SK28093A3 - N-phenyl-2-pyrimidinamine derivatives, process for their preparation and their pharmaceutical compositions - Google Patents

Abstract

There are described N-phenyl-2-pyrimidinamine derivatives of the formula I <IMAGE> in which R1 denotes 4-pyrazinyl, 1-methyl-1H-pyrrolyl, phenyl substituted by amino or amino-lower alkyl, in which the amino group is in each case free, alkylated or acylated, 1H-indolyl or 1H-imidazolyl bonded to a five-membered ring carbon atom, or pyridyl which is bonded to a ring carbon atom, unsubstituted or substituted by lower alkyl and unsubstituted or substituted by oxygen on the nitrogen, 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 (II> in which R9 stands for hydrogen or lower alkyl, X stands for oxo, thio, imino, N-lower alkylimino, hydroximino or O-lower alkylhydroxyimino, Y stands for oxygen or the group NH, n stands for 0 or 1 and R10 stands for an aliphatic radical having at least 5 C atoms or for an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclic-aliphatic radical, 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. These compounds can be used e.g. for the therapy of cancers.

Description

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

When X is oxo, thio, imino, N (lower alkyl) imino, hydroximino or O- (lower alkyl) hydroximino, C = X is respectively residue C = 0, residue C = S, residue C = NH, C = N (lower alkyl) residue, residue C = N-OH or CNO- (lower alkyl) residue. 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 a, R _3, and Ro are preferably methyl or ethyl.

The specification below denotes radicals having up to 7 carbon atoms, preferably up to 4 carbon atoms.

The aliphatic radical R 10 with at least 5 carbon atoms preferably has no more than 22 carbon atoms, typically having no more than 10 carbon atoms and is an unsubstituted aliphatic substituted or preferably substituted or preferably hydrocarbon radical, i. unsubstituted alkynyl, alkenyl or preferably an alkyl radical such as an alkyl radical containing 5 to 7 carbon atoms, for example an n-pentyl radical. The aromatic residue Rio has. up to 20 carbon atoms and is substituted or unsubstituted, for example meaning unsubstituted or substituted naphthyl radical, in particular

A 2-naphthyl radical, or preferably a phenyl radical, wherein the substituents are preferably selected from the group consisting of cyano, unsubstituted or hydroxy, amino or 4-methylpiperazinyl substituted lower alkyl, in particular methyl, trifluoromethyl , a free, etherified or esterified hydroxyl group, a free, alkylated or acylated amino group, and a free or esterified carboxyl group.

In the aromatic and aromatic radical R 10, the aromatic radical consists of an aromatic radical as defined above 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 the aforementioned radical is benzyl, for example. group.

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 cyclic and substituted or preferably unsubstituted radical, for example in particular a 5- or 6-membered cyclic radical such as preferably cyclohexyl residue.

In the cycloaliphatic-aliphatic moiety of the radical R 10, the cycloaliphatic radical is as defined above 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.

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, 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 three-cyclic 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 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 hydroxy group is preferably a lower alkoxy group. The esterified hydroxy group is preferably a hydroxy group esterified with an organic carboxylic acid such as lower and alkanoic acid, or a mineral acid such as hydrohalic acid, for example a (lower alkane) oyloxy group or especially a halogen atom such as an atom iodine, bromine or especially fluorine or chlorine.

An alkylated amino group is, for example, a (lower alkyl) amino group such as a methylamino group, or a (lower alkyl) amino group such as a dimethyl amino group. An acylated amino group is, for example, an (lower and 1 k) anoylamino group or a nonoylamino group.

An esterified carboxyl group is, for example, a (lower and 1 k) oxycarbonyl group such as a methoxycarbonyl group.

A substituted phenyl group can carry up to 5 substituents, such as a fluorine atom, and especially in the case of larger substituents, the phenyl group is generally substituted by 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.

Between the groups of formula (I) may be converted to a salt in the compound of the group or residues having 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, can form addition salts with inorganic acids such as sulfuric or phosphoric acid, carboxylic or sulphonic aliphatic mono- or di-carboxylic trifluoroacetic acids. , acetic acid, succinic acid, hydroxymaleinic acid, citric acid, oxalic acid or lysine, or aromatic carboxylic acids are benzoic acid, 2-acetoxybenzoic acid, salicylic acid or aliphatic-aromatic acid are mandelic acid and 1 or heteroaromatic carboxylic acid on the acid. Other malic acid, mis acid, for example s are hydrochloric acid, acid, or with suitable organic acids, for example with acids such as propionic acid, malic acid, amino acid, amino acid Fumaric acid such as arginine acid,

2-phenoxybenzoic acid, 4-aminoacidylic acid, carboxylic acids, cinnamic acid, acids such as nicotinic acid or isonicotinic acid, or aliphatic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, or 2-hydroxyethanesulfonic acid or aromatic sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid or naphthalene-2-sulfonic acid. In the presence of a plurality of basic groups, mono- or polyaddition salts with acids may be formed.

Compounds of formula I with acidic groups, for example with a free carboxyl group in the R 10 moiety, may form metal-derived salts or ammonium salts, such as alkali or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts 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 a heterocyclic base, for example N-ethylpiperidine or N, N ' dimethylpiperazin.

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

Pharmaceutically unsuitable salts can also be used for the isolation or purification and for the compounds which are further used as intermediates. However, only pharmaceutically usable non-toxic salts are suitable for therapeutic use and are therefore preferred with respect to T i and m i.

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 and optionally their corresponding salts.

The compounds of the formula I have valuable pharmacological properties and can be used, for example, as anti-tumor 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 names. Serine / threonine names include protein kinase C, while the tyrosine kinases PDGF (Patelate-derived Growth Factor) -receptor-tyrosine kinase.

The compounds of formula I, wherein Ru and _Rs are H, selectively inhibit the enzyme protein kinase C.

Phospholipids and calcium-dependent protein kinase C is present in cells in several species (tissue-specific distribution of species) and is 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 by direct 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 described by T. Uchida and CRF 11burn in J. Biol. Chem.259, 12311-4 (1984). . The determination of the inhibitory effect of the compounds of the formula I on protein kinase is carried out by the method described by D. Fabro et al. B i ochem. Biophys. 239: 102-111 (1985). In this test, the compounds of formula I inhibit protein kinase C already at an IC 50 concentration of between about 0.1 and 10 µmol / l, in particular between about 0.05 and 5 µmol / l. In contrast, compounds of formula I inhibit other enzymes such as protein kinase A, protein phosphorylase kinase and certain types of protein tyrosine kinases, such as protein tyrosine kinase EGF- (Epidermal Growth Factor) -receptor, to a much higher extent , such as 100-fold higher concentration. This indicates the selectivity of the compounds of formula I. In view of the limitation of side effects, it is important that the protein kinase inhibitors are as selective as possible and that as little as possible affect other enzymes, especially when affecting the activity of these other enzymes is not related to the disease being treated. no similar or synergistic effect.

Based on the protein kinase C inhibitory effect, the compounds of formula I in which R a and R e are hydrogen and their pharmaceutically usable salts can be used as tumor-inhibiting, immunomodulatory and antibacterial active agents, as an anti-atherosclerosis, AIDS, disease cardiovascular system and diseases of the central nervous system.

As can be expected from the protein kinase C inhibitory activity described above, they show compounds of formula I in which R1. and Ra represents a hydrogen atom, and their pharmaceutically usable salts, with antiproliferative properties which can be directly demonstrated by the following further test.

In this test, 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 minimum baseline 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 oxide. dioxide. The carcinoma cells are then inoculated into a 96 well microtiter plate and incubated overnight under the above conditions. The test substance is then added (day 1) 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. Following the incubation, the cells are fixed with 3.3% (w / v) solution of gut 1-aldehyde, 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 directly proportional to the number of cells by means of a photometer (Titertek 11 iskan) at a wavelength of 665 nm. From the results obtained, the IC 50 is calculated in a computer system using the following formula:

0H ₆ 6s (test) - OHees (Beginning) -------------------------------------- ----------------------- x 100.

OH & en (k ont ro 1 a) - OH ₆₆ s (top)

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 µmol / L.

On the basis of the properties described, the compounds of formula I, wherein R and R are _{H, and} used mainly as tumor-inhibiting active ingredients, for example for the treatment of bladder cancer. 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 on Re is hydrogen do not only inhibit protein kinase but also inhibit, even at an IC 50 concentration of between about 0.01 and 5 µmol / l ether, especially between about 0.05 and 1 µmol. liter of certain tyrosine kinases, such as especially PDGF-receptor kinase or abl-kinases e.g.

1

Ί ad v-abl-kinase. The compounds of formula I, wherein at least one of R ₄ and _R other than H and is, for example lower alkyl, especially a methyl group are particularly selective for the above PDGF Abl tyrosine kinase and substantially do not inhibit protein kinase C.

PDGF (P1ate1et-derived Growth Factor) is very often a growth factor that plays an important role in both normal growth and the pathological cell proliferation that occurs during carcinogenesis and vascular smooth muscle cell disease, for example in atherosclerosis and thrombosis.

Inhibition of protein kinase C and PDGF receptor kinase acts in this sense to the isynerg vases 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 immunocomponents 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 above specified compounds of formula I inhibit PDGF-dependent cell-free receptor phosphorylation at a concentration of from 0.005 to 5 (mol / liter), in particular at a concentration of 0.01 to 1.0 and especially a concentration of 0.01 to 0.1 (µmol) l. Inhibition of PDGF-receptor tyrosine kinase in an intact cell has been demonstrated by Western

Plot-analysis, also analogously as described

E. Andrejauskas-Buchdenger and U.Regenass in Cancer Research 52, 5353-5358 (1992). In this assay, inhibition of PDGF-receptor-autophosphorylation in ligand-stimulated BALB / c cells is measured by anti-phosphotyrosis of the new antibody. The above-specified compounds of formula I inhibit PDGF receptor tyrosine kinase activity at a concentration of 0.005 to 5 µmol / l iter, in particular at a concentration of 0.01 to 1.0 µmol / l iter, and especially at a concentration of 0.01 to 0.1zumo1 / 1 iter. These compounds also inhibit cell growth of PDGF-dependent cell lines, namely murine BALB / c 3T3 fibroblasts, at a concentration of less than 1.0 µmol / l iter.

The abovementioned α-abl-tyrosine kinase is determined by the methods of N. Lydon et al., Oncogene Research 5, 161-173 (1990) and JFGei ss 1er-a et al., Cancer Research 52, 4492-. 4498 (1992). Substrates such methods using / Ra1 ^p / n -angiotensi II / gamma ³² P / ATP.

Due to the properties described, the compounds of the formula I can be used not only as tumor-inhibiting active substances, but also as agents for atherosclerosis and thrombosis. In addition, other uses are contemplated for the aforementioned protein kinase C modulators and may be of particular use in 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 are those of formula I in which one or d.va of R ', R _s, R _6, R _7, and R is, or is nitro or a group of formula II in which

R ₃ 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 aliphatic radical having at least 5 carbon atoms or an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic-3 or heterocyclic-aliphatic radical, and the other of R _4, R a, R _a, R / and R 'independently of one another are hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, when perazíny1 ovou, piperidinyl, pyrrolidinyl or a morpholinyl group, a lower alkanoyl group, a trifluoromethyl group, a free, etherified or esterified hydroxy group, a free, alkylated or acylated amino group or a free or esterified carboxyl group, the other substituents being as defined above, and salts of these compounds with at least one nasoT transition group.

Particularly preferred compounds are those compounds of formula I wherein

R1 is 4-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 or acylated with a lower alkanoyl or benzoyl group, a bonded 1H-indolyl or 1H-imidazolyl group on a carbon atom of a five-membered ring, or an unsubstituted or lower alkyl-substituted pyridyl group which is unsubstituted or unsubstituted on a carbon atom on a ring carbon atom .

R @ 1 and R @ ₃ independently of one another represent a hydrogen atom or a lower alkyl group, one or two of R @ ₄ , R @ ₅ , R @ ₅ , R @ 6 and R @ 8 are optionally nitro, fluoro substituted lower alkoxy or of formula II in which R 0 represents a hydrogen atom or a lower alkyl group, X represents an oxo group, a thio group, an imino group, an N (lower alkyl) imine group, a hydroxyimine group

4

or an O- (lower and 1-alkyl) hydroximino group,

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 always unsubstituted or substituted by cyano, lower alkyl, hydroxy (lower and 1-alkyl), amino (lower alkyl), (4-methylpiperazines) - (lower alkyl), tri-fluoromethyl, hydroxy, lower alkoxy, (lower alkanoyl) oxy, halogen, amino, (lower and 1-alkyl) amino, di (lower and 1 alkyl) amino, (lower and 1 alkoyl) amino, benzoylamino, carboxyl or (lower and 1 alkoxy) carbonyl, phenyl lower alkyl radical in which the phenyl group is unsubstituted or substituted as described above , cycloalkyl or cycloalkenyl radical of up to 30 carbon atoms, cycloalkyl (lower alkyl) or cycloalkenyl (lower alkyl) radical in each case having up to 30 carbon atoms in the 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, oxygen and sulfur, to which one or two benzene residues may be fused, or lower alkyl substituted by such a monocyclic radical, and the other of R 4, R s, R _e, R ₇ and R ₈ independently of one another are hydrogen, lower alkyl that is unsubstituted or substituted by amino, (lower and 1 alkyl) amino, di (lower alkyl) amino, piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl, lower alkanoyl, trifluoromethyl, hydroxy, lower alkoxy, (lower and 1 kanoyl) oxy, halogen, amino, (lower and alkyl) amino, di (lower and 1-yl) amine groups, (lower and 1-kanoyl) amine, benzoylamino, carboxyl, or (lower and 1-alkoxy) carbonyl, and salts thereof. 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 on the nitrogen atom by an oxygen atom,

R ~ and R ₃ are hydrogen, fh

Rs

R ₆

R 7

Re represents a hydrogen atom or a lower alkyl group, represents a hydrogen atom, a lower alkyl group or a fluorine-substituted lower alkoxy group, represents a hydrogen atom, represents a nitro group, a fluorine-substituted lower group

alkoxy a group or radical of the general formula II, in which r ₉ means a hydrogen atom, X means oxo group n means 0 a R i o means and 1 fat hydrocarbon Rest with 5 to 22 atomam i alkyl, hair dryers Rest , which is

unsubstituted or substituted by cyano, lower alkyl, (4-methylpiperazin-1) (lower and alkyl), lower alkoxy, halogen or carboxyl, cycloalkyl and up to 30 carbon atoms or monocyclic a radical having 5 or 6 ring members and 1 to 3 ring sulfur atoms, and is a hydrogen atom, and pharmaceutically acceptable salts of these groups capable of being converted to a salt.

compounds with at least one

6

Particularly preferred compounds are those compounds of formula (I) in which they are present

R 1 is in each case bonded to the carbon atom by a pyridyl group or an N-oxido-pyridyl group,

R 2 and R 3 are hydrogen,

Ra represents a hydrogen atom or a lower alkyl group,

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

Re represents a hydrogen atom,

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

Ro represents a hydrogen atom,

X is oxo, n is 0 and

R is a pyridyl bonded to a carbon atom, unsubstituted or halogen, cyano, lower alkoxy, carboxyl, lower alkyl or 4-methylpiperazinylmethyl substituted phenyl, a (C7 -C7) alkyl group, a thienyl group , 2-naphthyl or cyclohexyl, and

R a 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 and R _e are hydrogen or one of R "and R is lower alkyl and the other of R and R and the other of the substituents are as defined above, and pharmaceutically acceptable salts thereof with at least one group capable of moving to a salt thereof.

Furthermore, the compounds according to the invention are particularly preferred

7 of a compound of formula I wherein:

R 1 represents a pyridyl group attached to a carbon atom, R 1, R 3, R 6, or R 6. , R _5, R _d and R e are hydrogen, and

R? is n-nitro or a radical of formula II in which

R> is a hydrogen atom,

X is oxo, n is 0 and

R 10 represents a pyridyl group attached to a carbon atom, unsubstituted or fluorine, chlorine, cyano, lower alkoxy, carboxyl, lower and alkyl, or

4-methylpiperazinylmethyl-substituted phenyl, C5-C7alkyl, thienyl or cyclohexyl, and pharmaceutically acceptable salts thereof.

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

With respect to protein kinase C inhibition, the most preferred compounds of the invention are those compounds of formula I in which R and R5 are hydrogen and the other general substituents are as defined above, and the pharmaceutically usable salts of these compounds with at least one group able to convert to salt.

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

The invention also relates to a process for the preparation of the compounds of the formula I and their salts with at least one group capable of being converted into a salt comprising the steps of:

a) a compound of formula III

(ΠΙ) in which R τ-t and R 1 = independently of one another denotes a lower alkyl group and R 1, R 2 and R 5 have the meanings given above, wherein the functional groups present in the compound of formula III are, except for those involved in the reaction; in protected form, or a salt of this compound is reacted with a compound of formula IV

(IV) wherein the general substituents are as defined above, wherein the functional groups present in the compound of formula (IV) are, with the exception of the quanidine group involved in the reaction, optionally in protected form, or cleaved with the salt of the compound and the protecting group,

9 or sa

b) in order to prepare a compound of formula I wherein R 1, R 5, R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6, and Ra have the above meanings except for the n-t-group and the fluorine-substituted lower alkoxy group, said compound of formula V

(V) wherein one or two of R 13, R 13, R 13, R 13 and R 13? means, respectively. denote an amino group and the others of Ria, Ria, Ris, Rie and R11, independently of one another, represent a hydrogen atom, a lower alkyl group which is unsubstituted or substituted by a free or alkylated amino group, piperazinyl, piperidinyl, pyrrolidine a dnyl or morpholinyl group, a lower alkanoyl group, a trifluoromethyl group, a free or etherified or esterified hydroxy group, a free, alkylated or alkylated amino group or a free or esterified carboxyl group, and other general substituents are as defined above, wherein the functional groups present in the compound of formula (V) are, with the exception of the amine group or amine groups involved in the reaction, optionally in protected form, in reaction with a compound of formula (VI)

HO-C (= X) - (Y) n -R10 (VI) wherein the general substituents have the meanings given above, wherein the functional groups present in the compound of formula VI are, except for the OC (- X) - involved in the reaction , optionally in a protected form, or with a reactive derivative of a compound of formula (VI) and subsequently deprotecting, or

c) converting a compound of formula I wherein R 1 is a pyridyl group by treatment with a suitable compound for the preparation of a compound of formula I wherein R 1 is a pyridyl group substituted with an oxygen atom on the nitrogen atom and other general substituents as defined above of an oxidizing agent to an N-oxido compound, followed by optionally converting a compound of formula I obtained by the process of steps a to c into their salt or converting a salt of a compound of formula I into a free compound of formula I.

In the following part of the description, an embodiment of the above variants of the methods according to the invention will be explained in more detail.

General information:

The final compounds of formula (I) may contain substituents which, as well as the protective groups in the starting materials, may be used to prepare further final compounds of formula (I). an easily cleavable group that is not part of the desired final group of compound (I) unless otherwise indicated.

Protecting groups, their introduction and cleavage are exemplified by the 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-Ver1ag, Stuttgart 1,974, as well as in Theodor W. Green

Synthesis, J. W & I and Sohn, New York 1981. Characteristic of the protecting groups is that they are readily cleavable, i.e., &lt; tb &gt; without undesirable side reactions, for example with 1 vytolytic, reducing, photolytic or else under physiological conditions.

Hydroxy-protecting groups are, for example, acyl radicals, such as, for example, halogen-substituted lower alkanoyl, such as 2,2-dichloroacetyl, or acyl radicals derived from half-carbonic esters, in particular tert-butyloxycarbones 1, optionally substituted benzyloxycarbones 1, for example 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl or 2-halogeno (lower and 1-alkoxy) carbonyl such as 2,2,2-trifluoromethoxycarbonyl, further a trityl residue, a formyl residue or an organic silyl or stannyl residue, further readily cleavable etherified groups such as tert-lower and alkyl, for example tert-butyl, 2-oxa- or 2-1-α-aliphatic or cyclic and hydrocarbon radicals, especially 1- (lower alkoxy - lower) and 1-alkyl or 1- (lower and 1-alkyl) thio (lower alkyl), for example methoxymethyl, 1-methoxy yetyl, 1-ethoxyethyl, methylthiomethyl,

1-methylthioethyl or 1-ethylthioethyl, or 2-oxa or 2-thiocycloalkyl having 5 to 6 ring atoms, for example tetrahydrofuryl or

2-tetrahydropyranyl or the corresponding thiaanalogs, as well as an optionally substituted 1-phenyl (lower and 1-alkyl) group, such as an optionally substituted benzyl or diphenylmethyl group, wherein, for example, a halogen atom such as a chlorine atom, lower and 1-alkoxy a group such as a methoxy group and / or a nitro group.

For example, the protected amino group may be in the form of an easily cleavable acylamine group, an arylmethylamine group, an etherified mercaptoamine group, a 2-acyl (lower and 1 k) -1-enylamine group, a silyl or stable 1 amine group, or an azide group. .

In the corresponding acylamino group, the acyl radical of a carboxylic acid with, in particular, optionally substituted with, for example, an atom or a nitro group, for example, acyl, for example up to 18 halogen atoms and 1-carboxylic acid halogen, lower substituted benzoic acid or half ester; or arylic acid or .alpha.-alkoxy carboxylic selines. Such acyl groups are, for example, a lower alkanoyl group such as a formyl, acetyl or propionyl group, and a halo (lower alkanoyl) group such as

2-haloacetyl, especially 2-chloroacetyl,

2-bromoacetyl, 2-iodoacetyl, 2,2,2-trifluoroacetyl or 2,2,2-trichloroacetyl, optionally with, for example, a halogen atom, lower alkoxy or nitro-substituted benzoyl, such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzyl, or in the 1-position of the lower alkyl radical branched or in the 1 or 2 position a suitably substituted (lower alkoxy) carbonyl group, for example tert-butyloxycarbonyl, an arylmethoxycarbonyl group having one or two aryl radicals which preferably consists of a phenyl group optionally mono- or poly-substituted, for example, by a lower alkyl group, in particular a tertiary lower and an alkyl group such as butyl, by a lower alkoxy group such as methoxy, by hydroxy , halogen, such as chlorine, and / or nitro a naphtha such as an optionally substituted benzyloxycarbonyl group, for example a 4-nitrobenzyloxycarbonyl group or a diphenylmethoxycarbonyl group, for example a benzhydryloxycarbonyl group or a di- (4-methoxyphenyl) methoxycarbonyl group, aroylmethoxycarbonyl group, for example an aroyl group, such as a bromine atom, a substituted benzoyl group, for example a phenylacetyloxycarbonyl group, a 2-halo (lower alkoxy) carbonyl group, for example

2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl) ethoxycarbonyl in which the substituents are independently of one another optionally substituted, for example by a lower alkyl group, lower alkoxy, aryl, halogen or nitro-substituted, aliphatic, ariphatic, cycloaliphatic or aromatic hydrocarbon radical having up to 15 carbon atoms, as the corresponding optionally substituted lower alkyl, phenyl (lower and 1-alkyl), a cycloalkyl or phenyl radical such as a 2-trimethylsilylethoxycarbonyl group or a 2- (di-butylmethylsilyl) ethoxycarbonyl group; or

2-triarylsilyl-ethoxycarbonyl, such as 2-trienylsilyl-ethoxycarbonyl.

Other acyl moieties to be considered as amino-protecting groups are the corresponding organic phosphoric, phosphonic or phosphinic acid radicals, such as the di (lower and lower alkyl) phosphoryl radicals, such as dimethyphosphoryl radicals, diethylphosphoryl radicals, di-n-propylphosphoryl radicals. or a diisopropyl phosphoryl radical, a dicycloalkyl phosphoryl radical, for example a dicyclohexylphosphoryl radical, an optionally substituted diphenylphosphoryl radical, for example a diphenylphosphoryl radical, for example a nitro-substituted di- (phenyl (lower alkyl) phosphoryl radical) , for example, a dibenzylphosphoryl radical or a di- (4-nitrobenzyl) phosphoryl radical, an optionally substituted phenyloxyphenyl phosphonyl radical, for example a phenyloxyphenyl phosphonyl radical, a di (lower alkyl) phosphinyl radical, for example a diethylphosphinyl radical, or optionally substituted dif ny 1 fosfiny1ový radical, e.g., d 1 and females fosfiny1ový residue.

In an arylmethylamino group which includes a mono-, di- or in particular three arylmethylamino group, the aryl radicals are in particular optionally substituted phenyl radicals. Such groups are, for example, the benzylamino group, the diphenylmethylamino group, and in particular the three-amino group.

The etherified mercapto group in the amine group protected by this group is preferably an arylthio group or an aryl (lower and alkyl) thio group in which the aryl moiety is in particular optionally, for example, a lower alkyl group such as a methyl group or a tertiary group. a butyl group, a lower alkoxy group such as a methoxy group, a halogen atom such as a chlorine atom, and / or an nitro substituted phenyl radical. The 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 residue is, for example, the corresponding (lower and 1 can) carboxylic acid residue, benzoic acid optionally substituted with, for example, a lower alkyl group such as is a methyl group or a tert-butyl group, a lower alkoxy group such as a methoxy group, a halogen atom such as a chlorine atom and / or an nitro group, or in particular a half carbonate ester, for example a half (lower alkyl) ester . Corresponding protecting groups are, in particular, 1- (lower and 1-alkoyl) prop-1-en-2-yl, for example 1-acetylprop-1-en-2-yl, or 1- (lower and 1-alkoxy) carbonylprop 1-en-2-yl, for example 1-ethoxycarbonylprop-1-en-2-yl.

Preferred amino-protecting groups are acyl radicals of the half-esters of carbonic acid, in particular a tert-butoxycarbonyl radical, for example a 4-nitro-benzyloxycarbonyl radical or a diphenylmethoxycarbonyl radical, or a 2-halogen (lower alkoxy) carbonyl radical such as 2, A 2,2-trichloroethoxycarbonyl radical, a trityl radical or a formyl radical. The cleavage of the protecting groups which are not part of the desired final product of the 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 genolysis or chemical reduction, optionally sequentially or simultaneously.

The protected amine group is converted to the amine group in a manner known per se by various procedures depending on the nature of the protecting group, preferably by solvolysis or reduction. The 2-halo (lower and 1-alkoxy) carbonyl amino group (optionally after conversion of the 2-bromo (lower alkoxy) carbonylamino group to 2-iodo (lower alkoxycarbonylamino group, aroylmethoxycarbonylamino group or 4-nitrobenzyloxycarbonylamino group may be cleaved by, for example) an agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid The aroylmethoxycarbonyl group may also be cleaved by treatment with a nucleophilic, preferably a 1'-forming agent such as sodium thiophenoxide and 4-nitrobenzyloxycarbones An optionally substituted diphenylmethoxycarbonylamino group, a tertiary (lower and 1-alkoxy) carbonylamino group, or a 2-trisubstituted silylethoxycarbonylamino group may also be cleaved by treatment with a suitable amine group. an optionally substituted benzyloxycarbonylamino group can be cleaved, for example, by hydrogenolysis, i.e. by the addition of an acid such as formic acid or trifluoroacetic acid. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, an optionally substituted triarylmethylamine or formylamino group may be cleaved, for example, by treatment with an acid such as a mineral acid such as hydrochloric acid or an organic acid such as formic, acetic or tri Fluoroacetic acid, optionally in the presence of water, and the amine group protected by a silyl group can be released, for example, by hydrolysis or alcoholysis. The amino group protected with 2-haloacetyl, for example 2-chloro, racetyl, may be liberated by treatment with thiourea in the presence of a base or by treatment with a thiolate salt such as an alkali metal thiourea and subsequent solvolysis, in particular alcoholysis or hydrolysis of the resulting condensation product. The amino group protected with a 2-substituted silyl ethoxycarbonyl group can be converted to the free amine group by treatment with a fluoride anionic acid salt of hydrogen fluoride.

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

Method a

R 11 and R 11 are preferably a hunting group

The free functional groups in the compound of the formula III which are preferably protected by readily cleavable protective groups are, in particular, the amino groups in the radical R @ 1 and the imine group of the 1H-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 I.

Said reaction is carried out in a suitable solvent or suspension medium, for example in a suitable alcohol such as 2-methoxyethanol, or in a suitable lower alkanol, for example isopropanol, at a temperature from ambient temperature (about 20 ° C) to 150 ° C, e.g. heating to reflux. In particular, when a compound of formula (I) 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, the starting compounds of formula IV, wherein one or two of the radicals R a, R _5, R, R and R independently of one another are hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated am s new group , piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl, lower alkanoyl, trifluoromethyl, free, etherified or esterified hydroxy, free, alkylated or acylated amino or free or esterified carboxyl.

The starting material of formula III is obtained by reacting a compound of formula VII (VH)

2 'in which the general substituents have the meanings given above, with a compound of formula (VIII) R ₁₈ R 19 _{/ R 11}

--N \ R ₃ R, 2 (m) in which R 1a and R 1a are lower alkyl and the other substituents have the meanings given above, carried out under conditions analogous to those described in the European patent application published under number 233461.

Typical representatives of the compound of formula (VIII) are N, N-dimethyldimethyl acetyl and N, N-dimethylacetamide dimethylacetyl. 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.

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

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

HN (R, ₁ ) -R in which the general substituents have

The starting material of the general acid addition salt by reaction of the above-mentioned meanings.

of formula IV is obtained in the form of a compound of formula IX

(K) wherein the general substituents have the above meanings, with cyanamide (NC-NHa). This reaction is carried out in a suitable solvent or suspension medium, for example a suitable alcohol such as a lower alkanol, for example ethanol, in the presence of an equimolar amount of salt-forming acid at a temperature from ambient to 150 ° C, for example reflux. condenser.

Mode b

The free functional groups in the compound of formula V or VI, which are preferably protected by readily cleavable protective groups, are in particular an amino group, but also a hydroxy group and a carboxyl group which do not have to participate in the desired reaction, e.g. i.

The reactive derivative of a compound of formula VI in which X is an oxo group is, in particular, a reactive (activated) ester, reactive anhydride or a reactive cyclic amide. The same applies to derivatives in which X has any of the meanings given above.

In particular, the reaction-activated (activated) esters of the acid of formula (vi) are esters unsaturated on a carbon-binding atom, for example of the vinyl type, such as the actual vinyl esters (which can be obtained by reesterification of the corresponding ester with vinyl acetate; , carbamoyl inyl esters (which may be obtained, for example, by treating the corresponding acid with an isoxazoline reagent; 1,2-oxazoline or Woodward method) or 1- (lower and 1-alkoxy) in esters (which may be obtained by treatment (lower and Or alkoxy esters of a new type such as N, N'-di substituted amine esters (which may be obtained by treatment with a suitable N, N'-d isubstituted carbodiimide, for example N, N'- dicyclohexylcarbidimide to the corresponding acid; carbidimide method) or N, N-disubstituted amidino esters (which may be obtained by treating the corresponding acid with N, N-disubstituted cyanamide), suitable aryl esters, especially phenyl esters suitably substituted with electron affinity substituents (which, for example, may be obtained by treatment with a suitably substituted phenol, e.g. eno 1 u, 4-methyls 1 phony 1 pheno1

2,4,5-trifluorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol to the corresponding acid in the presence of a condensation agent such as N, N'-dicyclo hexyl kar point iimide; activated aryl ester method), cyanomethyl esters (which can be obtained, for example, by treatment with the corresponding acid in the presence of a base in the presence of a chloroacetonitrile; cyanomethyl ester method), thioesters, especially phenylthioesters optionally substituted with e.g. thiophenols optionally substituted, for example, with an nitro group on the corresponding acid, or by the anhydride or carbide imide method; the active thiolester method), amine or amidoesters (which may be obtained, for example, by treatment with an N-hydroxyamino or N-hydroxyamido compound such as N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide or 1-hydroxybenzotriazole to the corresponding acid, for example following the anhydride or carbide imidine method; the active N-hydroxyester method, or silyl esters (which can be obtained by treatment with a silencing agent, on the an example of hexamethylsilazane to the corresponding acid and which readily reacts with the hydroxy group but not with the amine 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 thienyl chloride, phosphorus pentachloride or oxalyl chloride; new method), 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 and 1-alkyl) esters of acid carbonic acid (which may be obtained, for example, by treatment with (lower and 1-alkyl) halogenoic esters, in particular chloroformic or 1- (lower alkoxy) carbonyl-2-lower and 1-alkoxy) -1,2-dihydroquinoline, e.g. 1- (lower alkoxy) carcarbones of 1-2-ethoxy-1,2-dihydroquinoline, corresponding to cu acid; mixed carbonic acid anhydride method) or anhydrides with dihydrogenated, in particular di-phosphoric acid (which may be obtained, for example, by the action of phosphorous oxychloride on the corresponding acid; oxyphosphoric acid method) or anhydrides with organic acids, as mixed anhydrides with organic carboxylic acids (which may be obtained by treatment with an optionally substituted halide (lower and 1 kana) - or phenylalkanic acid, for example phenyl acetic, pivalic or trifluoroacetic acid chloride; mixed carboxylic acid anhydride method) or with organic sulfonic acids ( which may be obtained by treating a salt, for example an alkali metal salt of the corresponding acid, with a suitable organic sulfonic acid halide, for example a chloride (lower alkane) or an aryl acid, in particular a methane or p-toluenesulfonic acid chloride; mixed sulfonic anhydride type) 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 treatment of the corresponding acid with the N, N'-carbonyl di imidazole, imidazolium method) or pyrazoles; for example 3,5-dimethylpyrazole (which may be obtained, for example, via an acid hydrazide by treatment with acetyl acetone; pyrazolidide method).

Acid derivatives of formula VI which are used as acylating agents can also be prepared in situ. Thus, for example, Ν, Ν'-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, for example N, N '-d icyk1ohexy1 kar point i im idu. It is furthermore possible to form amino or amidoesters of acids used as acylating agents in the presence of a starting material of the general formula V to be acylated by reacting a mixture of a starting acid and an amino compound in the presence of an N, N'-isubstituted ester. carbodiimide, for example N, N'-dicyclohexylcarbodiimide, and N-hydroxyamide, for example N-hydroxysuccinimide, optionally in the presence of a suitable base such as 4-dimethylamine opyridine.

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 can 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. if the carboxyl group involved in the reaction is in the form of the anhydride, it may also be an acid-binding agent, with cooling or heating to a temperature of, for example, from about -30 ° C to about 150 ° C, in particular from 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 1-5-phenyl-1,2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methyloxazole iumperchororate, or suitable acyloamine compounds, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. Conventional acid-binding condensers are, for example, alkali metal carbonates or alkali metal hydrogen carbonates, for example sodium carbonate and potassium carbonate or sodium hydrogen carbonate or potassium hydrogen carbonate (usually together with sulfate), or organic bases, such as pyridine or sterically hindered three (lower alkyl) amines, for example N, N-diisopropyl-N-ethylamine.

The starting material of formula V is obtained by reduction of the N-itro group or a nitro group in a compound of formula I in which one or two radicals R a, R _5, R®, R ₇ and R a is optionally represent 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. The hydrogenation catalyst used is preferably palladium on activated carbon (5%) and in this case the hydrogenation is preferably carried out under normal pressure.

Sooda c

A suitable oxidizing agent for converting a compound of formula I wherein R 1 is a pyridyl group to 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 at below 100 ° C and preferably at ambient temperature or at a slightly elevated temperature (20 to 70 ° C).

Acid addition salts of compounds of formula I are obtained in a conventional manner, for example by reacting an acid with a suitable anion exchange agent.

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

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

The above processes, together with the methods of cleavage of the 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 a temperature in the 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 the container and, if necessary, under an inert gas atmosphere, for example under a nitrogen atmosphere.

In view of all the substituents present in the molecule, for example because of the easily hydrolyzable residues, particularly gentle reaction conditions, such as particularly short reaction times, the use of mildly acidic or basic reagents at low concentrations must be adhered to stoichiometric quantities of the reaction. selection of 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 and 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 under reaction conditions. or used in the form of a reaction derivative or salt. The starting materials are those which lead to the compounds described above 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.

The invention also relates to a method for treating warm-blooded animals suffering from 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 the formula I or a useful salt thereof for the inhibition of PDGFreceptor kinase or a compound of the formula I in which R * and Rb are hydrogen or a pharmaceutically acceptable salt thereof for the inhibition of protein kinase. C for warm-blooded animals or for 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 mode of administration and the actual disease state, for example an effective daily dose of about 1 to 1000 mg. substances according to the invention.

The invention also relates to pharmaceutical compositions comprising an effective amount, in particular an effective amount for the prophylaxis or therapy of the aforementioned diseases, the active compounds 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 starch may also contain a binder, for example h1 ini flux of magnesium sulfate, starches such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and optionally disintegrating agents. agents, for example starches, agar, alginic acid or a salt thereof, for example sodium alginate, and / or effervescent mixtures or adsorbents, colorants, flavors and sweeteners.

active compounds of the invention parenterally administrable solutions are preferred suspensions

Pharmacologically, further use in the form or of infusion solutions, by which aqueous solutions or in the case, for example, containing an active carrier alone, for example mannitol, can be used. The pharmaceutical preparations and / or may contain excipients, stabilizing agents, emulsifying agents, solubilizing osmotic pressure and / or buffers.

The lyophilized preparation solutions, the substance, optionally together with the preparation before itself, can be sterilized substances, for example preservative wetting agents and / or agents, salts for the control

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, dragee, dissolution or lyophilization processes, and contain about 1 to 100% %, in particular about 1 to about 20%, of the active compound (s).

In the following, the invention will be further elucidated by means of specific examples thereof, which are illustrative only and not in any way limit the scope of the invention, as clearly defined by the claims. In these examples, the Rf values were determined on thin-layer silica gel plates (commercially available from Merck, Darmstadt, 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-023346 1) in 250 ml of isopropanol is added 41.3 g (0.17 mol) of 3-nitrophenyl guanidine nitrate suspended in 50 ml of isopropanol. After the addition of 7.49 mol) of sodium hydroxide, the yellow suspension is heated to boiling below 0 ° C, washed subsequently with a reflux condenser 8 of the suspension and filtered.

The suspension obtained is washed with 200 ml of isopropanol and the solid is washed for 200 hours. After cooling to a solid, the suspension was stirred for 30 minutes (0.19 temperature filter temperature), separated by suspension in 200 mL of ethanol and washed with diethyl ether to give the product.

Melting point:

Rf = 0.75 (1: 1 v / v)

200 sa

300 ml of water, filtered and

After re-watering.

ml of ethanol mixture to give the desired product

12-213 ° C, 9: 1 chloroform / methanol)

The starting material is obtained as follows:

Stage 1. 1

To a yellow suspension of 82.83 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 an exothermic reaction, 75.7 g (0.9 mol) of cyanamide (50% in water) are added and the resulting reaction mixture is heated under reflux for 21 hours. After cooling to 0 ° C, the reaction mixture was filtered, and the solid was washed six times with a 1: 1 v / v mixture of ethanol and diethyl ether. After drying under high vacuum at 40 ° C, it is obtained

3-nitrofenylguanidinnitrát.

Mp .: 205-207 ° C.

Stage 1. 2 g (0.35 mol) of sodium are introduced into 260 ml of toluene, followed by suspension of sodium in toluene at 100 [deg.] 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, followed by the addition of 23.7 (0.52 mol) of dimethylamine. After 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 at 0 ° C over 30 minutes, and the mixture is then heated under reflux for one minute. 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

GO mg (0.38 mmol 1 µl) of N- (3-aminophenyl) -4- (3-pyridyl-2-pyrimidinamine) is dissolved in 5 ml of pyridine, 56.5 µl ( (46 mmol) of 4-chlorobenzoyl chloride and the resulting 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-ch1órbenzoy1amido) phenyl / 4- (3-pyridyl) -2-pyrimidineamine.

Melting point: 238-240 ° C,

Rf = 0.66 (9: 1 chloroform / methanol).

The starting material is obtained as follows:

Stage 2.1

A suspension of 17.0 g (0.053 mol) of N- (3-nitrophenyl) -4- (3-pyridyl) -2-pyrimidine in 1700 ml of tetrahydrofuran is stirred for 21 hours with 1.7 g of palladium ha and activated carbon ( 5%) under a hydrogen atmosphere at normal pressure. The suspension is filtered and the filtrate is concentrated in a rotary evaporator. The yellow solid which remained was then stirred overnight in 200 ml of methylene chloride. After filtration and drying, N- (3-aminophenyl) -4- (3-pyridyl) 2-pyrimidine is obtained.

Melting point: 89-90 ° C,

Rf = 0.38 (9: 1 chloroform / methanol).

Example 3

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

Melting point: 207-209 ° C,

Rf = 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 5 ml of pyridine was stirred at ambient temperature under nitrogen for 24 hours. After the addition of 30 mg (0.23 mmol) of 2-pyridinecarboxylic acid chloride, the mixture was stirred for 18 hours, followed by an additional 25 mg (0.19 mmol) of 2-pyridinecarboxylic acid chloride and stirred for 72 hours at 25 ° C. 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-) is obtained from the corresponding eluate fraction. pyridyl) -2-pyrimidinimine.

Melting point: 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-pyrimidine is obtained. Starting from 3-pyridine carboxylic acid chloride.

Melting point: 217-220 ° C,

Rf = 0.29 (1: 0 MeOH / CHCl3).

Example 6

Following a procedure analogous to that described in Example 4, N- [3- (4-pyridyl) carboxamidophenyl] -4- (3-pyridyl) -2-pyrimidineamine was prepared from 4-pyridinecarboxylic acid chloride.

Melting point: 224-226 ° C,

Rf = 0.29 (9: 1 chloroform / methanol). Example 7 ί

To a solution of N- (3-aminophenyl) -4- (3-pyridyl) -2-pyrimidine (100 mg, 0.33 mmol) in pyridine (5 mL) was added pentafluorobenzoyl (53 µL, 0.43 mmol). The mixture was stirred under a nitrogen atmosphere 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-pyrimidine amine.

Melting point: 234-244 ° C,

Rf = 0.41 (9: 1 chloroform / methanol)

Example 8

To a solution of 50 mg (0.19 mmol) of N- (3-aminophenyl) -4- (3-pyridyl) -2-pyrimidine in 1 ml of pyridine is added 28 mg (0.19 mmol) 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 treated twice with 2.5 ml of absolute ethanol to give N- [3- (2-carboxybenzoylamino) phenyl] -4- (3-pyridyl) -2-pyrimidinamine.

Melting point: 206-209 ° C,

Rf = 0.07 (9: 1 chloroform / methanol)

Example 9

A solution of 100 mg (0.38 mmol) of N- (3-aminophenyl) -4- (3-pyridyl) -2-pyrimidine amine and 105 µl (0.46 mmol) of caproic anhydride in 5 ml of pyridine is stirred at 25 ° C for 24 hours under a nitrogen atmosphere, 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-hexanoyl-amidophenyl) -4- (3-pyridyl) from the corresponding eluate fraction. 42

- p y r i d i n m m η. Melting point: 18 0 - 1 δ 4 ° C, Rf - 0,78 (9: 1 by volume of chloroform and methanol).

Example 10 g (5.68 mmol) of 3-dimethylamino-1- (2-pyridyl) -2-propene-

Of 1-one (EP-A-23346 1) is dissolved in 8 ml of isopropanol, then 1.38 g (5.68 mmol) is added to the obtained solution.

3-nitrophenyl-guanidine nitrate. After the addition of 0.25 g (6.24 mmol) of sodium hydroxide, the yellow suspension was heated to reflux for 20 hours, cooled to 0 ° C for one week and filtered and the solid was washed with 30 IU 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-pyrimidines n. 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) of 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-pyrimidine amine 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-pyrimidine was prepared from 2-methoxybenzoyl chloride and purified.

Melting point: 115-117 ° C,

Rf = 0.75 (9: 1 chloroform / methanol).

Example 13

In a manner analogous to that described in Example 2, 4-fluorobenzoyl chloride was prepared from

N- / 3- (4-fluoro--benzoylamido) phenyl / 4- (3-pyridyl) -2-pyrimidineamine. Melting point: 215-216 ° C,

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

Example 14

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

Melting point: 220-222 ° C,

Rf = 0.31 (9: 1 chloroform / methanol).

Example 15

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

Melting point: 139-141 ° C,

Rf = 0.35 (9: 1 chloroform / methanol).

Example 16

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

Melting point: 205-206 ° C,

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

Example 17

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

Melting point: 214-216 ° C,

Rf = 0.64 (9: 1 chloroform / methanol).

Example 18

In a manner analogous to that described in Example 2, by reaction of 100 mg (0.38 mmol) of N- (3-aminophenyl) -

4- (4-Pyridyl) -2-pyrimidinamine 58 µl (0.46 mmol) of 4-chlorobenzoyl chloride preparates N- [3- (4-chlorobenzoylamino) phenylene] 1 '-4 (4-pyridyl) -2-pyrimidinamino.

Melting point: 258-261 ° C,

Rf = 0.37 (9: 1 chloroform / methanol).

The starting material is obtained as follows:

Stuoeň 18.1

In a manner analogous to that described in Step 2.1, from 300 mg of (1, Omol) N- (3-nitrophenyl) -4- (4-pyridyl) -2-pyrimidinamine (see Example 11) under a hydrogen atmosphere N- (3-aminophenyl) -4- (4-pyridyl) -2-pyrimidinamine is obtained. Melting point: 200-202 ° C,

Rf = 0.27 (95: 5 v / v chloroform / methanol).

Example 19

Following a procedure analogous to that described in Example 2, N- (3- / 4- (4-methylpiperazinomethyl) benzoyl) was prepared from 98 mg (0.3 mmol) of 4- (4-methylpiperazinomethyl) benzoyl chloride. amí do / feny 1 / -4 - ζ 3 - pyridy 1) - 2 - pyrimidinamín η.

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-pyrimidine per 4.0 ml (34.6 mmol) of benzoyl chloride. oridu 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 ° 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 the suspension is filtered. N- (5-benzoylamino-2-methylphenyl) -4- (3-pyridyl) -2-pyrimidine is obtained. Separation of this product after chromatographic separation.

Melting point: 173-176 ° C,

Rf value = 0.65 (9: 1, chloroform / methanol).

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-nitro-toluene 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 has been carried out, 8.32 g (0.198 mol) of camomamide dissolved in 8.3 ml of water are added. The brown reaction mixture was heated to reflux for 25 hours, then cooled to 0 ° C and filtered. After washing with ethanol / diethyl ether (1: 1 v / v) 4 times, 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 L of isopropanol was added 248.2 g (0.96 mol) of 2-methyl-5-nitrophenylguanidine nitrate. After adding

The resulting reddish suspension was refluxed for 42 hours with 42.5 g of sodium hydroxide. 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-pyrimidinamine is obtained. .

M.p .: 195-198 ° C,

Rf = 0.68 (9: 1 v / v methylene chloride / methanol).

Stage 20.3

A suspension of 143.0 g (0.46 mol) of N- (2-methyl-5-nitrophenyl) -4 (3-pyridyl) -2-pyrimidine in 7.15 liters of ethyl acetate is stirred in the presence of 14, 3 g of palladium on charcoal (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-pyrimidine is obtained.

Melting point: 138-140 ° C,

Rf = 0.36 (9: 1 v / v methylene chloride / methanol).

Example 21

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

Melting point: 211-213 ° C,

Rf = 0.33 (methylene chloride / methanol / 25% aqueous ammonia solution, 95: 5: 1 by volume).

Example 22

In a manner analogous to that described in Example 20, N- (5- (4-methylbenzoyl) amide) is prepared from 0.23 ml (1.7 mmol) of p-toluene. 2-Methylphenyl] -4- (3-pyridyl) -2-pyrimidinamine.

Melting point: 102-106 ° C,

Rf = 0.4 (mixture of methylene chloride and methanol in volume ratio)

9: 1).

Example 23

In a manner analogous to that described in Example 20, N- [5- (2-naphthoylamido) -2-methylphenyl] -4- (3-carboxylic acid) is obtained from 330 mg (1.73 mmol) of 2-naphthoyl chloride. -pyridyl) -2-pyrimidinimine.

M.p .: 97-101 ° C, = 0.45 (9: 1 v / v methylene chloride / methanol).

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,

R f = 0.39 (9: 1 v / v methylene chloride / methanol).

Example 25

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

Melting point: 88-92 ° C,

R f = 0.39 (9: 1 v / v methylene chloride / methanol).

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-trifluoromethoxyphenyl guanidine nitrate gives N- (3-trifluoromethoxyphenyl) -4- (3-pyridyl) -2-pyrimidinamine.

R _f · 0.7 (chloroform / methanol 9: 1 by volume).

The starting material is prepared as follows:

P roduct 26.1

In a manner analogous to that described in Step 1.1, 2.0 g (11.3 mmol) of 3-trifluoromethoxyaniline and 1.4 g (16.6 mol) of cyanamide (50% in water) were prepared. 3-trifluórmetoxyfenylguanidinnitrát.

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

Example 27

In a manner analogous to that described in Example 1, from 1.0 g (5.68 mmol) of 3-dimethylamino-1- (3-pyrrolidinyl) -2-propen-1 -one and 1.78 g (5.68 mmol) of 3- (1,1,2,2-tetratol-6-enoxy) phenylguanidine in nitrile gives N- (3- / 1,1,2, 2-Tetrafluoroethoxy / phenyl) -4- (3-pyridyl-2-pyrimidines ⁾ ;

Rf = 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-tetrafluoroethoxy) aniline and 1.26 g (15 mol) of cyanamide (50% in water) to prepare 3- (1,1,2,2-tetrafluoroethoxy) phenylguanidine nitrate.

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

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) of 3- nitro 5metylfenylguanidínnitrát.

Rf = 0.1 (mixture of methylene chloride, methanol and 25% aqueous ammonia in a ratio of 150: 10: 1 by volume).

Example 29

In a manner analogous to that described in Example 1, from 1.0 g (5.68 mol) of 3-methylamino-1- (3-pyridyl) -2-propen-1-one, and 1.76 g (5.68 mmol) of 3-nitro-5-trifluoromethylphenylguanidinate give N- (3-nitro-5-trifluoromethylphenyl) -4- (3- pyridyl) -2-pyrimidineamine.

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

The starting material is prepared as follows:

Stuoeň 29.1

In a manner analogous to that described in step 1.1, 3.06 g (10 mmol) of 3-nitro-5-trifluoromethyl aniline and 1.26 g (15 moles) of cyanamide (50% in water) are prepared. nitro-5-metylfenylguanidínnitrát.

Rf = 0.2 (mixture of methylene chloride, methanol and 25% aqueous ammonia solution, 150: 10: 1 by volume).

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 the obtained suspension are added. 3-Chloroperoxybenzoic acid is added After 2 hours, an additional 10 ml of methylene chloride is added and the suspension is stirred at ambient temperature for 20 hours. and a 25% aqueous solution of ammonia in a ratio of 90: 10: 1 by volume gives the corresponding eluate fraction to give N- (3-nitrophenyl) -4- (NOxido-3-pyridyl) -2-pyrimidinamine.

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-benzoylamino-5-methylphenyl) -4- (3-pyridyl) -2-pyrimidine chloride are obtained and the suspension of 3- Chorobenzenecarboperoxoic.

The solid is immediately suspended in 6 ml of methylene, and the mixture is stirred for 25 minutes in a solution of 25% aqueous ammonia, followed by the use of methanol.

is added

Mon 2 2

90: 10: 1, chromatograph after methylene chloride, volume ratio from corresponding eluate fraction

N- (3-benzoylamido-5-methylphenyl) -4- (N-oxido-3-pyridyl) -2-pyrimidine.

Rf = 0.3 (90: 10 0: 1 methylene chloride / methanol / 25% aqueous ammonia), mp 295-300 ° C.

Example 32

Tablets containing 20 mg of the active ingredient, for example one of the compounds of the formula I described in Examples 1 to 31, and having the following composition are prepared in a conventional manner:

Ingredients:

Active substance

Wheat starch

0 mg mg

Milk sugar

Colloidal silicic acid

The 1 mesh has mg

Magnesium stearate mg

Pretty

145 mg

P r o o r:

The active compound is mixed with wheat starch, milk sugar and colloidal silicic acid and sieved. A further portion of wheat starch is left on the water bath with left grains 5 times with water and the above powder mixture is added to the sebum obtained, then thoroughly mixed to obtain a slightly plastic mass. 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 notched tablets weighing 145 mg.

Example 33

Tablets containing 1 mg of the active ingredient, e.g.

of formula (I) as described in 1: examples 1 to 31, following Ingredients: Active substance 1 mg Wheat starch 60 mg Milk sugar 50 mg Colloidal silicic acid 5 mg talc 9 mg Magnesium stearate 1 mg

Total 1 2δ mg

P r o o r:

The active ingredient is mixed with wheat starch, milk sugar and colloidal silicic acid and sieved. A further portion of wheat starch is allowed to freeze in a water bath with 5 times the amount of water and the above powder mixture is added to the sebum obtained, 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 obtained is compressed into fracture-milled tablets having a weight of 126 mg.

Example 34

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

Ingredients:

Active substance 2500 mg talc 200 mg Colloidal silicic acid 5 0 mg

Preparation:

The active ingredient is thoroughly mixed with talk and colloidal silicic acid, then the resulting mixture is sieved through a 0.5 mm mesh sieve and is filled in hard gelatin capsules of appropriate size in 11 mg portions.

Claims (48)

N-phenyl-2-pyrimidine-novel derivatives of the general formula I (I) in which: R1 is 4-pyrazinyl, 1-methyl-1H-pyrrolyl, phenyl substituted with amino or amino (lower alkyl), the amino group being either free or alkylated or acylated, 1H-indolyl bonded to a carbon atom of a five-membered ring, a 1 H imidazolyl group bonded to a carbon atom of a five-membered ring, or a pyridyl group which is bound to a ring carbon atom, optionally substituted by a lower alkyl group and optionally substituted at nitrogen by an oxygen atom, R; and R 3 independently of one another is either a hydrogen atom or a lower alkyl group, one or two of R ₄ , R ₅ , R 5, R f and R a is optionally an nitro group, a lower fluorine-substituted alkoxy group or a group of formula II; 54 -N (Ro) -C (= X) - (Y), -R-o (II) wherein R 8 represents a hydrogen atom or a lower alkyl group, X represents an oxo group, a thio group, an imino group of an N - (lower and alkyl) imino group, a hydroximino group, or an O - (lower and 1 alkyl) hydroximino group; group Y is oxygen or NH, n is 0 or 1 and R 10 denotes an aliphatic radical having at least 5 carbon atoms or an aromatic, aromatic and fatal, cyclic and fatal, cyclic and fatal, a heterocyclic or heterocyclic-a1 and fatal radical, and the rest of Ra, R5, Re , R 7 and R 8, independently of one another, are hydrogen, lower alkyl optionally substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl, a lower alkanoyl group, a trifluoromethyl group, a free, etherified or esterified hydroxyl group, a free, alkylated or acylated amino group or a free or esterified carboxyl group, and salts of these compounds with at least one salt-capable group. 2. The compound of claim 1 of formula I, wherein one or two of R n, R _{5, R,} R? and _R is, or are n itro radical or a radical of the formula II in which Ro represents a hydrogen atom or a lower alkyl group, X represents an oxo group, a thio group, an imino group, an N55 (lower and lower alkyl) imino group, a hydroxyimino group or an O- (lower alkyl group) 1) hydroxyimino group, Y is oxygen or NH, n is 0 or 1 and Rio is an aliphatic radical having at least 5 carbon atoms or an aromatic, aromatic-a1 and menstrual, cycle-aliphatic, cyclo loa1 the menstrual a1 and menstrual, heterocycloalkyl one cyclic or heterocyk1 icko-A1 and menstrual radical, and the other of R a, R _p , R _e , R? and R _e, independently of one another, represent a hydrogen atom, a lower alkyl group which is unsubstituted or substituted by a free or alkyl amino group, a perazinyl group, a peridinyl group, a pyrrolidinyl group or a morpholinyl group, a lower alkanoyl group, three A fluoromethyl group, a free, hydroxy group, an etherified or esterified free, alkylated or acylated amino group or a free or esterified carboxyl group, the other substituents being as defined in claim 1, and salts thereof with at least one salt-capable group. Compounds according to claim 1 of the general formula I, in which R1 is 4-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 lower alkanoyl or benzoyl, on the carbon atom of the five-membered ring bound by 1 H-indolyl or 1 H -imidazolyl or on a ring carbon atom bound by an unsubstituted or lower alkyl-substituted pyridyl group which is unsubstituted on the nitrogen atom or substituted by an oxygen atom, R 2 and R ₃ independently of one another, are H or lower alkyl, and 1 U is 1 s, one or two of R *, _R, R, R, and R is optionally are n itro-a group of the. a fluorine-substituted lower alkoxy group or a group of the formula II in which Ro represents a hydrogen atom or a lower alkyl group, X is oxo, thio, imino, N (lower alkyl) imine, hydroxyimino or O- (lower alkyl) hydroximino, Y is oxygen or NH, n is 0 or 1 and R 10 is 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-methylpiperazines 1) - (lower alkyl) group, tri-fluoromethyl, hydroxy, lower alkoxy, (lower alkanoyl) oxy, halogen, amine, (lower and 1alkyl) an amino group, a di (lower and 1 alkyl) amino group, a (lower alkanoyl) amine group, a benzoylamino group, a carboxyl group or a (lower and 1 alkoxy) carbonyl group, a phenyl (lower alkyl) radical in which is in which the phenyl group is unsubstituted or substituted as described above, a cycloalkyl or cycloalkenyl radical of up to 30 carbon atoms, a cycloalkyl (lower alkyl) or cycloalkenyl (lower an alkyl radical having in each case up to 30 carbon atoms in the cycloalkyl or cycloalkynyl moiety, a monocyclic radical having 5 or 6 ring members and 1 to 3 ring atoms selected from the group consisting of nitrogen, oxygen and sulfur to which they may be fused one or two benzene radicals, or lower alkyl substituted by such monocyk1 ickým residue and the other of R, _R, R, R and R independently of one another 5.7 represents a hydrogen atom, a lower alkyl group which is unsubstituted or substituted by an amino group, (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 and alkyl) amino, (lower and 1-canoyl) amino, benzoylamino, carboxyl or (lower alkoxy) carbonyl, and salts of these compounds with at least one salt-capable group. Compounds 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 on the nitrogen atom by an oxygen atom, R 8 and R ₃ are hydrogen, Ra 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 5 represents a hydrogen atom, Ry is n-nitro, fluoro substituted lower alkoxy a group or radical of the general of formula II, v which r ₉ means a hydrogen atom, X means an oxo group n means 0 a Rio means a 1 i f a t i c k ý hydrocarbon Rest with 5 to 22 atomam i alkyl, bitches Rest , which is unsubstituted or substituted by cyano, lower alkyl, (4-methylpiperazinyl) (lower alkyl, lower alkoxy, halogen or carboxyl, cycloalkyl and up to 30 carbon atoms or monocyclic radical with 5 or 6 ring members) and 1 to 3 ring sulfur atoms, and R 6 represents a hydrogen atom, and pharmaceutically usable salts of these compounds with at least one salt-capable group. Compounds according to claim 1 of the general formula I, in which R 1 is in each case bonded to a carbon atom by a pyridyl group or an N-oxido-pyridyl group, R 5 and R 5 represent a hydrogen atom, a hydrogen atom or a lower alkyl group, R _p is H, lower alkyl or criminal if U is 1uórmety1 s, Re represents a hydrogen atom, R? represents a nitro group, a fluorine-substituted lower and a 1-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 group attached to a carbon atom, unsubstituted or halogen, by a cannano group, a lower alkoxy group, a carboxyl group, a lower alkyl group, or 4-methylpiperazinylmethyl-substituted phenyl, C7-C7alkyl, thienyl, 2-naphthyl or cyclohexyl, and R 6 represents a hydrogen atom, and pharmaceutically usable salts of these compounds with at least one salt-capable group. Compounds according to any one of claims 1 to 5 of the general formula I, in which R 1 and R 3 are hydrogen and the other substituents have the meanings given in the corresponding claim, and pharmaceutically usable salts of these compounds with at least one salt-capable group. Compounds according to any one of claims 1 to 5 of the general formula I, in which at least one of the radicals R <and R <5> is lower alkyl and the other substituents have the meanings given in the corresponding claim, and pharmaceutically usable salts of these compounds with at least one transitionable group. na so ľ. Compounds according to claim 1 of the general formula I, in which R 1 represents a bounded pyridyl group on a carbon atom, R 5, R 5, R ₄ , R ₅ , R e and R e are hydrogen and R? is n-nitro 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 substituted by a fluorine atom, a chlorine atom, a cyano group, a lower alkoxy group, a carboxyl group, a lower alkyl group or a 4-methylpiperazinimethyl-substituted phenyl group, an alkyl group of 5 to 7 atoms carbon, thienyl or cyclohexyl, and pharmaceutically acceptable salts thereof. 9. N- (3-Nitrophenyl) -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof according to claim 1. 10. N- [3- (4-Chlorobenzoylamido) phenyl] -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof according to claim 1. 11. N - (3 - B e z y 1 am id ph y y 1) - 4 - (3 - pyridy 1) - 2 - pyrimidin amide and is a pharmaceutically usable salt according to claim u 1. N- [3- (2-Pyridyl) carboxamidophenyl] -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof according to claim 1. 13. N- [3- (3-Pyridyl) carboxamidophenyl] -4- (3-pyridyl-2-pyrimidinedamine) and a pharmaceutically acceptable salt thereof according to claim 1. 14. N- [3- (4-Pyridyl) carboxamidophenyl] -4- (3-pyridyl) -2-pyrimidine and a pharmaceutically acceptable salt thereof according to claim 1. N- (3-Pentafluorobenzoylaminophenyl) -4- (3-pyridinyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof according to claim 1. N- [3- (2-Carboxybenzoylamido) phenyl] -4- (3-pyridyl-2-pyrimidineamine) and a pharmaceutically acceptable salt thereof according to claim 1. N- (3-n-Hexanoylamidophenyl) -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof according to claim 1. 18. N- (3-Nitrophenyl) -4- (2-pyridyl) -2-pyrimidine and a pharmaceutically acceptable salt thereof according to claim 1. 19. N- (3-Nitrophenyl) -4- (4-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof according to claim 1. 20. N- [3- (2-Methoxybenzoylamido) phenyl] -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof according to claim 1. 21. N- [3- (4-Fluorobenzoylamido) phenyl] -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof according to claim 1. 22. N- [3- (4-Cyanobenzoylamido) phenyl] -4- (3-pyridyl-2-pyrimidineamine) and a pharmaceutically acceptable salt thereof according to claim 1. 23. N- [3- (2-Thienylcarboxamido) phenyl] -4- (3-pyridyl) -2-pyrimidine and a pharmaceutically acceptable salt thereof according to claim 1. N- (3-Cyclohexylcarboxamidophenyl) -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof according to claim 1. 25. N- [3- (4-Methylbenzoylamido) phenyl] -4- (3-pyridyl) -2-pyrimidine and a pharmaceutically acceptable salt thereof according to claim 1. 26. N- [3- (4-Chlorobenzoylamido) phenyl] -4- (4-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof according to claim 1. 27. N- [3- [4- (4-Methylpiperazinomethyl) benzoylamino] phenyl] -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof according to claim 1. 28. N- (5-Benzoylamido-2-methylphenyl) -4- (3-pyridyl) -2-pyrimidine and a pharmaceutically acceptable salt thereof according to claim 1. 29. N- [5- [4- (4-Methylpiperazinomethyl) benzoylamido] -2-methylphenyl] -4- (3-pyridyl) -2-pyrimidine and a pharmaceutically acceptable salt thereof according to claim 1. N- [5- (4-Methylbenzoylamido) -2-methylphenyl] -4- (3-pyridyl) -2-pyrimidine and a pharmaceutically acceptable salt thereof according to claim 1, 31. N- [5- (2-Naphthylamido) -2-methylphenyl] -4- (3-pyridyl) -2-pyridineamine and a pharmaceutically acceptable salt thereof according to claim 1. 32. N- [5- (4-Chlorobenzoylamido) -2-methylphenyl] -4- (3-pyridyl) -2-pyrimidine amine and a pharmaceutically acceptable salt thereof according to claim 1. N- [5- (2-Methoxybenzoylamido) -2-methylphenyl] -4- (3-pyridyl) -2-pyrimidine and a pharmaceutically acceptable salt thereof according to claim 1. 34. N- (3-Trifluoromethoxyphenyl) -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof according to claim 1. N- (3- / 1,1,2,2-tetrafluoroethoxy / phenyl) -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof according to claim 1. 36. N- (3-Ni-5-methylphenyl) -4- (3-pyridyl-2-pyrimidine) and a pharmaceutically acceptable salt thereof according to claim 1. N- (3-Nitro-5-trifluoromethylphenyl) -4- (3-pyridyl) -2-pyrimidinamine and a pharmaceutically acceptable salt thereof according to claim 1. 38. N- (3-Nitrophenyl) -4- (N-oxido-3-pyridyl) -2-pyrimidinamine according to claim 1. 39. N- (3-Benzoylamido-5-methylphenyl) -4- (N-oxido-3-pyridyl) -2-pyrimidine according to claim 1. A compound of formula I according to any one of the claims 1-39, or a pharmaceutically acceptable salt thereof, with at least one salt-convertible group for use in the treatment of the human or animal body. 41. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, with at least one salt-capable group, together with a pharmaceutical carrier. 42. A pharmaceutical composition for treating tumors in a warm-blooded animal, including a human, comprising an anti-tumor effective dose of a compound of formula I according to any one of claims 1 to 39, or a salt thereof with at least one group capable of a salt, together with a pharmaceutical carrier. Use of a compound of formula I according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, with at least one group capable of being converted into a salt for the manufacture of a pharmaceutical composition in the chemotherapy of tumors. Use of a compound of formula I according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, with at least one salt-capable group for the manufacture of a pharmaceutical composition for use in the treatment of atherosclerosis. Use of a compound of formula I according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, with at least one group capable of converting to a salt for tumor chemotherapy. Use of a compound of formula I according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, with at least one salt group for the treatment of atherosclerosis. 47. A method of treating a warm-blooded animal, including a human, comprising administering to a warm-blooded animal suffering from a cancer an anti-tumor effective dose of a compound of formula I according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof. to salt. 48. A process for the preparation of a compound of formula (I) according to claim 1 or a salt of said compound with at least one salt-capable group, comprising: a) a compound of formula (III) wherein: _t and R &_lt; s &gt; independently represent a lower alkyl group and R &lt;, R &gt; and R &lt; 1 &gt; have the meanings given above, the functional groups present in the compound of formula III being optionally in protected form or a salt thereof reacts with a compound of formula IV (IV) wherein the generally defined 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 b) to obtain a compound of formula I, wherein R, _R, R, R and R are defined as above with the exception of nitro and fluoro substituted lower alk.oxylovej groups, the compound of formula V (V) wherein one or two of R _13, Rτ-, and R *, Rie and Rir is, or is amino and the other from R, R> and R _ls, Ria and R? independently of one another, represents a hydrogen atom, a lower alkyl group which is unsubstituted or substituted by a free or alkylated amino group, a piperazinyl group, a piperidinyl group, a 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 amino group or a free or esterified carboxyl group, and other generally defined substituents have the meanings given above, wherein the functional groups present in the compound of formula V are reacted with a compound of formula VI, with the exception of the amine group (s) involved in the reaction, optionally in protected form. HO-C (= X) - (Y) n-R, ο (VI) in which the generally defined 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 reaction derivative of a compound of the general formula VI and subsequently deprotecting, or (c) for the preparation of a compound of formula (I) in which R 1 is a pyridyl group which is substituted on an nitrogen atom with an oxygen atom and the other generally defined substituents have the meanings given above, converting a compound of formula I in which R 1 is a pyridyl group by treating the N-oxide compound with a suitable oxidizing agent followed by optionally converting a compound of formula I obtained by the methods of steps a) to c) into a salt thereof or converting a salt of a compound of formula I into a free compound