SK280620B6 - N-phenyl-2-pyrimidinamine derivative, process of its preparation, the use of the derivative when preparing a pharmaceutical composition - Google Patents

Abstract

There are described N-phenyl-2-pyrimidinamine derivatives of the formula (I) in which R1 denotes a pyrazinyl group, 1-methyl-1H-pyrrolyl group, a phenyl-substituted group, 1H-indolyl group bonded to a five-membered ring carbon atom, or pyridyl which is bonded to a ring carbon atom, R2 and R3 independently of one another each denote hydrogen or lower alkyl, one or two of the radicals R4, R5, R6, R7 and R8 each denote nitro, fluorine-substituted lower alkoxy or a radical of the formula (II) -N(R9)-C(=X)-Y)n-R10, in which X, Y, R9, R10 and n have their meanings given in the Description, and the remainder of the radicals R4, R5, R6, R7 and R8 independently of one another each denote hydrogen, lower alkyl which is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl, lower alkanoyl, trifluoromethyl, free, etherified or esterified hydroxyl, free, alkylated or acylated amino or free or esterified carboxyl. There is further disclosed a process for preparing these derivatives as well as their use for the preparation of compositions for the therapy of cancers.

Description

Technical field

The present invention relates to N-phenyl-2-pyrimidinamine derivatives, to a process for their preparation, to medicaments containing them, and to their use for the preparation of pharmaceutical compositions for the treatment of warm-blooded animals.

BACKGROUND OF THE INVENTION

European patent application EP-A-23361 describes

4,5,6-substituted-N- (substituted phenyl) -2-pyrimidinamine derivatives having antiallergic, particularly antihistaminic activity. We have recently surprisingly found that structurally related but novel compounds of the following general formula (1) have antitumor activity.

SUMMARY OF THE INVENTION

The present invention provides N-phenyl-2-pyrimidinamine derivatives of formula (1)

in which

R ¹ is pyrazinyl, 1-methyl-1H-pyrrolyl, phenyl substituted with amino or amino (lower alkyl), which is either free or alkylated with lower alkyl or acylated (lower alkane) -yl a 1H-indolyl group bound to a carbon atom of a five-membered ring, a 1H-imidazolyl group bound to a carbon atom of a five-membered ring, or a pyridyl group which is bound at a carbon atom of the ring optionally substituted by a lower alkyl group and optionally substituted at nitrogen by an oxygen atom;

R ² and R ³ independently of one another are a hydrogen atom, or lower alkyl, one or two of R ^4, R ^5, R ^6, R ⁷ and R ^s is optionally represent a nitro group, a lower alkoxy group substituted with fluorine or a group of formula (II)

-N (R ⁹ ) -C (= X) - (Y) _n -R 10 (II) wherein

R ⁹ represents a hydrogen atom or a lower alkyl group,

X is oxo, thio, imino, N- (lower alkyl) imino, hydroxyimino, or O- (lower alkyl) hydroxyimino,

Y is oxygen or NH, n is 0 or 1 and

R ¹⁰ represents an alkyl, alkenyl or alkynyl group containing in each case at least 5 and not more than 22 carbon atoms, phenyl or naphthyl, which is in each case unsubstituted or substituted by cyano, lower alkyl, hydroxy-lower alkyl), amino (lower alkyl), (4-methylpiperazinyl) (lower alkyl), trifluoromethyl, hydroxy, lower alkoxy, (lower alkanoyl) oxy, halogen, amino, (lower alkylamino, di (lower alkylamino, (lower alkanoyl) amino, benzoylamino), carboxamino) (lower alkoxy) carbonyl group containing up to 20 carbon atoms, a phenyl (lower alkyl) group in which the phenyl radical is unsubstituted or substituted as described above and contains up to 20 carbon atoms, a cycloalkyl or cycloalkenyl group containing up to 30 carbon in each case cycloalkyl (lower alkyl or cycloalkenyl (lower alkyl) in which the cycloalkyl or cycloalkenyl radical contains in each case not more than 30 carbon atoms, a monocyclic group having 5 or 6 ring members and 1 to 3 ring atoms selected from the group consisting of nitrogen, oxygen and a sulfur atom to which one or two benzene radicals, or a lower alkyl group which is substituted by such a monocyclic group, may be fused, and the others of R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ independently of one another a hydrogen atom, a lower alkyl group which is optionally substituted by an amino or alkylated amino group containing up to 14 carbon atoms, a piperazinyl group, a piperidinyl group, a pyrrolidinyl group or a morpholinyl group, a lower alkanoyl group, a trifluoromethyl group, free, hydroxy, etherified or esterified an alkylated hydroxy group containing up to Ί carbon atoms, an amino group, an alkylated amino group containing up to 14 carbon atoms or an acylated amino group containing up to 7 carbon atoms, a carboxyl group or an esterified carboxyl group containing up to 7 carbon atoms, and salts of these derivatives containing at least one salt capable of conversion.

1-Methyl-ΙΗ-pyrrolyl is preferably 1-methyl-1H-pyrrol-2-yl or 1-methyl-1H-pyrrol-3-yl.

A phenyl group R ¹ substituted with an amino group or an amino (lower alkyl group, wherein the amino group is either free or alkylated or acylated) is substituted at any position (ortho, meta, or para) with a phenyl group in which there is one alkylated amino group, preferably a mono- or di (lower alkyl) amino group, for example a dimethylamino group, and the lower alkyl radical of the amino (lower alkyl) group is preferably a linear alkyl group having 1 to 3 carbon atoms, in particular methyl or ethyl.

The 1 H-indolyl group bonded to the carbon atom of the five-membered ring consists of 1 H-indol-2-yl or 1 H-indol-3-yl.

On a ring carbon atom bound by an unsubstituted or lower alkyl group substituted by a pyridyl group, the lower alkyl group is substituted or preferably unsubstituted 2-, 4- or preferably 3-pyridyl, for example 3-pyridyl, 2-methyl-3-pyridyl or 4- methyl-3-pyridyl. The pyridyl group which is substituted on the nitrogen atom by an oxygen atom is a residue derived from pyridine-N-oxide, i. j. With an N-oxidopyridyl residue.

A fluorine-substituted lower alkoxy group is a lower alkoxy group which carries at least one, but preferably several, fluorine substituents, in particular trifluoromethoxy or 1,1,2,2-tetrafluoroethoxy.

When X is oxo, thio, imino, N- (lower alkylimino, hydroxyimino or O- (lower alkyl) hydroxyimino), C = X is C = O, C = S, C = NH respectively C = N- (lower alkyl), C = N-OH or CNO (lower alkyl).

Preferably X is oxo.

Preferably n is 0, which means that Y is absent.

If Y is present, it is preferably NH.

The lower alkyl groups R ¹ , R ² , R ³ and R ⁹ are preferably methyl or ethyl.

The specification below denotes residues of up to 7 carbon atoms, preferably up to 4 carbon atoms.

The aliphatic radical R ¹⁰ having at least 5 carbon atoms preferably has no more than 22 carbon atoms, typically having no more than 10 carbon atoms and is a substituted or preferably unsubstituted aliphatic hydrocarbon radical, ie a substituted or preferably unsubstituted alkynyl, alkenyl or preferably alkyl radical such as an alkyl radical containing 5 to 7 carbon atoms, for example an n-pentyl radical. The aromatic radical R ¹⁰ has up to 20 carbon atoms and is substituted or unsubstituted, for example meaning an unsubstituted or substituted naphthyl radical, in particular a 2-naphthyl radical, or preferably a phenyl radical, the substituents being preferably selected from cyano, unsubstituted or hydroxy, amino or a 4-methylpiperazinyl group substituted with a lower alkyl group, in particular a methyl group, a trifluoromethyl group, a free, etherified or esterified hydroxyl group, a free, alkylated or acylated amino group and a free or esterified carboxyl group.

In the aromatic-aliphatic radical R ¹⁰ , the aromatic radical is a defined aromatic radical and the aliphatic radical is preferably a lower alkyl group, in particular a C 1 -C 2 alkyl group which is substituted or preferably unsubstituted, and for example benzyl.

The cycloaliphatic radical R ¹⁰ has in particular up to 30, in particular up to 20 and in particular up to 10 carbon atoms, and is a polycyclic and substituted or preferably unsubstituted radical, for example in particular a 5- or 6-membered cycloalkyl radical, preferably a cyclohexyl radical.

In the cycloaliphatic-aliphatic radical R ¹⁰ , the cycloaliphatic radical is as defined above and the aliphatic radical is preferably a lower alkyl group, in particular an alkyl group having 1 to 2 carbon atoms, which is substituted or preferably unsubstituted.

The heterocyclic radical R ¹⁰ preferably contains up to 20 carbon atoms and is preferably a saturated or unsaturated monocyclic radical having 5 or 6 ring members and 1 to 3 heteroatoms, which is preferably selected from the group consisting of nitrogen, oxygen and sulfur, for example thienyl. or a 2-, 3- or 4-pyridyl radical or a bi- or tricyclic radical in which, for example, one or two benzene radicals are fused to said monocyclic radical (fused).

In the heterocyclic-aliphatic radical R ¹⁰ , the heterocyclic radical is a radical as defined above, and the aliphatic radical is preferably a lower alkyl group, especially an alkyl group having 1 to 2 carbon atoms, which is substituted or preferably unsubstituted.

The etherified hydroxyl group is preferably a lower alkoxy group. The esterified hydroxy group is preferably a hydroxy group esterified with an organic carboxylic acid such as a lower alkanoic acid or a mineral acid such as hydrohalic acid, for example (lower alkanoyloxy) or in particular a halogen atom such as iodine, bromine or especially fluorine or chlorine.

An alkylated amine group is, for example (a lower alkyl amine group such as a methylamino group, or a di (lower alkyl amine group such as a dimethylamino group). An acylated amine group is, for example, a (lower alkjanoylamino group or a bezoylamino group).

An esterified carboxyl group is, for example (a lower alkoxycarbonyl group such as a methoxycarbonyl group.

A substituted phenyl group can carry up to 5 substituents, such as fluorine atoms, and in particular in the case of larger substituents, the phenyl group is generally substituted with one to three substituents. Examples of substituted phenyl are, in particular, 4-chlorophenyl, pentafluorophenyl, 2-carboxyphenyl, 2-methoxyphenyl, 4-fluorophenyl, 4-cyanophenyl and 4-methylphenyl.

Groups which can be converted to a salt in a compound of formula (I) include groups or moieties with basic or acidic properties. Compounds with at least one basic group or at least one basic radical, for example a free amino group or a pyrazinyl or pyridyl radical, may form acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example with aliphatic mono- or dicarboxylic acids such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, citric acid, oxalic acid or amino acids such as arginine or lysine, or aromatic carboxylic acids such as benzoic acid, 2-phenoxybenzoic acid, 2acetoxybenzoic acid, salicylic acid, 4-aminosalicylic acid, or aliphatic- aromatic carboxylic acids such as mandelic acid or cinnamic acid, or heteroaromatic carboxylic acids such as nicotinic acid or isonicotinic acid, or aliphatic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, or 2-hydroxyethanesulfonic acid, or aromatic are, for example, benzenesulfonic acid, p-toluenesulfonic acid or naphlalene-2-sulfonic acid. In the presence of a plurality of basic groups, mono- or polyaddition salts with acids may be formed.

The compounds of formula (I) with acidic groups, for example with a free carboxyl group in the radical ^R10, may form salts derived from metal or ammonium salts, such as those derived from alkali or alkaline earth metal such as sodium, potassium, magnesium salts or calcium salts, or ammonium salts with ammonia or a suitable organic amine, for example a tertiary monoamine, for example triethylamine or tri- (2-hydroxyethyl) amine, or with a heterocyclic base, for example N-ethylpiperidine or N, N'-dimethylpiperazine.

Compounds of formula (I) which contain both acidic and basic groups may form internal salts.

Pharmaceutically unsuitable salts can be used to isolate or purify the compounds which are further used as intermediates. However, only pharmaceutically usable non-toxic salts are suitable for therapeutic use and are therefore preferred salts.

Due to the close relationship between the new compounds in free form and these compounds in the form of their salts, even those salts which can be used as intermediates, for example in the purification of new compounds or for their identification, they are understood in the preceding and following text. free compounds, optionally also their corresponding salts.

The compounds of formula (I) possess valuable pharmacological properties and can be used, for example, as antitumor agents or as anti-atherosclerosis agents.

Protein phosphorylation has long been known as an essential process in cell differentiation and multiplication. This phosphorylation is catalyzed by protein kinases that are divided into serine / threonine kinases and tyrosine kinases. Serine / threonine kinases include protein kinase C, while platelet-derived Growth Factor-receptor-tyrosine kinase PDGF-tyrosine kinases.

Compounds of formula (I) in which R ⁴ and R ⁸ are hydrogen selectively inhibit the protein kinase C enzyme.

Phospholipids and calcium-dependent protein kinase C are present in cells in several species (tissue-specific species distribution) and are involved in various basic processes such as signal transduction, proliferation and differentiation, as well as hormone and neurotransmitter secretion. Activation of this enzyme occurs either through receptors mediated by cell membrane phospholipid hydrolysis or directly by interaction with certain tumor growth promoting agents. Cell functions that are controlled by protein kinase C may be affected by modulating the enzymatic activity of protein kinase C.

To determine the inhibitory effect on protein kinase C, pig brain protein kinase C is used, which is purified according to the procedure of T. Uchida and CR Filbumm in J. Biol. Chem. 259, 12311-4 (1984). Determination of the protein kinase inhibitory effect of the compounds of formula (I) is carried out by the method of D. Fabro et al. in Árch. Biochem. Biophys. 239: 102-111 (1985). In this test, compounds of formula (I) already inhibit protein kinase C at a concentration of 1C _{50 of} between about 0.1 and 10 pmol / l, in particular between about 0.05 and 5 pmol / l. In contrast, the compounds of formula (I) inhibit other enzymes such as protein kinase A, protein phosphorylase kinase and certainly protein-tyrosine kinase types, such as protein-tyrosine kinase EGF- (Epidermal Growth Factor) -receptor, far away higher, for example 100 times higher, concentration. This indicates the selectivity of the compounds of formula (I). In order to limit the side effects, it is important that the protein kinase inhibitors are, as far as possible, selective and have little effect on other enzymes, especially when affecting the activity of these other enzymes has no consistent or synergistic effect on the disease being treated. .

Based on the protein kinase C inhibitory effect, compounds of formula (I) wherein R ⁴ and R ⁸ are hydrogen and their pharmaceutically usable salts can be used as tumor-inhibiting, immunomodulatory and antibacterial active agents, as well as anti-atherosclerosis, AIDS , cardiovascular diseases, and central nervous system diseases.

As expected from the protein kinase C inhibitory activity described above, the compounds of formula (I) wherein R ⁴ and R ⁸ are hydrogen and their pharmaceutically usable salts have antiproliferative properties that can be directly demonstrated by the following tests.

In this assay, the inhibitory effect of the compounds of formula (I) on the growth of human bladder cancer T24 cells is determined. These cells are added to Eagle's minimal base medium, which is enriched with 5% (v / v) fetal calf serum, and incubated in a humidified incubator at 37 ° C in the presence of air containing 5 volume percent carbon dioxide. The cancer cells are then inoculated into a 96 well microtiter plate and incubated overnight under the conditions indicated. The test substance is then added (1 day) in serial dilutions. The microtiter plates are then incubated under the above conditions for 5 days. During this time period, at least 4 cell divisions occur in control cell cultures. After the incubation, the cells are fixed

3.3% (w / v) glutaraldehyde solution, washed with water and stained with 0.05% (w / v) aqueous methylene blue solution. After washing, the dye is eluted with 3% (w / v) aqueous hydrochloric acid. The optical density (OH) for each well is then measured, which is proportional to the number of cells using a photometer (Titertekmultiskan) at a wavelength of 665 nm. From the results obtained, 1C _{50 is} calculated in a computer system using the following formula:

OH ₆₆₅ (test) - OH ₆₆₅ (start) ______________________________________ x 100. OH ₆₆₅ (control) - OH ₆₆₅ (start)

The IC ₅₀ value is defined as the concentration of drug at which the number of cells in the well at the end of the incubation period is only 50% of the number of cells in the control culture. The IC ₅₀ values determined for compounds of formula (I) are in the range of about 0.1 to about 10 pmol / L.

In view of the properties described, the compounds of formula (I) in which R ⁴ and R ⁸ represent a hydrogen atom can be used in particular as tumor-inhibiting active substances, for example for the treatment of bladder tumors. In addition, their use in the function of the aforementioned protein kinase C modulators is contemplated and can be used, in particular, for the treatment of diseases affected by protein kinase inhibition.

Compounds of formula (I) in which R ⁴ and R ⁸ are hydrogen not only inhibit protein kinase but also inhibit, even at an IC _{50 of} between about 0.01 and 5 pmol / liter, especially between about 0.05 and 1 pmol / liter, certain tyrosine kinases, such as in particular PDGF-receptor kinase or abl-kinase, for example v-abl-kinase. Compounds of formula (1) in which at least one of the radicals R ⁴ and R ^{8 are} different from hydrogen and represent, for example, a lower alkyl group, such as a methyl group in particular, are particularly selective for said PDGF- and abl-tyrosine kinase and practically do not inhibit protein kinase C.

Platelet-derived Growth Factor (PDGF) is a very common growth factor that plays an important role in both normal growth and the pathological cell proliferation that occurs in carcinogenesis and vascular smooth muscle cell diseases such as atherosclerosis and thrombosis. .

In this respect, inhibition of protein kinase C and PDGF receptor kinase acts quasi-synergistically in the same direction with respect to the regulation of cell growth.

In vitro inhibition of PDGF receptor tyrosine kinase activity is measured in PDGF receptor immunocomplexes of BALB / c 3T3 cells by a procedure analogous to that described by E. Andrejauskas-Buchdunger and U. Regenass in Cancer Research 52, 5353-5358 (1992). . The aforementioned compounds of the formula (I) mentioned above inhibit PDGF-dependent cell-free receptor phosphorylation at a concentration of from 0.005 to 5 pmol / liter, in particular at a concentration of 0.01 to 1.0 and in particular a concentration of 0.01 to 0.1 pmol / liter. l. Inhibition of PDGF-receptors tyrosine kinase in an intact cell was demonstrated by Western blot analysis, also analogously to E. Andrejauskas-Buchdenger and U. Regenass in Cancer Research 52, 5353-5358 (1992). In this assay, the inhibition of ligand-stimulated PDGF-receptor autophosphorylation in mouse BALB / c cells is measured with an anti-phosphotyrosine antibody. The compounds of formula (1) specified above inhibit PDGF receptor tyrosine kinase activity at a concentration of 0.005 to 5 pmol / liter, in particular at a concentration of 0.01 to 1.0 pmol / liter, and in particular at a concentration of 0.01 to 0, 1 pmol / liter. These compounds also inhibit cell growth from PDGF-dependent cell lines, namely mouse fibroblasts BALB / c 3T3, at a concentration of less than 1.0 μιηοΐ / liter.

Said inhibition in abl-tyrosine kinase is determined by the methods described by N. Lydon et al., Oncogene Research 5, 161-173 (1990) and JF Geissler et al., Cancer Research 52, 4492-4498 (1992). [Val ^5] -angiotensin II and [gamma- ³² P] -ATP are used as substrates in these methods.

In view of the properties described, the compounds of the formula I can be used not only as tumor-inhibiting active substances, but also as agents against atherosclerosis and thrombosis. In addition, other uses are contemplated for said protein kinase C modulators and may be used, in particular, for the treatment of diseases in which beneficial responses can be achieved by inhibiting PDGF-receptor kinase.

In addition, the compounds of formula (I) suppress the formation of resistance (resistance to a wide variety of active agents) to other chemotherapeutic agents in cancer therapy or abolish existing resistance to other chemotherapeutic agents.

Preferred compounds of the invention are those compounds of formula (I) wherein one or two of R ⁴ , R ⁵ , R ⁶ , R ^7, and R ⁸ is respectively. are nitro or a group of formula (11) in which:

R ⁴ represents a hydrogen atom or a lower alkyl group,

X is oxo, thio, imino, N- (lower alkyl) imino, hydroxyimino or O- (lower alkyl) hydroxyimino,

Y is an oxygen atom or NH, n is 0 or 1 and

R ¹⁰ represents an alkyl or alkenyl group containing in each case at least 5 and not more than 22 carbon atoms, phenyl or naphthyl, which is in each case unsubstituted or substituted by cyano, lower alkyl, hydroxy (lower alkyl), amino (lower alkyl), (4-methylpiperazinyl) (lower alkyl), trifluoromethyl, hydroxy, lower alkoxy, (lower alkynoyl) oxy, halogen, amino, (lower alkyl) amino, di (lower alkylamino, (lower alkanoyl) amino, benzoylamino, carboxy or (lower alkoxy) carbonyl and containing up to 20 carbon atoms, phenyl (lower alkyl) in which the phenyl radical is unsubstituted or substituted as described above and contains at most 20 carbon atoms, cycloalkyl or cycloalkenyl containing in each case not more than 30 carbon atoms v, a cycloalkyl (lower alkyl) or cycloalkenyl (lower alkyl) group in which the cycloalkyl or cycloalkenyl radical contains in each case not more than 30 carbon atoms, a monocyclic group having 5 or 6 ring members and 1 to 3 ring atoms selected from nitrogen, oxygen and sulfur, to which may be fused to one or two benzene radicals, or lower alkyl substituted by such a monocyclic group, and the other of R ^4, R ^s, R ^6, R ⁷ and R ⁸ independently of one another are a hydrogen atom, a lower alkyl group which is unsubstituted or substituted by a free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl group, a lower alkanoyl group, a trifluoromethyl group, a free, etherified or esterified hydroxy group, a free, alkylated or a free or esterified carboxyl group, the other substituents being as defined above, and salts of these derivatives containing at least one group capable of being converted to a salt.

Particularly preferred compounds are those compounds of formula (1) wherein:

R ¹ represents pyrazinyl, 1-methyl-1H-pyrrolyl, amino or amino (lower alkyl substituted phenyl), in which the amino group is always free, alkylated with one or two lower alkyl radicals, acylated with lower alkanoyl or benzoyl, to a 5-membered ring carbon atom bonded by an 1H-indolyl or 1 H-imidazolyl group or on a ring carbon atom bound by an unsubstituted or lower alkyl substituted pyridyl group which is unsubstituted or substituted by an oxygen atom on the nitrogen atom,

R ² and R ³ independently of one another are H or lower alkyl, one or two of R ^4, R ^5, R ^6, R ^7, and ^R is, respectively. are nitro, fluoro substituted lower alkoxy or a group of formula (II) in which:

R ₉ represents a hydrogen atom or a lower alkyl group,

X is oxo, thio, imino, N- (lower alkylimino, hydroxyimino, or O- (lower alkyl) hydroxymino,

Y is oxygen or NH, n is 0 or 1 and

R ¹⁰ represents an aliphatic hydrocarbon radical having 5 to 22 carbon atoms, a phenyl or naphthyl radical which is in each case unsubstituted or substituted by cyano, lower alkyl, hydroxy (lower alkyl), amino (lower alkyl), (4-methylpiperazinyl) ) (lower alkyl), trifluoromethyl, hydroxy, lower alkoxy, (lower alkanoyl) oxy, halogen, amino, (lower alkyl) amino, di (lower alkylamino, (lower alkanoyl) amino, benzoylamino) a carboxyl group or a (lower alkoxy) carbonyl group, a phenyl (lower alkyl) radical in which the phenyl group is unsubstituted or substituted as described above, a cycloalkyl or cycloalkenyl radical of up to 30 carbon atoms, a cycloalkylflower alkyl or a cycloalkenyl (lower alkyl) a radical of up to 30 carbon atoms each a cycloalkyl or cycloalkenyl moiety, a monocyclic radical having 5 or 6 ring members and 1 to 3 ring atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom to which one or two benzene residues may be fused or a lower alkyl group which is substituted with such a monocyclic radical, and the others of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another represent a hydrogen atom, a lower alkyl group which is unsubstituted or substituted by amino, (lower alkyl amino, di (lower) alkyl-amino, piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl, lower alkanoyl, trifluoromethyl, hydroxy, lower alkoxy, (lower alkanoyl) oxy, halogen, amino, (lower alkyl) amino, di ( lower alkyl) amino, (lower alk anoyl, amino, benzoylamino, carboxyl or (lower alkoxy) carbonyl group, and pharmaceutically usable salts of these compounds with at least one salt-capable group.

Particularly preferred compounds of the invention are those compounds of formula (I) wherein:

R ¹ represents a pyridyl group attached to the ring carbon atom which is unsubstituted or substituted by an oxygen atom on the nitrogen atom,

R ² and R ³ are H,

R ⁴ represents a hydrogen atom or a lower alkyl group,

R ⁵ represents a hydrogen atom, a lower alkyl group or a fluorine-substituted lower alkoxy group,

R ⁶ represents a hydrogen atom,

R ⁷ represents a nitro group, a fluorine-substituted lower alkoxy group or a radical of formula (II) in which:

R ⁹ represents a hydrogen atom,

X is oxo, n is 0 and

R ¹⁰ is C 5 -C 22 alkyl, phenyl which is unsubstituted or substituted by cyano, lower alkyl, (4-methylpiperazinyl) (lower alkyl), lower alkoxy, halogen, or carboxyl by cycloalkyl; up to 30 carbon atoms or a monocyclic radical having 5 or 6 ring members and 1 to 3 ring sulfur atoms, and

R ⁸ represents a hydrogen atom, and pharmaceutically usable salts of these compounds with at least one salt-capable group.

Particularly preferred compounds of the invention are those compounds of formula (I) wherein:

Each R ¹ is the carbon atom bonded pyridyl or N-oxido-pyridyl, R ² and R ³ are H,

R ⁴ represents a hydrogen atom or a lower alkyl group,

R ⁵ represents a hydrogen atom, a lower alkyl group or a trifluoromethyl group,

R ⁶ represents a hydrogen atom,

R ⁷ represents a nitro group, a fluorine-substituted lower alkoxy group or a radical of formula (U) in which:

R ⁹ represents a hydrogen atom,

X is oxo, n is 0 and

R ¹⁰ represents a pyridyl group attached to a carbon atom, unsubstituted or halogen, cyano, lower alkoxy, carboxyl, lower alkyl or 4-methylpiperazinylmethyl substituted phenyl, (C 5 -C 7) alkyl, thienyl, 2, - naphthyl or cyclohexyl, and

R ⁸ represents a hydrogen atom, and pharmaceutically usable salts of these compounds with at least one salt-capable group.

Particularly preferred compounds of the invention are those compounds of formula (I) wherein:

R ⁴ and R ⁸ represent a hydrogen atom or one of R ⁴ and R ⁸ represents a lower alkyl group and the other of R ⁴ and R ⁸ and the other general substituents have the meanings indicated, and pharmaceutically usable salts of these compounds with at least one salt-capable group .

Further particularly preferred compounds of the invention are those compounds of formula (I) wherein:

R ¹ represents a pyridyl group attached to a carbon atom,

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁸ represent a hydrogen atom and

R ⁷ represents a nitro group or a radical of formula (II) wherein

R ⁹ represents a hydrogen atom,

X is oxo, n is 0 and

R ¹⁰ represents a pyridyl-bonded pyridyl group, unsubstituted or fluorine atom, chlorine atom, cyano, lower alkoxy, carboxyl, lower alkyl or 4-methylpiperazinylmethyl substituted phenyl, (C 5 -C 7) alkyl, thienyl or a cyclohexyl group, and pharmaceutically acceptable salts thereof.

The most preferred compounds of the invention are exemplified compounds of formula (I) and pharmaceutically acceptable salts thereof with at least one salt-converting group.

In view of the inhibition of protein kinase C, the most preferred compounds of the invention are those compounds of formula (I) wherein R ⁴ and R ⁸ are hydrogen and the other general substituents are as defined above, and pharmaceutically usable salts of these compounds with at least one salt-converting group. .

The compounds of formula (I) and salts of these compounds with at least one salt-converting group are prepared in a manner known per se.

The present invention also provides a process for the preparation of compounds of formula (I) and salts thereof with at least one group capable of being converted into a salt comprising the steps of:

(a) a compound of formula (III)

wherein R ¹¹ and R ¹² independently of one another are lower alkyl and R ¹ , R ² and R ³ are as defined above, wherein the functional groups present in the compound of formula (III) are, except for those involved in the reaction, optionally in protected form, or a salt thereof is reacted with a compound of formula (IV)

RF * ^IV1 l in which the substituents are as defined above, with the functionality present in the compound of formula (IV) are, with the exception of the guanidino group participating in the reaction, optionally in protected form, or a salt thereof, and the protecting groups are cleaved or

(b) for the preparation of a compound of formula (I) wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above except for nitro and fluoro substituted lower alkoxy, the compound of formula (V)

V ¹ R ¹⁵

wherein one or two of R ¹³ , R ¹⁴ , R ¹⁵ , R ^16, and R ¹⁷ is, respectively. denote an amino group and the others of R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently of one another represent a hydrogen atom, a lower alkyl group which is unsubstituted or substituted by a free or alkyl amino group, piperazinyl group, piperidinyl group, pyrrolidinyl group or a morpholinyl group, a lower alkanoyl group, a trifluoromethyl group, a free or etherified or esterified hydroxy group, a free, alkylated or acylated amine group or a free or esterified carboxyl group, and other general substituents have the meanings indicated, the functional groups present in the compound (V) are reacted, with the exception of the amine group (s) involved in the reaction, optionally in protected form, with a compound of formula (VI)

HO-C (= X) - (Y) n-R ¹⁰ (VI), in which the general substituents are as defined above, wherein the functional groups present in the compound of formula (VI) are with the exception of HO-C (= X) - participating in the reaction, optionally in protected form, or with a reactive derivative of a compound of formula (VI), subsequently deprotecting or

c) to obtain a compound of formula (I), wherein ^R1 is pyridyl, which is N-substituted by oxygen, and the other substituents are as defined above, converting a compound of formula (I), wherein R ¹ means a pyridyl group, by treating the N-oxide compound with a suitable oxidizing agent, followed by optionally converting the compound of formula (I) obtained according to steps a to c into their salt or converting the salt of the compound of formula (I) to the free compound of formula (I).

The embodiments of the methods of the invention will be described in more detail below.

General information:

The final compounds of formula (I) may contain substituents which, like the protecting groups in the starting materials, may be used to prepare other final compounds of formula (I). Accordingly, only a readily cleavable group that is not part of the desired final group of compound (1), unless otherwise indicated by the context, is referred to herein as a protecting group.

Protecting groups, their introduction and cleavage are exemplified in Protective Groups in Organic Chemistry, Plenum Press, London, New York 1973 and Methoden der Organischen Chemie, Houben-Weyl, 4th Ed. Bd. 15/1, Georg-Thieme-Verlag, Stuttgart 1974, as well as in Theodor W. Greene Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1981. Characteristic of protecting groups is that they are easily, i.e. without undesirable side reactions, cleavable, for example, solvolytically, reducing, photolytically or else under physiological conditions, would occur.

Hydroxy-protecting groups are, for example, acyl radicals, such as optionally halogen-substituted lower alkanoyl radicals, such as 2,2-dichloroacetyl, or acyl radicals derived from carbonic acid esters, in particular tert-butyloxycarbonyl, optionally substituted benzyloxycarbonyl, for example 4- nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl or 2-halo (lower alkoxy) carbonyl such as 2,2,2-trichloroethoxycarbonyl, further a trityl residue, a formyl residue or an organic silyl or stannyl residue, further readily cleavable etherified groups such as tert-lower alkyl, for example tert-butyl, 2-oxa or 2-thiaaliphatic or cycloaliphatic hydrocarbon radicals, in particular 1- (lower alkoxy lower alkyl) or 1- (lower alkyl) thio (lower alkyl), for example methoxymethyl, 1- methoxyethyl, 1-ethoxyethyl, methylt iomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa or 2-thiacycloalkyl of 5 to 6 ring atoms, for example tetrahydrofuryl or 2-tetrahydropyranyl, or the corresponding thiaan analogs, as well as optionally substituted 1-phenyl ( a lower alkyl group such as an optionally substituted benzyl or diphenylmethyl group, wherein, for example, a halogen atom such as a chlorine atom, a lower alkoxy group such as a methoxy group and / or a nitro group are suitable as a phenyl substituent.

For example, the protected amino group may be in the form of an easily cleavable acylamino group, arylmethylamino group, etherified mercaptoamine group, 2-acylphenyl alk) -1-enylamino group, silyl- or stannylamine group, or azide group.

In the corresponding acylamino group, the acyl radical is, for example, an acyl radical of an organic carboxylic acid having, for example, up to 18 carbon atoms, in particular, for example, a halogen atom or an aryl substituted alkanecarboxylic acid or alternatively e.g. halogen, lower alkoxy or nitro substituted benzoic acid. of carbonic acid. Such acyl groups are, for example, lower alkanoyl such as formyl, acetyl or propionyl, halogen (lower alkanoyl) such as 2-haloacetyl, especially 2-chloroacetyl, 2-bromoacetyl, 2-iodoacetyl, 2,2 , 2-trifluoroacetyl or 2,2,2-trichloroacetyl, optionally for example halogen, lower alkoxy and nitro substituted benzoyl, for example benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or in the 1-position of the lower alkyl moiety branched or in the 1 or 2 position a suitably substituted (lower alkoxy) carbonyl group, for example a tert-butyloxycarbonyl group, an arylmethoxycarbonyl group with one or two aryl radicals, preferably consisting of a phenyl group optionally mono- or polysubstituted e.g. alk a lower alkyl group such as a butyl group, a lower alkoxy group such as a methoxy group, a hydroxy group, a halogen atom such as a chlorine atom and / or a nitro group such as an optionally substituted benzyloxycarbonyl group such as a 4-nitrobenzyloxycarbonyl group; a diphenylmethoxycarbonyl group such as a benzhydryloxycarbonyl group or a di- (4-methoxyphenyl) methoxycarbonyl group, an aroylmethoxycarbonyl group wherein the aroyl group optionally represents, for example, a halogen atom such as a bromine atom, a substituted benzoyl group such as a phenylacyloxycarbonyl halogeno group; a carbonyl group, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl-ethoxycarbonyl group, in which the substituents are independently j one of the other optionally substituted, for example, lower alkyl, lower alkoxy, aryl, halogen or nitro substituted, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radicals of up to 15 carbon atoms, as the corresponding optionally substituted lower alkyl, phenyl (lower alkyl, a cycloalkyl or phenyl radical such as a 2-trimethylsilyl-ethoxycarbonyl or 2- (di-n-butylmethylsilyl) ethoxycarbonyl or a 2-triarylsilylethoxycarbonyl group such as a 2-triphenylsilylethoxycarbonyl group.

Other acyl residues suitable as amino-protecting groups are the corresponding organic phosphoric, phosphonic or phosphinic acid radicals, such as a di (lower alkylphosphoryl radical, such as a dimethylphosphoryl radical, a diethylphosphoryl radical, a di-n-propylphosphoryl radical or a diisopropylphosphoryl radical). , for example, a dicyclohexylphosphoryl radical, an optionally substituted diphenylphosphoryl radical, for example a diphenylphosphoryl radical, optionally for example a nitro substituted di (phenyl (lower alkyl)) phosphoryl radical, for example a dibenzylphosphoryl radical or a di- (4-nitrobenzyl) phosphoryloxyphenyl radical, optionally substituted phenyloxyphenyl, a di (lower alkyl) phosphinyl radical, for example a diethylphosphinyl radical, or an optionally substituted diphenylphosphinyl radical, for example diphenyl phosphinyl residue.

In the arylmethylamino group, which includes mono-, diallyl and especially triarylmethylamino, the aryl radicals are in particular optionally substituted phenyl radicals. Such groups are, for example, benzylamino, diphenylmethylamino and especially tritylamino.

The etherified mercapto group in the amino group protected by this group is preferably arylthio or aryl (lower alkylthio), in which the aryl radical is in particular optionally, for example, lower alkyl such as methyl or tert-butyl, lower alkoxy such as methoxy, halogen atom such as a chlorine atom and / or a nitro-substituted phenyl radical, and a corresponding amino-protecting group is, for example, 4-nitrophenylthio.

In a 2-acyl (lower alk) -1-en-1-yl moiety useful as an amino-protecting group, the acyl moiety is, for example, the corresponding (lower alkane) carboxylic acid, benzoic acid moiety optionally substituted by a lower alkyl group such as methyl or tert. a butyl group, a lower alkoxy group such as a methoxy group, a halogen atom such as a chlorine atom, and / or a nitro group, or in particular a half carbonate ester, for example a half (lower alkyl ester of carbonic acid). alkanoyl) prop-1-en-2-yl, for example 1-acetylprop-1-en-2-yl, or 1- (lower alkoxy) carbonylprop-1-en-2-yl, for example 1-ethoxycarbonylprop- 1-en-2-yl.

Preferred amino-protecting groups are acyl radicals of half-carbonic acid esters, in particular a tert-butyloxycarbonyl radical, for example a 4-nitrobenzyloxycarbonyl radical or a diphenylmethoxycarbonyl radical, or a 2-halo (lower alkoxy) carbonyl radical, such as a 2,2,2-trichloroethoxycarbonyl radical. a trityl residue or a formyl residue. The cleavage of the protecting groups which are not part of the desired final product of formula (I) is carried out in a known manner, for example by solvolysis, in particular by hydrolysis, alcoholysis or acidolysis, or by reduction, in particular by hydrogenolysis or chemical reduction, optionally sequentially or simultaneously.

The protected amine group is converted to the amine group in a known manner by various procedures depending on the nature of the protecting group, preferably by solvolysis or reduction. 2-Halogen (lower alkoxycarbonylamino) (optionally after conversion of 2-bromo (lower alkoxycarbonylamino) to 2-iodo (lower alkoxycarbonylamino, aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino) may be cleaved, for example, by treatment with a suitable chemical, e.g. The aroylmethoxycarbonylamino group can also be cleaved by treatment with a nucleophilic, preferably salt-forming agent, such as sodium thiophenoxide, and the 4-nitrobenzyloxycarbonylamino group can also be cleaved with an alkali metal dithionite, for example sodium dithionite. a substituted diphenylmethoxycarbonylamino group, a tert- (lower alkoxy) carbonylamino group or a 2-trisubstituted silylethoxycarbonylamino group may be cleaved by treatment with a suitable acid, for example formic acid and for example, trifluoroacetic acid, an optionally substituted benzyloxycarbonylamino group can be cleaved, for example, by hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, or an optionally substituted triarylmethylamine or formylamino group, for example hydrochloric or organic acid, for example formic acid, acetic acid or trifluoroacetic acid, optionally in the presence of water, and the silyl-protected amino group can be released, for example, by hydrolysis or alcoholysis. An amino group protected by 2-haloacetyl, for example 2-chloroacetyl, can be liberated by treatment with thiourea in the presence of a base or with a thiolate salt, such as thiolate alaklického metal of thiourea, and subsequent solvolysis, the ^one in which the substituents are as defined above, with a compound of formula (VIII), in particular by alcoholysis or hydrolysis of the resulting condensation product. The amino group protected with a 2-substituted silylethoxycarbonyl group can be converted to the free amine group by treatment with a hydrofluoric acid salt providing fluoride anions.

A hydroxy group protected with a suitable acyl group, an organic silyl group or an optionally substituted 1-phenyl (lower alkyl group may be released in a manner analogous to the release of an appropriately protected amino group. is preferably liberated by catalytic hydrogenation, for example in the presence of a hydrogenation catalyst consisting of palladium on carbon, a hydroxy-protected 2,2-dichloroacetyl group is liberated, for example, by basic hydrolysis and a hydroxyl group cterified by lower tertiary alkyl or 2-oxa- or 2-thiaaliphatic or cycloaliphatic the group is liberated by acidolysis, for example by treatment with a mineral acid or a strong carboxylic acid such as trifluoroacetic acid. a silyl moiety, such as a trimethylsilyl moiety, can be liberated by a hydrofluoric acid salt that provides fluoride anions, such as tetrabutylammonium fluoride.

Method a

R ¹¹ and R ^{12 are} preferably methyl

The free functional groups in the compound of formula (III), which are preferably protected by readily cleavable protecting groups, are in particular the amino groups in the radical R ^{@ 1} and the imine group of the ind-indolyl group. The latter group may, for example, be protected with a benzyl group.

The free functional groups in the compound of formula (IV) which are preferably protected by readily cleavable protective groups are, in particular, an amine group, but also a hydroxy group and a carboxyl group.

The salt of the compound of formula (IV) is preferably an acid addition salt, for example nitrate, or one of the acid addition salts mentioned for the final product of formula (1).

Said reaction is carried out in a suitable solvent or suspending medium, for example in a suitable alcohol such as 2-methoxyethanol, or in a suitable lower alcohol, for example isopropanol, at a temperature from ambient temperature (about 20 ° C) to 150 ° C, e.g. to reflux. In particular, when a compound of formula (IV) is used in the form of a salt, the salt is converted to the free compound, preferably in situ, by the addition of a suitable base such as an alkali metal hydroxide such as sodium hydroxide.

Preferably, starting from compounds of formula (IV) wherein one or two of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another is hydrogen, lower alkyl, which is unsubstituted or substituted with free or an alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl, lower alkanoyl, trifluoromethyl, free, etherified or esterified hydroxy group, a free, alkylated or acylated amino group, or a free or esterified carboxyl group.

The starting material of formula (111) is obtained by reacting a compound of formula (VII) ¹¹ * ¹¹ Κχ ^{Ε0 ΊΤ} \ · .ζ wherein R ¹⁸ and R ¹⁹ are lower alkyl and the other substituents are as above, by the conditions under which the analogous to the conditions described in European Patent Application Publication No. 233461. Typical representatives of the compound of formula (VIII) are Ν, Ν-dimethylformamide dimethylacetal and Ν, Ν-dimethyl acetamide dimethylacetal. This reaction is carried out by heating the reactants of formulas (VII) and (VIII) in the absence or, if necessary, in the presence of a solvent at a temperature of 50 to 150 ° C, for a period of 4 to 24 hours.

Alternatively, the starting material of formula (III) is also obtained by reacting a compound of formula (VII) with an ester of formula

R 1 -C (= O) -O-CH ₂ -CH ₃ , wherein R ¹ is as defined above, and reacting the obtained product with an amine of formula

HN (R) -R ¹² , wherein the general substituents have the previously mentioned meanings.

The starting material of formula (IV) is obtained in the form of an acid addition salt by reaction of a compound of formula (IX)

(IXI, in which the general substituents are as previously known, with cyanamide (NC-NH ₂ ). This reaction is carried out in a suitable solvent or suspension medium, for example in a suitable alcohol such as a lower alkanol, for example ethanol, in the presence of equimolar the amount of salt-forming acid at a temperature from ambient to 150 ° C, for example at reflux.

Method b

Free functional groups in the compound of formula (V) or (VI), which are preferably protected by easily removable protective groups, are especially amino, but also hydroxy and carboxy groups which are not to participate in the desired reaction, for example an amino group in the radical R ¹ .

In particular, the reactive derivative of a compound of formula (VI) in which X is oxo is a reactable (activated) ester, a reactable anhydride or a reactable cyclic amide. The same is true for the de9 rivals in which X has any of the meanings given above.

The reactive (activated) esters of the acid of formula (VI) are, in particular, unsaturated esters of a bonded carbon atom, for example of the vinyl type, such as vinyl esters proper (which can be obtained by reesterification of the corresponding ester with vinyl acetate; active vinyl ester method); carbamoyl vinyl esters by treating the corresponding acid with an isoxazoliated reagent; 1,2-oxazolium or Woodward method) or 1- (lower alkoxy) vinyl esters (which can be obtained by treating the corresponding acid with a (lower alkoxy) acetylene; ethoxyacetylene method) or amidine type esters such as N, N '-disubstituted amidinoesters (which may be obtained by treatment with a suitable N, N'-disubstituted carbodiimide, for example, N, N'-dicyclohexylcarbodiimide on the corresponding acid; carbodiimide method) or Ν, dis-disubstituted amidinoesters (which may be obtained by N, N- disubstituted suitable aryl esters, especially phenyl esters optionally substituted with electron affinity substituents (which can be obtained, for example, by treatment with a suitably substituted phenol, for example 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol,

2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol to the corresponding acid in the presence of a condensing agent such as Ν, Ν'-dicyclohexylcarbodiimide; activated aryl ester method), cyanomethyl esters (which can be obtained, for example, by treatment with chloroacetone nitrile on the corresponding acid in the presence of a base; cyanomethyl ester method), thioesters, in particular phenylthioesters optionally substituted, for example with nitro by the anhydride or carbodiimide method (active thiolester method), amino or amidoesters (which can be obtained, for example, by treatment with N-hydroxyamino- or N-hydroxyamido compounds, such as N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide or 1- hydroxybenzotriazole to the corresponding acid, for example following the anhydride or carbodiimidine method; active N-hydroxyester method) or silyl esters (which may be obtained by treatment with a silylating agent, for example hexamethyldisilazane, for the corresponding acid and which readily reacts with the hydroxyl group but not the amino group).

The acid anhydrides of the formula (VI) may be symmetrical or preferably mixed anhydrides thereof, for example anhydrides with inorganic acids such as acid halides, in particular acid chlorides (which can be obtained by treating the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride); azides (which can be obtained from the corresponding acid ester via the corresponding hydrazide and its treatment with nitrous acid; azide method), anhydrides with half carbonic acid derivatives, such as half esters, for example with half (lower alkyl) carbonic esters (which can be obtained for example by treatment with (lower alkyl) esters of halogen-, in particular chloroformic or 1- (lower alkoxy) carbonyl-2-lower alkoxy) -1,2-dihydroquinoline, for example 1- (lower alkoxy) carbonyl-2-ethoxy-1,2 dihydroquinoline, to the corresponding acid; mixed carbonic acid O-alkyl anhydride method) or anhydrides with dihalogenated, in particular dichlorophosphoric acid (which can be obtained, for example, by treating the corresponding acid with phosphorous oxychloride; oxyphosphoric acid method) or with organic acid anhydrides such as mixed anhydrides with organic carboxylic acids ( may be obtained by treatment with an optionally substituted halide (lower alkane) or phenylalkanecarboxylic acid, for example phenylacetic, pivalic or trifluoroacetic chloride; mixed carboxylic acid anhydride method) or with organic sulfonic acids (which may be obtained by treatment with a suitable organic sulfonic acid halide, for example chloride) alkane) - or aryl acids, especially m- or p-toluenesulfonic acid chloride per salt, for example an alkali metal salt of the corresponding acid; sulfonic acid selins) as well as symmetrical anhydrides (which can be obtained, for example, by condensation of the corresponding acid in the presence of carbodiimide or from 1-diethylaminopropin; symmetric anhydride method).

Suitable cyclic amides are in particular amides with 5-membered aromatic diazacyclides, such as amides with imidazoles, for example imidazole (which can be obtained, for example, by treating the corresponding acid with the Ν, Ν'-carbonyldiimidazole method) or pyrazoles, for example 3,5-dimethylpyrazole (which can be obtained, for example, via an acid hydrazide by treatment with acetylacetone; pyrazolidone method).

Acid derivatives of formula (VI) which are used as acylating agents may also be formed in situ. Thus, for example, N, N'-disubstituted amidinoesters can be prepared in situ by reacting a mixture of the starting material of formula (V) and the acid used as acylating agent in the presence of a suitable N, N-disubstituted carbodiimide such as N, N ' dicyclohexylcarbodiimide. Further, it is possible to form amino or amidoesters of acids used as acylating agents in the presence of a starting material of formula (V) to be acylated by reacting a mixture of a starting acid and an amino compound in the presence of an N, N-disubstituted carbodiimide such as N , N'-dicyclohexylcarbodiimide and N-hydroxyamide, for example N-hydroxysuccinimide, optionally in the presence of a suitable base such as 4-dimethylaminopyridine.

Preferably, said reaction is carried out by reacting a reactive carboxylic acid derivative derived from a compound of formula (VI) with a compound of formula (V) wherein the amine or hydroxyl group involved in the reaction is in free form.

The reaction may be carried out in a manner known per se and the reaction conditions depend in particular on whether and how the carboxyl group is activated by an acylating agent, the reaction usually being carried out in the presence of a suitable solvent or diluent or a mixture thereof and, if necessary, in the presence of a condensing agent be in the form of the anhydride, also the acid binding agent, when cooling the reaction or heating to a temperature, for example, from a temperature range of about -30 ° C to about 150 ° C, especially about 0 ° C to about 100 ° C, preferably from ambient temperature (about 20 ° C) to 70 ° C, in an open or closed reaction vessel and / or under an atmosphere of an inert gas such as nitrogen.

Conventional condensing agents are, for example, carbodiimides, for example Ν, Ν'-diethyl-, Ν, Ν'-dipropyl-, N, N'-dicyclohexyl- or N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole or 1,2-oxazolium compounds, for example 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methyl-oxazolium chloride, or suitable acylamine compounds, for example 2- ethoxy-1-ethoxycarbones 1-1,2

SK 280620-6

dihydroquinoline. Typical acid-binding condensers are, for example, alkali metal carbonates or alkali metal bicarbonates, such as sodium carbonate or potassium carbonate, or sodium bicarbonate, or potassium bicarbonate (usually together with sulfate), or organic bases such as pyridine or sterically hindered three ( lower alkyl) amines such as N, N-diisopropyl-N-ethylamine.

The starting material of formula (V) is obtained by reduction of the nitro or nitro groups in the compound of formula (1) in which one or two of the radicals R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are respectively. are nitro. This reduction can be carried out, for example, by catalytic hydrogenation in a suitable solvent, such as a suitable acyclic or cyclic ether, for example tetrahydrofuran. Palladium on activated carbon (5%) is preferably used as the hydrogenation catalyst and in this case the hydrogenation is preferably carried out under normal pressure.

Method c

A suitable oxidizing agent for converting a compound of formula (I) in which R ¹ is a pyridyl group into an N-oxide compound is preferably a suitable peroxyacid, for example a suitable peroxybenzoic acid, in particular m-chloroperoxybenzoic acid. The reaction is carried out in a suitable solvent of an inert nature such as a halogenated hydrocarbon, preferably methylene chloride, at a temperature between about -20 ° C and about 150 ° C, especially between about 0 ° C and the boiling point of the solvent used, generally below 100 ° C. And preferably at ambient temperature or at a slightly elevated temperature (20-70 ° C).

The acid addition salts of the compounds of formula (I) are obtained in a conventional manner, for example by reacting the acid with a suitable anionic agent.

Conversely, acid addition salts of the compounds of formula (I) may be converted to the free compounds of formula (I) in the same manner, for example, by treatment with a suitable basic agent.

Mixtures of isomers may be separated into the individual isomers in a known manner, for example by fractional crystallization or chromatography.

Said processes, together with methods for cleavage of protecting groups and additional process steps, are carried out in a manner known per se, for example in the absence or presence of preferably inert solvents or diluents and, if necessary, in the presence of condensing agents or catalysts, at reduced or elevated temperatures. for example, in a temperature range of about -20 ° C to about 150 ° C, in particular from about 0 ° C to about 70 ° C, preferably from about 10 ° C to about 50 ° C, especially at ambient temperature, in a suitable reaction vessel and, if necessary, under an inert gas atmosphere, for example under a nitrogen atmosphere.

Particularly gentle reaction conditions, such as particularly short reaction times, the use of mildly acidic or basic reagents at low concentrations, adherence to the stoichiometric amounts of the reactants, should be used, if necessary, with respect to all substituents present in the molecule, e.g. suitable catalysts, solvents and temperature and / or pressure conditions.

The invention also relates to those embodiments starting from a compound which is obtained as an intermediate in a process step, in which the missing process steps are carried out or in which the process is interrupted at some stage, or in which the starting material is formed after reaction conditions or used in the form of a reaction derivative or a salt. The starting materials are those which lead to the compounds which have already been described as being particularly valuable.

New starting materials and / or intermediates as well as processes for their preparation are also within the scope of the invention. Preferably, such starting materials are used and reaction conditions are selected which lead to the compounds mentioned in this patent application as being particularly preferred.

Also described is a treatment of warm-blooded animals suffering from a cancer comprising administering to a warm-blooded animal in need of such treatment an effective amount of a tumor-inhibiting compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention furthermore relates to the use of a compound of formula (I) or a useful salt thereof for inhibiting PDGF-receptor kinase or a compound of formula (I) in which R ⁴ and R ⁸ are hydrogen or a pharmaceutically acceptable salt thereof for inhibiting protein kinase C in warm-blooded animals or in the manufacture of pharmaceutical preparations for use in the therapeutic treatment of the human or animal body. A warm-blooded animal having a body weight of about 70 kg is administered, depending on the active ingredient used, the age and the individual condition of the patient, the route of administration and the current disease state, an effective dose, for example a daily dose of about 1 to 1000 mg, in particular 50 to 500 mg. of the active ingredient according to the invention.

The invention also relates to pharmaceutical compositions which contain an effective amount, in particular an effective amount for the prophylaxis or therapy of the aforementioned diseases, an active ingredient together with pharmaceutically acceptable carriers and which are suitable for topical, enteral, for example oral or rectal or parenteral administration, the preparations may be inorganic or organic and solid or solid.

For oral administration, in particular, tablets or gelatin capsules are used which contain the active ingredient together with diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycerin, and / or lubricants such as kieselguhr, talc, stearic acid or salts thereof, for example magnesium stearate or calcium stearate, and / or polyethylene glycol. The tablets may also contain a binder, for example magnesium aluminosilicate, starches, for example corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and optionally disintegrating agents, for example starches, agar, alginic acid or a salt thereof. sodium and / or effervescent mixtures or adsorbents, colorants, flavors and sweeteners.

The pharmacologically active compounds of the invention may further be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferred isotonic aqueous solutions or suspensions, which solutions may be prepared, for example, in the case of lyophilized preparations which contain the active ingredient alone, optionally together with a carrier, for example mannitol, before use. The pharmaceutical preparations may be sterilized and / or contain adjuvants, for example preservatives, stabilizing agents, wetting agents and / or emulsifying agents, solubilizing agents, salts for regulating the osmotic pressure and / or buffers.

Said pharmaceutical preparations, which may if desired contain other pharmacologically active substances, such as antibiotics, are prepared by known methods, for example by conventional mixing, granulating, draining, dissolving or lyophilizing processes, and contain about 1 to 100%, in particular about 1 to about 20% of active ingredient or active ingredients.

In the following, the invention will be explained in more detail by means of specific examples and embodiments thereof, which are illustrative only, the scope of which is clearly defined by the wording of the claims. In these examples, the value of _Rf provided the plates with a thin layer of silica gel (commercially available as Merck, Darmstadt, Federal Republic of Germany).

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a solution of 30 g (0.17 mol) of 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one (described in EP-A-0233461) in 250 ml of isopropanol is added 41.3 g (0 17 mol) of 3-nitrophenylguanidine nitrate suspended in 50 ml of isopropanol. After the addition of 7.49 g (0.19 mol) of sodium hydroxide, the yellow suspension was heated to reflux for 8 hours. After cooling to 0 ° C, the suspension is filtered and the solid is washed with 200 ml of isopropanol and suspended in 300 ml of water, followed by stirring for 30 minutes, filtered and the separated solid is washed with 200 ml of water. After resuspending in 200 ml of ethanol and washing with 200 ml of a 1: 1 v / v mixture of ethanol and diethyl ether, the desired product is obtained. Melting point: 212-213 ° C,

_Rf = 0.75 (chloroform: methanol in a ratio of 9: 1)

The starting material is obtained as follows: Step 1.1

To a yellow suspension of 82.88 g (0.6 mol) of 3-nitroaniline in 200 ml of ethanol was added dropwise 42 ml (0.6 mol) of 65% nitric acid. After the exothermic reaction is completed, it is added

75.7 g (0.9 mol) of cyanamide (50% in water) and the resulting reaction mixture was heated to reflux for 21 hours. After cooling to 0 ° C, the reaction mixture is filtered and the solid is washed six times with a 1: 1 mixture of ethanol and diethyl ether. After drying under high vacuum at 40 ° C, 3-nitrophenylguanidine nitrate is obtained.

Mp .: 205-207 ° C.

Stage 1.2

8 g (0.35 mol) of sodium are introduced into 260 ml of toluene, followed by suspension of sodium in toluene at 100 ° C by means of a vibrating stirrer. After cooling to 0 ° C, 17 ml (0.42 mol) of methanol are added dropwise with stirring, and the mixture is then stirred at 75 ° C for 45 minutes. A solution of 38.5 ml (0.35 mol) of 3-acetylpyridine and 28 ml (0.35 mol) of ethyl formate in 300 ml of toluene is then added dropwise over a period of 45 minutes at 25 ° C with ice-cooling. The yellow suspension was stirred at 25 ° C for 16 hours, then 23.7 (0.52 mol) of dimethylamine was added. After the addition of 100 ml of toluene, the mixture is stirred at 25 ° C for 45 minutes, then a solution of 20 ml of acetic acid in 150 ml of toluene is added dropwise over 30 minutes at 0 ° C, and the mixture is then heated under reflux for one hour. . After cooling to 25 ° C, the mixture is filtered, the filter residue is washed with 500 ml of a 1: 1 by volume mixture of toluene and hexane, and then the filtrate is concentrated until crystallization begins. After cooling to 0 ° C, filtration and drying at 80 ° C under high vacuum, 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one is obtained. M.p .: 81-82 ° C.

Example 2

Dissolve 100 mg (0,38 mmol) of N- (3-aminophenyl) -4- (3-pyridyl-2-pyrimidinamine) in 5 ml of pyridine, add 58,5 μ1 (0,46 mmol) of 4- The mixture was stirred at ambient temperature for 24 hours, 10 mL of water was added to the reaction mixture, cooled to 0 ° C and filtered, washed with water and dried to give N- / 3- (4-chlorobenzoylamido) phenyl. / 4- (3-pyridyl) -2-pyrimidineamine.

Melting point: 238-240 ° C,

_{R f} = 0.66 (chloroform: methanol in a ratio of 9: 1).

The starting material is obtained as follows: Step 2.1

A suspension of 17.0 g (0.058 mol) of N- (3-nitrophenyl) -4- (3-pyridyl) -2-pyrimidinamine in 1700 ml of tetrahydrofuran is stirred for 21 hours with 1.7 g of palladium on activated carbon (5%) under atmosphere of hydrogen at normal pressure. The suspension is filtered and the filtrate is concentrated in a rotary evaporator. The yellow solid product remaining was stirred overnight in 200 mL of methylene chloride. After filtration and drying, N- (3-aminophenyl) -4- (3-pyridyl) -2-pyrimidinamine is obtained.

Mp: 89-90 ° C, _Rf = 0.38 (chloroform: methanol in a ratio of 9: 1).

Example 3

To a solution of 100 mg (0.38 mmol) of N- (3-aminophenyl) -4- (3-pyridyl) -2-pyrimidinamine in 5 ml of pyridine is added 53 μoy (0.46 mmol) of bezoyl chloride and the resulting mixture is stirred under nitrogen atmosphere at ambient temperature for 24 hours. To the reaction mixture was added 10 mL of water, cooled to 0 ° C, filtered and the solid was washed with water. After drying under high vacuum, N- (3-benzoylamidophenyl) -4- (3-pyridyl) -2-pyrimidinamine is obtained.

Melting point. Mp 207-209 ° C, R _f = 0.53 (9: 1 chloroform: methanol).

Example 4

A solution of 100 mg (0.38 mmol) of N- (3-aminophenyl) -4- (3-pyridyl) -2-pyrimidinamine and 59 mg (0.46 mmol) of 2-pyridinecarboxylic acid chloride in 5 ml of pyridine is stirred at temperature ambient under nitrogen for 24 hours. After 30 mg (0.23 mmol) of 2-pyridinecarboxylic acid chloride was added, the mixture was stirred for 18 hours, followed by an additional 25 mg (0.19 mmol) of 2-pyridinecarboxylic acid chloride and stirred at 25 ° for 72 hours. C. After addition of 10 ml of water and cooling to 0 ° C, the mixture is filtered and the collected solids are washed with water. After chromatography on silica gel, eluting with a 9: 1 mixture of chloroform and methanol, N- [3- (2-pyridyl) carboxamidophenyl] -4- (3-pyridyl) is obtained from the corresponding eluate fraction. -2-pyrimidineamine.

M.p .: 187-190 ° C, Rf = 0.58 (9: 1 chloroform / methanol).

Example 5

In a manner analogous to that described in Example 4, N- [3- (3-pyridyl) carboxamidophenyl] -4- (3-pyridyl) -2-pyrimidinamine is obtained. Starting from 3-pyridinecarboxylic acid chloride.

Melting point: 217-220 ° C,

_Rf = 0.29 (methanol-chloroform in a ratio of 1: 0).

Example 6

In a manner analogous to that described in Example 4, N- [3- (4-pyridyl) carboxamidophenyl] -4- (3-pyridyl) -2-pyrimidinamine is prepared from 4-pyridinecarboxylic acid chloride.

Mp .: 224-226 ° C, Rf = 0.29 (9: 1 chloroform / methanol).

Example 7

To a solution of 100 mg (0.38 mmol) of N- (3-aminophenyl) -4- (3-pyridyl) -2-pyrimidinamine in 5 ml of pyridine is added 63 μΐ (0.46 mmol) of pentafluorobenzoyl chloride and the mixture is stirred under an atmosphere nitrogen at ambient temperature for 17 hours. To the brown reaction solution was then added 10 ml of water and the mixture was cooled to 0 ° C and filtered. The separated solid was recrystallized from ethanol-acetone to give crystalline N- (3-pentafluorobenzoylamidophenyl) -4- (3-pyridinyl) -2-pyrimidinamine.

Mp: 234-244 "C, _Rf = 0.41 (chloroform: methanol in a ratio of 9: 1).

Example 8

To a solution of 50 mg (0.19 mmol) of N- (3-aminophenyl) -4- (3-pyridyl) -2-pyrimidinamine in 1 ml of pyridine was added 28 mg (0.19 mmol) of phthalic anhydride. After 2.5 hours, an additional 14 mg (0.095 mmol) of phthalic anhydride was added to the yellow reaction mixture, and the mixture was stirred at 25 ° C for 20 hours. The suspension is filtered and the solid is washed with cold pyridine. The residue was digested twice with 2.5 ml of absolute ethanol to give N- [3- (2-carboxybenzoylamido) phenyl-4- (3-pyridyl) -2-pyrimidinamine].

M.p .: 206-209 ° C, R _f = 0.07 (9: 1 chloroform / methanol).

Example 9

A solution of 100 mg (0.38 mmol) of N- (3-aminophenyl) -4- (3-pyridynyl) -2-pyrimidinamine and 105 μΐ (0.46 mmol) of caproic anhydride in 5 ml of pyridine is stirred at 25 ° C for 24 hours under nitrogen, then concentrated in a rotary evaporator. The residue is flash chromatographed on silica gel, eluting with a 95: 5 mixture of chloroform and methanol, to give N- (3-n-hexanoylamidophenyl) -4- (3-pyridyl) -2-pyrimidinamine from the corresponding eluate fraction. .

Melting point: 180-184 ° C, Rf = 0.78 (9: 1, chloroform / methanol).

Example 10 1g (5.68 mmol) of 3-dimethylamino-1- (2-pyridyl) -2-propen-1-one (EP-A-233461) is dissolved in 8 ml of isopropanol, followed by the addition of 1, 38 g (5.68 mmol) of 3-nitrophenylguanidine nitrate. After the addition of 0.25 g (6.24 mmol) of sodium hydroxide, the yellow suspension was heated to reflux for 20 hours, then cooled to 0 ° C and filtered and the solid was washed with 30 ml of isopropanol. The mixture was stirred for 20 minutes in 15 ml of ethanol, filtered and the solid washed with cold ethanol to give N- (3-nitrophenyl) -4- (2-pyridyl) -2-pyrimidinamine. Melting point 213-219 ° C.

Example 11

To a solution of 1 g (5.68 mmol) of 3-dimethylamino-1- (4-pyridyl) -2-propen-1-one (US patent 4281000) in 8 ml of isopropanol is added 1.38 g (5.68 mmol) 3-nitrophenylguanidine nitrate and 0.25 g (6.24 mmol) of sodium hydroxide. The yellow suspension was heated to reflux for 20 hours, then cooled to 0 ° C. After washing with 30 ml of isopropanol, the solid is suspended in 15 ml of isopropanol, filtered, resuspended in 15 ml of water and filtered again. After drying under high vacuum, N- (3-nitrophenyl) -4- (4-pyridyl) -2-pyrimidinamine is obtained. Melting point: 282-284 C.

Example 12

In a manner analogous to that described in Example 2, N- [3- (2-methoxybenzoylamido) phenyl] -4- (3-pyridyl) -2-pyrimidinamine was prepared from 2-methoxybenzoyl chloride.

Melting point: 115-117 ° C,

_Rf = 0.76 (chloroform: methanol in a ratio of 9: 1).

Example 13

In a manner analogous to that described in Example 2, N- [3- (4-fluorobenzoylamido) phenyl] -4- (3-pyridyl) -2-pyrimidinamine was prepared from 4-fluorobenzoyl chloride. Melting point: 215-216 ° C,

Rf = 0.34 (9: 1 chloroform / methanol).

Example 14

In a manner analogous to that described in Example 2, N- [3- (4-cyanobenzoylamido) phenyl] -4- (3-pyridyl) -2-pyrimidinamine was prepared from 4-cyanobenzoyl chloride.

Melting point: 220-222 ° C,

_Rf = 0.31 (chloroform: methanol in a ratio of 9: 1).

Example 15

In a manner analogous to that described in Example 2, N- [3- (2-thienylcarboxamido) phenyl] -4- (3-pyridyl) -2-pyrimidinamine was prepared from 2-thiophenecarboxylic acid chloride.

Melting point: 139-141 ° C,

_Rf = 0.35 (chloroform: methanol in a ratio of 9: 1).

Example 16

In a manner analogous to that described in Example 2, N- (3-cyclohexylcarboxamidophenyl) -4- (3-pyridyl) -2-pyrimidinamine was prepared from cyclohexanecarboxylic acid chloride.

Melting point: 205-206 ° C,

Rf = 0.36 (chloroform: methanol = 9: 1).

Example 17

Following a procedure analogous to that described in Example 2, N - [3- (4-methylbenzoylamido) phenyl-4- (3-pyridyl) -2-pyrimidinamine] was prepared from 4-methylbenzoyl chloride. Melting point: 214-216 ° C,

_Rf = 0.64 (chloroform: methanol in a ratio of 9: 1).

Example 18

In a manner analogous to that described in Example 2, by reacting 100 mg (0.38 mmol) of N- (3-aminophenyl) -4- (4-pyridyl) -2-pyrimidinamine with 58 μΐ (0.46 mmol) 4-Chlorobenzoyl chloride was prepared using N- [3- (4-chlorobenzoylamido) phenyl] -4- (4-pyridyl) -2-pyrimidinamine. Melting point: 258-261 ° C,

_Rf = 0.37 (chloroform: methanol in a ratio of 9: 1).

The starting material is obtained as follows: Step 18.1

Using a procedure analogous to that described in Step 2.1, from 300 mg (1.0 mmol) of N- (3-nitrophenyl) -4- (4-pyridyl) -2-pyrimidinamine (see Example 11) under a hydrogen atmosphere was obtained. N- (3-aminophenyl) -4- (4-pyridyl) -2-pyrimidineamine.

Melting point: 200-202 ° C, R 1 = 0.27 (95: 5 chloroform / methanol).

Example 19

In a manner analogous to that described in Example 2, N- (3- (4- (4-methylpiperazinomethyl) benzoylamido) phenyl) was prepared from 98 mg (0.3 mmol) of 4- (4-methylpiperazinomethyl) benzoyl chloride. 4- (3-pyridyl) -2-pyrimidineamine.

Melting point: 198-201 ° C.

Example 20

A solution of 8.0 g (28.85 mmol) of N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-pyrimidinamine and 4.0 ml (34.6 mmol) of benzoyl chloride in 320 ml of pyridine is stirred at ambient temperature under nitrogen for 23 hours. The reaction mixture is then concentrated under high vacuum, 200 ml of water are then added to the residue and, after cooling to 0 DEG C., the mixture is filtered. After drying at 80 ° C under high vacuum, the crude product is suspended in a 95: 5 by volume mixture of methyl chloride and methanol and filtered. N- (5-benzoylamido-2-methylphenyl) -4- (3-pyridyl) -2-pyrimidinamine is obtained. Separation of this product after chromatographic separation. Melting point: 173-176 ° C,

_Rf = 0.65 (chloroform: methanol in a ratio of 9: 1).

The starting product is obtained as follows:

Stage 20.1

To a yellow suspension of 20.0 g (0.13 mol) of 2-amino-4-nitrotoluene in 50 ml of absolute ethanol was added dropwise 9.1 ml (0.13 mol) of 65% nitric acid over 5 minutes. After the exothermic reaction, 8.32 g (0.198 mol) of cyanamide dissolved in 8.3 ml of water are added. The brown reaction mixture was heated at reflux for 25 hours, then cooled to 0 ° C and filtered. After washing 4 times with a 1: 1 by volume mixture of ethanol and diethyl ether, 2-methyl-5-nitrophenylguanidine nitrate is obtained.

Melting point: 219-226 ° C.

Stage 20.2

To a solution of 170 g (0.96 mol) of 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one in 2.0 liters of isopropanol was added 248.2 g (0.96 mol) of 2-methyl 5-nitrofenylguanidínnitrátu. After the addition of 42.5 g of sodium hydroxide, the resulting reddish suspension is heated to reflux for 12 hours. After cooling to 0 ° C, filtration, washing with 2.0 L of isopropanol, and washing three times with 499 ml of methanol and drying, N- (2-methyl-5-nitrophenyl) -4- (3-pyridyl) -2 is obtained. -pyrimidmamín.

Melting point: 195-198 ° C,

_Rf = 0.68 (methylene chloride: methanol = 9: 1).

Stage 20.3

A suspension of 143.0 g (0.46 mol) of N- (2-methyl-5-nitrophenyl) -4- (3-pyridyl) -2-pyrimidinamine in 7.15 liters of ethyl acetate is stirred in the presence of 14.3 g of palladium activated carbon (10% Pd) under a hydrogen atmosphere at normal pressure for 6.5 hours. The suspension is then filtered and the filtrate is concentrated in a rotary evaporator. The crude product obtained is recrystallized from methylene chloride. N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-pyrimidinamine is obtained.

Melting point: 138-140'C,

_Rf = 0.36 (methylene chloride: methanol = 9: 1).

Example 21

Following a procedure analogous to that described in Example 20, N- (5- [4- (4-methylpiperazinomethyl) benzoylamido) -2-methylphenyl] was prepared from 10.68 g (32.8 mmol) of 4- (4-methylpiperazinomethyl) benzoyl chloride. / 4- (3-pyridyl) -2-pyrimidineamine.

Melting point: 211-213 ° C,

_Rf = 0.33 (methylene chloride: methanol: 25% aqueous ammonia at a ratio of 95: 5: 1).

Example 22

In a manner analogous to that described in Example 20, N- [5- (4-methylbenzoylamido) -2-methylphenyl] -4- (3-pyridyl) was prepared from 0.23 ml (1.7 mmol) of p-toluyl chloride. -2-pyrimidinamine.

Mp: 102-106 ° C, _{R f} = 0.4 (methylene chloride: methanol = 9: 1).

Example 23

Following a procedure analogous to that described in Example 20, N- [5- (2-naphthoylamido) -2-methylphenyl] -4- (3-pyridyl) was prepared from 330 mg (1.73 mmol) of 2-naphthoyl chloride. -2-pyrimidineamine.

Melting point: 97-101 ’C,

_Rf = 0.45 (methylene chloride: methanol = 9: 1).

Example 24

In a manner analogous to that described in Example 20, N- (5- (4-chlorobenzoylamido) -2-methylphenyl) -4- (3-pyridyl) was prepared from 0.22 ml (1.73 mmol) of 4-chlorobenzoyl chloride. ) -2-pyrimidineamine.

Melting point: 216-219 ° C,

_Rt = 0.39 (methylene chloride: methanol = 9: 1).

Example 25

In a manner analogous to that described in Example 20, N- [5- (2-methoxybenzoylamido) -2-methylphenyl] -4- (3-pyridyl) was prepared from 0.28 ml (1.87 mmol) of 2-methoxybenzoyl chloride. ) -2-pyrimidineamine.

Melting point: 88-92 ° C,

_Rf = 0.45 (methylene chloride: methanol = 9: 1).

Example 26

In a manner analogous to that described in Example 1, from 1.0 g (5.68 mmol) of 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one and 1.53 g ( 68 mmol) of 3-trifluoromethoxyphenylguanidine nitrate gives N- (3-trifluoromethoxyphenyl) -4- (3-pyridyl) -2-pyrimidinamine.

Rf = 0.7 (9: 1, chloroform / methanol).

The starting material is prepared as follows:

Stage 26.1

In a manner analogous to that described in step 1.1, 3-trifluoromethoxyphenylguanidine nitrate was prepared from 2.0 g (11.3 mmol) of 3-trifluoromethoxyaniline and 1.4 g (16.6 mol) of cyanamide (50% in water).

R _f = 0.1 (methylene chloride: methanol: 25% aqueous ammonia at a volume ratio of 150: 10: 1).

Example 27

In a manner analogous to that described in Example 1, carbon black 1.0 g (5.68 mmol) of 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one and 1.78 g (5, 68 mmol) of 3- (1,1,2,2-tetrafluoroethoxy) phenylguanidine nitrile gives N- (3- / 1,1,2,2-tetrafluoroethoxy / phenyl) -4- (3-pyridyl-2-pyrimidinamine). 0.75 (9: 1 chloroform / methanol).

The starting material is prepared as follows:

Stage 27.1

In a manner analogous to that described in Step 1.1, from 2.09 g (10 mmol) of 3- (1,1,2,2-tetrafluoroethoxyjaniline and 1.26 g (15 mol) of cyanamide (50% in water) Preparation of 3- (1,1,2,2-tetrafluoroeloxy) phenylguanidine nitrate.

Rf = 0.15 (150: 10: 1 methylene chloride / methanol / 25% aqueous ammonia).

Example 28

In a manner analogous to that described in Example 1, 1 g (5.68 mmol) of 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one and 1.46 g (5 mmol) of carbon black was added. 68 mmol) of 3-nitro-5-methylphenylguanidine nitrate gives N- (3-nitro-5-methylphenyl) -4- (3-pyrimidinamine).

_Rf = 0.72 (chloroform: methanol in a ratio of 9: 1)

The starting material is prepared as follows:

Stage 28.1

In a manner analogous to that described in step 1.1, 3- (3-nitro-5-methylaniline) and 1.26 g (15 mol) of cyanamide (50% in water) were prepared from 1.52 g (10 mmol). nitro-5-metylfenylguanidínnitrát.

Rf = 0.1 (150: 10: 1 methylene chloride / methanol / 25% aqueous ammonia).

Example 29

In a manner analogous to that described in Example 1, from 1.0 g (5.68 mol) of 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one and 1.76 g ( 68 mmol) of 3-nitro-5-trifluoromethylphenylguanidine nitrate gives N- (3-nitro-5-trifluoromethylphenyl) -4- (3-pyridyl) -2-pyrimidinamine.

Rf = 0.8 (9: 1 chloroform / methanol).

The starting material is prepared as follows:

Stage 29.1

In a manner analogous to that described in Step 1.1, 3-nitro-3-nitro-5-trifluoromethylaniline and 1.26 g (15 mol) of cyanamide (50% in water) were prepared from 2.06 g (10 mmol). 5-metylfenylguanidínnitrát.

Rf = 0.2 (methylene chloride / methanol / 25% aqueous ammonia = 150: 10: 1).

Example 30

200 mg (0.68 mmol) of N- (3-nitrophenyl) -4- (3-pyridyl) -2-pyrimidinamine are suspended in 5 ml of methylene chloride and 225 mg (0.71 mmol) of acid are added to the obtained suspension.

3-chloroperoxybenzoic acid. After 2 hours an additional 10 mL of methylene chloride was added. The suspension is stirred at ambient temperature for 20 hours. After filtration and flash chromatography of the solid residue, eluting with methylene chloride / methanol / 25% aqueous ammonia (90: 10: 1), N- (3-nitrophenyl) -4- is obtained from the corresponding eluate fraction. (N-oxido-3-pyridyl) -2-pyrimidineamine.

Rf = 0.4 (90: 10: 1 methylene chloride / methanol / 25% aqueous ammonia), mp 252-258 ° C.

Example 31

150 mg (0.39 mmol) of N- (3-benzoylamido-5-methylphenyl) -4- (3-pyridyl) -2-pyrimidinamine are suspended in 6 ml of methylene chloride and 129 mg (0.41 mol) are added to the obtained suspension. of 3-chloroperoxybenzoic acid. After 22 hours, the mixture is filtered and the solid is flash chromatographed eluting with methylene chloride / methanol / 25% aqueous ammonia (90: 10: 1) to give N- (3-benzoylamido-3-benzoylamide) as the eluent fraction. 5-methylphenyl) -4- (N-oxido-3-pyridyl) -2-pyrimidineamine. _Rf = 0.3 (methylene chloride: methanol: 25% aqueous ammonia at a volume ratio of 90: 10: 1), mp: 295-300 "C.

Example 32

Tablets containing 20 mg of the active ingredient, for example one of the compounds of formula (I) described in Examples I to 31, are prepared in a conventional manner and have the following composition:

Ingredients:

Active Substance20 mg

Wheat starch60 mg

Milk sugar 50 mg

Colloidal Silicic Acid 5 mg Talc9 mg

Magnesium stearate1 mg

Total 145 mg

Preparation:

The active ingredient is mixed with wheat starch, milk sugar and colloidal silicic acid and sieved. A further portion of the wheat starch in the water bath is lubricated with a 5-fold amount of water and the powder mixture is added to the sebum, followed by thorough mixing until a slightly plastic mass is obtained. The plastic is passed through a sieve with a mesh width of 3 mm, dried and the resulting dry granulate is sieved again. The remaining portion of wheat starch, talc and magnesium stearate are then admixed and the mixture is compressed into fracture notch tablets weighing 145 mg.

Example 33

Tablets containing 1 mg of the active ingredient, such as one of the compounds of formula (I) described in Examples 1 to 31, and having the following composition are prepared in a conventional manner:

Ingredients:

Active Substance1 mg

Wheat starch60 mg

Milk sugar 50 mg

Colloidal silicic acid 5 mg

Talc 9mg

Magnesium stearate1 mg

Together

126 mg

Preparation:

The active ingredient is mixed with wheat starch, milk sugar and colloidal silicic acid and sieved. An additional portion of wheat starch in the water bath is lubricated with 5 times the amount of water and the powder mixture is added to the sebum, followed by mixing thoroughly until a slightly plastic mass is obtained. The plastic is passed through a sieve with a mesh width of 3 mm, dried and the resulting dry granulate is sieved again. The remaining portion of wheat starch, talc and magnesium stearate are then admixed and the resulting mixture is compressed into fracture-milled tablets weighing 126 mg.

Example 34

Capsules containing 10 mg of the active ingredient, for example one of the compounds of formula (I) described in Examples 1 to 31, are prepared in a conventional manner and have the following composition:

Ingredients:

Active Substance 2500 mg

Talc 200 mg

Colloidal silicic acid 50 mg

Preparation:

The active ingredient is thoroughly mixed with talc and colloidal silicic acid, followed by sieving through a sieve having a mesh width of 0.5 mm and filling in hard gelatin capsules of appropriate size in 11 mg portions.

Claims (45)

PATENT CLAIMS An N-phenyl-2-pyrimidinamine derivative of the general formula (1) in which ^R1 is pyrazinyl, 1-methyl-lH-pyrrolyl, phenyl substituted by amino, or amino (lower alkyljovou group, wherein the amino group is either free or alkylated by lower alkyl, or acylated (lower alkane) oyl. a 1H-indolyl group attached to a carbon atom of a five-membered ring, a 1H-imidazolyl group attached to a carbon atom of a five-membered ring, or a pyridyl group attached to a carbon atom of the ring optionally substituted by a lower alkyl group and optionally substituted at nitrogen by an oxygen atom R ² and R ³ independently of one another represent either a hydrogen atom or a lower alkyl group, one or two of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ respectively represent a nitro group, a lower alkoxy group substituted by fluorine or a group of formula (II) -N (R ⁹ ) -C (= X) - (Y) _n -R ¹⁰ (II) wherein R ⁹ represents a hydrogen atom or a lower alkyl group, X is oxo, thio, imino, N- (lower alkyl) imino, hydroxyimino, or O- (lower alkyl) hydroxyimino, Y is oxygen or NH, n is 0 or 1 and R ¹⁰ represents an alkyl, alkenyl or alkynyl group containing in each case at least 5 and not more than 22 carbon atoms, phenyl or naphthyl, which is in each case unsubstituted or substituted by cyano, lower alkyl, hydroxy (lower alkyl), amino (lower alkyl), (4); -methylpiperazinyl) (lower alkyl, trifluoromethyl, hydroxy, lower alkoxy, (lower alkanoyloxy), halogen, amino, (lower alkyl amino, di (lower alkyl amino, (lower alkanoyl) amino, or lower-alkoxy, benzoylamino, benzoylamino) 20 carbon atoms, phenyl (lower alkyl) in which the phenyl radical is unsubstituted or substituted as described above and contains up to 20 carbon atoms, a cycloalkyl or cycloalkenyl group containing not more than 30 carbon in each case cycloalkyl (lower alkyl or cycloalkenyl (lower alkyl) in which the cycloalkyl or cycloalkenyl radical contains in each case not more than 30 carbon atoms, a monocyclic group having 5 or 6 ring members and 1 to 3 ring atoms selected from nitrogen, oxygen and a sulfur atom to which one or two benzene radicals, or a lower alkyl group which is substituted by such a monocyclic group, may be fused, and the others of R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ independently of one another a hydrogen atom, a lower alkyl group which is optionally substituted by an amino or alkylated amino group containing up to 14 carbon atoms, a piperazinyl group, a piperidinyl group, a pyrrolidinyl group or a morpholinyl group, a lower alkanoyl group, a trifluoromethyl group, free, hydroxy, etherified or ester a forged hydroxy group having up to 7 carbon atoms, an amino group, an alkylated amino group having up to 14 carbon atoms or an acylated amino group having up to 7 carbon atoms, a carboxyl group or an esterified carboxyl group having up to 7 carbon atoms, and salts of the N-phenyl-2-pyrimidineamine derivative containing at least one salt convertible group. The N-phenyl-2-pyrimidineamine derivative according to claim 1 of the general formula (I), wherein one or two of R ⁴ , R ³ , R ⁶ , R ⁷ and R ⁸ is respectively. R 2 represents a nitro group or a group of the general formula (II) in which R ⁹ represents a hydrogen atom or a lower alkyl group, SK 280620-6 X is oxo, thio, imino, N- (lower alkylimino), hydroxyimino or O- (lower alkyl) hydroxyimino, Y is oxygen or NH, n is 0 or 1 and R ¹⁰ represents an alkyl or alkenyl group containing in each case at least 5 and not more than 22 carbon atoms, phenyl or naphthyl, in each case unsubstituted or substituted by cyano, lower alkyl, hydroxy (lower alkyl), amino (lower alkyl), (4-methylpiperazinyl) (lower alkyl, trifluoromethyl, hydroxy, lower alkoxy, (lower alkanoyloxy), halogen, amino, (lower alkyl amino, di (lower alkylamino), (lower alkanoyl amino, benzoylamino, alkoxy or carboxy, or (lower) , phenyl (lower alkyl) in which the phenyl radical is unsubstituted or substituted as described above and contains up to 20 carbon atoms, a cycloalkyl or cycloalkenyl group containing up to 30 carbon atoms in each case a cycloalkyl (lower alkyl or cycloalkenyl) group in which the cycloalkyl or cycloalkenyl radical always contains at most 30 carbon atoms, a monocyclic group having 5 or 6 ring members and 1 to 3 ring atoms selected from the group consisting of nitrogen, oxygen and a sulfur atom to which one or two benzene radicals, or a lower alkyl group which is substituted by such a monocyclic group, may be fused, and the others of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another are hydrogen , lower alkyl which is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl, lower alkanoyl, trifluoromethyl, free, etherified or esterified hydroxy, free, alkylated or acylated and or a free or esterified carboxyl group, the other substituents being as defined in claim 1, and the pharmaceutically acceptable salts of the N-phenyl-2-pyrimidineamine derivative containing at least one salt-capable group. An N-phenyl-2-pyrimidinamine derivative according to claim 1 of the general formula (I) in which R ¹ represents a pyrazinyl, 1-methyl-1H-pyrrolyl, amino or amino (lower alkyl substituted phenyl) group, in which the amino group is always free, alkylated with one or two lower alkyl radicals acylated with a lower alkanoyl or benzoyl group on an atom a 5-membered ring carbon bonded with an 1H-indolyl or 1H-imidazolyl group or a unsubstituted or lower alkyl substituted pyridyl group on a ring carbon atom which is unsubstituted or substituted with an oxygen atom on the nitrogen atom, R ² and R ³ independently of one another are H or lower alkyl, one or two of R ^4, R ^5, R ^b, R ⁷ and R ⁸ is, respectively. means a nitro group, a fluorine-substituted lower alkoxy group or a group of formula (11) in which: R ⁹ represents a hydrogen atom or a lower alkyl group, X is oxo, thio, imino, N- (lower alkylimino, hydroxyimino or O- (lower alkyl) hydroxyimino, Y is oxygen or NH, n is 0 or 1 and R ^w represents an alkyl group containing 5 to 22 carbon atoms, a phenyl or naphthyl group, which is in each case unsubstituted or substituted by cyano, lower alkyl, hydroxy (lower alkyl), amino (lower alkyl), (4-methylpiperazinyl) (lower alkyl) , trifluoromethyl, hydroxy, lower alkoxy, (lower alkanoyl, oxy, halogen, amino, (lower alkyl, amino, di (lower alkyl, amino), (lower alkanoyl, amino, benzoylamino, carboxy, or (lower alkoxy) phenyl, unsubstituted or substituted as previously described, cycloalkyl or cycloalkenyl of up to 30 carbon atoms, cycloalkyl (lower alkyl or cycloalkenyl) in which the cycloalkyl or cycloalkenyl radical contains in each case not more than 30 carbon atoms, a monocyclic group having 5 or 6 ring members and 1 to 3 ring atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom to which one or two benzene residues may be fused or a lower alkyl group which is substituted by such a monocyclic group, and the others of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another represent a hydrogen atom, a lower alkyl group which is unsubstituted or substituted by amino, (lower alkyl amino, di (lower alkyl amino) , piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl, lower alkanoyl, trifluoromethyl, hydroxy, lower alkoxy, (lower alkanoyloxy), halogen, amino, (lower alkylamino, di (lower alkylamino), di (lower alkylamino), or a lower alkoxycarbonyl group; and pharmaceutically usable salts of the N-phenyl-2-pyrimidineamine derivative containing at least one salt-capable group. The N-phenyl-2-pyrimidinamine derivative according to claim 1 of the general formula (I) in which R ¹ represents a pyridyl group attached to the ring carbon atom which is unsubstituted or substituted by an oxygen atom on the nitrogen atom, R ² and R ³ are H, R ⁴ represents a hydrogen atom or a lower alkyl group, R ⁵ represents a hydrogen atom, a lower alkyl group or a fluorine-substituted lower alkoxy group, R ⁶ represents a hydrogen atom, R ⁷ represents a nitro group, a fluorine-substituted lower alkoxy group or a radical of formula (II) in which: R ⁹ represents a hydrogen atom, X is oxo; n is 0 and R ¹⁰ is C 5 -C 22 alkyl, phenyl which is unsubstituted or substituted by cyano, lower alkyl, (4-methylpiperazinyl) (lower alkyl, lower alkoxy, halogen or carboxyl, cycloalkyl radical of up to Or a monocyclic radical having 5 or 6 ring members; and 1 to 3 ring sulfur atoms, and R ⁸ represents a hydrogen atom, and pharmaceutically usable salts of the N-phenyl-N-pyrimidineamine derivative with at least one salt-converting group. An N-phenyl-2-pyrimidinamine derivative according to claim 1 of the general formula (I) in which R &^lt; ¹ > in each case represents a bonded pyridyl group or an N-oxidopyridyl group on a carbon atom, R ² and R ³ are H, R ⁴ represents a hydrogen atom or a lower alkyl group, R ⁵ represents a hydrogen atom, a lower alkyl group or a trifluoromethyl group, R ⁶ represents a hydrogen atom, R ⁷ represents a nitro group, a fluorine-substituted lower alkoxy group or a radical of formula (II) in which: R ⁹ represents a hydrogen atom, X is oxo, n is 0 and R ¹⁰ represents a pyridyl-bonded pyridyl group, unsubstituted or halogen, cyano, lower alkoxy, carboxyl, lower alkyl or 4-methylpiperazinylmethyl substituted phenyl, (C 5 -C 7) alkyl, thienyl, 2- naphthyl or cyclohexyl, and R ⁸ represents a hydrogen atom, and the pharmaceutically usable salts of the N-phenyl-2-pyrimidinamine derivative containing at least one salt-capable group. An N-phenyl-2-pyrimidineamine derivative according to any one of claims 1 to 5 of the general formula (I) in which R ⁴ and R ⁸ are hydrogen and the other substituents have the meanings given in the corresponding claim, and pharmaceutically usable salts thereof. a phenyl-2-pyrimidinamine derivative comprising at least one salt-capable group. An N-phenyl-2-pyrimidineamine derivative according to any one of claims 1 to 5 of the general formula (I) in which at least one of the radicals R ⁴ and R ⁸ represents a lower alkyl group and the other substituents have the meanings given in the corresponding claim. useful salts of the N-phenyl-2-pyrimidinamine derivative containing at least one salt-capable group. An N-phenyl-2-pyrimidineamine derivative according to claim 1 of the general formula (1) in which R ¹ represents a pyridyl group attached to a carbon atom, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁸ represent a hydrogen atom and R ⁷ represents a nitro group or a radical of formula (II) wherein R ⁹ represents a hydrogen atom, X is oxo, n is 0 and R ¹⁰ represents a pyridyl bonded to a carbon atom, unsubstituted or fluorine, chlorine, cyano, lower alkoxy, carboxyl, lower alkyl or 4-methylpiperazinylmethyl substituted phenyl, (C 5 -C 7) alkyl, thienyl or a cyclohexyl group, and pharmaceutically usable salts of the N-phenyl-2-pyrimidineamine derivative containing at least one salt capable group. The N-phenyl-2-pyrimidinamine derivative of the Formula I according to claim 1 which is N- (3-nitrophenyl) -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. 10. A compound according to claim 1 which is N- [3- (4-chlorobenzoylamido) phenyl] -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. . The N-phenyl-2-pyrimidinamine derivative of the Formula I according to claim 1 which is N- (3-benzoylamidophenyl) -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. 12. A compound according to claim 1 which is N- [3- (2-pyridyl) carboxamidophenyl] -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. . 13. A compound according to claim 1 which is N- [3- (3-pyridyl) carboxamidophenyl] -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. . 14. A compound according to claim 1 which is N- [3- (4-pyridyl) carboxamidophenyl] -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. . 15. A compound according to claim 1 which is N- (3-pentafluorobenzoylaminophenyl) -4- (3-pyridinyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. 16. A compound according to claim 1 which is N- [3- (2-carboxybenzoylamido) phenyl] -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. . 17. A compound according to claim 1 which is N- (3-n-hexanoylamidophenyl) -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. 18. A compound according to claim 1 which is N- (3-nitrophenyl) -4- (2-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. An N-phenyl-2-pyrimidinamine derivative of the Formula I according to claim 1 which is N- (3-nitrophenyl) -4- (4-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. 20. A compound according to claim 1 which is N- [3- (2-methoxybenzoylamido) phenyl] -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. . The N-phenyl-2-pyrimidineamine derivative of the general formula (1) according to claim 1 which is N- [3- (4-fluorobenzoylamido) phenyl] -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. . The N-phenyl-2-pyrimidinamine derivative of the Formula I according to claim 1 which is N- [3- (4-cyanobenzoylamido) phenyl] -4- (3-pyridyl-2-pyrimidinamine) and a pharmaceutically acceptable salt thereof. A compound of formula (I) according to claim 1 which is N- [3- (2-ticnylcarboxamido) phenyl] -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. . An N-phenyl-2-pyrimidinamine derivative of the Formula I according to claim 1 which is N- (3-cyclohexylcarboxamidophenyl) -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. 25. A compound according to claim 1 which is N- [3- (4-methylbenzoylamido) phenyl] -4- (3-pyridyl) -2-pyrimidinamine or a pharmaceutically acceptable salt thereof. . SK 280620-6 The N-phenyl-2-pyrimidineamine derivative of the Formula I according to claim 1 which is N- [3- (4-chlorobenzoylamido) phenyl] -4- (4-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. . 27. A compound according to claim 1 which is N- [3- [4- (4-methylpiperazinomethyl) benzoylamido] phenyl] -4- (3-pyridyl) -2-pyrimidinamine. and a pharmaceutically acceptable salt thereof. An N-phenyl-2-pyrimidinamine derivative of the Formula I according to Claim 1 which is N- (5-benzoylamido-2-methylphenyl) -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. 29. A compound according to claim 1 which is N- [5- [4- (4-methylpiperazinomethyl) benzoylamido] -2-methylphenyl] -4- (3-pyridyl) - 2-pyrimidinamine and a pharmaceutically acceptable salt thereof. An N-phenyl-2-pyrimidinamine derivative of the Formula I according to claim 1 which is N- [5- (4-methylbenzoylamido) -2-methylphenyl] -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. A compound of formula (I) according to claim 1 which is N- [5- (2-naphthoylamido) -2-methylphenyl] -4- (3-pyridyl) -2-pyrimidinamine and its a pharmaceutically acceptable salt. An N-phenyl-2-pyrimidineamine derivative of the formula (1) according to claim 1 which is N- [5- (4-chlorobenzoylamido) -2-methylphenyl] -4- (3-pyridyl) -2-pyrimidinamine and its a pharmaceutically acceptable salt. An N-phenyl-2-pyrimidinamine derivative of the formula (1) according to claim 1 which is N- [5- (2-methoxybenzoylamido) -2-methylphenyl] -4- (3-pyridyl) -2-pyrimidinamine and its a pharmaceutically acceptable salt. The N-phenyl-2-pyrimidinamine derivative of the general formula (1) according to claim 1 which is N- (3-trifluoromethoxyphenyl) -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. An N-phenyl-2-pyrimidinamine derivative of formula (I) according to claim 1 which is N- (3- / 1,1,1,2-tetrafluoroethoxy / phenyl) -4- (3-pyridyl) -2- pyrimidinamine and a pharmaceutically acceptable salt thereof. An N-phenyl-2-pyrimidinamine derivative of the Formula I according to claim 1 which is N- (3-nitro-5-methylphenyl) -4- (3-pyridyl-2-pyrimidinamine) and a pharmaceutically acceptable salt thereof. An N-phenyl-2-pyrimidinamine derivative of the Formula I according to claim 1 which is N- (3-nitro-5-trifluoromethylphenyl) -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof. An N-phenyl-2-pyrimidinamine derivative of the Formula I according to claim 1 which is N- (3-nitrophenyl) -4- (N-oxido-3-pyridyl) -2-pyrimidinamine. An N-phenyl-2-pyrimidinamine derivative of the Formula I according to claim 1 which is N- (3-benzoylamido-5-methylphenyl) -4- (N-oxido-3-pyridyl) -2-pyrimidinamine. An N-phenyl-2-pyrimidinamine derivative of the Formula I according to any one of claims 1 to 39, or a pharmaceutically acceptable salt of said N-phenyl-2-pyrimidinamine derivative comprising at least one group capable of being converted into a salt for use as a medicament. 41. A pharmaceutical composition comprising an N-phenyl-2-pyrimidineamine derivative of formula (I) according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof comprising at least one group capable of being converted to a salt together with a pharmaceutical. carrier. A pharmaceutical composition for the treatment of tumors of warm-blooded animals, including humans, comprising an antitumor dose of an N-phenyl-2-pyrimidineamine derivative of formula (1) according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof comprising at least one. a group capable of being converted into a salt together with a pharmaceutical carrier. Use of an N-phenyl-2-pyrimidinamine derivative of the general formula (I) according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, comprising at least one group capable of being converted into a salt for the manufacture of a pharmaceutical composition for use in cancer chemotherapy. Use of an N-phenyl-2-pyrimidinamine derivative of the general formula (I) according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, comprising at least one group capable of being converted into a salt for the manufacture of a pharmaceutical composition for use in the treatment of cancer. 45. A process for the preparation of N-phenyl-pirimidínamínového derivative of the formula (I) according to claim 1 or a salt of the derivative containing at least one group capable of conversion into a salt, characterized by, a) a compound of formula (III) is that in which R ¹¹ and R ¹² independently of one another represents a lower alkyl group and R ¹ , R ² and R ³ have the meanings given above, wherein the functional groups present in the compound of the general formula (III) are, optionally in protected form, other than those involved in the reaction. or a salt thereof reacts with a compound of formula (IV) wherein the substituents are as defined above, wherein the functional groups present in the compound of formula (IV) are, except in the guanidine group involved in the reaction, optionally in protected form. , or a salt of this compound and a protecting group is cleaved, or (b) for the preparation of a compound of formula (I) wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above except for nitro and fluoro substituted lower alkoxy, wherein one or two of R ¹³ , R ¹⁴ , R ¹⁵ , R ^16, and R ¹⁷ is, respectively. are amino and the others of R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently of one another are hydrogen, lower alkyl which is unsubstituted or substituted by a free or alkylated amino group, piperazinyl group, piperidinyl group, pyrrolidinyl or morpholinyl; a lower alkanoyl group, a trifluoromethyl group, a free or etherified or esterified hydroxy group, a free, alkylated or acylated amino group or a free or esterified carboxyl group, and other general substituents have the meanings indicated above, the functional groups present in the compound of formula (V) being with the exception of the amine group (s) involved in the reaction, optionally in protected form, with a compound of formula (VI) HO-C (= X) - (Y) n-R ¹⁰ (VI), in which the general substituents are as defined above, wherein the functional groups present in the compound of formula (VI) are with the exception of HO-C (= X) ), participating in the reaction, optionally in protected form, or with a reactive derivative of a compound of formula (VI), subsequently deprotecting, or (c) in order to prepare a compound of formula (I) wherein: ^R1 is pyridyl, which is N-substituted by oxygen, and the other substituents are as defined above, converting a compound of formula (I), wherein R ¹ zanemená pyridyl group, with a suitable oxidizing agent to the N-oxido-compound, thereafter optionally converting a compound of formula (1) obtained by the methods of steps a) to c) into a salt thereof, or converting a salt of a compound of formula (1) into a free compound of formula (I).