N,N-di-ness. alkanolamine, the hydroxy-group, NISS. alkoxygroup, NISS. alkanoyl, NISS. alkanoyloxy, cyano, a nitro-group, carboxypropyl, NISS. alkoxycarbonyl, carbarnoyl, N-ness. allylcarbamate, N,N-di-ness. allylcarbamate, medinova, guanidine, uraidla group, mercaptopropyl, NISS. allylthiourea or halogen.

The most preferred heterocyclic radical is pyrrolidinyl, piperidyl, NISS. alkylpiperazine, di-ness. alkylpiperazine, morpholine, tetrahydropyranyl, pyridyl, pyridyl substituted by a hydroxy-group or nits. alkoxygroup, and benzodioxolyl, preferably pyrrolidinyl, piperidyl, NISS. alkylpiperazine, di-ness. alkylpiperazine or morpholinyl.

Heterocyclic radical R1is the same as defined above for heterocyclic the ski radical, provided that it is linked to Q through a ring carbon atom if X is not present. Preferred heterocyclic radical R1is benzodioxolyl, pyridyl, substituted hydroxy-group or nits. alkoxygroup, or, particularly preferably indolyl, substituted with halogen and NISS. the alkyl. If R1denotes pyridyl, substituted hydroxy-group, the hydroxy-group is preferably attached to the ring carbon atom adjacent to the ring nitrogen atom.

Unsubstituted or substituted aromatic radical R1contains up to 20 carbon atoms and is unsubstituted or substituted, for example, in each case unsubstituted or substituted by phenyl.

Preferably unsubstituted aromatic radical R1denotes phenyl. Substituted aromatic radical R1preferably denotes phenyl, contains one or more substituents, independently from each other selected from the group comprising unsubstituted or substituted ness. alkyl, alkylamino, N,N-di-ness. alkylamino, N-ness. alkanolamines, N,N-di-ness. alkanolamines, the hydroxy-group, NISS. alkoxygroup, NISS. alkanoyl, NISS. alkanoyloxy, a cyano, a nitro-group, carboxypropyl, NISS. alkoxycarbonyl, carbarnoyl, N-ness. allylcarbamate, N,N-di-ness. allylcarbamate is, amedieval, guanidine, ureido group, mercaptopropyl, NISS. allylthiourea and halogen. The most preferred substituted or substituted aromatic radical R1denotes phenyl, substituted by one or more radicals, independently of one another selected from the group comprising ness. alkyl, an amino group, a hydroxy-group, NISS. alkoxygroup, halogen and benzyloxy.

Halogen preferably denotes fluorine, chlorine, bromine or iodine, most preferably fluorine, chlorine or bromine.

With1-C7-Alkylen may be branched or unbranched and preferably represents C1-C3-alkylen.

With1-C7-Alkylen G preferably represents C1-C3-alkylene, most preferably a methylene (-CH2-).

If G does not denote With1-C7-alkylen, it preferably represents-C(=O)-.

With1-C7-Alkylen X preferably represents C1-C3-alkylene, most preferably a methylene (-CH2-or ethane-1,1-diyl (-CH(CH3)-).

Q preferably represents-NH-.

Salts are preferably pharmaceutically acceptable salts of compounds of formula I.

Such salts are formed, for example, in the form of molecular salts with acids, preferably with organic or inorganic acids, the C compounds of the formula I, containing a basic nitrogen atom, preferably pharmaceutically acceptable salts.

In the presence of negatively charged radicals, such as carboxypropyl or alphagraph, salt can also be formed with bases, e.g. metal salt or ammonium, such as salts of alkaline metal or alkaline earth metal, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines.

If a molecule contains a basic group and an acidic group, the compounds of formula I may also form internal salts.

For isolation or purification it is also possible to use pharmaceutically unacceptable salts, for example, the picrate or perchlorate. However, for therapeutic purposes can only be used pharmaceutically acceptable salt free connection (if it is necessary to pharmaceutical compositions), and therefore, these salts are preferred.

Due to the close affinity of the compounds in free form and in the form of their salts, including salts, which can be used as intermediates, for example in the purification or identification of compounds proposed in the present invention, the above and below any reference to the free compounds should be understood as referring also to the corresponding salts, if it is appropriate yalecourses.

The compounds of formula I possess valuable pharmacological useful characteristics. In particular, they have a specific inhibitory activity of interest to pharmacology. They are particularly effective as inhibitors proteincontaining and/or (furthermore) as inhibitors of serine/trainingtraining; they can, for example, effectively inhibit the tyrosine kinase activity of the receptor for epidermal growth factor (EGF-R and ErbB-2 kinase. These 2 receptor proteincontaining together with representatives of their group rb-3 and rb-4 play a key role in the transmission of signals in a large number of mammalian cells, including human cells, in particular epithelial cells, cells of the immune system and cells of the Central and peripheral nervous system. For example, in various types of cells induced by EGF activation-related receptor proteincontaining is a prerequisite for cell division and, hence, the proliferation of groups of cells. Most importantly, overexpression of EGF-R (HER-1) and/or rb-2 (HER-2) was observed in a significant part of many human cancers. For example, found that EGF-R sverkhekspressiya with non-small cell lung cancer, squamous cell carcinoma (head and neck), breast cancer, stomach, colon and prostate cancer and gliomas. Discovered that rb-2 sverkhekspressiya with non-small cell lung cancer, squamous cell carcinoma (head and neck), cancer of the breast, stomach and ovary, as well as gliomas.

In addition to inhibition of tyrosine kinase activity of EGF-R, the compounds of formula I in various degrees inhibit other proteincontaining that are involved in signal transmission mediated by trophic factors, in particular receptor group endothelial growth factor vascular (VEGF) (e.g., KDR, Flt-1, Flt-3), and abl kinase, especially v-abi kinase of the Src group, especially c-Src, Lck and Fyn, other representatives of the group of EGF receptors, such as rb-3 (HER-3) and rb-4 (HER-4), CSF-1, Kit receptor, FGF and cyclin-dependent kinase CDK1 and CDK2, each of which plays a role in growth regulation and transformation in mammalian cells, including human cells.

Inhibition of tyrosine kinase activity of EGF-R can be demonstrated using known techniques, for example, using recombinant intracellular domain of the EGF receptor [EGF-R ICD; see, for example, the publication .McGlynn and others, Europ. J.Biochem. 207. 265-275 (1992)]. Compared with the control without inhibitor compounds of formula I inhibit the enzyme activity by 50% (IC50), for example, when the concentration of the component from 0.0005 to 0.5 μm, preferably from 0.001 to 0.1 μm.

At the same time or instead of inhibiting the activity of the tyrosine kinase EGF-R in the compounds of formula I also inhibit other members of this group of receptors, such as rb-2. Inhibitory activity (IC50) is in the approximate range of 0.001 to 0.5 micron. Inhibition of tyrosine kinase ErbB-2 (HER-2) can be determined, for example, by methods similar to protein kinase EGF-R [see publication .House and others, Europ. J. Biochem. 140, 363-367 (1984)]. Kinase ErbB-2, you can select and determine its activity according to the methods which are in themselves known, for example, in accordance with the publication Takama and others, Science 232, 1644 (1986).

According to the invention unexpectedly discovered that compounds of the formula I in particular was very actively inhibit the activity of tyrosine kinase receptors, VEGF group. Therefore, the compounds proposed in the present invention are highly effective dual inhibitor of receptor groups EGF and VEGF. Inhibition of KDR and Flt-1 and inhibition induced by growth factor proliferation of HUVECS described in the publication J.Wood and others, Cancer Res. 60, 2178-2189 (2000). The compounds of formula I inhibit, for example, the activity of the KDR tyrosine kinase with values IC50constituting from about 1 nm to about 1 μm, preferably from about 5 nm to about 0.5 μm.

Effect of compounds of formula I on EGF induced phosphorylation of EGF-R can be determined in cell line of epithelial carcinoma human A431 using ELISA (enzyme-linked immunosorbent assay), as described in publicat and U.Trinks and others, J. Med. Chem. 37:7. 1015-1027 (1994). In this last analysis (EGF-R ELISA) the compounds of formula I have the meanings IC50constituting from about 0.001 to 1 micron.

The compounds of formula I actively inhibit the growth of sverkhekspressiya EGF-R cells NCI-H596 non-small cell lung cancer [see, for example, the publication W.Lei, and others, Anticancer Res. 19 (1A), 221-228 (1999)] with values IC50constituting from about 0.01 to 1 μm. In the same range of activity of the compounds of formula I are also actively inhibit the growth of sverkhekspressiya rb-2 cells VT breast cancer person. Used modified methods of research publications Toueg etc., Int. J. Cancer 43, 851 (1989). Inhibitory activity of compounds of the formula I, in brief, is determined as follows: cells NCI-H596 (wells volume 10000 ál) was placed in 96-well plates to micrometrology. The compounds [dissolved in dimethyl sulfoxide (DMSO)] was added in a series of concentrations (serial dilution) so that the final concentration of DMSO did not exceed 1% (vol./vol.). After addition of tablets incubated for 3 days and during this time the control culture, not containing these compounds, able to endure at least 3 cycles of cell division. The growth of cells NCI-H596 determined using the methylene blue staining: after incubation, the cells are fixed with glucaro the first aldehyde, washed with water and paint of 0.05% methylene blue. After the stage of washing the dye elute with 3% Hcl and the optical density (OD) in terms of the hole of the tablet for micrometrology measuring device Titertek Multiskan (Titertek, Huntsville, AL, USA) at 665 nm. The values of the IC50determined using a computer program according to the formula:

In these experiments, the values of the IC50presented as a concentration considered investigational compounds, which leads to the number of cells, which is 50% less than obtained for the control without addition of inhibitor. The compounds of formula I possess inhibitory activity with IC values50in the range from about 0.01 to 1 micron.

The compounds of formula I are also able to inhibit the growth of tumor cells in vivo, as shown, for example, the following study: the study is based on the growth inhibition of squamous cell lung carcinoma line NCI-H596 [ATS NTV 178; American Type Culture Collection, Rockville, Maryland, USA; see publication Santon, J.B., and others, Cancer Research 46, 4701-4705 (1986) and the publication Ozawa, S., and others, Int. J.Cancer 40, 706-710 (1987)], which are transplanted into female Nude mice of BALB/c (Bomholtgard, Denmark). This detects carcinoma growth, which correlates with the degree of ekspressirovali EGF-R. Tumor revealed after subcutaneous injection of cells [min is 2×10 6cells in 100 μl phosphate buffered saline (SFF) or environment] mice (4-8 mice). Injections were performed subcutaneously in the left side of the mouse in the middle between the tail and head. Before treatment for these tumors was performed serial passage of not less than three consecutive transplantations. During this time the growth rate of tumors stabilized. The passage of the tumors was performed not more than 12 times. In experiments on the treatment of fragments of the tumor mass of approximately 25 mg transplanted subcutaneously into the left flank of the animals using a needle trocar No. 12 during anaesthesia using Forene® (Abbott, Schwitzerland). Tumor growth and body weight were determined 2 times a week. Treatment always started after tumor volume becomes equal to from 100 to 250 mm, the Volume of tumor was calculated by the known formula: Length×diameter2×π/6 [see Evans, B.D., and others, Brit. J. Cancer 45, 466-8 (1982)]. Antitumor activity was represented as T/C % (average increase of tumors in the treated animals divided by the average increase of tumors in control animals and multiplied by 100%). The dose of the active ingredient comprising from 3 to 100 mg/kg, detected a clear suppression of tumor growth, for example,/%, which is less than 50.

The compounds of formula I can inhibit other proteinkinase the kinase, involved in signal transmission mediated by trophic factors, for example abl kinase, especially such as v-abl kinase (IC50is, for example, from 0.01 to 5 μm), kinases of the src group, especially such as c-src kinase (IC50is, for example, from 0.1 to 10 μm) and serine/trainingin, for example, protein kinase C, each of which participates in growth regulation and transformation in mammalian cells, including human cells.

The above inhibition of the tyrosine kinase v-abl explore the techniques described in the publication N.Lydon and others, Oncogene Research 5, 161-173 (1990) and in the publication J.F.Geissler and others, Cancer Research 52, 4492-4498 (1992). In these methods as substrates using [Val5]-angiotensin II and [γ-32P]-ATP.

Therefore, the compounds of formula I which inhibit the tyrosine kinase activity of EGF-R or other specified proteincontaining applicable, for example, in the treatment of benign or malignant tumors. The compounds of formula I, for example, is able to simultaneously suppress the growth of tumors with impaired regulation of the activity of EGF-R and/or rb-2, as well as to inhibit the vascularization of solid tumors stimulated by VEGF. This combined activity leads to improved antitumor effect (see also WO 02/41882). In addition, the use of dual inhibitor reduces the risk of drug interactions is the behaviour and reduces additional full drug burden compared with combined therapy. The compounds of formula I are able to slow tumor growth or cause regression of tumors and prevent tumor metastasis and growth of metastases. They preferably can be applied in the case of epidermal hyperproliferation (psoriasis), for the treatment of neoplasms of epithelial character, e.g. carcinomas of the breast and leukemia. In addition, the compounds of formula I can be used for the treatment of immune system disorders that involve multiple proteincontaining or, preferably, a separate proteincontaining and/or (furthermore) serine/trainingtraining; the compounds of formula I can also be used for the treatment of disorders of the Central or peripheral nervous system in which the transmission of signals involved several proteincontaining or, preferably, one proteincontaining and/or (furthermore) serine/trainingtraining.

In General, the present invention also relates to the use of compounds of formula I for the inhibition of the above kinases, preferably to apply for dual inhibition of groups of receptors, EGF and VEGF.

Connections proposed in the present invention can be used singly, and in combination with other pharmacologically active compounds, for example, in conjunction with inhibitors fer the clients synthesis of polyamines, inhibitors of protein kinase C, inhibitors of other tyrosinekinase, a cytokine, a negative growth regulators, for example, TGF-β or IFN-β, an aromatase inhibitor, an antiestrogen and/or cytotoxic drugs.

In preferred groups of compounds of formula I listed below in the present invention, the definitions of the substituents listed above in the present invention, it is advisable to use, for example, to replace more General definitions, for example, to replace more General definitions with more specific definitions or, preferably, by definition, is described as being preferred.

Preference is given to the compound of formula I, in which

R1denotes a heterocyclic radical or an unsubstituted or substituted aromatic radical;

G denotes a1-C7-alkylen;

Q represents-NH - or-O-; and

X or is absent, or represents C1-C7-alkylene, provided that the heterocyclic radical R1attached through a cyclic carbon atom when X is absent;

or its salts.

Preference is also given to the compound of formula I, in which

R1denotes a heterocyclic radical, or an unsubstituted or substituted aromatic radical;

G denotes a1-C7-alkylen;

Q represents-NH-; and

<> X or is absent, or represents C1-C7-alkylene, provided that the heterocyclic radical R1attached through a cyclic carbon atom when X is absent;

or its salts.

Particular preference is given to the compound of formula I, in which

R1denotes a heterocyclic radical containing up to 20 carbon atoms, or unsubstituted or substituted aromatic radical containing up to 20 carbon atoms;

G represents C1-C3-alkylen;

Q represents-NH-; and

X or is absent, or represents C1-C3-alkylene, provided that the heterocyclic radical R1attached through a cyclic carbon atom when X is absent;

or its salts.

Special preference is also given to the compound of formula I, in which

R1denotes phenyl, benzodioxolyl, pyridyl, substituted hydroxy-group or nits. alkoxygroup, indolyl, substituted with halogen and NISS. the alkyl, or phenyl, substituted by one or more radicals, independently of one another selected from the group comprising ness. alkyl, hydroxy-group, NISS. alkoxygroup, halogen and benzyloxy;

G represents-CH2- or-C(=O)-;

Q represents-NH - or-O-, provided that Q represents-O-, when G represents-C(=O)-; and

X or is absent, or represents-CH2 - or-CH(CH3)-, provided that the substituted pyridyl or indolyl R1attached through a cyclic carbon atom when X is absent;

or its salts.

Special preference is also given to the compound of formula I, in which

R1denotes phenyl, benzodioxolyl, pyridyl, substituted hydroxy-group or nits. alkoxygroup, or phenyl substituted by one or more radicals, independently of one another selected from the group comprising ness. alkyl, hydroxy-group, NISS. alkoxygroup, halogen and benzyloxy;

G represents-CH2-;

Q represents-NH-; and

X or is absent, or represents-CH2- or-CH(CH3)-, provided that the substituted pyridyl R1attached through a cyclic carbon atom when X is absent;

or its salts.

Special preference is also given to the compound of formula I in which a1-C7-alkylen G is attached to the phenyl in position 3 or 4, most preferably in position 4.

Most particular preference is also given to the compound of formula I, set forth below in the examples, or its salts, preferably pharmaceutically acceptable salts.

Also especially preferred are compounds of formula I, which - according to the above-described assays of inhibition of tyrosine kinase - inhibited HER-1, HER-2 and KDR when value is x IC 50constituting less than 300 nm, most preferably constitute less than 100 nm.

Most particular preference is also given to compounds of the formula I which inhibit the tyrosine kinase activity of at least one representative of the group of EGF receptors and simultaneously at least one representative of the group of VEGF receptors (dual inhibition of groups of receptors EGF and VEGF), when values of the IC50according to the above-described assays of inhibition of tyrosine kinase in the range from 0.5 nm to 0.5 μm, preferably in the range from 1 nm to 300 nm.

Especially preferred are additionally the compounds of formula I in which G represents C1-C7-alkylen, because the amino group of these compounds can form pharmaceutically acceptable salts of these compounds, which usually leads to increased solubility and improved physico-chemical characteristics.

In a preferred embodiment, the present invention relates to isolated compounds of the formula I, preferably to isolated compound ((R)-1-phenylethyl)-[6-(4-piperazine-1-ylmethylene)-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-amine or its salts, preferably pharmaceutically acceptable salts.

The term "isolated" connection means that the connection is removed from its PE the original environment (for example, the natural environment if it is in nature, including human or animal, which, for example, produces such a connection after the introduction of other compounds). For example, a natural compound found in their natural environment, is not isolated, but the same connection, separated from some or all together with him in the natural environment materials, it is isolated even if it is then re-injected into the natural system. Such compounds may be part of a composition and still be isolated in the sense that such compositions are not part of their natural environment. Thus, the connection is at least partially purified compared to the status in the environment in which it is found, and therefore is not a natural product.

In an important embodiment, the isolated compound has a purity sufficient to allow its use for pharmaceutical purposes, in particular for the preparation of pharmaceutical compositions.

The compounds of formula I or its salts can be obtained by known methods (see, for example, WO 03/013541 A1, published February 20, 2003), preferably according to the method in which

a) to obtain the compounds of formula I in which G represents C1-C7-alkylen, the compound of formula II

,

in which Hal denotes halogen, G denotes a1-C7-alkylene and R1, Q and X have the meanings specified for compounds of formula I, is introduced into reaction with piperazine;

b) to obtain the compounds of formula I in which G represents-C(=O)- or1-C6-alkylen-C(=O)-in which the carbonyl group is attached to pieperazinove fragment, the compound of formula III

in which the substituents and symbols have the meanings specified for compounds of formula I, is introduced into reaction with piperazine; or

to obtain the compounds of formula I in which G represents C1-C7-alkylen, compound of formula I in which G represents-C(=O)- or C1-C6-alkylen-C(=O)-in which the carbonyl group is attached to pieperazinove fragment injected into reaction with a reducing reagent to obtain the corresponding compounds in which G denotes a1-C7-alkylen;

in which the functional group contained in the source connections of the methods a)to C) and are not intended to participate in the reaction, if necessary, are in protected form, and the protective group, which contains, hatshepsuts, and these initial compounds can also be in the form of salts, provided that contains salobra the ith group and the possible reaction with the salt;

and, if necessary, the thus obtained compound of the formula I is converted into another compound of formula I, a free compound of formula I is transformed into salt obtained salt of a compound of the formula I is converted into the free compound or another salt, and/or a mixture of isomeric compounds of formula I is separated into the individual isomers.

Description options method:

For method a):

The reaction between the compound of formula II and piperazine (preferably protected by one of its ring nitrogen atoms, such as preferably N-tert-butoxycarbonylmethyl) is preferably carried out in a suitable inert solvent, preferably N,N-dimethylformamide, in the presence of a base such as potassium carbonate, at temperatures from room temperature (RT) to 100°C. Alternatively, the reaction between the compound of formula II and piperazine (preferably in a protected form, such as N-tert-butoxycarbonylmethyl) is carried out in a suitable solvent, for example, ness. alcohols, such as ethanol, in the presence of, for example, a suitable catalyst, such as NaI, preferably at the boiling point of the used solvent. In the compound of formula II Hal preferably represents chlorine.

For method b):

The reaction of the compound of formula III with piperazine (preferably protected by one of egonolsen nitrogen atoms, such as preferably N-tert-butoxycarbonylmethyl) is preferably carried out in a suitable inert solvent such as N,N-dimethylformamide, in an inert atmosphere, for example, in an atmosphere of argon or nitrogen, in the presence of diethylthiophosphate, preferably at about 0°C.

For method):

Reductive reagent used in the method), preferably represents alumoweld lithium or diisobutylaluminium. The reaction is preferably carried out under the conditions described in example 79 or 141 in WO 03/013541 A1, respectively.

Additional stages of the method

In the advanced stages of a method carried out, if necessary, functional groups of the parent compounds, which should not participate in the reaction, may be contained in unprotected form or may be protected, for example, one or more protective groups. 3 Quiroga protective groups are completely or partially remove one of the known methods, preferably by the methods described in the examples.

Protective groups and their introduction and removal are described, for example, "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, and in the publication "Methods der organischen Chemie", Houben-Weyl, 4th edition, Vol.15/1, Georg-Thieme-Verlag, Stuttgart 1974, and in the publication Theodora W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York 1981. Feature protective group is t is, that you can remove them easily, i.e. without the occurrence of undesired secondary reactions, for example by solvolysis, recovery, photolysis or alternatively under physiological conditions.

However, the final products of formula I can also contain substituents, which can also be used as protective groups for the source of substances intended for other end products of formula I. Thus, in the scope of the present description only easily removable group that is not a component of the particular desired end product of formula (I) is called the "protecting group ", unless the context otherwise indicated.

General conditions of implementation of the method

The following terms apply in General to all the ways mentioned above and below in the present invention, when are the preferred conditions for reaction, especially above or below:

All stages of the method described in the present invention, can be performed under known conditions of the reaction, preferably under those specifically indicated, in the absence of or usually in the presence of solvents or diluents, preferably solvents or diluents which are inert to the reagents and dissolve them, in the absence or in the presence of catalysts, condensation isonatremic reagents for example, ion exchangers, typically kationoobmennikom, for example, N+form, depending on the nature of the reaction and/or reactants at reduced, normal or elevated temperature, for example at a temperature in the range from about -100 to about 190°C.; preferably from about -80 to about 150°C., for example, from -80 to -60°C., at RT, -20 to 40°C, 0 to 100°C. or at the boiling point of the used solvent, at atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example in the atmosphere of argon or nitrogen.

The present invention also relates to such variants of the method, in which the starting material used, the compound obtained at any stage as an intermediate product, and have missed the stage, or stop at any stage, or get a starting material for the reaction conditions, or use the specified starting material in the form of a reactive derivative or salt, or the compound obtained by the method proposed in the present invention, under these reaction conditions, and then processes the specified connection in situ. In a preferred embodiment, use of such source materials, which lead to the compounds description is authorized above in this invention as preferred.

In a preferred embodiment, the compound of formula I obtained using the method and stages of the method described in the examples.

The compounds of formula I, including their salts, can also be obtained in the form of hydrates, or their crystals can include for example the solvent used for crystallization (see the form of the solvate).

Educt

New source materials and/or intermediates and methods for their production are also objects of the present invention. In a preferred embodiment, use of such source materials and choose the conditions of the reactions, so that you can get the preferred connection.

Source materials used in the above methods a)to C)are known, they can be obtained by known methods (see also EP 682027, WO 97/02266, WO 97/27199, WO 98/07726 and WO 03/013541 A1), or they are commercially available; in particular, they can be obtained by the techniques described in the examples.

Upon receipt of the original substances available functional groups that should not participate in the reaction, if necessary, must be protected. Preferred protective groups, their introduction and their removal are described above or in the examples. Instead of the appropriate starting compounds and intermediate products in the reaction it is also possible to use salt when the service is provided that contains a salt-forming group and possible reaction with the salt. When above and below in the present invention uses the term initial matter, we always include their salts, where appropriate and possible.

The compound of formula II can be obtained, for example, by the reaction of compounds of formula IV

in which G represents C1-C7-alkylene and R1, Q and X have the meanings specified for compounds of formula I, for example, thionylchloride, preferably with thionyl chloride, in the presence or in the absence of pyridine, in an inert solvent, for example toluene or in a mixture of composition 1:1 acetonitrile with dioxane, preferably at temperatures between -10 to 0°C or at RT.

The compound of formula IV can be obtained, for example, by the reaction of compounds of formula V

in which R2means NISS. alkyl, preferably methyl or ethyl, and R1, Q and X have the meanings specified for compounds of formula I

lithium aluminum hydride, in an inert solvent, preferably ethers, for example cyclic ethers, such as tetrahydrofuran, preferably at the boiling point of the used solvent. Alternatively, the compound of formula IV can be obtained by the reaction of compounds of formula V with diisobutylaluminium the house in an inert solvent, for example, in tetrahydrofuran or a mixture of composition 1:1 dichloromethane with dioxane, preferably at RT.

The compound of formula V in which Q represents-NH-, can be obtained, for example, by the reaction of compounds of formula VI

in which Hal denotes halogen, preferably chlorine, and R2is the same as defined above for the compounds of formula V with the compound of the formula H2N-X-R1in which R1and X have the meanings specified for compounds of formula I, (i) in a suitable solvent, such as alcohols, preferably ness. alcohols, such as n-butanol, preferably at the boiling point of the used solvent, or (ii) under the conditions of catalysis, for example, when the reaction conditions Buchwald, such as described at the stage of Step 133.1 example 133 in WO 03/013541 A1.

The compound of formula V in which Q represents-O-, can be obtained, for example, by the reaction of compounds of formula VI, which is preferably protected on the N atom pyrrolopyrimidine fragment, with a compound of formula HO-X-R1in which R1and X have the meanings specified for compounds of formula I, in a suitable inert solvent such as N,N-dimethylformamide and in the presence of a base such as potassium carbonate, at elevated temperatures, preferably at about 100°C.

Alternatively, the complex is th ether carboxylic acids of compounds of formula VI can first restore to the corresponding alcohol, for example, under the conditions described above for obtaining the compounds of formula IV, and then enter into reaction with the compound of the formula H2N-X-R1for example, under the conditions described above for obtaining the compounds of formula V in which Q represents-NH-, or enter into reaction with the compound of the formula HO-X-R1for example, under the conditions described above for obtaining the compounds of formula V in which Q represents-O-.

The compound of formula III can be obtained, for example, by the reaction of compounds of formula V with LiOH, preferably in a mixture of dioxane with water, at elevated temperatures, preferably under the conditions described on the stage 141.4 example 141 in WO 03/013541 A1.

The rest of the original substance are known, they can be obtained by known methods, or they are available for sale; or, in particular, can be obtained by the techniques described in the examples.

Pharmaceutical compositions, methods and applications

The present invention also relates to pharmaceutical compositions which include a compound of formula I or its pharmaceutically acceptable salt as an active ingredient, and which can be used, preferably in the treatment of the diseases mentioned above. Compositions intended for enteral administration, such as nasal, transbukkalno, rectal or, preferably, oral administration is for parenteral administration, such as intravenous, intramuscular or subcutaneous injection of warm-blooded animals, preferably humans, are especially preferred. The compositions contain the active ingredient in pure form or, preferably, together with a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the treated disease and the species, age, weight and individual condition, individual pharmacokinetic data and method of administration.

The present invention also relates to prodrugs of the compounds of formula I, which in vivo into a compound of formula I as such. Therefore, any reference to a compound of formula I should be understood as referring to the corresponding prodrugs of the compounds of formula I, if it is appropriate and expedient.

The present invention also relates to compounds of formula I, or their pharmaceutically acceptable salts as such or in the form of pharmaceutical compositions intended for use in the method for prophylactic or preferably therapeutic treatment of the human body, the method thereof, preferably in the form of compositions intended for the treatment of tumors and for the treatment of proliferative diseases, first of all tumors, preferably decree is the R above.

The present invention also relates to a method and to the use of compounds of the formula I or their pharmaceutically acceptable salts for the preparation of pharmaceutical compositions that include the compounds of formula I or their pharmaceutically acceptable salt as an active component (active ingredient).

If necessary, these pharmaceutical compositions may also contain additional active ingredients, for example, cytotoxic agents, and/or they can be used in combination with known methods of treatment, for example, the introduction of the hormone or radiation therapy.

A preferred pharmaceutical composition which is suitable for the introduction of a warm-blooded animal, preferably to people or used on an industrial scale mammal suffering from a disease that is affected by inhibition proteincontaining, preferably dual inhibition of groups of receptors EGF and VEGF, preferably from the tumor, including the amount of the compounds of formula I effective to inhibit proteincontaining, preferably for dual inhibition of groups of receptors EGF and VEGF, or its pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier.

Also is the preferred Pharma is eticeskaja composition, intended for the preventive or preferably therapeutic treatment of tumors and other proliferative diseases in a warm-blooded animal, preferably human, or used on an industrial scale of a mammal in need of such treatment, preferably suffering from such disease, comprising as active ingredient a compound of formula I or its pharmaceutically acceptable salt in such a quantity that is prophylactically or, preferably therapeutically active against these diseases.

The pharmaceutical compositions comprise from approximately 1 to approximately 95% active ingredient introduced forms of single doses in a preferred embodiment, comprise from about 20 to about 90% of the active ingredient and forms that are not one-time doses, in the preferred embodiment, include from about 5 to about 20% of the active ingredient. Forms single doses represent, for example, tablets, coated and uncoated, ampoules, vials, suppositories or capsules. Examples are capsules containing from about 0.05 g to about 1.0 g of the active substance.

The pharmaceutical composition proposed in the present invention, is prepared by a method which is in itself known, for example, technology usually is about mixing, granulating, coating, dissolving or lyophilization.

The present invention also relates to a method or the method of treatment of one of the pathological conditions mentioned above in the present invention, preferably the disease that is affected by inhibition proteincontaining, preferably dual inhibition of groups of receptors EGF and VEGF, preferably corresponding tumors. The compounds of formula I or their pharmaceutically acceptable salts can be introduced as such or in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in a quantity effective against these diseases, a warm-blooded animal, such as man, in need of such treatment, the compounds are preferably applied in the form of pharmaceutical compositions. In the case of an individual with a body weight of approximately 70 kg, administered daily dose is from about 0.1 to about 5 g, preferably from about 0.5 to about 2 g of compound proposed in the present invention.

The present invention also preferably relates to the use of compounds of formula I or its pharmaceutically acceptable salt, preferably the compounds of formula I, which indicates that it is the preferred, or its pharmaceutically who priemlemoj salt as such or in the form of a pharmaceutical composition together with at least one pharmaceutically acceptable carrier, for therapeutic and preventive treatment of one or more of the diseases mentioned above in the present invention, preferably the disease that is affected by inhibition proteincontaining, preferably dual inhibition of groups of receptors EGF and VEGF, preferably tumor, especially if the disease affects the inhibition proteincontaining, preferably dual inhibition of groups of receptors, EGF and VEGF.

The present invention also preferably relates to the use of compounds of formula I or its pharmaceutically acceptable salt, preferably the compounds of formula I, which indicates that it is the preferred, or its pharmaceutically acceptable salts, for the preparation of pharmaceutical compositions intended for therapeutic and preventive treatment of one or more of the diseases mentioned above in the present invention, preferably the tumor, especially if the disease affects the inhibition proteincontaining, preferably dual inhibition of groups of receptors, EGF and VEGF.

The compound of formula I also can be successfully used in combination with other antiproliferative agents. Such is antiproliferative agents include, but not limited to, aromatase inhibitors, antiestrogens, inhibitors of topoisomerase I, topoisomerase II inhibitors, agents, active against microtubules, alkylating agents, inhibitors discontinuties inhibitors farnesyltransferase inhibitors SOH-2, MMP inhibitors, mTOR inhibitors; antineoplastic antimetabolites, platinum compounds, compounds decreasing the protein kinase activity, and other antiangiogenic compounds, agonists of gonadorelin, antiandrogens, benhamadi, bisphosphonates, antiproliferative antibodies and temozolomide (TEMODAL®).

The term "aromatase inhibitors" as used in the present invention refers to compounds that inhibits the production of estrogen, i.e. conversion of the substrates Androsterone and testosterone into estrone and estradiol, respectively. The term includes, but is not limited to, steroids, preferably exemestane and formestane, and, preferably, asteroidy, preferably aminoglutethimide, vorozole, fadrozole, anastrozole, and especially preferably letrozole. Exemestane can be entered, for example, in the form in which it is sold, for example, under the trade name AROMASIN™. Formestane you can enter, for example, in the form in which it is sold, for example, under the trade name LENTARON™. Fadrozole you can enter, n is the sample, in the form in which it is sold, for example, under the trade name IFEMA™. Anastrozole can be entered, for example, in the form in which it is sold, for example, under the trade name ARIMIDEX™. Letrozole can be entered, for example, in the form in which it is sold, for example, under the trade name FEMARA™ or FEMUR™. Aminoglutethimide can be entered, for example, in the form in which it is sold, for example, under the trade name of ORIMETEN™.

The combination proposed in the present invention, including antineoplastics tool, which is an aromatase inhibitor, is particularly useful for the treatment of hormonal receptorpositive breast tumors.

The term "antiestrogens" when used in the present invention refers to a compound that counteracts the effects of estrogen at the level of the estrogen receptor. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifenetreated. Tamoxifen can be entered, for example, in the form in which it is sold, for example, under the trade name NOLVADEX™. Relativelylarge you can enter, for example, in the form in which it is sold, for example, under the trade name EVISTA™. Fulvestrant can be prepared as disclosed in U.S. patent No. 4659516, or it can be entered, for example, is the form in which it is sold, for example, under the trade name FASLODEX™.

The term "inhibitors of topoisomerase I" when used in the present invention includes, but is not limited to, topotecan, irinotecan, 9-nitrocamptothecin and macromolecular conjugate of camptothecin PNU-166148 (compound A1 in WO 99/17804). Irinotecan can be entered, for example, in the form in which it is sold, for example, under the trade name CAMPTOSAR™. Topotecan can be entered, for example, in the form in which it is sold, for example, under the trade name COSMEGEN™.

The term "topoisomerase II inhibitors" as used in this invention includes, but is not limited to, anthracyclines doxorubicin (including liposomal composition, for example, CAELYX™), epirubicin, idarubitsin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and podophyllotoxin of etoposide and teniposide. Etoposid you can enter, for example, in the form in which it is sold, for example, under the trade name ETOPOPHOS™. Teniposide you can enter, for example, in the form in which it is sold, for example, under the trade name VM 26-BRISTOL™. Doxorubicin can be entered, for example, in the form in which it is sold, for example, under the trade name ADRIBLASTIN™. Epirubicin can be entered, for example, in the form in which it is sold, for example, under t is rhovyl name FARMORUBICIN™. Idarubitsin you can enter, for example, in the form in which it is sold, for example, under the trade name ZAVEDOS™. Mitoxantrone can be entered, for example, in the form in which it is sold, for example, under the trade name NOVANTRONE™.

The term "agents active against microtubules" refers to stabilizing and destabilizing microtubules microtubules means, including, but not limited to, taxanes paclitaxel and docetaxel, Vinca alkaloids for example vinblastine, preferably vinblastine, vincristine, preferably vincristina and vinorelbine, discodermolide and epothilone, such as epothilone In or D. Paclitaxel can be entered, for example, in the form in which it is sold, for example, TAXOL™. Docetaxel can be entered, for example, in the form in which it is sold, for example, under the trade name TAXOTERE™. Vinblastine you can enter, for example, in the form in which it is sold, for example, under the trade name VINBLASTINE R.P.™. Vincristina you can enter, for example, in the form in which it is sold, for example, under the trade name FORMISTIN™. Discodermolide can be obtained, for example, as disclosed in U.S. patent No. 5010099.

The term "alkylating agent" when used in the present invention includes, but is not limited tol is to them, cyclophosphamide, ifosfamide and melphalan. Cyclophosphamide can be entered, for example, in the form in which it is sold, for example, under the trade name COLLASTIN™. Ifosfamide can be entered, for example, in the form in which it is sold, for example, under the trade name of HOLOXAN™.

The term "inhibitors discontinuties" or "HDAC inhibitors" refers to compounds that inhibit discontinuation and which possess antiproliferative activity.

The term "inhibitors farnesyltransferase" refers to compounds that inhibit farnesyltransferase and which possess antiproliferative activity.

The term "inhibitors SOH-2" refers to compounds that inhibit the enzyme cyclooxygenase type 2 (SOH-2) and which possess antiproliferative activity, such as celecoxib (celebrex®), rofecoksib (VIX®) and lumiracoxib (SOH).

The term "MMP inhibitors" refers to compounds that inhibit matrix metalloproteinases (MMP) and which possess antiproliferative activity.

The term "mTOR inhibitors" refers to compounds that inhibit target of rapamycin in mammals (mTOR) and which possess antiproliferative activity, such as sirolimus (rapamune®), everolimus (certican™), CCI-779 and AWT.

The term "antineoplastics antimetabolic the s includes but not limited to, 5-fluorouracil, tegafur, capecitabine, cladribine, cytarabine, fludarabine, ferritin, gemcitabine, 6-mercaptopurine, hydroxyurea, methotrexate, edatrexate and salts of such compounds and, in addition, ZD 1694 (RALTITREXED™), LY231514 (ALIMTA™), LY264618 (LOMETREXOL™) and OGT719.

The term "platinum compounds" as used in this invention includes, but is not limited to, carboplatin, cisplatin and oxaliplatin. Carboplatin can be entered, for example, in the form in which it is sold, for example, under the trade name of CARBOPEAT™.

Oxaliplatin can be entered, for example, in the form in which it is sold, for example, under the trade name of ELOXATIN™.

The term "compounds that reduce the activity of protein kinases and other angiogenic compounds" as used in this invention includes, but is not limited to, compounds that reduce the activity of, for example, endothelial growth factor vascular (VEGF), epidermal growth factor (EGF), c-Src, protein kinase C, platelet-derived growth factor (PDGF), protein kinase Bcr-Abl, c-kit, Flt-3 and receptor insulin-like growth factor I (IGF-IR) and cyclin-dependent kinase (CDK), and antiangiogenic compounds with mechanisms of action, not a reduction in the activity of protein kinases.

Compounds that reduce the activity of VEGF, preferred are compounds which inhibit the VEGF receptor, preferably a tyrosine kinase activity of the VEGF receptor and compounds binding to VEGF, and, in particular, they are compounds, proteins and monoclonal antibodies in General and specifically disclosed in WO 98/35958 (described compounds of formula (I). WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819, WO 01/55114, WO 01/58899 and EP 0769947; described in the publication .Prewett etc. in Cancer Research 59 (1999) 5209-5218, in the publication F.Yuan etc. in Proc. Natl. Acad. Sci. USA, vol.93, pp.14765-14770, December 1996, Z.Zhu, etc. in Cancer Res. 58, 1998, 3209-3214, and in the publication J.Mordenti etc. in Toxicologic Pathology, vol.27, no.1, pp 14-21, 1999; WO 00/37502 and WO 94/10202; angiostatin™, described in the publication .S.O''reilly and other Cell 79, 1994, 315-328; and endostatin™, described in the publication .S.O''reilly and other Cell 88, 1997, 277-285;

compounds that reduce the activity of EGF, preferably are compounds which inhibit the EGF receptor, preferably preferably, the tyrosine kinase activity of the EGF receptor and compounds binding to EGF, and, in particular, they are compounds, in General and in particular as described in WO 97/02266 (described compounds of the formula (IV), EP 0564409, WO 99/03854, EP 0520722, EP 0566226, EP 0787722, EP 0837063, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and, preferably, WO 96/33980;

compounds that reduce the activity of c-Src, include, but are not limited to, compounds that inhibit the activity of the protein is insincerity c-Src, described below, and the inhibitors interact with SH2, such as disclosed in WO 97/07131 and WO 97/08193;

compounds that inhibit the activity proteinkinase c-Src, include, but are not limited to, compounds related to structural classes: pyrrolopyrimidine, preferably pyrrolo[2,3-d]pyrimidines, purines, pyrazolidine, preferably, Pirat[3,4-(1]pyrimidines, pyrazolidine, preferably, Pirat[3,4-(1]pyrimidines and pyridopyrimidines, preferably - pyrido[2,3-C1]pyrimidines. The term preferably refers to compounds disclosed in WO 96/10028, WO 97/28161, WO 97/32879 and WO 97/49706;

compounds that reduce the activity of protein kinase C, are preferably derivatives of staurosporine disclosed in EP 0296110 (pharmaceutical preparations described in WO 00/48571), and these compounds are inhibitors of protein kinase C;

other specific compounds that reduce the activity of protein kinases and which can also be used in combination with the compounds proposed in the present invention are imatinib (Gleevec®/Gleevec®), RX, iressa® (ZD1839), PKI166, RTC, ZD6474, GW2016, CHIR-200131, CEP-7055/CEP-5214, CP-547632 and KRN-633;

antiangiogenic compounds that have a mechanism of action that is not a reduction in the activity of protein kinases include, but are not limited to, for example, thalidomide (THALIDOMIDE) celecoxib (celebrex), SU5416 and ZD6126.

The term "agonist of gonadorelin" when used in the present invention includes, but is not limited to, abarelix, goserelin and gosereline. Goserelin disclosed in U.S. patent No. 4100274 and you can enter, for example, in the form in which it is sold, for example, under the trade name ZOLADEX™. Abarelix can be prepared, for example, as disclosed in U.S. patent No. 5843901.

The term "anti-androgens" when used in the present invention includes, but is not limited to, bikalutamid (CASODEX™), which can be prepared, for example, as disclosed in U.S. patent No. 4636505.

The term "benhamadi" refers to bengamin and their derivatives with antiproliferative activity.

The term "bisphosphonates" for use in the present invention includes, but is not limited to, trigonomy acid, clodronate acid, tiludronic acid, pamidronovu acid, alendronate acid, ibandronate acid, risedronate acid and zolendronic acid. "Etidronate acid" can be administered, for example, in the form in which it is sold, for example, under the trade name DIDRONEL™. "Clodronate acid" can be administered, for example, in the form in which it is sold, for example, under the trade name BONEFOS™. "Tiludronate acid" can be administered, n is the sample, in the form in which it is sold, for example, under the trade name SKELID™. "Pamidronovu acid" can be administered, for example, in the form in which it is sold, for example, under the trade name AREDIA™. "Alendronate acid" can be administered, for example, in the form in which it is sold, for example, under the trade name FOSAMAX™. "Ibandronate acid" can be administered, for example, in the form in which it is sold, for example, under the trade name BONDRONAT. "Risedronate acid" can be administered, for example, in the form in which it is sold, for example, under the trade name ACTONEL™. "Zolendronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name ZOMETA™.

The term "antiproliferative antibodies" as used in this invention includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, erlotinib (Tarceva™), bevacizumab (Avastin™), rituximab (Rituxan®), PR64553 (anti-CD40) and C antibodies.

For the treatment of acute myeloid leukemia (AML) the compounds of formula I can be used in combination with standard anti-leukemia drugs, preferably in combination with drugs used to treat AML. Preferably the compounds of formula I can be introduced in combination with, for example, inhibitors of f is psytrancer and/or other drugs, used for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubitsin, carboplatinum and RX.

The structure of the active agents have code numbers, generic or trade names that are listed in the latest edition of "The Merck Index" or in databases, for example. Patents International (e.g. IMS World Publications).

The above compounds that can be used in combination with the compound of the formula I, can be obtained and entered as provided in the guidelines in this technical field, for example, in the above-cited documents.

Examples:

The following examples are intended to illustrate the present invention without limiting its scope.

Temperature measured in degrees Celsius. If not specified, the reaction is conducted CT.

Values of Rfthat show the ratio of the distance traveled by each substance to the distance travelled by the eluent front, are determined on plates coated with silica gel (Merck, Darmstadt, Germany) using thin-layer chromatography using the appropriate solvent system.

Conditions for HPLC (high performance liquid chromatography):

Column: (250×4.6 mm)filled with material reversed phase C18-Nucleosil (silica gel with an average particle size of 5 to which are covalently attached to octadecylsilane, Macherey &Nagel, Düren, Germany). Detection by absorption in the ultraviolet region at a wavelength of 215 nm. The retention times (tR) are given in minutes. Flow rate: 1 ml/min Gradient mode: 20%→100% a) in b) over 14 min + 5 min 100% a), a): Acetonitrile + 0.05% of triperoxonane acid (TFA); b: water + 0.05% of TFA.

Used abbreviated forms of words and abbreviations have the following meanings:

VOStert-butoxycarbonyl
DMFN,N-dimethylformamide
MS-ERmass spectroscopy (spraying electrons)
TPLmelting point
TLCthin-layer chromatography
tRthe retention time

Starting material: Tert-butyl ether 4-{4-[4-((R)-1-phenylethylamine)-7H-pyrrolo[2,3-d]pyrimidine-6-yl]-benzyl}-piperazine-1-carboxylic acid

A mixture of 1.6 g (4 mmol) [6-(4-chloromethylene)-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-((R)-1-phenylethyl)-amine (receipt, see example 9, stage 9.3 in WO 03/013541 A1) in 50 ml DMF is treated with 1.56 g (8,mmol) N-BOC-piperazine and 2.76 g (20 mmol) of anhydrous potassium carbonate and the mixture is heated at 65°C for 1 h The reaction mixture is cooled and the inorganic salts are removed by filtration (Hyflo Super Cel®; Fluka, Buchs, Switzerland). DMF is evaporated under reduced pressure and the residue purified using flash chromatography using first a mixture of dichloromethane/ethanol 95:5, and then a mixture of dichloromethane/ethanol 9:1. The desired compound obtained as solids; TPL 244-246°C; MS-ER+: (M+N)+=513; TLC Rf(dichloromethane/ethanol 9:1) 0,46.

Example 1: ((R)-1-Phenylethyl)-[6-(4-piperazine-1-ylmethylene)-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-amine

Tert-butyl ether 4-{4-[4-((R)-1-phenylethylamine)-7H-pyrrolo[2,3-d]pyrimidine-6-yl]-benzyl}-piperazine-1-carboxylic acid (1.8 g, 3.5 mmol) is dissolved in 150 ml of dioxane at low heat. To this solution was added 4 n hydrochloric acid in dioxane (Aldrich, Buchs, Switzerland) (5 ml, 20 mmol) and the mixture is stirred at a temperature equal to from 50 to 60°C for 1 h, the resulting suspension is diluted with 75 ml of methanol is stirred for another 1 h at boiling under reflux, and then the mixture is cooled and the solvent is evaporated. The residue is dissolved in dilute hydrochloric acid and washed with ethyl acetate. The aqueous phase is treated with solid potassium carbonate to alkaline reaction and evaporated. The residue, which contains inorganic salts, purified using the lash-chromatography using a mixture of dichloromethane/methanol 7:3, containing 1% concentrated ammonia. Pure fractions dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate and evaporated and get the desired compound in the form of solids; TPL 240-242°C; MS-ER+: (M+N)+=413; TLC Rf(a mixture of dichloromethane/methanol 7:3, containing 1% concentrated ammonia) to 0.35; HPLC tR=6,86 minutes

Example 2: Capsules filled with dry substance

5000 Capsules, each of which contains as an active ingredient 0.25 g of the compound obtained in example 1 is prepared as follows:

Composition

the active ingredient1250
talc180 g
wheat starch120 g
magnesium stearate80 g
lactose20 g

Method of preparation: These materials are crushed into powder and pass through a sieve with openings of 0.6 mm Portions mixture of 0.33 g placed in gelatin capsules using a machine for filling capsules.

Example 3: Soft capsules

5000 soft gelatin Capsules from, each of which contains in ka is este active ingredient 0.05 g of the compound, obtained in example 1 is prepared as follows:

Composition

the active ingredient250 g
PEG 4001 l
Tween 801 l

Method of preparation: the Active ingredient is crushed into a powder and suspended in PEG 400 (polyethylene glycol having Mg equal to from about 380 to about 420, Fluka, Switzerland), and Tween® 80 (polyoxyethylenesorbitan. Atlas Chem. Ind. Inc., USA, supplied by the company Fluka, Switzerland) and the mill, fine grinding is subjected to wet milling to obtain a particle size of about 1 to 3 μm. Then portions of a mixture of 0.43 g placed in capsules soft gelatin using a machine for filling capsules.

1. The compound of the formula I

in which R1denotes phenyl;
G denotes a1-C7-alkylen;
Q represents-NH - and
X denotes a1-C7-alkylen,
or its salt.

2. The compound of formula I according to claim 1, in which
R1denotes phenyl;
G denotes a1-C3-alkylen;
Q represents-NH - and
X denotes a1-C3-alkylen,
or its salt.

3. The compound of formula I according to claim 1, in which
R1denotes phenyl;
G about who appoints-CH 2-;
Q represents-NH - and
X denotes-CH2- or-CH(CH3)-,
or its salt.

4. The compound of formula I according to claim 1, which is a ((R)-1-phenylethyl)-[6-(4-piperazine-1-ylmethylene)-7H-pyrrolo[2,3-d]pyrimidine-4-yl]-amine or its pharmaceutically acceptable salt.

5. The compound of formula I according to any one of claims 1 to 4, is able to inhibit proteincontaining or their pharmaceutically acceptable salts, intended for use in the method of treatment of the human or animal.

6. Pharmaceutical composition having the ability to inhibit proteincontaining comprising the compound of the formula I according to any one of claims 1 to 5, or its pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier.

7. The use of the compounds of formula I according to any one of claims 1 to 5, or its pharmaceutically acceptable salts for the preparation of pharmaceutical compositions intended for the treatment of disease that is affected by inhibition proteincontaining.

8. The method of obtaining the compounds of formula I according to claim 1, or salts of such compounds, which consists in the fact that the compound of formula II

in which Hal denotes halogen, G denotes a1-C7-alkylene and R1, Q and X have the meanings specified for compounds of formula I, is introduced into reaction with PI is arasina;
when the functional group contained in the original compounds and are not intended to participate in the reaction, if necessary, are in protected form, and the protective group, which contains, hatshepsuts, and these initial compounds can also be in the form of salts provided that contain a salt-forming group and possible reaction with the salt;
and, if necessary, the thus obtained compound of the formula I is converted into another compound of formula I, a free compound of formula I is transformed into salt obtained salt of a compound of the formula I is converted into the free compound or another salt, and/or a mixture of isomeric compounds of formula I is separated into the individual isomers.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to new pyridine derivatives or to their pharmaceutically acceptable salts of general formula 1: wherein R1, R2, R3, R4, R5, R6 and R7 are independently chosen from the group including hydrogen atom, halogen, amino, C1-C6lower alkyl, C2-C6lower alkenyl, C1-C6lower alkoxy, C1-C10alkylamino, C4-C9cycloalkylamino, C4-C9heterocycloalkylamino, C1-C10aralkylamino, arylamino, acylamino, saturated heterocyclyl, acyloxy, aryl, heteroaryl, C1-C10aralkyl, aryloxy; X represents oxygen or sulphur atom; Y represents oxygen atom or N-R8, wherein R8 is chosen from the group including hydrogen atom; aforesaid aryl group is chosen from phenyl, naphthyl and condensed phenyl group; aforesaid heteroaryl and saturated heterocyclic groups represent pentagonal or hexagonal heterocyclic ring containing 1 to 2 heteroatoms chosen from oxygen, nitrogen and sulphur atom; or condensed heterocyclic ring; and aforesaid aryl and heteroaryl groups are those that 1 to 4 assistants chosen from group including halogen, C1-C6lower alkyl, C1-C6lower alkoxy are substituted. And specified compounds or their pharmaceutically acceptable salt of formula 1 are not compounds as follows 6-methyl-3,4-dihydro-pyrano[3,4-c]pyridin-1-one, 5-vinyl-3,4-dihydro-pyrano[3,4-c]pyridin-1-one, 6-methyl-8-furan-2-yl-3,4- dihydropyrano[3,4-c]pyridin-1-one, 3-tert-butyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-8-one and dimethyl ether (3S)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-[2,7]naphthyridine-3,5-dicarboxylic acids.

EFFECT: compounds possess inhibitory action with respect to formation of cytokines involved in inflammatory reactions, can be used as a therapeutic agent for treatment of inflammatory diseases, immune diseases, chronic inflammations; it provides antiinflammatory and analgesic action.

21 cl, 7 tbl, 144 ex

FIELD: chemistry.

SUBSTANCE: described is novel application of 2-methylthio-5-methyl-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-on. Substance possesses anti-viral activity with respect to flue A (H5N1) virus, West Nile virus and other viral infections. Wide-spectrum anti-viral activity is discovered for the first time.

EFFECT: obtaining anti-viral substance with wide spectrum of action.

1 cl, 8 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diazaindoledicarbonylpiperazinyl compounds of formula I, including its pharmaceutically acceptable salts, which possess antiviral activity and can be used for HIV-infection treatment. In compounds of formula I Q represents , T represents -C(O)- or -CH(CN)-; R1 represents hydrogen; R3 represents hydrogen; R5 is independently selected from group including halogen, cyano, XR9 and B; R2 and R4 are absent; R6 represents hydrogen; -- represents carbon-carbon bond; -Y- is selected from group including , each of R10, R11, R12, R13, R14, R15, R16 and R17 represents H; R18 is selected from group including C(O)-phenyl, isoquinolyl, quinazolyl; D is selected from group including cyano, 5-member heteroaryl containing 3 heteroatoms selected from nitrogen and oxygen; A is selected from group including phenyl, pyridinyl; B is selected from group including -C(O)CH3; piperazinyl; 5-, 6-member heteroaryl containing 1-3 N atoms and possibly O atom; where said heteroaryl optionally is substituted with from one to three similar or different substituents selected from F; F is selected from group including (C1-6)alkyl, phenyl, pyridinyl, COOR26, -COR21, and -CONR24R25; where phenyl is optionally substituted with (C1-6)alkoxy, CF3, or halogen atom; R9, R24, R25 and R26 each is independently selected from group including hydrogen and (C1-6)alkyl; X represents O; R27 represents piperazinyl, N-methylpiperazinyl, or 3-pirazolyl. Invention also relates to pharmaceutical composition.

EFFECT: obtaining compounds and pharmaceutically acceptable salts, which possess antiviral activity and can be used for treatment of HIV infection.

19 cl, 50 dwg, 4 tbl, 43 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry, medicine.

SUBSTANCE: selective antituberculous agents represent substituted 7-aryl(heteryl)-4,7-dihydro-1,2,4-triazole/1,5-a/pyrimidines of general formula A or B or their pharmaceutically acceptable additive sodium or potassium salts of the compound B, where in the formula A R1 = hydrogen atom; R2= aryl selected from the possibly substituted phenyl or heteryl selected from the thienyl, pyridyl, indolyl, pyrrolyl with substituted phenyl having 1-3 substituting groups selected from the group including methoxy-, nitro- and hydroxyl- groups; in the formula B R1 = hydrogen atom, C1-C12 alkyl or C1-C12 thioalkyl; R2 = aryl selected from the possibly substituted phenyl or heteryl selected from the thienyl, pyridyl, indolyl, pyrrolyl with substituted phenyl having 1-3 substituting groups selected from the group including methylenedioxy-, hydroxyl-, bromine, C1-C6 alkyl and C1-C6 alkoxy groups and substituted heteryl having substituting group selected from bromine, C1-C6 alkoxy and C1-C6 alkyl groups. The invention refers also to the method for preparation of the compounds with general formula A including the heating of the equimolar amounts of aryl- or heteroarylaldehyde, acetoacetic ester and aminotriazole in the aliphatic alcohol under ultrasonic action and to the pharmaceutical composition.

EFFECT: in comparison with the analogues the claimed agents possess higher activity and lower toxicity.

4 cl, 8 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones with general formula (I), including all their enantiomeric and diastereomeric forms, as well as their pharmaceutically used salts, which inhibit undesirable or excessive excretion of cells of phlogistic cytokines, chosen from "ФНО-α" and "ИЛ-1β" and can be used for treating congestive heart failure, for example. In formula (I): R is: a) -O[CH2]kR3, where k=0; or b) -NR4aR4b; R3 is substituted or unsubstituted with phenyl, in which substitutes are chosen from halogen, C1-C4 alkyl; one of R4a and R4b is a independently a hydrogen atom; and the other of R4a and R4b is b) -[C(R5aR5b)]mR6; R5a and R5b each is independently a hydrogen atom, straight, or branched alkyl C1-C4, R6 is substituted or unsubstituted with alkyl C1-C4, in which substitutes are chosen from -OR7, cyano, phenyl, 6-member saturated heterocycle, containing a heteroatom in form of nitrogen, unsubstituted 5-6-member heteroaryl, containing 1-2 heteroatoms, chosen from nitrogen and oxygen; group R7 is a hydrogen atom, water soluble cation, alkyl C1-C4, index m assumes values from 0 to 5; R1 is: a) unsubstituted or substituted by 1-2 substitutes, chosen from halogen or C1-6alkyl, phenyl; L is a bridge group, chosen from: 1) -[C(R12)2]n-, where each R12 denotes hydrogen or together with two R12 groups form a carbonyl group, n= 1-2 ; 2) -[C(R12)2]nNR12[C(R12)2]n-, chosen from -[CH2]nNHC(O)- group, where n=1-2; and 3)-[C(R12)2]nO[C(R12)2]n-, where n=0; each R2 fragment is independently chosen from hydrogen; Z is O.

EFFECT: agents are highly effective.

24 cl, 4 dwg, 10 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new pyrrolopyrimidinone derivatives with formula (I) and their pharmaceutically used salts, with inhibition properties towards GSK-3, as well as to intermediate compounds with formula (Ic). In compounds with formula (I) and formula (Ic)

A1 is -(CH2)2- or -(CH2)3-; A is a single bond or a group, which links A1 and G1 in form of A1 -C(=O)-G1, A1- (C=O)-O-G1, A1 -(C=O)-NR101-G1, A1-O-(C=O)-G1, A1 -NR104-G1, A1-NR105-(C=O)-G1, A1-NR106-S(=O)2-G1, A1-NR107-(C=O)-O-G1 or A1-NR108-(C=O)-NR109-G1; G1 is a single bond or a bivalent group, which can be obtained through removal of two hydrogen atoms from any alicyclic hydrocarbon with 3-6 carbon atoms, phenylene, monocyclic or cyclic aromatic heterocyclic compound with 2-9 carbon atoms, with 1-2 heteroatoms in a ring, chosen from O or N, or monocyclic heterocyclic compound 2-6 carbon atoms, with 1-2 heteroatoms in a ring, chosen from O or N; A3 is a single bond or bivalent acyclic aliphatic hydrocarbon group with 1-3 carbon atoms, which links G1 with A4 of the same or different carbon atom; A4 is a single bond or a group, which links A3 with G2 in form of A3-C(=0)-G2, A3-C(=0)-0-G2, A3-C(=0)-NR121-G2, A3-O-G2, A3-NR124-G2, A3-NR125-C(=0)G2 or A3-S-G2. Description of other radical is given in the formula of invention.

EFFECT: compounds can be used in treating such diseases as diabetes, neurodegenerative diseases and others.

43 cl, 3 tbl, 513 ex

FIELD: pharmacology.

SUBSTANCE: described are C-6 modified indazolyl pyrrolotriaxolines of formula I and their pharmaceutically acceptable salts, where R is selected from group consisting of phenylm phenyl substituted with halogen atom, non-substituted oxazolyl, thienyl, thiazolyl, pyridyl, pyrazinyl; R1 is selected from group consisting of methyl, ethyl and isopropyl; R2 is selected from group consisting of benzyl, imidazolylethyl, (methylimidazolyl)-ethyl, pyperidinylethyl, pyridinylpropyl and other, given in item 1 of invention formula, X is selected from group consisting of bond, O, NR3; and N(R3)2; R3 is independently selected from group consisting of hydrogen, methoxyethyl, diethylaminoethyl, pyrrolidinylethyl. Also described are pharmaceutical composition for treatment of proliferative disease, methods of disease treatment. Compounds of formula I inhibit tyrosine kinase activity of growth factor receptors such as HER1, HER2 and HER4, which makes them useful as anti-cancer agents.

EFFECT: compounds are anti-cancer agents and are useful for treatment of other diseases connected with pathways of signal transduction acting through growth factor receptors.

23 cl, 4 tbl, 175 ex

FIELD: medicine.

SUBSTANCE: invention relates to group of the new compounds presented by structural formulas A-K ,

and their pharmaceutically acceptable isomers, salts, salvates and to polymorphous forms.

EFFECT: inhibitory action with respect to thrombin receptors.

20 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: new 5-sulphanyl-4H-1,2,4-triazole derivatives of general formula I (meaning of radicals R1-R3 are indicated in the description of the invention), methods of their preparation by liquid-phase parallel synthesis and pharmaceutical composition are claimed.

EFFECT: claimed compounds display high affinity to some subtypes of somostatin receptors of the SST2 and SST5 subtypes and possibility of their usage for treatment of pathological states or diseases involving one or more of the given somostatin receptors

9 cl, 708 ex

FIELD: chemistry.

SUBSTANCE: in formulas (I) and (Ia) . A is 1-cyclopentene-1,2-diyl; Z1 and Z2 are O; E is phenyl substituted with 1-4 substituting groups selected from halogen, Y is phenyl substituted with 1-2 substituting groups selected from halogen, C1-C6alcoxy, halogen C1-C6alcoxy; the meaning of other radicals are indicated in the formula of the invention. The invention refers also to the pharmaceutical composition including the compound of the invention, to the application of the said compound at preparation of the medicinal agent and to the application for DHODH inhibition.

EFFECT: compound of the present invention can find application as medicinal agent inhibiting dehydroorotate dehydrogenase.

9 cl, 18 ex

FIELD: medicine.

SUBSTANCE: therapy of rectal cancer is ensured by preoperative beam therapy "РОД" 5 Gy during 5 days, in combination with local microwave hyperthermia at temperature 42.5-43°C during 60 minutes for 3, 4 and 5 days after beam therapy sessions. A composite mixture containing sodium alginate, 2% dimethyl sulfoxide and 5-fluorouracil is introduced through rectum at exposition 6 hours in 1, 2 and 4 days prior to beam therapy sessions. For 3 and 5 days, at the same exposition, said composite mixture containing metronidazole instead of 5-fluorouracil is introduced. Further, surgical procedure follows.

EFFECT: due to selected introduction regiment of chemotherapeutical preparations as parts of the composite mixture, the method provides high concentration thereof in rectal tumours without side effect, ensures high degree of beam pathomorphism in vast majority of the patients of said category, the absence of recurrent tumour and dissemination within 3 postoperative years.

2 ex

FIELD: medicine.

SUBSTANCE: treatment of benign prostate hyperplasia is ensured by oral introduction of a biologically active food additive "Photostim" as a photosensitiser within the first 10 therapeutic days in a dose 2.5 ml. Further, "Photostim" is dosed 5 ml once a day. The whole therapeutic course implies introduction of 100 ml. Starting from the 7-8 therapeutic day, suprapubic region and perineum are exposed to laser radiation of wave length 665-670 nm, power density 100 J/cm2 in continuous radiation condition, by noninvasive transcutaneous action of two fields, 20 minutes on each area as specified. Therapeutic course includes15 daily sessions. A monochromatic light source is a photodynamic therapy complex that comprises high-light semiconductor light-emitting diodes "ELAN" of array radiation wavelength 665-670 nm, in continuous radiation conditions, power density of working array radiation in focal plane 30-60 mWt/cm2 and irradiation spot area in focal plane 40 cm2.

EFFECT: reduction of recovery period, ensured absence of intraoperative injuries, prevention of postoperative complications and cicatricial changes.

2 cl, 1 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition for making a parenteral preparation contains a pharmaceutical agent, a water-soluble polymer, a nonpolymeric additive and a solvent. The water-soluble polymer is chosen from the group: dextran, gelatin, 2-hydroxyethy starch, poly(N-vinylpyrrolidone), human blood serum albumin or their mixture. The nonpolymeric additive is chosen from the group: (C10-C18)acyl-sorbite, oligooxyethylene(C10-C18)acyl-sorbite, (C10-C18)alkyl oligooxyethylene glycol ester. The solvent represents mixed water and ethanol, or dimethyl sulphoxide, or N-methyl-2-pyrrolidone, or 2-pyrrolidone. The pharmaceutical agent, said water-soluble polymer, nonpolymeric additive and residual solvent are found in the preparation as a noncovalent complex.

EFFECT: improved bioavailability of the pharmaceutical agents and therapeutic dose decline.

2 cl, 1 dwg, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to Bcl-2 proteins, fragments thereof, and to application thereof in patients with a malignant tumour. The declared proteins and peptide fragments particularly are applicable in vaccine compositions for treatment of malignant tumour. Besides, the invention concerns the methods of treatment with application of specified compositions. Also, an aspect of the invention is production of T-cells and receptors thereof which are specifically recognise declared proteins and peptide fragments.

EFFECT: higher clinical effectiveness with respect to tumours.

61 cl, 5 ex, 2 tbl, 12 dwg

FIELD: medicine.

SUBSTANCE: 5 days prior to chemotherapy, during chemotherapy and within 5 days after, phyto tea "Gastro-intestinal tea" is introduced orally in a dose 1/2 glass 3 times a day, within 4-6 courses of adjuvant chemotherapy.

EFFECT: reduced rate of gastroenteric complications associated with adjuvant chemotherapy of gastric carcinoma that is ensured by action of the phyto-tea reducing gastro-intestinal toxicity of chemotherapy.

1 ex

Lung cancer therapy // 2367436

FIELD: medicine.

SUBSTANCE: Irinotecan, Cisplatin and Aranose are introduced sequentially in doses making 1/4 of maximum tolerated every 10-20 minutes in two-fold or three-fold administration regimen.

EFFECT: method provides antitumourigenesis ensured by combined effect of the preparations and improved therapy tolerance.

2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: inventions cover preparing the biologically active compounds of chlorine series -photosensitiser (PS) for photodynamic therapy (PDT). The PS contains chlorine e6 with N-methyl-D-glucamine and sodium in molar ratios as follows 1:2:1, and a cryostabiliser. The PS has structural formula (I): Also, th invention discloses the method for making the photosensitiser for photodynamic therapy according to which chlorine e6 is suspended in apyrogenic water; N-methyl-D-glucamine and sodium hydroxide (NaOH) are added in stirring. The prepared chlorine e6 salt solution is filtered with the cryostabiliser added in estimated amount, and lyophilised.

EFFECT: said PS shows prolonged storage-stability, improved service properties and the consumer appeal, extended storage life as a medical preparation.

4 cl, 1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: according to the invention, a matrix tablet contains trimetazidine, polymer of methacrylic acid, wax and adjuvants. Montanic glycolic wax is used preferentially. A core tablets are film coated.

EFFECT: tablet provides prolongation of antiischemic effect to 8 or 12 hours and intake of preparation once or twice a day.

16 cl, 1 dwg, 1 tbl, 7 ex

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