Derivatives of n-phenyl-2-pyrimidinamine or their salts and pharmaceutical compositions on their basis with antitumor activity

 

(57) Abstract:

Derivatives of N - phenyl-2-pyrimidinamine formula I

< / BR>
where R denotes the associated carbon atom of the pyridyl or N - oxidability, R2, R3, R6, R8, R9is hydrogen, R4is hydrogen or lower alkyl, R5is hydrogen, lower alkyl or trifluoromethyl, R7-nitro, fluoro-substituted lower alkoxy or a residue of formula II-N(R9)-C(O)-R10, R10- the associated carbon atom of the pyridyl, C5-C7-alkyl, thienyl, 2-naphthyl, cyclohexane or optionally substituted by halogen, cyano, lower alkoxyl, carboxyla, lower alkyl or 4-methylpiperazine, phenyl, or their salts. Farmcampsite, based on the connection I have antitumor activity. 2 C. and 25 C. p. F.-ly, 2 Il, 2 tab.

The invention relates to derivatives of N-phenyl-2-pyrimidinamine formula

< / BR>
where R1means associated carbon atom of the pyridyl and N-oxidability, R2and R3mean hydrogen, R4is hydrogen or lower alkyl, R5is hydrogen, lower alkyl or trifluoromethyl, R6is hydrogen, R7- nitro, fluoro-substituted lower alkoxy or a residue of formula II

-N(R9)-C(=O)-R10(II)

detil or cyclohexyl, or optionally substituted by halogen, cyano, lower alkoxyl, carboxyla, lower alkyl or 4-methylpiperazine phenyl, R8hydrogen, or salts of these compounds with at least one salt-forming group.

Associated carbon atom to the pyrimidine ring pyridyl means 2-, 4-, or 3-pyridyl, preferably 3-pyridyl.

Fluoro-substituted lower alkoxy means lower alkoxyl carrying one, preferably several fortuntately, in particular, triptoreline or 1,1,2,2-tetrafluoroethoxy.

The prefix "lower" in the context of this invention means radicals having 1-7 carbon atoms, preferably 1-4 carbon atoms.

Lower alkyl means preferably methyl or ethyl.

An aliphatic radical R10at least 5 C atoms is preferably not more than 22 C atom, as a rule, not more than 10 C atoms and denotes a substituted or preferably unsubstituted alkynylaryl, alkanniny or preferably an alkyl radical, as, for example, C5-C7-alkyl, for example n-pentyl. An aromatic radical R10has up to 20 C atoms and is unsubstituted or substituted, for example, respectively neoprene preferably from cyano, unsubstituted or substituted by hydroxy, amino or 4-methylpiperazine (lower alkyl), such as, in particular, methyl, trifloromethyl, free, esterified hydroxy, free, alkylated or acylated amino and free or esterified carboxy. In the aromatic-aliphatic radical R10aromatic portion has the above definition, and the aliphatic part represents preferably lower alkyl, such as, for example, C1-C2-alkyl, which is substituted or preferably unsubstituted, for example, benzyl. Cycloaliphatic radical R10has, in particular, to 30, mainly to 20, and first to 10 C atoms is mono - or polycyclic, and substituted or preferably unsubstituted, for example, in particular, 5 - or 6-tier cycloalkenyl radical, as, for example, preferably cyclohexyl. In cycloaliphatic-aliphatic radical, the radical R10denotes a cycloaliphatic part, as described above, and the aliphatic part represents preferably lower alkyl, e.g. C1-C2-alkyl, which is substituted or preferably unsubstituted. Heterocyclic radical R10contains, in caimi links and 1 to 3 heteroatoms, which are preferably selected from nitrogen, oxygen and sulfur, in particular, for example, thienyl or 2-, 3 - or 4-pyridyl or bi - or tricyclic radical, where, for example, on the specified monocyclic radical condensed (Annelida) one or two benzene radicals. In geterotsiklicheskikh-aliphatic radical, the radical R10denotes a heterocyclic as defined above and the aliphatic part represents preferably lower alkyl, such as, for example, C1-C2-alkyl, which is substituted or preferably unsubstituted. Esterified simple ether hydroxyl group preferably denotes lower alkoxy. Esterified complex ether hydroxyl group is esterified complex ether hydroxyl group, preferably an organic carboxylic acid, such as lower alanovoy acid, or with inorganic acid, such as halogen acid, such as lower alkanoyloxy or, in particular, halogen, such as iodine, bromine or, in particular, fluorine or chlorine.

Alkilirovanny amino is, for example, lower alkylamino, as, for example, methylamino, or di-lower alkylamidoamines.

Esterified complex ether carboxyl represents, for example, the lowest alkoxycarbonyl, as, for example, methoxycarbonyl.

Substituted phenyl radical may carry up to 5 substituents, such as fluorine, however, particularly with larger substituents, typically replaced only one triple. As examples for substituted phenyl note 4-chlorophenyl, pentafluorophenyl, 2-carboxyphenyl, 2-methoxyphenyl, 4-forfinal, 4-cyanophenyl and 4 were.

Soleobrazutaya group in the compound of formula I represent groups or radicals with basic or acidic properties. Connection with at least one basic group or at least one basic radical, for example, one free amino group, one PersonalEdition or one piridiletilen can form salts accession acid, for example, with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, for example aliphatic mono - and dicarboxylic acids, such as, for example, triperoxonane acid, acetic acid, propionic acid, glycolic acid, amber is citric acid, oxalic acid, or amino acids, such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-aminosalicylic acid, aromaticheski-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such as nicotinic acid or isonicotinoyl acid, aliphatic sulfonic acids, such as methane-, ethane - or 2-oxetanemethanol, or aromatic sulphonic acids, such as, for example, benzoyl-, p-toluene - or naphthalene-2-acid. If there are several basic groups can form salts accession mono - or PolicyKit.

The compounds of formula I with acid groups, for example, a free carboxyl group in the radical R10, can form metal salts or ammonium, as, for example, salts of alkaline or alkaline earth metals, for example salts of sodium, potassium, magnesium or calcium or ammonium salts with ammonia or suitable organic amines, such as, for example, Triticum monoamines, for example triethylamine or tri-(2-oxyethyl)-amine, or heterocyclic OS is to sour, and basic groups can form internal salts.

For isolation or purification of compounds, also used as an intermediate product, can be used pharmaceutically unsuitable salts. For therapeutic use apply only pharmaceutically usable, non-toxic salts, which are consequently preferred.

Due to the close relationship between the new compounds in free form and in the form of their salts, including those salts that can be used as intermediate products, for example, when cleaning new compounds or for their identification, under the free compounds mentioned above and listed below, it should be understood also the corresponding salts.

The compounds of formula I have valuable pharmacological properties and can be used, for example, as an antitumor agent and as an agent against atherosclerosis.

Phosphorylation of proteins has long been known as an important tool in the differentiation and proliferation of cells. Phosphorylation is catalyzed by protein kinases, which are divided into serine/trionychinae and tyrosine kinase. To serine/trionychinae concerns about the ASS="ptx2">

The compounds of formula I, where R4and R8denote hydrogen, selectively inhibit the enzyme protein kinase C.

Protein kinase C-dependent phospholipid or calcium, is found inside cells in several species (species distribution in tissue characteristics) and participates in various key processes, such as signal transduction, proliferation and differentiation, as well as extraction of hormones and neurotransmitters. Activation of this enzyme is carried out either by hydrolysis of the phospholipids of the cell membrane with receptors, either by direct interaction with certain biologically active substances that accelerate tumor growth. Cellular functions controlled by protein kinase C, may be exposed to changes in the enzymatic activity of protein kinase C.

To determine an overwhelming effect on protein kinase C use the protein kinase C from pig brain, which is purified according to the method described by T. Uchida and C. R. Filburn in the journal J. Biol. Chem. 259, 12311-4 (1984). The definition of the overwhelming effects on the protein kinase C compounds of the formula I is carried out according to method D. Fabro et al., Arch. Biochem. Biophys. 239, 102-111 (1985). In this test, compounds of formulas is RNO between 0.05 and 5 mmol/L. In contrast, the compounds of formula I inhibit other enzymes, such as protein kinase A, patientstreatment and certain types proteincontaining, for example, proteincontaining receptor EGF (epidermal growth factor), only with significantly elevated concentrations of, for example, a hundred times. It shows the selectivity of the compounds of formula I. Taking into account the reduction of unwanted side effects, it is important that substances that inhibit the protein kinase C, were also selective. Thus other enzymes are possibly insignificant impact, in particular, if the effect of the activity of other enzymes, given treatable disease, is not ravnodeystvuiushchey or sinergeticheskogo effect.

Based on the inhibitory effect on protein kinase C the compounds of formula I, where R4and R8denote hydrogen, and their salts used in the pharmaceutical industry, can be used as a suppressing tumor growth, immunomodulating and antibacterial biologically active substances, in addition, as a measure against atherosclerosis, diseases of the immune system of AIDS, and diseases of the cardiovascular system and Central the formula I, where R4and R8denote hydrogen, and their salts used in the pharmaceutical industry, have properties against a rapid increase of neoplasms that can be demonstrated by the following experiment: to determine the inhibitory effect of compounds of the formula I on the growth of human cancer cells T24 bladder. These cells are incubated in minimal supportive environment Eagle", which add 5% (v/v) embryonic calf serum in a humid incubator at a temperature of 37oC and 5 volume% CO2in the air. Cancer cells (1000 - 1500) subcultured in 96-cellular microtiter plates and incubated in the above conditions during the night. The test substance add diluted in the first day. Tablets incubated in the above conditions for 5 days. During this period of time the control culture are at least 4 cell division. After incubation, the cells fixed with 3.3% (weight/volume) aqueous glutaraldehyde solution, washed with water and paint to 0.05% (weight/volume) aqueous methylene blue solution. After washing the dye elute 3% (weight/volume) aqueous hydrochloric acid. Then measure the optical density (OD) in each echeneididae using a computer system when using the formula

< / BR>
The value of the IC50determine the concentration of biologically active substances, in which the number of cells in each cell at the end of the incubation time reaches only 50% of the number of cells in the control cultures. Thus obtained value of the IC50are for compounds of formula I is between about 0.1 and 10 µmol/L.

On the basis of the described properties of the compounds of formula I, where R4and R8denote hydrogen, can be used as biologically active substances that suppress tumor growths, for example, for the treatment of bladder tumors.

In addition, they can be used, as described above, to change the protein kinase C, and, in particular, for diseases requiring suppression of protein kinase C.

The compounds of formula I, where R4and R8denote hydrogen, partially inhibit not only the protein kinase C, and when the concentration of the IC50between about 0.01 and 5 mmol/l, in particular between about 0.05 and 1 µmol/l, specific tyrosine kinase, such as PDGF-receptor-kinase or abl-kinase, for example, v-abl-kinase. The compounds of formula I where the radical R4different from hydrogen, and denotes, for example, lower alkyl, as SS="ptx2">

PDGF (growth factor platelet derived) is a very frequently occurring growth factor that plays an important role in normal growth and in pathological cell proliferation, such as, for example, in the case of cancer and diseases of smooth muscle cells of blood vessels, such as atherosclerosis and thrombosis.

Suppression of protein kinase C and protein kinase receptor PDGF acts in this sense, with quasienergies effect in the same direction relative to the regulation of cell growth.

Inhibition of tyrosine kinase activity of the receptor, PDGF stimulates, measured in vitro in the immune complexes of the PDGF receptor cells BALB/c3T3, similarly to the description of E. Andrejaukas-Buchdunger and U. Regenass in Cancer Research 52, 5353-5358 (1992).

The above compounds of formula I inhibit PDGF-dependent cell-free phosphorylation of the receptor at a concentration of 0.005 - 5 µmol/l, in particular from 0.01 to 1.0, mostly from 0.01 to 1.0 mmol/L. Suppression of tyrosine kinase to the PDGF receptor in intact cells can be traced using the graphical analysis of Western (Western), also similar to the description in the above publication in Cancer Research. In this test, suppression of stimulated legenday autophosphorylation of the PDGF receptor in AWT the tyrosine kinase activity of the PDGF receptor at a concentration of 0.005 - 5 mmol/l, in particular from 0.01 to 1.0, preferably 0.01 - 0.1 µmol/L. in Addition, these compounds at concentrations below 1.0 mmol/l also inhibit the growth of cells of a cell line-dependent PDGF, namely mouse fibroblast BALB/c3T3.

The above-mentioned suppression of v-abL-tyrosine kinase is determined by the methods of N. Lydon et al., Oncogene Research 5, 161-173 (1990) and J. F. Geissler et al., Cancer Research 52, 4492 - 4498 (1992). The substrates used [Val5]-angiotensin II and [32P]-ATP.

On the basis of the described properties of the compounds of formula I can be used not only as biologically active substances that suppress tumor lesions, but also as a tool against atherosclerosis and thrombosis. In addition, they are treated as modulators of protein kinase C and can be used in particular for the treatment of diseases requiring the suppression of the kinase activity of the PDGF receptor.

In addition, the compounds of formula I inhibit the formation of resistance (resistance to many drugs) in the treatment of cancer and other chemotherapeutics or eliminate existing resistance to other chemotherapeutic agents.

In the first preferred are the trace of the steel substituents have the above for formula I values, and their pharmaceutically acceptable salts, containing at least one salt-forming group;

derivatives of N-phenyl-2-pyrimidinamine formula I, in which R4means the lower alkyl and the other substituents have the above for formula I values, and their pharmaceutically acceptable salts, containing at least one salt-forming group;

derivatives of N-phenyl-2-pyrimidinamine formula I, where R1means associated carbon atom of the pyridyl, R2, R3, R4, R5, R6and R8mean hydrogen, and R7means the nitro-group or a residue of formula II, where R9means hydrogen, R10is a linked carbon atom of the pyridyl, C5-C7alkyl, thienyl, cyclohexyl or optionally substituted by fluorine, chlorine, cyano, lower alkoxyl, carboxyla, lower alkyl or 4-methylpiperazine phenyl, and their pharmaceutically acceptable salts.

Of these compounds, especially preferred are the following compounds

N-(3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-[3-(4-chlorobenzylamino)-phenyl] -4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable Sol(2-pyridyl)carboxamide] -4- (3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-[3-(3-pyridyl)carboxamide] -4- (3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-[3-(4-pyridyl)carboxamide] -4- (3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-(3-pentafluorobenzenesulfonyl)-4- (3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-[3-(2-carboxybenzoyl)-phenyl] -4- (3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-(3-p-hexanolactone)-4- (3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-(3-nitrophenyl)-4- (4-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-[3-(2-methoxybenzamido)-phenyl] -4- (3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-[3-(4-perbenzoate)-phenyl]-4- (3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-[3-(4-cyanobenzoyl)-phenyl] -4- (3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-[3-(2-thienylboronic)-phenyl] -4- (3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-(3-cyclohexylcarbonyl)-4- (3-pyridyl-2-pyrimidinamine, or its pharmaceutically acceptable the al;

N-[3-(4-chlorobenzylamino)-phenyl] -4- (4-pyridyl-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N - {3-[4-(4-methylpiperazine)-benzoylamino] -phenyl}-4- (3-pyridyl-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-(5-benzoylamino-2-were)-4- (3-pyridyl-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-{5-[4-(4-methylpiperazine)-benzoylamino]-2-were}-4- (3-pyridyl-2-pyrimidinamine, or its pharmaceutically acceptable salt;

N-[5-(4-methylbenzylamino)-2-were] -4- (3-pyridyl-2-pyrimidinamine, or its pharmaceutically acceptable salt.

The compounds of formula I and salts of these compounds with at least one salt-forming group can be obtained in the following ways:

a) compound of formula III

< / BR>
where R11and R12independently from each other signify lower alkyl, and R1, R2and R3have the above values, and, if in a compound of formula III has a functional group, they can be optionally protected, with the exception of the groups participating in the reaction, or a salt of this compound is subjected to interaction with the compound of the formula IV

< / BR>
where the substituents have the above significance, or it is involved in the reaction, are optionally in protected form, and otscheplaut existing protective group;

b) to obtain the compounds of formula I where the radicals R4, R5, R6and R8have the above significance, and R7means the residue of formula II-N(R9)-C(= O)-R10the compound of formula V

< / BR>
where the radical R16means the amino group and the radicals R13, R14, R15and R17mean hydrogen, and the other substituents having the above meanings, is subjected to the interaction with the compound of the formula VI

HO-C(=O)-R10(IV)

where the substituents and symbols have the above meanings, and are available in the connection formula VI functional groups, with the exception of participating in the reaction HO-C(=O)-groups are optionally in protected form, or subjected to interaction with reactive derivatives of compounds of formula VI and otscheplaut, if necessary, existing protective group;

to obtain the compounds of formula I, where R1means N-oxidability, and where the other substituents and symbols have the above values, the compound of formula I, where R1means pyridyl, transform, using a suitable oxidizing agent in N-oxidisation, and when th salt of the compounds of formula I is converted into the free compound.

The implementation of the above variants of the method explained in the following way:

In General:

The ultimate substances of the formula I can contain substituents that can be used as a protective group in the source materials for the production of other final compounds of the formula I. Therefore, as a "protective group" in the context of this text, if no other means is called only such easy tsepliaeva group, which is not a part corresponding to the end of the substances of the formula I.

Protective groups, their introduction and removal are described, for example, "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, and in "Methods der organischen Chemie", Houden-Weyl, 4th. Edition, Bd. 15/1, Georg-Thieme-Verlag, Stuttgard 1974, and in Theodora W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York, 1981. Typical protective groups is that they can be chipped off without undesirable side reactions, for example, convolutions, rehabilitation, or photolytic also under physiological conditions.

Hydroxyl protective groups are, for example, allergically, as in this case, for example, substituted with halogen low alkanoyl, as for example, 2,2-dichloroacetyl, or allergically complex floor is for example, 4-nitrobenzenesulfonyl, or diphenylmethylene, or 2-halogen(low alkoxycarbonyl), as, for example, 2,2,2-trichlorocyanuric, in addition, trityl or formyl, or organic silyl or stannyl-radicals, in addition, easily otsepleniya esterified simple ether group, such as tert.-lower alkyl, for example tert.-butyl, 2-oxa - or 2-Realitatea or cycloaliphatic hydrocarbon radicals, primarily 1-(lower alkoxy)lower alkyl or 1-(lower alkylthio)lower alkyl, for example, methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 1-oxa - or 2-tazelaar with 5-6 ring atoms, for example, tetrahydrofuran or 2-tetrahydropyranyl, or appropriate dianalove, and in this case, the substituted 1-(phenyl)lower alkyl, in this case, substituted benzyl or diphenylmethyl, and as the substituents of the phenyl radicals are considered, for example, halogen, namely chlorine, lower alkoxy, such as methoxy, and/or nitro.

A protected amino group may be, for example, can easily split acylamino, arylmethylidene-etherified simple live mercaptamine-, 2-acyl-lower ALK-1-enylamine the cyl is for example, allergical organic carboxylic acids containing, for example, up to 18 carbon atoms, in particular, alkenylboronic acid substituted in this case, for example, halogen or aryl, or benzoic acid substituted in this case, for example, by halogen, lower alkoxy or nitro, or complex Palmyra carbonic acid. Such acyl groups are, for example, the lowest alkanoyl, as, for example, formyl, acetyl or propionyl, halogen-lower alkanoyl, as, for example, 2-halogenoacetyl, in particular, 2-chloro-, 2-bromo-, 2-iodine-, 2,2,2-Cryptor - or 2,2,2-trichloroacetyl, in this case, benzoyl, substituted with halogen, lower alkoxy or nitro, for example benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or branched in the first position of the lower alkyl radical or substituted appropriately in 1 or 2 position the lower alkoxycarbonyl, in particular, tert.-lowest alkoxycarbonyl, for example, tert.-butyloxycarbonyl, arylethoxysilanes with one or two aryl radicals, represented in this case preferably through lower alkyl, in particular tert.-lower alkyl, such as tert. -butyl, lower alkoxy, such as methoxy group, hydroxyl group, haloperoxidase, for example, 4-nitrobenzenesulfonyl, or substituted diphenylmethylene, for example, benzylaminocarbonyl or di-(4-methoxyphenyl)-methoxycarbonyl, roulettecasino where arolina group is in this case, for example, benzoyl, substituted preferably by halogen, such as bromine, for example, ventilatsioonil, 2-halogen-lower alkoxycarbonyl, for example, 2,2,2-trichlorocyanuric, 2-pomatoceros or 2-iodoxybenzoic, or 2-(tizamidine silyl)-etoxycarbonyl, where the substituents independently of one another mean in this case substituted, for example, lower alkyl, lower alkoxy, aryl, halogen or nitroaromatics, analiticheskii, cycloaliphatic or aromatic hydrocarbon radical containing up to 15 C atoms, such as, for example, corresponding, in this case, substituted lower alkyl, phenyl(lower alkyl), cycloalkyl or phenyl, such as 2-[three(lower alkyl)silyl]etoxycarbonyl, such as 2-trimethylsilylethynyl or 2-(di-n-butylmethylether)etoxycarbonyl, or 2-trainsimulator, as, for example, 2-trivinylcyclohexane.

Others considered as aminosidine groups, acyl radicals also Prester, di(lower alkyl)phosphoryl, for example, dimethylphosphoric, diethylphosphate, di-n-propylphosphonic or diisopropoxyphosphoryl, dicyclohexylphosphino, for example, dicyclohexylphosphino, in this case unsubstituted or substituted diphenylphosphoryl, in this case di-(phenyl-lower alkyl)-phosphoryl, for example, dibenzoyltartaric or di-(4-nitrobenzyl)-phosphoryl, in this case substituted phenoxyphenylacetic, for example, phenoxyphenylacetic, di(lower alkyl)-phosphinyl, for example, diethylphosphinic, or in this case substituted diphenylphosphinyl, for example, diphenylphosphinyl.

In kilmacanogue representing mono-, di - or, in particular, triarylmethane, aryl radicals are, in this case, for example, substituted phenyl radicals. Such groups are, for example, benzyl, diphenylmethyl - and, in chastnoe, titilatingly.

Esterified simple air mercaptopropyl in protected so radical, the amino group is, first and foremost, aaltio or aryl(lower alkyl)thio, where aryl refers to in this case, phenyl, substituted, for example lower alkyl, such as, for example, stands or tert.-bootrom, lower alkoxy, such as methoxy, halogen, such as, ltio.

In use as aminosidine group 2-acyl-lower ALK-1-EN-1-nilradical acyl represents the corresponding radical lowest alkenylboronic acid, in this case substituted, for example lower alkyl, such as, for example, stands or tert.-bootrom, lower alkoxy, such as methoxy, halogen, such as chlorine and/or nitro, benzoic acid, or, in particular, complex Palmyra of carbonic acid, such as lower alkylphosphine carbonic acid. Suitable protective groups are, first of all, 1-(lower alkanoyl)-prop-1-EN-2-yl, such as 1-acetyl-prop-1-EN-2-yl, or 1-(lower alkoxycarbonyl)-prop-1-EN-2-yl, for example 1-etoxycarbonyl-prop-1-EN-2-yl.

Preferred aminosidine groups are acyl radicals of complex profirov coal acids, in particular tert.-butyloxycarbonyl, and this case, for example, as specified, substituted benzyloxycarbonyl or diphenylmethylene, or 2-halogen-(lower alkoxycarbonyl), as, for example, 2,2,2-trichlorocyanuric, in addition, trityl or formyl. Cleavage of the protective groups that are not part of the required end product of formula I is known sposobami, in particular, hydrogenolysis or chemical recovery, in this case, stepwise or simultaneously.

A protected amino group frees known and depending on the type protective groups in various ways, preferably by means of solvolysis or recovery. 2-Halogen(lower alkoxycarbonyl) [in this case, after converting a 2-bromo(lower alkoxycarbonylmethyl) 2-iodine(lower alkoxycarbonylmethyl)] , kolmetsooniline or 4 nitrobenzisoxazole can be, for example, by treatment with an appropriate chemical reagent, such as zinc in the presence of the corresponding carboxylic acid, such as aqueous acetic acid. Kolmetsooniline can also be split by treatment with a nucleophilic, preferably salt-forming reagent, such as, for example, thiophenol sodium, and 4 nitrobenzisoxazole also by treating the alkali metal, for example, dithionite sodium. In this case replaced by diphenylethylenediamine, tert.-lower alkoxycarbonyl or 2-(tizamidine silyl)ethoxycarbonylethyl can be converted by treatment of the corresponding acid, for example, ant ginalisa, i.e. by treatment with hydrogen in the presence of relevant analizator hydrogenation, such as, for example, palladium catalyst; in this case replaced by triarylmethane or formylamino, for example, by treatment with acid, such as mineral acid, e.g. hydrochloric acid, or organic acid, such as formic, acetic or triperoxonane acid, in this case, in the presence of water, and an amino group protected by an organic silyl group can be liberated, for example, by means of hydrolysis or alcoholysis. The amino group protected by 2-halogenoacetyl, for example, 2-chloroacetyl, can be liberated by treatment with thiourea in the presence of a base, or salt of thiol acids, as, for example, alcoholysis or hydrolysis, of the resulting condensation product. The amino group protected by 2-substituted cillatokiohotel, can also be converted into a free amino group by treatment with salt, producing floridamiami, hydrofluoric acid.

Hydroxyl group, protected through the corresponding acyl group, an organic silyl group, or in this case through the substituted 1-phenyl(lower alkyl), liberation is cut substituted 1-phenyl(lower alkyl), for example, benzyl, released, preferably by catalytic hydrogenation, for example, in the presence of a catalyst of palladium on coal. Hydroxyl group protected by 2,2-dichloroacetyl are exempt, for example, through basic hydrolysis, a hydroxyl group esterified tert. -lower alkyl group, 2-oxa - or 2-thia-aliphatic or cycloaliphatic hydrocarbon radical, through acidosis, for example, by treatment with a mineral acid or a strong carboxylic acid, for example, triperoxonane acid. Hydroxyl group esterified with an organic silyl radical, for example, trimethylsilyl, can also be released using Floridiana salt of hydrofluoric acid, for example, tetrabutylammonium fluoride.

Method a:

Preferably R11and R12denote methyl.

Free functional groups in the compound of formula IV, preferably protected easily atmasamyama protective groups are, in particular, amino-, hydroxy - and carboxy groups.

Salt of the compounds of formula IV is preferably a salt of joining acids, such as nitrate or one of the salts of joining the solvent or suspendium agent, for example, a suitable alcohol, such as 2-methoxyethanol, or a suitable lower alkanol, for example, isopropanol, at a temperature between room temperature (about 20oC) and 150oC, for example, under conditions of reflux. In particular, if the compound of formula IV is used as a salt, this salt, preferably in situ, is converted by an appropriate base, such as hydroxide of alkali metal, e.g. sodium hydroxide, in free connection.

Preferably originate from compounds of formula IV where one or two of the radicals R4, R5, R6, R7and R8independently of one another denote hydrogen, lower alkyl, which is unsubstituted or substituted by free or alkilirovanny amino group, piperazinil, piperidinium, pyrrolidinium or morpholinyl, lower alkanoyl, trifluoromethyl, free, etherified simple or complex ester, a hydroxyl group, alkilirovanny or acylated amino group or a free or esterified by a complex ester of a carboxyl group.

Starting material of formula III is produced by the interaction of the compounds of formula VII

< / BR>
where the substituents have to enter the steel substituents have the abovementioned meanings, similar to the method described in EP 233461A. Typical representatives of compounds of formula VIII is N,N-dimethylformamide-dimethylacetal and N,N-dimethylacetamide, dimethylacetal. The reaction is carried out after hours, for example, 4 - 24-hour heating of the reactants of formulas VII and VIII<in the presence, or, if necessary, in the presence of a solvent to a temperature between about 50oC and 150oC.

The source material of the formula III get an alternative method by converting the compounds of formula VII complex ester of the formula R3-C(= O)-O-CH2-CH3where R3have the above significance, and reaction of the resulting product with an amine of the formula H-N(R11)-R12where the substituents have the above values.

The source material of the formula IV obtained as salt accession salts by reacting the compounds of formula IX

< / BR>
where the substituents have the abovementioned meanings, with cyanamide (NC-NH2). The reaction is carried out in an appropriate solvent or suspendium agent, for example, the corresponding alcohol, for example, the corresponding lower alkanol, as, for example, ethanol, in the presence of equimolar amounts of salt-forming acid at temperature functional group in the compound of formula VI, protected preferably easily tsepliaeva group and represents, in particular, carboxyl group, which should not participate in the desired reaction.

The reactive derivative of the compound of formula VI represents, in particular, reactive (activated) ester, reactive anhydride or a reactive cyclic amide.

Reactive (activated) esters of the acids of formula VI are, in particular, related to carbon atom radical esterified unsaturated esters, such as vinyl ester, such as, for example, directly challenging the vinyl ethers (which can be obtained by transesterification of the corresponding complex ester with vinyl acetate; the method of activated vinyl ester), complex carbamoylphenoxy esters (obtainable, for example, by treating the appropriate acid isoxazolyl reagent; method 1,2-oxazole or Woodward), or complex of 1-(lower alkoxy)vinyl ether (which can be obtained, for example, by treating the appropriate acid lowest alkoxyethanol; ethoxyacetylene method), or esters of the type amedume acid corresponding N,N'-disubstituted-carbodiimide, for example, N,N'-dicyclohexylcarbodiimide; carbodiimide method), or N,N'-disubstituted complex amicinemici (which can be obtained by treating the corresponding acid with N,N'-disubstituted-cyanamide; cyanamide method), the corresponding complex akrilovye esters, in particular, difficult phenyl esters, respectively, substituted by substituents that attracts electrons (which can be obtained by treating the corresponding acid respectively substituted phenol, for example 4-NITROPHENOL, 4-methylsulfinylphenyl, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazonium, in the presence of a condensing means, as for example, N,N'-dicyclohexylcarbodiimide; method of activated complex arolovich esters), complex cannetille esters (which can be obtained by treating the corresponding acid with chloroacetonitrile in the presence of a base; complex method canotilho ether), complex tiefer, in particular, in this case a complex phenylthiomethyl, substituted, for example nitro (which can be obtained by treatment of the appropriate acid in this case substituted, for example, nitrothiazole, including using anhydrous or carbodiimide method; the method is activated with testwuide acid compound N-oxyamino or N-acetamido, for example, N-oxysuccinimide, N-oxopiperidine, N-acceptilation or 1-oxybenzoates, for example, anhydrous or carbodiimide method; method, activated ester of N-hydroxy acid) or complex Silovye esters (which can be obtained by treating the corresponding acid silylium means, for example, hexamethyldisilazane, but not amino groups).

Anhydrides of the acid of formula VI may be symmetric or preferably mixed anhydride of this acid, as, for example anhydrides with inorganic acids, such as, for example, galogenangidridy acid, in particular, acid anhydrides, which can be obtained by treating the corresponding acid with thionyl chloride, phosphorochloridate or oxalylamino; method chloranhydride acid), azides (obtainable from the corresponding complex acid ester via the corresponding hydrazide and treatment with nitric acid; azide method), anhydrides poluprovodnikov carbonic acid, as, for example, the corresponding esters, for example, lowest ethyl profirov carbonic acid (which can be obtained by treating the corresponding acid complex lower alkylamino esters of halogen, such as, for example, alkoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; the method of mixed anhydrides O-alkylphenol acid, or anhydrides dihalogenoalkane, in particular, deklarirovannoe phosphoric acid (which can be obtained by treating the corresponding acid with phosphorus oxychloride; method of phosphorus oxychloride), or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (which can be obtained by treating the corresponding acid with halogenerator substituted lower alkane - or phenylalaninol acid, for example phenylacetic acid chloride, pavlinovoi or triperoxonane acid; method of mixed anhydrides of carboxylic acids or organic sulfonic acids (obtainable by treating a salt, such as salt of the alkali metal of the appropriate acid, the corresponding organic halogenerator sulfonic acids, such as, for example, the acid chloride of the lower alkane - or aryl-, for example methane - or p-toluenesulfonic acid; method of mixed anhydrides of sulfonic acids) and symmetric anhydrides (obtainable by condensation of the corresponding acid in the presence of a carbodiimide or 1-diethylaminopropyl; method of symmetrical anhydrides).

The corresponding cyclic amide, midazol (which can be obtained by treating the corresponding acid with N, N'-carbonyldiimidazole; imidazolidinyl method), or pyrazole, for example, 3,5-dimethylpyrazole (which are, for example, through the acid hydrazide by treatment with acetylacetone; pyrazolidine method).

Derivatives of acids of formula VI used as alleluya funds may also be formed in situ. Thus can be obtained in situ, for example, N,N'-disubstituted complex amidinami by the reaction of a mixture of starting material of the formula V and the acid used as Alliluyeva funds, in the presence of the corresponding N,N-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodiimide. In addition, it is possible to obtain a complex amino - or aminoether acids used as Alliluyeva funds, in the presence of Allilueva starting material of the formula V by converting a mixture of the corresponding starting substances of acid and amine in the presence of N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodiimide, and N-oxyamino or N-acetamide, for example, N-oxysuccinimide, in this case, in the presence of an appropriate base, for example, 4-dimethylaminopyridine.

Preferably the mules: VI convert the compound of formula V, where involved in the reaction of amino or hydroxyl group exists in a free form.

The reaction may be carried out in a known manner. Moreover, the reaction conditions, primarily depend on the set, and how carboxyl group Alliluyeva funds. Usually the reaction is carried out in the presence of a suitable solvent or diluent or a mixture thereof and, if necessary, in the presence of a condensing means, that for example, if participating in the reaction, the carboxyl group is an anhydride, could also be a means of binding acid. The reaction is carried out while cooling or heating, for example, in the temperature range from approximately -30oC to approximately +150oC, in particular from approximately 0oC to +100oC, preferably from room temperature (about 20oC) up to 70oC, in an open or closed reaction vessel and/or in the atmosphere of inert gas such as nitrogen. The usual condensing means are, for example, carbodiimide, for example, N,N'-diethyl-N, N'-dipropyl-, N, N'-DICYCLOHEXYL - or N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide corresponding carbonyl compounds, for example, carbonyldiimidazole or compounds 1,2-oxazo the Il-5-methylisoxazole-perchlorate, or appropriate acylaminorhodanines, for example, 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline. Conventional acid condensing means are, for example, carbonates of alkali metals or hydrogen carbonates of alkali metals, e.g. sodium carbonate or potassium or sodium bicarbonate or potassium (usually together with a sulfate), or organic bases, such as pyridine or spatial employed three(lower alkyl)amines, such as N, N-aminobutiramida-N-ethylamine.

The source material of the formula V is obtained by recovery of the nitro group(s) in the compound of the formula I where the radical R7denotes the nitrogroup. This recovery can be performed, for example, by catalytic hydrogenation in an appropriate solvent, such as, for example, tetrahydrofuran. As the hydrogenation catalyst used is preferably palladium on charcoal (5%) and hydrogenation in this case is carried out at normal pressure.

Method c:

Appropriate oxidant for the conversion of compounds of formula I, where R1means pyridyl, N-oxidisation is preferably the corresponding nagkalat, for example, corresponding to perbenzoic the measures halogenated hydrocarbon, as, for example, preferably methylene chloride, at a temperature between about -20oC and 150oC, mainly between about 0oC and the boiling point of the respective solvent, usually below 100oC, and preferably at room temperature or easily rising temperature (20oC - 70oC).

Salt accession acid compounds of the formula I get a known manner, for example by treatment with an acid or a corresponding anion exchange reagent.

Salt accession acids can be translated into the free compounds, for example, by processing the respective main tool.

Mixtures of isomers can be separated into individual isomers in the usual way, for example, by fractionated crystallization, chromatography, etc.

The above-described methods, including methods of removal of protective groups and additional activities relating to fashion, are, if not stated otherwise, in a known manner, for example, in the presence or absence, preferably, inert solvents and diluents, if necessary in the presence of a condensing means or catalysts, at low or stupid things, from approximately 0oC to about 70oC, preferably from about 10oC to about 50oC, mainly at room temperature, in an appropriate vessel and, if necessary, in the atmosphere of inert gas such as nitrogen.

However, given all of the substituents in the molecule, if necessary, for example, in the presence of easily hydrolyzable residue, you must apply a particularly gentle conditions for the reaction, as, for example, a short duration of reaction, the use of weakly acidic or weakly basic means at the lower concentration, stoichiometric ratios of quantities, choice of suitable catalysts, solvents, temperature and/or pressure.

The invention relates also to those embodiments of the method, which originate from the compound obtained at any stage of the method as an intermediate product and perform the missing step of the way or interrupt method on any stage or get a starting material under the reaction conditions or is used in the form of a reactive derivative or salt. Thus preferably extend from such starting substances, which according to the invention results in the TBA and are chosen such reaction conditions, under which achieves compounds mentioned as particularly preferred.

Compounds according to the invention can be used for the treatment of warm-blooded animals suffering from neoplastic diseases, and warm-blooded animal in need of such treatment, give required for tumor suppression amount of the compounds of formula I or its pharmaceutically acceptable salt. In addition, the compounds of formula I or its pharmaceutically acceptable salt can be used to inhibit the kinase activity of the PDGF receptor. The compounds of formula I, where R4and R8mean hydrogen, or its pharmaceutically acceptable salt can be used to inhibit protein kinase C in warm-blooded animals. The compounds of formula I and their pharmaceutically acceptable salts can be used to obtain farmacevticheskih drugs used in the treatment of human or animal organisms. The body weight of approximately 70 kg, depending on species, age, individual condition, mode of application and the appropriate clinical picture appointed effective doses, for example daily doses of about 1 to 1000 mg, in particular 50 to 500 mg.

The invention also concerns esto, in particular, for the prevention or treatment of one of the above diseases, the active substance together with a pharmaceutically applicable fillers, suitable for local, internal, such as oral or rectal, or parenteral use and which may be inorganic or organic, solid or liquid. For oral use, in particular, tablets or gelatin capsules containing a biologically active substance together with diluents, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose and/or glycerol, and/or lubricants, for example silica, talc, stearic acid or its salts, such as magnesium stearate or calcium, and/or polyethylene glycol. Tablets may also contain binders, such as magnesium silicate and aluminum, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and, if necessary, dispersing agents, for example starches, agar, alginic acid or its salt, such as sodium alginate, and/or effervescent mixtures, or adsorbents, colorants, flavorings and sweet substances. In addition, pharmacologists is s or of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions. And they are, for example, in freeze-dried preparations containing biologically active substance alone or together with an excipient, for example mannitol, can be made before use. The pharmaceutical preparations can be sterilized and/or may contain auxiliary substances, such as preserving, stabilizing, wetting and/or emulsifying detergents that dissolve tool, salts for regulating osmotic pressure and/or buffer solution. Data of pharmaceutical preparations, which, if necessary, may contain other pharmacologically effective substances, such as antibiotics, are produced in a known manner, for example, using conventional methods: mixing, granulating, drazhirovanija, dissolution or lyophilization and contain from about 1% to 100%, particularly from about 1% to about 20% of the active substances (active substances).

The following examples explain the invention without limiting it in any form. Values of Rfdetermine silikagelevye thin-layer plates (Merck, Darmstadt, Germany). With the/v), temperatures are indicated in degrees Celsius.

Example 1. To a solution of 30 g (to 0.17 moles) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-it (described in EP 0233461A) in 250 ml add to 41.3 g (to 0.17 moles) nitrate 3-nitrophenylhydrazine, suspended in 50 ml of isopropanol. After adding 7,49 g (to 0.19 mol) of caustic soda yellow suspension is boiled for 8 hours under reflux. After cooling to 0oC is filtered and optionally washed with 200 ml of isopropanol. Product filtering suspended in 300 ml of water and stirred for 30 minutes, filtered and washed with 200 ml of water. After re-suspension in 200 ml of ethanol and washing with 200 ml of ethanol-simple diethyl ether (1:1) to obtain N-(3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine; melting point 212 - 213oC, Rf= 0,75 (chloroform : methanol = 9:1).

The source material was obtained as follows:

Step 1.1: To a yellow suspension of 82,88 g (0.6 mmol) of 3-nitroaniline in 200 ml of ethanol are added dropwise 42 ml (0.6 mol) of nitric acid (65%). After the weakening of the exothermic reaction add to 75.7 g (0.9 mol) of cyanamide (50% in water) and the reaction mixture is boiled for 21 hours under reflux. After cooling to 0oC is filtered off and washed 6 times with the are square-nitrate 3-nitrophenylhydrazine; melting point 205 - 207oC.

Step 1.2: 8 g (of 0.35 moles) of sodium in 260 ml of toluene at 100oC suspended using a vibration mixer. After cooling to 0oC dropwise while cooling add 17 ml (at 0.42 moles) of methanol and then stirred for 45 minutes at 75oC. When 25oC dropwise while cooling with ice add a solution of 38.5 ml of 0.35 moles) 3-acetylpyridine and 28 ml of 0.35 moles) of a compound ethyl ester of formic acid in 300 ml of toluene for 45 minutes. The yellow suspension is stirred for 16 hours at a temperature of 25oC and then mixed with 23.7 g (0,52 moles) of dimethylamine. After submitting 100 ml of toluene is stirred for 45 minutes at 25oC, then at 0oC added dropwise a solution of 20 ml of acetic acid in 150 ml of toluene for 30 minutes and then boiled for 1 hour under reflux. After cooling to 25oC is filtered off, washed with 500 ml of tawalkana (1:1) and the filtrate is concentrated until the onset of crystallization. After cooling to 0oC, filtering off and drying at 80oC at high pressure, a 3-dimethylamino-1-(pyridyl)-2-propen-1-he; melting point 81 - 82oC.

Example 2. 100 mg (0.38 mmol) of N-(3-AMINOPHENYL)-4-(3-pishevaya for 24 hours at room temperature. The reaction mixture is mixed with 10 ml of water, cooled to 0oC and filtered. After washing with water and drying receive N-[3-(4-chlorobenzylamino)-phenyl]-4-(3-pyridyl)-2-pyrimidinamine; melting point 238 - 240oC. Rf= 0,66 (chloroform : methanol = 9:1).

The source material was obtained as follows:

Stage 2.1: a Suspension of 17.0 g (0,058 moles) M-(3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine in 1700 ml of tetrahydrofuran is stirred with 1.7 g of palladium on charcoal (5%) in hydrogen atmosphere under normal pressure for 21 hours. The suspension is filtered and the filtrate concentrated on the rotary evaporator apparatus. The remaining yellow solid product is stirred overnight in 200 ml of methylene chloride. After filtration and drying receive N-(3-AMINOPHENYL)-4-(3-pyridyl)-2-pyrimidinamine; melting point 89 - 90oC, Rf= 0,38 (chloroform : methanol = 9:1).

Example 3. A solution of 100 mg (range 0.38 moles) of N-(3-AMINOPHENYL)-4-(3-pyridyl)-2-pyrimidinamine in 5 ml of pyridine is mixed with 53 μl ones (0.46 mmol) of benzoyl chloride and stirred under nitrogen atmosphere for 24 hours at room temperature. The reaction mixture is mixed with 10 ml of water, cooled to 0oC, filtered and washed with water. After wise 207 - 209oC, Rf= 0,53 (chloroform : methanol = 9:1).

Example 4. A solution of 100 mg (range 0.38 moles) of N-(3-AMINOPHENYL)-4-(3-pyridyl)-2-pyrimidinamine and 59 mg (0,46 mmol) of acid chloride of 2-pyridylcarbinol acid in 5 ml of pyridine was stirred at room temperature under nitrogen atmosphere for 4 hours. After adding 30 mg (0.23 mmol) of acid chloride of 2-pyridylcarbinol acid is stirred for 18 hours, then add another 25 mg (0,19 mmol) of acid chloride of 2-pyridylcarbinol acid and stirred for 72 hours at a temperature of 5oC. After adding 10 ml of water and cooling to 0oC is filtered off and washed with water. In the chromatographic separation (silica gel, CHCl3/MeOH = 9:1) to obtain N-[3-(2-pyridyl)-carboxamidine]-4-(3-pyridyl)-2-pyrimidinamine; melting point 187 - 190oC, Rf= 0,58 (chloroform : methanol = 9:1).

Example 5 Analogously to example 4 of the acid chloride of 3-pyridineboronic acid get N-[3-(-pyridyl-carboxamidine]-4-(3-pyridyl)-2-pyrimidinamine; melting point 217 - 220oC, Rf= 0,29 (chloroform : methanol = 9:1).

Example 6. Analogously to example 4 of the acid chloride of 4-pyridineboronic acid get N[3-(4-pyridyl)-carboxamidine] -4-(3-p is the Example 7. A solution of 100 mg (0.38 mmol) of N-(3-AMINOPHENYL)-4-(3-pyridyl)-2-pyrimidinamine in 5 ml of pyridine is mixed with 63 μl ones (0.46 mmol) of pentafluorobenzylbromide and stirred under nitrogen atmosphere at room temperature for 17 hours. The brown reaction mixture is mixed with 10 ml of water, cooled to 0oC and filtered. The residue is recrystallized from ethanol-acetone and receive a crystalline product, N-(3-pentafluorobenzenesulfonyl)-4-(3-pyridyl)-2-pyrimidinamine; melting point 234 - 244oC, Rf= 0,41 (chloroform : methanol = 9:1).

Example 8. 28 mg (0,19 mmol) of phthalic anhydride acid added to a solution of 50 mg (0,19 mmol) of N-(3-AMINOPHENYL)-4-(3-pyridyl)-2-pyrimidinamine in 1 ml of pyridine. After 2.5 hours, the yellow reaction solution is mixed even with 14 mg (0,095 mmol) of phthalic anhydride acid and stirred for 20 hours at 25oC. the Suspension is filtered, washed with a little cold pyridine. The residue is extracted after twice washing with 2.5 ml of absolute ethanol and receive N-[3-(2-carboxymethylamino)-phenyl]-4-(3-pyridyl)-2-pyrimidinamine; melting point 206 to 209oC, Rf= 0,07 (chloroform : methanol = 9:1).

Example 9. A solution of 100 mg (0.38 mmol) of N-(3-AMINOPHENYL)-4-(3-pyridyl)-2-Piri 25oC in nitrogen atmosphere and then concentrated on a rotary evaporator apparatus. The residue is purified by thin layer chromatography (silica gel, chloroform : methanol 95:5) then get N-(3-n-hexanolactone)-4-(3-pyridyl)-2-pyrimidinamine; melting point 180 - 184oC, Rf= 0,78 (chloroform : methanol = 9:1).

Example 10. 1 g (of 5.68 mmol) of 3-dimethylamino-1-(2-pyridyl)-2-propen-1-it (EP 233461A) dissolved in 8 ml of isopropanol and mixed 1.38 g (of 5.68 mmol) nitrate 3-nitrophenylhydrazine. After adding 0.25 g (6,24 mmol) sodium hydroxide yellow suspension is heated at reflux conditions for 20 hours, then cooled to 0oC, filtered and washed with 30 ml of isopropanol. Product filtering is stirred for 20 minutes in 15 ml of ethanol, filtered and washed with a little cold ethanol. Get N-(3-nitrophenyl)-4-(2-pyridyl)-2-pyrimidinamine; melting point 213 - 219oC.

Example 11. To a solution of 1 g (of 5.68 mmol) of 3-dimethylamino-1-(4-pyridyl)-2-propen-1-she (U.S. patent 4281000) in 8 ml of isopropanol added to 1.38 g (of 5.68 mmol) nitrate 3-nitrophenylhydrazine and 0.25 g (6,24 mmol) sodium hydroxide. The yellow suspension is heated for 20 hours under reflux and then cooled on throwaway. After drying under high vacuum to obtain N-(3-nitrophenyl)-4-(4-pyridyl)-2-pyrimidinamine; melting point 282 - 284oC.

Example 12. Analogously to example 2 from 2-methoxybenzylamine receive N-[3-(2-methoxybenzamido)-phenyl]-4-(3-pyridyl)-2-pyrimidinamine; melting point 115 - 117oC, Rf= 0,76 (chloroform : methanol = 9:1).

Example 13. Analogously to example 2 from 4-tormentilla receive N-[3-(4-tormentilla)-phenyl] -4-(3-pyridyl)-2-pyrimidinamine; melting point 215 - 216oC, Rf= 0,34 (chloroform : methanol = 9:1).

Example 14. Analogously to example 2 from 4-cyanobenzaldehyde receive N-[3-(4-cyanobenzoyl)-phenyl] -4-(3-pyridyl)-2-pyrimidinamine; melting point 220 - 222oC, Rf= 0,31 (chloroform : methanol = 9:1).

Example 15. Analogously to example 2 of the acid chloride of 2-thiophencarboxylic acid get N-[3-(2-thienylboronic)-phenyl] -4-(3-pyridyl)-2-pyrimidinamine; melting point 139 - 141oC, Rf= 0,35 (chloroform : methanol = 9:1).

Example 16. Analogously to example 2 from acid chloride cyclohexanecarbonyl acid get N-(3-cyclohexylcarbonyl)-4-(3-pyridyl)2-pyrimidinamine; melting point 205 - 206oC, Rf= 0,36 (benzoylamino)-phenyl] -4-(3-pyridyl)-2-pyrimidinamine; melting point 214 - 216oC, Rf= 0,64 (chloroform : methanol = 9:1).

Example 18. Analogously to example 2 in the processing of 100 mg (0.38 mmol) of N-(3-AMINOPHENYL)-4-(4-pyridyl)-2-pyrimidinamine with 58 μl (0.46 mmol) of 4-chlorobenzylchloride receive N-[3-(4-chlorobenzylamino)-phenyl]-4-(4-pyridyl)-2-pyrimidinamine; melting point 258 - 261oC, Rf= 0,37 (CHCl3: methanol = 9:1).

The source material was obtained as follows:

Step 18.1: Similar to step 2.1 in the processing of 300 mg (1.0 mmol) of N-(3-nitrophenyl)-4-(4-pyridyl)-2-pyrimidinamine (see example 11) in an atmosphere of hydrogen is produced N-(3-AMINOPHENYL)-4-(4-pyridyl)-2-pyrimidinamine; melting point 200 - 202oC, Rf= 0,27 (CHCl3: methanol = 95:5).

Example 19. Analogously to example 2 from 98 mg (0.3 mmol) of 4-(4-methylpiperazine)-benzoyl chloride N get-{3-[4-(4-methylpiperazine)-benzoylamino] -phenyl} -4-(3-pyridyl)-2-pyrimidinamine; melting point 198 - 201oC.

Example 20. A solution of 8.0 g (28,85 mmol) of N-(5-amino-2-were)-4-(3-pyridyl)-2-pyrimidinamine and 4.0 ml (34.6 mmol) of benzoyl chloride in 320 ml of pyridine is stirred at room temperature under nitrogen atmosphere for 23 hours. The reaction mixture is concentrated under high vacuo the high vacuum, the crude product is suspended with CH2Cl2methanol (95%5) and filtered. Get N-(5-benzoylamino-2-were) -4-(3-pyridyl)-2-pyrimidinamine. After chromatographic separation receive a different amount of this product; melting point 173 - 176oC, Rf= 0,65 (CHCl3: methanol = 9:1).

The source material was obtained as follows:

Stage 20.1: To a yellow suspension of 20.0 g (of 0.13 moles) of 2-amino-4-nitrotoluene in 50 ml of absolute ethanol is added dropwise within 5 minutes add to 9.1 ml of 0.13 moles) of 65% nitric acid. After the weakening of the exothermic reaction add 8,32 g (0,198 moles) of cyanamide dissolved in 8.2 ml of water. The brown reaction mixture was refluxed for 25 hours, cooled to 0oC and filtered. After 4 times washing with 100 ml of ethanol-simple diethyl ether (1:) and drying receive nitrate 2-methyl-5-nitrophenylamino; melting point 219 - 226oC.

Stage 20.2: To a solution of 170 g (of 0.96 moles) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-it in 2.0 l of isopropanol add 248,2 g (of 0.96 moles) of nitrate 2-methyl-5-nitrophenylhydrazine. After you have added 42.5 g of caustic soda reddish suspension is refluxed for 12 hours. After cooling the methanol and drying receive N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine, melting point 195 - 198oC, Rf= 0,68 (methylene chloride : methanol = 9:1).

Stage 20.3: Suspension 143,0 g (0,46 moles) of N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine in 7,15 l complex ethyl ester of acetic acid is stirred with 14.3 g of palladium on charcoal (10% Pd) in hydrogen atmosphere under normal pressure for 6.5 hours. The suspension is filtered and the filtrate concentrated on the rotary evaporator apparatus. The crude product is recrystallized from methylene chloride. Get N-(5-amino-2-were)-4-(3-pyridyl)-2-pyrimidine; melting point 138 - 140oC. Rf= 0,36 (methylene chloride : methanol = 9:1).

Example 21. Analogously to example 20 is 10.68 g (32,8 moles) of 4-(4-methylpiperazine)-benzoyl chloride N get-{ 5-[4-(4-methylpiperazine)-benzoylamino] -2-were} -4-(3-pyridyl)-2-pyrimidinamine; melting point 211 to 213oC, Rf= 0,33 (methylene chloride : methanol : 25% aqueous ammonia solution = 95:5:1).

Example 22. Analogously to example 20 from 0,23 ml (1.7 mmol) of p-colourglide receive N-[5-(4-methylbenzylamino)-2-were] -4-(3-pyridyl)-2-pyrimidinamine; melting point 102 - 106oC, Rf= 0,4 (methylene chloride : methanol = 9:1).

Example 23. Analogously to example the temperature of the melting point of 97 1012, Rf= 0,45 (methylene chloride : methanol = 9:1).

Example 24. Analogously to example 20 from 0,22 ml (1.73 mmol) of 4-chlorobenzylchloride receive N-[5-(4-chlorobenzylamino)-2-were] -4-(3-pyridyl)-2-pyrimidinamine.

Example 25. Analogously to example 20, and 0.28 ml (1,87 mmol) of 2-methoxybenzylamine receive N-[5-(2-methoxybenzamido)-2-were] -4-(3-pyridyl)-2-pyrimidinamine; melting point 88 - 92oC, Rf= 0,45 (methylene chloride : methanol = 9:1).

Example 26. Analogously to example 1 from 1.0 g (of 5.68 mmol) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-she and 1.53 g (of 5.68 mmol) nitrate 3-triphtalocyaninine get N-(3-trifloromethyl)-4-(3-pyridyl)-2-pyrimidinamine; Rf= 0,7 (chloroform : methanol = 9:1).

The source material was obtained as follows:

Stage 26.1: Analogously to stage 1.1 of from 2.0 g (11.3 mmol) of 3-triphtalocyaninine and 1.4 g (16.6 mmol) of cyanamide (50% in water) are nitrate 3-triphtalocyaninine; Rf= 0,1 (methylene chloride : methanol : 25% aqueous ammonia solution = 150:10:1).

Example 27. Analogously to example 1 from 1.0 g (of 5.68 mmol) of 3-dimethylamine-1-(3-pyridyl)-2-propen-1-she and 1.78 g (of 5.68 mmol) nitrate 3-(1,1,2,2-tetrafluoroethoxy)-phenylquinoline receive N-[3-(1,1,2,2-tetrafluoroethoxy)-phenyl] -4-(3-way:

Stage 27.1: Analogously to stage 1.1 of of 2.09 g (10 mmol) 3-(1,1,2,2-tetrafluoroethoxy)-aniline and 1.26 g (15 mmol) of cyanamide (50% in water) are nitrate 3-(1,1,2,2-tetrafluoroethoxy)-phenylquinoline; Rf= 0,15 (methylene chloride : methanol : 25% aqueous ammonia solution = 150:10:1).

Example 28. Analogously to example 1 from 1.0 g (of 5.68 mmol) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-she and 0.46 g (of 5.68 mmol) nitrate 3-nitro-5-methylvinylpyridine get N-(3-nitro-5-were)-4-(3-pyridyl)-2-pyrimidinamine; Rf= 0,72 (chloroform : methanol = 9:1).

The source material was obtained as follows:

Stage 28.1: Analogously to stage 1.1 of 1.52 g (10 mmol) 3-nitro-5-methylaniline and 1.26 g (15 mmol) of cyanamide (50% in water) are nitrate 3-nitro-5-methylvinylpyridine; Rf= 0,1 (methylene chloride : methanol : 25% aqueous ammonia solution = 150:10:1).

Example 29. Analogously to example 1 from 1.0 g (of 5.68 mmol) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-she and 1.76 g (of 5.68 mmol) nitrate 3-nitro-5-triftormetilfullerenov get N-(3-nitro-5-triptoreline)-4-(3-pyridyl)-2-pyrimidinamine; Rf= 0,8 (chloroform : methanol = 9:1).

The source material was obtained as follows:

Stage 29.1: Analogously to stage 1.1 of of 2.06 g (40 mmol) of 3-nitro-5-triptorelin and 1.26 g (a : 25% aqueous ammonia solution = 150:10:1).

Example 30. 200 mg (0.68 mmol) of N-(3-nitrophenyl) -4-(3-pyridyl)-2-pyrimidinamine suspended in 5 ml of methylene chloride and mixed with 225 mg (0.71 mmol) of 3-chloroperbenzoic acid. After 2 hours, add another 10 ml of methylene chloride. The suspension is stirred for another 20 hours at room temperature. After filtration and thin-layer chromatography (methylene chloride : methanol : 25% aqueous ammonia solution = 90:10:1) balance of receive N-(3-nitrophenyl)-4-(N-oxido-3-pyridyl)-2-pyrimidinamine; Rfof 0.4 (methylene chloride : methanol : 25% aqueous ammonia solution = 90:10:1), melting point 252 - 258oC.

Example 31. 150 mg (0.39 mmol) of N-(3-benzoylamino-5-were)-4-(3-pyridyl)-2-pyrimidinamine suspended in 6 ml of methylene chloride and mixed with 129 mg (0.41 mmol) 3-chloroperbenzoic acid. After 22 hours, filtered and the residue is purified by thin layer chromatography (methylene chloride : methanol : 25% aqueous ammonia solution = 90:10:1). Get N-(3-benzoylamino-5-were)-4-(N-oxido-3-pyridyl)-2 - pyrimidinamine; Rf= 0,3 (methylene chloride : methanol : 25% aqueous ammonia solution = 90:10:1), melting point 295 - 300oC.

Example 32. Tablets containing 20 mg of biologically active substances, for example, one described in the Eski active substance - 20 mg

Wheat starch 60 mg

Milk sugar 50 mg

Colloidal silicic acid 5 mg

Talc - 9 mg

Magnesium stearate 1 mg

Only 145 mg

Manufacturer: Biologically active substance is mixed with one part wheat starch, milk sugar and colloidal silicic acid and the mixture is passed through a sieve. Another part of the wheat starch lastresult using 5-fold amount of water in a water bath and powder mixture is mixed with this paste until it forms a weak plastic mass.

The plastic mass is forced through a sieve with openings of approximately 3 mm, dried and the resulting dry granulate is again passed through a sieve. Then the remaining wheat starch, talc and magnesium stearate is added to the mixture and the mixture is pressed into tablets weighing 145 mg.

Example 33. Tablets containing 1 mg of biologically active substances, for example, one described in examples 1 to 31 of the compounds of formula I are the following composition in the usual way:

The composition of

Biologically active substance 1 mg

Wheat starch 60 mg

Milk sugar 50 mg

Colloidal silicic acid 5 mg

Talc - 9 mg

The plastic mass is forced through a sieve with holes the size of 3 mm, dried and the resulting dry granulate is again passed through a sieve. Then add the remaining wheat starch, talc and magnesium stearate and the mixture is pressed into tablets weighing 126 mg.

Example 34. Capsules containing 10 mg of biologically active substances, for example, one of the compounds of formula I described in examples 1 to 31, are made in the usual way, as described below:

The composition of

Biologically active substance 2500 mg

Talc - 200 mg

Colloidal silicic acid 50 mg

Manufacturer: the Active substance is mixed with talc and colloidal silicic acid until the mixture becomes homogeneous, the mixture is passed through a sieve with holes of 0.5 mm and the weight portions 11 mg fill hard gelatin capsules of appropriate size.

In table. 1 presents data on the biological activity of compounds formulae action tested in accordance with wound these methods compounds on protein kinase.

In accordance with this test was used a mixture of different isoforms protein kinases C (PKC) (the first of three columns on the test). In contrast, in the next column with values IC50for PKC- " shows the data obtained for pure-isoform of PKC. In the last column summarizes data for compounds related growth factors PDGF.

We are talking about a growth factor that plays an important role both in normal and in pathological proliferation of cells and tissues neoplasms (cancer, carcinoma) and smooth muscles (atherosclerosis, thrombosis). Therefore, the table shows the values of the IC50to inhibit the activity of tyrosinekinase receptors that stimulate PDGF.

Studies have shown that all compounds of formula I possess anti-tumor activity.

On the basis of data obtained in tests in vitro were selected for the best connection, which then was already studied in experiments in vivo for antitumor activity using human c-sis and v-sis-downregulation of BALB/c3T3 cells, which are highly oncogenic, on hairless mice. The maximum tolerance dose for a single oral or intraperitoneal administration otepaeae activity occurred at the doses between 50 mg/kg and 6.3 mg/kg

Details were studied (in vivo) are also compounds of examples 1 and 21 (NN CPG 57148 and CPG 53506) on antitumor activity. The maximum tolerance dose for a single oral or intraperitoneal administration 57148B mice BALB/c mice was more than 500 mg/kg BAKB/c AMuLV (lagovirus) and BALB/c 3T3 v-sis-cells, which are sensitive to the sample to form colonies, were used for testing the connection 57148B on antitumor activity in mice female BALB/c mice (mouse hairless). Disposable daily dose intraperitoneal injection of 50, 12.5 or of 3.13 mg/kg CGP 57148B, introduced in the next 30 days. It was found a strong antitumor effect in relation to AMVuLV-transformed BALB/c3T3 tumors (Fig. 1). Similar antitumor tests using the v-sis-transformed BALB/c 3T3 cells were carried out with detection of dose-dependent antitumor activity (Fig. 2). The maximum value of T/C (100%) (treatment/control) 4% (AMuLV tumors) and 11% (v-sis-tumor) were obtained in cases where CGP 57148B was administered at a dose of 50 mg/kg body weight.

Test the antitumor activity of the composition with the compound CGP 53506 (compound of example 21).

Antitumor activity of CGP 53056 from the second line of BALB/c mice.

Used the composition contained 5 dimethyl sulfoxide, 0.5% Tween 80 and 94.5% of sodium chloride 0.9 per cent.

The schedule of treatment was as follows: Daily use of the drug for the next 15 days from the start of treatment on day 9 after transplantation of the tumor.

The results are presented in table. 2.

The compounds belong to the category of weakly - and srednetonnazhnyh substances tests conducted on mice and dogs).

1. Derivatives of N-phenyl-2-pyrimidinamine formula I

< / BR>
where R1means associated carbon atom of the pyridyl or N-oxidability, R2and R3mean hydrogen, R4is hydrogen or lower alkyl, R5is hydrogen, lower alkyl or trifluoromethyl, R6is hydrogen, R7- nitro, fluoro-substituted lower alkoxy or a residue of formula II

-N(R9)-C(=O)-R10< / BR>
where R9is hydrogen, R10means associated carbon atom of the pyridyl, C5- C7alkyl, thienyl, 2-naphthyl or cyclohexyl, or optionally substituted by halogen, cyano, lower alkoxyl, carboxyla, lower alkyl or 4-methylpiperazine phenyl, R8hydrogen, or salts of these compounds with at least one salt-forming group.the substituents have the above paragraph 1 values, and their pharmaceutically acceptable salts, containing at least one salt-forming group.

3. Derivatives of N-phenyl-2-pyrimidinamine under item 1 of the formula I, where R4means the lower alkyl and the other substituents have the above paragraph 1 values, and their pharmaceutically acceptable salts, containing at least one salt-forming group.

4. Derivatives of N-phenyl-2-pyrimidinamine under item 1, where R1means associated carbon atom of the pyridyl, R2, R3, R4, R5, R6and R8mean hydrogen, and R7means nitro or a residue of formula II, where R9means hydrogen, R10is a linked carbon atom of the pyridyl, C5- C7alkyl, thienyl, cyclohexyl or optionally substituted by fluorine, chlorine, cyano, lower alkoxyl, carboxyla, lower alkyl or 4-methylpiperazine phenyl, and their pharmaceutically acceptable salts.

5. The derived N-phenyl-2-pyrimidinamine under item 1, representing N-(3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

6. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-[3-(4-chlorobenzylamino)-phenyl]-4-(3-pyridyl)-2-pyrimidinediamine a N-(3-benzoylmethyl)-4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

8. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-[3-(2-pyridyl) carboxamide] -4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

9. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-[3-(3-pyridyl) carboxamide] -4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

10. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-[3-(4-pyridyl) carboxamide] -4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

11. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-(3-pentafluorobenzenesulfonyl)-4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

12. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-[3-(2-carboxymethylamino)-phenyl] -4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

13. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-(3-p-hexanolactone)-4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

14. The derived N-phenyl-2 - pyrimidinamine under item 1, representing the FDS is Noah N-phenyl-2 - pyrimidinamine under item 1, representing N-[3-(2-methoxybenzamido)-phenyl] -4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

16. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-[3-(4-perbenzoate)-phenyl] -4-(3-pyridinyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

17. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-[3-(4-cyanobenzoyl)-phenyl] -4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

18. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-[3-(2-thienylboronic)-phenyl] -4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

19. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-(3-cyclohexylcarbonyl)-4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

20. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-[3-(4-methylbenzylamino)-phenyl] -4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

21. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-[3-(4-chlorobenzylamino)-phenyl]-4-(4-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable the Teal)-benzoylamino] -phenyl} -4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

23. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-(5-benzoylamino-2-were)-4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

24. The derived N-phenyl-2 - pyrimidinamine under item 1, N represents-{ 5-[4-(4-methylpiperazine)-benzoylamino] -2-were} -4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

25. The derived N-phenyl-2 - pyrimidinamine under item 1, representing N-[5-(4-methylbenzylamino)-2-were] -4-(3-pyridyl)-2-pyrimidinamine, or its pharmaceutically acceptable salt.

26. Derivatives of N-phenyl-2 - pyrimidinamine formula 1 p. 1 representing antitumor activity.

27. Pharmaceutical composition having antitumor activity, containing the active ingredient and pharmaceutically acceptable excipients, characterized in that the active substance it contains a compound of the formula I on PP.1 - 26, in an effective amount.

 

Same patents:

The invention relates to new derivatives of salicylic acid f-ly Gets-NR-SO2-Ph1A Ph2(COOH)(OH), (I), where Het represents (R1, R2, R3-Het1That gets1represents a cyclic systemin which the free valence is associated with a group NR; X is a group: a) -O-CH=CH-, -CH=CH-O-, -CH= CH-S - or b) -CH=CH-CH=CH-, -CH=CH-CH=N-, -CH=N-CH=CH-, -CH=CH-N=CH-, -N= CH-CH= CH-; R1, R2and R3are substituents at the carbon atom in Het and represent hydrogen, C1-C6- alkyl, halogen, hydroxy - or benzyloxy; R is hydrogen or C1-C6- alkyl; Ph1- phenylene, Ph2is phenyl which may be substituted with halogen, lower alkyl or benzyloxypropionic, provided that the carboxy - and hydroxy-group are in the ortho-position to each other; And a represents - CC-, -CH=CH-, -CH2-CH2-, -CO-CH=CH-, -CH=CH-CO-

The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
where R is the specified value,

mixtures of their isomers or the individual is

The invention relates to new pyridinesulfonamide General formula I or their acceptable for agriculture salts, have a weed-killing activity, as well as to a method for their production and compositions for combating the growth of unwanted vegetation

The invention relates to new derivatives of arylsulfonamides, namely, potassium salt of N-(4,6-dimethylpyrimidin-2-yl)-N'-/2- (methoxycarbonyl)phenylsulfonyl/urea (potassium salt of sulfometuron-methyl), which may find application in forestry planting cedar (Siberian pine, Korean) and non-agricultural land use as a herbicide

The invention relates to a series of substituted 5-arylpyrimidines, to methods for their preparation, to pharmaceutical remedies containing these compounds and to their use in therapy, in particular in the treatment of a range of diseases and disorders of the Central nervous system (CNS)

The invention relates to new derivatives of sulfamethoxypyrazine and herbicides containing them as active ingredients

The invention relates to a derivative sulfonamida, to processes for their production and to their use as herbicides

The invention relates to a derivative of acrylic acid, useful in agriculture (especially as fungicides but also as plant growth regulators, insecticides and nematicides), to the processes of their production, agricultural (especially fungi) compositions containing them and to methods of using them to combat fungi, especially fungal infections of plants, for regulating the growth of plants and to destroy or suppress insect and nematode pests

The invention relates to a new method of treatment of patients, such as people with benign prostatic hyperplasia (BPH), which includes treatment by assigning a therapeutically effective amount of an inhibitor 5- reductase in combination with blocker1- adrenergic receptor
The invention relates to medicine, Nephrology

The invention relates to the class of pyrimidine compounds, which are suitable for the treatment of diseases and disorders of the Central nervous system (CNS), for example to prevent cerebral ischemic lesions, containing their pharmaceutical compositions and to methods for their preparation

The invention relates to 1,4-disubstituted the piperazines of General formula (I), which means the group-CO - or-CH2-OCO; D - heteroaryl selected from a range including 1, 3, 5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two substituents selected from a range, including mono-(C1-C6)-alkylamino, mono-(C3-C7)- alkynylamino-, di-(C1-C6)-alkylamino-,

(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases
The invention relates to medicine, surgery may be used in the treatment of acute pancreatitis
Up!