DE19851421A1 - New pyrimidines, their production and use - Google Patents

Abstract

The invention relates to novel pyrimidines of general formula (I) in which Ra to Rd, A and X are defined as in Claim No. 1. The invention also relates to the tautomers of the novel pyrimidines, the stereoisomers thereof, their mixtures and their salts, which comprise valuable properties. In addition, the invention relates to the production of the inventive pyrimidines, to the medicaments containing the pharmacologically effective compounds, and to the use of the inventive compounds. The compounds of general formula (I), in which Rc represents a cyano group, depict valuable intermediate products for producing the remaining compounds of general formula (I) which comprise valuable pharmacological properties, especially an antithrombotic effect.

Description

The present invention relates to new pyrimidines of the general formula

their tautomers, their stereoisomers, their mixtures and their Salts, especially their physiologically compatible salts with inorganic or organic acids or bases, which are worth have full properties.

The compounds of the above general formula I, in which R represents a cyano group, are valuable intermediates for the preparation of the other compounds of the general formula I, and the compounds of the above general formula I, in which R _{c is} an amino, 2-amino -1H-imidazolyl or R ₁ NH-C (= NH) group, and their tautomers and their stereoisomers have valuable pharmacological properties, in particular an antithrombotic effect, which is based on a thrombin-inhibiting effect.

The subject of the present application are thus the new ones Compounds of the general formula I above and their Her position that ent the pharmacologically active compounds medicinal products and their use.

In the general formula above means
R _a is a hydrogen atom, optionally substituted by a carboxy or C _1-3 alkoxycarbonyl C _1-3 substituted alkyl group or a trifluoromethyl group,
R _{b is} a C _1-3 alkyl group optionally substituted by a phenyl or C _5-7 cycloalkyl group, a C _4-7 alkyl group or a C _5-7 cycloalkyl group, the above-mentioned cycloalkyl groups being represented by 1 or 2 C _1-3 alkyl groups, through a carboxy, C _1-3 alkoxycarbonyl, carboxy-C _2-3 alkylaminocarbonyl or C _1-3 alkoxycarbonyl-C _1-3 alkylaminocarbonyl group and the above-mentioned phenyl group through fluorine -, chlorine or bromine atoms, by trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy groups mono- or disubstituted and the substituents may be the same or different,
a carbonyl group substituted by a C _1-6 alkyl or C _5-7 cycloalkyl group, a C _2-4 alkanoyl group substituted by 1 or 2 phenyl groups, one by a phenyl, thienyl, oxazole or thiazole -, imidazole, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl group substituted carbonyl group, the abovementioned heteroaromatic groups in each case by C _1-3 alkyl or phenyl groups and the abovementioned phenyl group by fluorine, chlorine or bromine atoms, mono- or disubstituted by trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy groups and the substituents can in each case be the same or different,
a C _1-6 alkylaminocarbonyl, phenyl-C _1-3 alkylaminocarbonyl or C _5-7 cycloalkylaminocarbonyl group, in each of which the alkyl, cycloalkyl and cycloalkenyl parts are substituted by R ₂ and additionally the alkyl and Cyclo alkyl parts can be substituted by 1 or 2 C _1-3 alkyl groups, or a phenylaminocarbonyl group, in the phenyl part by fluorine, chlorine or bromine atoms, by trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy groups mono- or disubstituted and the substituents can each be the same or different, in which
R _{2 is} a hydrogen atom,
a carboxy or C _1-3 alkoxycarbonyl group,
a C _1-3 -alkylaminocarbonyl-, di- (C _1-3 -alkyl) -aminocarbonyl-, N- (phenyl-C _2-3 -alkyl) -N- (C _1-3 -alkyl) -aminocarbonyl-, C _4-6 -cycloalkyleniminocarbonyl, morpholinocarbonyl, piperazinocarbonyl or N- (C _1-3 -alkyl) -piperazinocarbonyl group, the alkyl group in each of the aforementioned groups being additionally represented by a carboxy or C _2-3 - Alkoxycarbonyl group can be substituted,
R _{c is} a cyano, amino, (2-amino-1H-imidazol-4-yl) - or a RINH-C (= NH) group in which
R _{1 represents} a hydrogen atom, a hydroxy group, a C _1-3 alkyl group or a radical which can be split off in vivo,
R _{d is} a hydrogen atom or a C _1-3 alkyl group,
A is a phenylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy group, a C _3-7 cycloalkylene group or one optionally in the carbon skeleton a C _1-3 alkyl group substituted thienylene, oxazolylene, thiazolylene, imidazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group and
X is an oxygen or sulfur atom, a methylene or -NH group optionally substituted by a C _1-3 alkyl group.

A group which can be converted into a carboxy group in vivo is, for example, a hydroxmethyl group, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably a C _1-6 alkanol, a phenyl C _1-3 alkanol, a C _{1 -9-} Cycloalkanol, where a C _5-8 -cycloalkanol can additionally be substituted by one or two C _1-3 -alkyl groups, a C _5-8 -cycloalkanol in which a methylene group in the 3- or 4-position by an oxygen atom or by a given imino group, optionally substituted by a C _1-3 alkyl, phenyl C _1-3 alkyl, phenyl C _1-3 alkoxycarbonyl or C _2-6 alkanoyl group, and the cycloalkanol part is additionally replaced by one or two C _1-3 alkyl groups can be substituted, a C _4-7 cycloalkenol, a C _3-5 alkenol, a phenyl-C _3-5 -alkenol, a C _3-5 -alkinol or phenyl- C _3-5 alkynol with the measure that no bond to the oxygen atom starts from a carbon atom which is a double or triple bin dung, a C _3-8 cycloalkyl-C _1-3 alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms, which in the bicycloalkyl part can additionally be substituted by one or two C _1-3 alkyl groups, a 1, 3-dihydro-3-oxo-1-isobenzfuranol or an alcohol of the formula

R ₃ -CO-O- (R ₄ CR ₅ ) -OH,

by doing
R _{3 is} a C _1-6 alkyl, C _5-7 cycloalkyl, phenyl or phenyl C _1-3 alkyl group,
R _{4 is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl or phenyl group and
R _{5 represents} a hydrogen atom or a C _1-3 alkyl group,
or under a residue which can be split off from an imino or amino group in vivo, for example a hydroxyl group, an acyl group such as the benzoyl or pyridinoyl group or a C _1-16 alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, Pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C _1-16 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert. Butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C _1-6 -alkoxycarbonyl group such as benzyloxycarbonyl, phenylethoxypropoxycarbonyl _1- carbonyl _-3- alkylsulfonyl- C _2-4 -alkoxycarbonyl-, C _1-3 -alkoxy-C _2-4 -alkoxy-C _2-4 -alkoxy carbonyl- or R ₃ CO-O- (R ₄ CR ₅ ) -O -CO group in which R ₃ to R ₅ are defined as mentioned above,
to understand.

Furthermore, those included in the definition of the above mentioned saturated alkyl and alkoxy parts, which more than 2 Contain carbon atoms, including their branched isomers such as for example the isopropyl, tert-butyl, isobutyl group etc. a.

Preferred compounds of the above general formula I are those in which
R _a to R _d , and A are as defined above and
X represents an oxygen or sulfur atom or an --NH group optionally substituted by a C _2-3 alkyl group,
their tautomers, their stereoisomers and their salts.

Particularly preferred compounds of the above general formula I are those in which
R _a is a hydrogen atom, optionally substituted by a carboxy or C _1-3 alkoxycarbonyl C _1-3 alkyl group substituted,
R _{b is} a C _1-5 alkyl group, a C _1-3 alkyl group substituted by a phenyl or cyclohexyl group, a cyclohexyl, methylcyclohexyl or dimethylcyclohexyl group,
a carbonyl group substituted by a C _1-4 alkyl, cyclopentyl or cyclohexyl group, an acetyl group substituted by 1 or 2 phenyl groups, a carbonyl group substituted by a phenyl or oxazole group, the above-mentioned heteroaromatic group by methyl or Phe nyl groups and the above-mentioned phenyl group are mono- or disubstituted by C _1-3 alkyl or C _1-3 alkoxy groups and the substituents can in each case be the same or different,
a C _1-5 alkylaminocarbonyl, phenyl-C _1-3 alkylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl or methylcyclohexylaminocarbonyl group in which the alkyl and cycloalkyl parts are each substituted by R ₂ , or a phenylaminocarbonyl group in the phenyl part by Fluorine, chlorine or bromine atoms, mono- or disubstituted by methyl or methoxy groups and the substituents can each be the same or different, in which
R _{2 is} a hydrogen atom,
a carboxy or C-alkoxycarbonyl group,
a C _1-3 -alkylaminocarbonyl-, di- (C _1-3 -alkyl) -amino-, N- (phenyl-C _1-3 -alkyl) -N- (C _1-3 -alkyl) -aminocarbonyl-, C _4-6 cycloalkyleneiminocarbonyl, morpholinocarbonyl, piperazinocarbonyl or N- (C _1-3 alkyl) piperazinocar bonyl group, in addition in each of the groups mentioned above the alkyl part by a carboxy or C _1-3 alkoxycarbonyl group can be substituted
R _{c is} a cyano or an R ₁ NH-C (= NH) group in which R _{1 represents} a hydrogen atom, a hydroxy group, a C _1-3 alkyl group,
R _{d is} a C _1-3 alkyl group,
A is a phenylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy group and
X represents an oxygen or sulfur atom or an --NH group which is optionally substituted by a C _1-3 alkyl group,
their tautomers, their stereoisomers and their salts.

Very particularly preferred compounds of the general formula I above are those in which
R _{a is} a hydrogen atom,
R _{b is} a C _1-5 alkylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl or methylcyclohexylaminocarbonyl group, in which the alkyl and cycloalkyl parts are each substituted by R ₂ , in which
R _{2 is} a hydrogen atom,
a carboxy or C _1-3 alkoxycarbonyl group,
a C _1-3 -alkylaminocarbonyl-, di- (C _1-3 -alkyl) -amino-, N- (phenyl-C _1-3 -alkyl) -N- (C _1-3 -alkyl) -aminocarbonyl-, C _4-6 Cycloalkyleniminocarbonyll-, Morpholinocarbonyl-, Piperazinocarbonyl- or N- (C _1-3 -Alkyl) -piperazinocar bonylgruppe, in addition in each of the above-mentioned groups the alkyl part by a carboxy or C _1-3 -alkoxycarbonyl group can be substituted
R _{c is} a cyano or an R ₁ NH-C (= NH) group in which R _{1 represents} a hydrogen atom, a hydroxy group, a C _1-3 alkyl group,
R _{d is} a C _1-3 alkyl group,
A is a phenylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy group and
X represents an oxygen atom or an -NH group optionally substituted by a C _1-3 alkyl group,
their tautomers, their stereoisomers and their salts.

The following may be mentioned as particularly preferred compounds:

• a) N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] cyclo pentanecarboxamide,
• b) 1-Cyclohexyl-3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidine- 2-yl] urea,
• c) 1- (1,1-dimethylpropyl) -3- [4- (4-amidino-phenylamino) - 6-methyl-pyrimidin-2-yl] urea,
• d) 1- [1- (R, S) -ethoxycarbonyl-2-methyl-propyl-3- [4- (4-ami dino-phenoxy) -6-methyl-pyrimidin-2-yl] urea,
• e) 1- (1-methoxycarbonylmethylcarbamoylcyclopentyl) - 3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea and
• f) 1- (1-methoxycarbonylmethylcarbamoylcyclohexyl] - 3- [4- (4-amidino-phenylamino) -6-methyl-pyrimidin-2-yl] urea

as well as their stereoisomers and their salts.

The new compounds can be made according to known Ver produce driving, for example using the following methods:  

a. For the preparation of a compound of general formula I in which R _{c represents} an R ₁ NH-C (= NH) group:

Reaction of a compound of the general formula optionally formed in the reaction mixture

in the
A, X, Ra, Rb and Rd are defined as mentioned at the beginning and
Z _{1 represents} an alkoxy or alkylthio group optionally substituted by an aryl group, such as the methoxy, ethoxy, n-propoxy, isopropoxy, benzyloxy, methylthio, ethylthio, n-propylthio or benzylthio group, with an amine of the general formula

R ₁ -NH ₂ , (III)

in the
R ₁ is defined as mentioned at the beginning, or its salts.

The reaction is advantageously carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol / water, Tetrahydrofuran or dioxane at temperatures between 0 and 150 ° C, preferably at temperatures between 20 and 120 ° C, with ammonia or an appropriate acid addition salt such as for example, ammonium carbonate or ammonium acetate leads.

A compound of general formula II is obtained, for example, by reacting a compound of general formula I in which R _{c represents} a cyano group with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as Hydrochloric acid or by reacting an appropriate amide with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50 ° C, but preferably at 20 ° C, or a corresponding nitrile with hydrogen sulfide suitably in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and subsequent alkylation of the thioamide formed with a corresponding alkyl or aralkyl halide.

b. For the preparation of a compound of the general formula I in which R _{b represents} one of the acyl groups mentioned at the outset for R _b :

Implementation of a compound of the general formula

in the
A, X and R _a are defined as mentioned at the beginning and
R _c 'denotes a cyano group or one of the amidino groups mentioned at the outset for R _c , which are protected by a protective radical, means with a compound of the general formula

HO-R _b ', (V)

in the
R _b 'represents one of the acyl groups mentioned at the beginning for R _b , or with its reactive derivatives and
if necessary, subsequent separation of a protective residue used.

As reactive derivatives of a compound of the general Formula V includes their esters, halides or imidazolides Consider.

Implementation with a corresponding reactive Ver Binding of the general formula V is preferably in a corresponding amine as solvent, optionally in counter were another solvent such as methylene chloride or Ethers and optionally in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine at temperatures between 0 and 150 ° C, before preferably at temperatures between 50 and 100 ° C, leads.

The reaction with an acid of the general formula V is optionally in a solvent or solvent mixed like methylene chloride, dimethylformamide, benzene, toluene, Chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or Dioxane or in a corresponding amine of the general For mel IV optionally in the presence of a dehydrating By means of e.g. B. in the presence of isobutyl chloroformate, Orthocarbonic acid tetraethyl ester, orthoacetic acid trimethyl ester, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, Trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / - N-hydroxysuccinimide, N, N'-dicyclohexylcarbodiimide / 1-hydroxy benzotriazol, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyl uronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1,1,3,3- tetramethyluronium tetrafluoroborate / 1-hydroxybenztriazole, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride lenstoff, and optionally with the addition of a base such as pyri din, 4-dimethylaminopyridine, N-methylmorpholine or tri ethylamine expediently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, carried out.  

The subsequent splitting off of a protective residue takes place after known methods as described later.

c. For the preparation of a compound of the general formula I in which R _{b represents} one of the aminocarbonyl groups mentioned at the outset for R _b :

Implementation of a compound of the general formula

in the
A, X and R _a are defined as mentioned at the outset and a cyano group or one of the amidino groups mentioned at the outset for R _c , which are protected by a protective radical, means with a compound of the general formula

Z ₂ - R _b ", (VI)

in the
R _b "one of the aminocarbonyl groups mentioned at the beginning for R _b and
Z _{2 is} a leaving group such as a halogen atom, e.g. B. a chlorine or bromine atom, or
Z ₂ together with a hydrogen atom of the adjacent -CONH group represent a further carbon-nitrogen bond,
and, if necessary, subsequent separation of a protective residue used.

The reaction is advantageously carried out in a solvent such as tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethyl form amide or toluene, optionally in the presence of a base such as Sodium carbonate, potassium carbonate or sodium hydride or in Presence of a tertiary organic base such as N-ethyl-diiso  propylamine or N-methyl morpholine, which at the same time can serve as a solvent, if necessary in one Pressure vessel and under protective gas, for example under a stick fabric, at temperatures between 20 and 200 ° C, preferably at temperatures between 75 and 180 ° C.

The subsequent splitting off of a protective residue takes place after known methods as described later.

d. For the preparation of a compound of the general formula I in which X represents an oxygen or sulfur atom or an —NH group optionally substituted by a C _1-3 alkyl group and R _{c represents} a cyano group:

Implementation of a compound of the general formula

in the
R _a , R _b and R _d are defined as mentioned at the beginning and
Z _{3 is} a leaving group such as a halogen atom, e.g. B. is a chlorine or bromine atom, or an alkanesulfonyl group such as methane sulfonyl group, with a compound of the general formula

H - X '- A - CN, (VIII)

in the
A is defined as mentioned at the beginning and
X 'represents an oxygen or sulfur atom or an -NH group optionally substituted by a C _1-3 alkyl group.

The reaction is advantageously carried out in a solvent such as tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethyl form amide or toluene, optionally in the presence of a base such as  Sodium carbonate or potassium carbonate or in the presence of one tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which is also used as a solvent can serve, if necessary in a pressure vessel and under protective gas, for example under nitrogen, at tempera structures between 20 and 200 ° C, preferably at temperatures between 75 and 180 ° C.

e. To prepare a compound of the general formula I in which R _{b represents} one of the optionally substituted alkyl and cycloalkyl radicals mentioned at the outset for R _b and R _c denotes a cyano group:

Implementation of a compound of the general formula

in the
A, X, R _a and R _d are defined as mentioned at the outset, with a compound of the general formula

Z ₄ - R _b ''', (X)

in the
R _b '''a R _b for the aforementioned optionally substi tuted alkyl and cycloalkyl radicals and represents
Z _{4 is} a leaving group such as a halogen atom, e.g. B. a bromine or iodine atom.

The reaction is advantageously carried out in a solvent such as tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethyl form amide or toluene, optionally in the presence of a base such as Sodium carbonate or potassium carbonate or in the presence of one tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which is also used as a solvent  can serve, if necessary in a pressure vessel and under protective gas, for example under nitrogen, at tempera structures between 20 and 200 ° C, preferably at temperatures between 75 and 180 ° C.

f. For the preparation of a compound of the general formula I in which R _{1 represents} one of the acyl radicals mentioned at the outset when defining the radical R ₁ or those which can be split off in vivo:

Implementation of a compound of the general formula

in the
A, X, R _a , R _b and R _d are defined as mentioned at the outset, with a compound of the general formula

Z ₅ - R ₆ , (XII)

in the
R _{6 is} one of the radicals mentioned at the beginning of the radical R ₁ or acyl radicals which can be split off and in vivo
Z _{5 is} a nucleofugic leaving group such as a halogen atom, e.g. B. is a chlorine, bromine or iodine atom.

The reaction is preferably carried out in a solvent such as Me thanol, ethanol, methylene chloride, tetrahydrofuran, toluene, di oxane, dimethyl sulfoxide or dimethylformamide optionally in Presence of an inorganic or a tertiary organic Base, preferably at temperatures between 20 ° C and you temperature of the solvent used.  

With a compound of general formula XII, in which Z _{5 represents} a nucleofugic leaving group, the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethyl sulfoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium -tet.-butylate or N-ethyl diisopropylamine at temperatures between 0 and 60 ° C, leads through ge.

G. To prepare a compound of the general formula I in which R _{d is} in the 4-position and X is a methylene group which is optionally substituted by a C _1-3 alkyl group:

Implementation of a guanidine of the general formula

(R _a NR _b ) - (HN =) C - NH ₂ , (XIII)

in the
R _a and R _b are defined as mentioned above, with a 1,3-diketone of the general formula

R _d CO - CH ₂ - CO - X "- A - R _c , (XIV)

in the
A, R _c and R _d are defined as mentioned at the outset and X "denotes a methylene group which is optionally substituted by a C _1-3 alkyl group.

The reaction is preferably carried out in a polar solvent such as dimethylformamide or dimethyl sulfoxide at temperatures between 20 and 150 ° C, preferably between 50 and 120 ° C, carried out.

If, according to the invention, a compound of general formula I is obtained which contains an alkoxycarbonyl group, this can be converted into a corresponding compound of general formula I which contains a carboxy group by means of hydrolysis or
a compound of the general formula I which contains a carboxy group, this can be converted by esterification or amidation into a corresponding compound of the general formula I which contains one of the alkoxycarbonyl or aminocarbonyl groups mentioned at the outset.

The subsequent hydrolysis is conveniently either in Presence of an acid such as hydrochloric acid, sulfuric acid, phosphorus acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or their mixtures or in the presence of a base such as lithium hydro oxide, sodium hydroxide or potassium hydroxide in a suitable Solvents such as water, water / methanol, water / ethanol, Water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane at temperatures between -10 and 120 ° C, e.g. B. at temperatures between room temperature and the boil temperature of the reaction mixture.

The subsequent esterification is preferably carried out with a corresponding alcohol, halide or diazo compound in a suitable solvent.

The subsequent esterification with an appropriate alcohol is conveniently in a solvent or solution medium mixture such as methylene chloride, benzene, toluene, chlorobene zole, tetrahydrofuran, benzene / tetrahydrofuran or dioxane but preferably in an appropriate alcohol if in the presence of an acid such as hydrochloric acid or in the presence a dehydrating agent, e.g. B. in the presence of chlorine isobutyl formate, thionyl chloride, trimethylchlorosi lan, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesul fonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclo hexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuc cinimid, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole, Triphenylphosphine / carbon tetrachloride or triphenylphos phin / Azodicarbonsäurediethylester optionally in the presence a base such as potassium carbonate, N-ethyl-diisopropylamine or N, N-dimethylaminopyridine expediently at temperatures  between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C.

The subsequent esterification with an appropriate halogen nid is conveniently in a solvent such as methyl lene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dime thylformamide or acetone optionally in the presence of a Reaction accelerators such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or Potassium carbonate or in the presence of a tertiary organic Base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which can also serve as a solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, but preferably at temperatures between -10 and 80 ° C.

The subsequent esterification with an appropriate diazo compound is preferably in a suitable solvent such as diethyl ether, tetrahydrofuran or dioxane at temperatures between -10 and 40 ° C, but preferably at temperatures between 0 and 250 ° C.

In the implementations described above, given if reactive groups such as hydroxy, carboxy, Amino, alkylamino or imino groups during the reaction are protected by usual protective groups, which after the Implementation to be split off again.

For example, the trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group,
as protective residues for a carboxyl group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyra nyl group and
as a protective radical for an amino, alkylamino or imino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxy benzyl or 2,4-dimethoxybenzyl group and for the amino group in addition the phthalyl group into consideration.

The subsequent subsequent splitting off of one used Protective residue takes place, for example, hydrolytically in an aqueous solution Rigen solvent, for. B. in water, isopropanol / water, Te trahydrofuran / water or dioxane / water, in the presence of a Acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide, Na trium hydroxide or potassium hydroxide or by ether cleavage, e.g. B. in the presence of iodotrimethylsilane, at temperatures between between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

The removal of a benzyl, methoxybenzyl or benzyloxy However, carbonyl radical is carried out, for example, by hydrogenolysis, e.g. B. with hydrogen in the presence of a catalyst such as Pal ladium / coal in a solvent such as methanol, ethanol, Ethyl acetate, dimethylformamide, dimethylformamide / Ace clay or glacial acetic acid, optionally with the addition of an acid such as Hydrochloric acid at temperatures between 0 and 50 ° C, preferably however at room temperature and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

A methoxybenzyl group can also be split off in counter were an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or ace tonitrile / water at temperatures between 0 and 50 ° C but preferably at room temperature.

However, a 2,4-dimethoxybenzyl radical is split off preferably in trifluoroacetic acid in the presence of anisole.

The cleavage of a tert-butyl or tert-butyloxycarbonyl the rest is preferably done by treatment with an acid such as trifluoroacetic acid or hydrochloric acid optionally under  Use of a solvent such as methylene chloride, dioxane or ether.

A phthalyl radical is preferably cleaved in Presence of hydrazine or a primary amine such as methyl amine, ethylamine or n-butylamine in a solvent such as Methanol, ethanol, isopropanol, toluene / water or dioxane Temperatures between 20 and 50 ° C.

An allyloxycarbonyl radical is split off by Be deal with a catalytic amount of tetrakis (triphenyl phosphine) palladium (O) preferably in a solvent such as Tetrahydrofuran and preferably in the presence of an excess shot of a base such as morpholine or 1,3-dimedone Temperatures between 0 and 100 ° C, preferably at room temperature rature and under inert gas, or by treatment with a catalytic amount of tris (triphenylphosphine) rhodium (I) - chloride in a solvent such as aqueous ethanol and counter also in the presence of a base such as 1,4-diazabicyclo- [2.2.2] octane at temperatures between 20 and 70 ° C.

The compounds of general use as starting materials NEN formulas 1I to XIV, some of which are known from the literature are obtained by methods known from the literature, the white Their production is described in the examples.

So you get, for example, a connection of the general Formula II by reacting a corresponding nitrile, wel ches, for its part, expediently in accordance with the in the present The method described invention is obtained with a corresponding thio or alcohol in the presence of Hydrogen chloride or bromine. The pyrimi required for this dinderivate is conveniently obtained by the implementation of a correspondingly substituted pyrimidine with a correspond the nitrile. A nitrile so obtained may then be required if by means of alkylation, acylation and / or carbamoylation be converted into a desired starting compound.  

Furthermore, the compounds of general form mel I separated into their enantiomers and / or diastereomers will.

For example, the compounds obtained from general formula I, which occur in racemates, according to known methods (see Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and connections of the general my formula I with at least 2 asymmetrical carbon atoms due to their physico-chemical differences methods known per se, e.g. B. by chromatography and / - or fractional crystallization, in their diastereomers separate which, if they occur in racemic form, on finally, as mentioned above, separated into the enantiomers that can.

The separation of enantiomers is preferably carried out by columns separation on chiral phases or by recrystallization an optically active solvent or by reacting with one with the racemic compound salts or derivatives such as e.g. B. ester or amide-forming optically active substance, ins special acids and their activated derivatives or alcohols, and separating the diastereomer thus obtained Salt mixture or derivative, e.g. B. due to various Solubilities, being from the pure diastereomeric salts or Derivatives the free antipodes by the action of appropriate Funds can be released. Particularly common, optically active acids are e.g. B. the D and L forms of wine acid or dibenzoyl tartaric acid, di-o-tolyltartaric acid, apple acid, mandelic acid, camphorsulfonic acid, glutamic acid, Aspa ragic acid or quinic acid. Comes as an optically active alcohol for example (+) - or (-) - menthol and as optically more active Acyl radical in amides, for example the (+) - or (-) - menthyl oxycarbonyl radical into consideration.

Furthermore, the compounds of formula I obtained in their salts, especially for pharmaceutical use in  their physiologically compatible salts with inorganic or organic acids. Come as acids for this, for example hydrochloric acid, hydrobromic acid, Schwe rock acid, methanesulfonic acid, phosphoric acid, fumaric acid, Bern tartaric acid, lactic acid, citric acid, tartaric acid or maleic acid into consideration.

In addition, the new compounds of Formula I, if they contain a carboxy group, desired if necessary then in their salts with inorganic or ganic bases, especially for pharmaceutical applications convert them into their physiologically acceptable salts. The bases here are, for example, sodium hydroxide, Ka lium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and Triethanolamine into consideration.

As already mentioned at the beginning, the new compounds of the general formula I and their salts have valuable properties. Thus, the compounds of general formula I, in which R _{c represents} a cyano group, are valuable intermediates for the preparation of the other compounds of general formula I, and the compounds of general formula I, in which R _{c is} an amino, 2-amino -1H-imidazolyl or R ₁ NH-C (= NH) group, and their tautomers, their stereo isomers, their physiologically tolerable salts have valuable pharmacological properties, and their tautomers and their stereoisomers have valuable pharmacological properties, in particular an antithrombotic effect, which is preferably based on a thrombin-influencing effect, for example on a thrombin-inhibiting effect, on an effect which prolongs the thrombin time and on an inhibitory effect on related serine proteases such as, for. B. trypsin, urokinase factor VIIa, factor Xa, factor IX, factor XI and factor XII.

For example, the connections
A = N- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] -cyclopentanecarboxamide,
B = 1-cyclohexyl-3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate,
C = 1- (1,1-dimethylpropyl) -3- [4- (4-amidino-phenylamino) - 6-methyl-pyrimidin-2-yl] urea dihydrochloride hydrate,
D = 1- [1- (R, S) -ethoxycarbonyl-2-methyl-propyl-3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate and
E = 1- (1-methoxycarbonylmethylcarbamoyl-cyclopentyl) -3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate
examined for their effect on thrombin time as follows:
Material:
Plasma, from human citrate blood.
Test thrombin (cattle), 30 U / ml, Behring Werke, Marburg
Diethyl barbiturate acetate buffer, ORWH 60/61, Behring Werke, Marburg
Biomatic B10 coagulometer, Sarstedt
Execution:
The thrombin time was determined using a Biomatic B10 coagulometer from Sarstedt.

The test substance was in the prescribed by the manufacturer Test tubes with 0.1 ml human citrate plasma and 0.1 ml di ethyl barbiturate buffer (DBA buffer) was given. The approach was incubated for one minute at 37 ° C. By adding 0.3 U Test thrombin in 0.1 ml DBA buffer was the coagulation freak  tion started. Depending on the device, you enter Thrombin is the measurement of the time until the approach clots. Batches in which 0.1 ml of DBA buffer were used as a control were given.

According to the definition, the effective substance concentration at which the throm am doubled compared to the control.

The following table contains the values found:

For example, rats were able to apply ver bonds B and E up to a dose of 10 mg / kg IV no toxic side effects are observed. These connections are therefore well tolerated.

Due to their pharmacological properties, the new compounds and their physiologically tolerable salts for the prevention and treatment of venous and arterial thrombo diseases, such as the treatment of tie fen leg vein thrombosis, prevention of reocclusion after bypass surgery or angioplasty (PT (C) A), as well as the Occlusion in peripheral arterial diseases such as lungs embolism, disseminated intravascular coagulation, the Prophylaxis of coronary thrombosis, prophylaxis of the stroke in case and prevention of occlusion of shunts. Additional Lich are the compounds of the invention for antithroma botical support for thrombolytic treatment, such as with rt-PA or streptokinase, for prevention Long-term restenosis according to PT (C) A, to prevent the  Metastasis and growth of coagulation-dependent Tumors and of fibrin dependent, e.g. B. in the treatment of pulmonary fibrosis, suitable.

The necessary to achieve a corresponding effect Dosage is expediently 0.1 when administered intravenously to 30 mg / kg, preferably 0.3 to 10 mg / kg, and oral Administration 0.1 to 50 mg / kg, preferably 0.3 to 30 mg / kg, each 1 to 4 times a day. For this purpose, according to the invention provided compounds of formula I, optionally in com combination with other active substances, together with one or several inert customary carriers and / or diluents means, e.g. B. with corn starch, milk sugar, cane sugar, micro crystalline cellulose, magnesium stearate, polyvinylpyrrolidone, Citric acid, tartaric acid, water, water / ethanol, water / gly cerin, water / sorbitol, water / polyethylene glycol, propylene glycol kol, cetylstearyl alcohol, carboxymethyl cellulose or fat containing substances such as hard fat or their suitable Ge mix into common galenic preparations like tablets, Dragees, capsules, powder, suspensions or suppositories work.

The following examples are intended to illustrate the invention purify:  

Used abbreviations:
HOBT: 1-hydroxy-benzotriazole
TBTU: O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate

example 1 N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] benzamide hydrochloride a. 2-amino-4- (4-cyano-phenoxy) -6-methyl-pyrimidine

A solution of 6.2 g (0.055 mol) of potassium tert-butoxide, 6.55 g (0.055 mol) of 4-cyano-phenol and 7.2 g (0.05 mol) of 2-amino-4-chloro-6 -methyl-pyrimidine in 150 ml of dimethylformamide is heated in a microwave oven at 160 ° C. for 2.5 hours. After cooling, the reaction mixture is diluted with water and extracted with dichloromethane / methanol. The extract is concentrated, the crystalline residue is filtered and washed with methanol and diethyl ether.
Yield: 9.1 g (80.6% of theory),
Melting point: 221 ° C
C ₁₂ H ₁₀ N ₄ O (226.23)
Calculated: C 63.71; H 4.46; N, 24.76
Found: C 63.83; H 4.59; N 24.77.

b. N- [4-4-Cyano-phenoxy) -6-methyl-pyrimidin-2-yl] benzamide

A solution of 1.28 ml (0.011 mol) is added to a solution of 2.3 g (0.01 mol) of 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine in 50 ml of pyridine. Benzoyl chloride added dropwise in 10 ml of dichloromethane. The mixture is stirred at room temperature for 12 hours and the pyridine is then distilled off. The remaining residue is extracted with dichloromethane and 1 N hydrochloric acid. After drying the organic phases over sodium sulfate and evaporating the solvent, the mixture is purified by column chromatography on silica gel (cyclohexane / ethyl acetate = 2: 1).
Yield: 2.6 g (78.8% of theory),
Melting point: 137 ° C
C ₁₂ H ₁₀ N ₄ O (226.23)
Calculated: C 69.08 H 4.27 N 16.96
Found: C 69.33 H 4.42 N 17.08

c. N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] benzamide hydrochloride

1.65 g (0.005 mol) of N- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] benzamide are dissolved at 0 ° C. in 100 ml of an ethanolic solution saturated with hydrochloric acid and stirred overnight. The reaction mixture is then concentrated on a rotary evaporator, stirred with absolute ethanol and the solvent is distilled off again. The residue is dissolved in 100 ml of ethanol and mixed with 4.8 g (0.05 mol) of ammonium carbonate at room temperature. The mixture is stirred for 20 hours, the solvent is distilled off and the residue is chromatographed on silica gel (dichloromethane / methanol = 10: 1). The residue remaining after removal of the solvent is stirred up with ethyl acetate and filtered off.
Yield: 0.75 g (39.1% of theory),
Melting point: decomposes from 278 ° C
C ₁₉ H ₁₇ N ₅ O ₂ (347.37)
Mass spectrum: M ⁺ = 347

Example 2 N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] cyclopentane carboxamide hydrochloride a. N- [4- (4-Cyano-phenoxy) -6-methyl-pyrimidin-2-yl] cyclopen tancarboxamide

Prepared analogously to Example 1b from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, cyclopentane carboxylic acid chloride and pyridine.
Yield: 2.85 g (88.5% of theory),
Melting point: 164 ° C
C ₁₈ H ₁₈ N ₄ O ₂ (322.36)
Calculated: C 67.07 H 5.63 N 17.38
Found: C 66.81 H 5.53 N 17.37

b. N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] cyclopen tancarboxamide hydrochloride

Prepared analogously to Example 1c from N- [4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-2-yl] -cyclopentanecarboxamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.15 g (61.1% of theory),
Melting point: 212 ° C
C ₁₈ H ₂₁ N ₅ O ₂ (339.40)
Mass spectrum: M ⁺ = 339

Example 3 N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] -2-methyl benzamide hydrochloride hydrate a. N- [4- (4-Cyano-phenoxy) -6-methyl-pyrimidin-2-yl) -2-methyl benzamide

Prepared analogously to Example 1b from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, 2-methyl-benzoyl chloride and pyridine.
Yield: 2.5 g (72.6% of theory),
Melting point: 152 ° C
C ₂₀ H ₁₆ N ₄ O ₂ (344.37)
Calculated: C 69.76 H 4.68 N 16.27
Found: C 69.90 H 4.72 N 16.20

b. N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] -2-methyl benzamide hydrochloride hydrate

Prepared analogously to Example 1c from N- [4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-2-yl) -2-methylbenzamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.7 g (81.8% of theory),
Melting point: 253 ° C
C ₂₀ H ₁₉ N ₅ O ₂ (361.40)
Mass spectrum: (M + H) ⁺ = 362

Example 4 N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] phenylacetic acid acid amide hvdronhloride hydrate a. N- [4- (4-Cyano-phenoxy) -6-methyl-pyrimidin-2-yl] phenyls acetic acid amide

Prepared analogously to Example 1b from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, phenylacetic acid chloride and pyridine.
Yield: 0.8 g (23.2% of theory),
Melting point: 140 ° C
C ₂₀ H ₁₆ N ₄ O ₂ (344.37)
Calculated: C 69.76 H 4.68 N 16.27 Found: C 69.90 H 4.72 N 16.11

b. N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] phenyl Acetic acid amide hydrochloride hydrate

Prepared analogously to Example 1c from N- [4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-2-yl] phenylacetic acid amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.4 g (53.3% of theory),
Melting point: foams from 141 ° C
C ₂₀ H ₁₉ N ₅ O ₂ (361.40)
Mass spectrum: (M + H) ⁺ = 362

Example 5 N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] cyclohexane carboxamide hydrochloride a. N- [4- (4-Cyano-phenoxy) -6-methyl-pyrimidin-2-yl] cyclo hexane carboxamide

Prepared analogously to Example 1b from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, 2-cyclohexane carboxylic acid chloride and pyridine.
Yield: 3 g (89% of theory),
Melting point: 175 ° C

b. N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] cyclo hexane carboxamide hydrochloride

Prepared analogously to Example 1c from N- [4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-2-yl] cyclohexanecarboxamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.75 g (32.1% of theory),
Melting point: from 209 ° C
C ₁₉ H ₂₃ N ₅ O ₂ (353.42)
Mass spectrum: (M + H) ⁺ = 354

Example 6 N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] diphenyls acetic acid amide hydrochloride a. N- [4- (4-Cyano-phenoxy) -6-methyl-pyrimidin-2-yl] diphenyl acetic acid amide

Prepared analogously to Example 1b from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, 2-diphenylacetic acid chloride and pyridine.
Yield: 2.2 g (52.4% of theory),
Melting point: 198 ° C

b. N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] diphenyl Acetic acid amide hydrochloride

Prepared analogously to Example 1c from N- [4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-2-yl] diphenylacetic acid amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.4 g (61.8% of theory),
Melting point: 258 ° C
C ₂₆ H ₂₃ N ₅ O ₂ (437.50)
Mass spectrum: (M + H) ⁺ = 438

Example 7 N- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] -3-phenyl- 5-methyl-isoxazole-4-carboxamide hydrochloride a. N- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] -3-phenyl- 5-methyl-isoxazole-4-carboxamide

Prepared analogously to Example 1b from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, 3-phenyl-5-methyl-isoxazole-4-carbon acid chloride and pyridine.
Yield: 1.2 g (29.2% of theory),
Melting point: 160-162 ° C

b. N- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] -3-phenyl- 5-methyl-isoxazole-4-carboxamide

Prepared analogously to Example 1c from N- [4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-2-yl] cyclohexylamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.6 g (44.5% of theory),
Melting point: from 204 ° C
C ₂₃ H ₂₀ N ₆ O ₃ (428.45)
Mass spectrum: (M + H) ⁺ = 429

Example 8 N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] -2,6-dimeth oxybenzamide hydrochloride a. N- [4- (4-Cyano-phenoxy) -6-methyl-pyrimidin-2-yl] -2,6-di methoxybenzamide

Prepared analogously to Example 1b from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, 2,6-dimethyoxybenzoyl chloride and pyridine.
Yield: 0.7 g (17.9% of theory),
Melting point: from 194 ° C

b. N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] -2,6-di methoxyhenzamide hydrochloride

Prepared analogously to Example 1c from N- [4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-2-yl] -2,6-dimethoxybenzamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.05 g (78.8% of theory),
Melting point: from 265 ° C (decomposition)
C ₂₁ H ₂₁ N ₅ O ₄ (407.43)
Mass spectrum: (M + H) ⁺ = 408

Example 9 N- [4- (4-Amidino-phenoxy) -6-methyl-pyrimidin-2-yl] -3-methyl butane carboxylic acid amide hydrochloride a. N- [4- (4-Cyano-phenoxy) -6-methyl-pyrimidin-2-yl] -3-methyl butane carboxamide

Prepared analogously to Example 1b from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, 3-methyl-butanecarboxylic acid chloride and pyridine.
Yield: 1.4 g (45% of theory),
Melting point: 140 ° C

b. N- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] -3-methyl- butane carboxamide

Prepared analogously to Example 1c from N- [4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-2-yl] -3-methyl-butanecarboxamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.4 g (93.6% of theory),
Melting point: 231 ° C
C ₁₇ H ₂₁ N ₅ O ₂ (327.38)
Mass spectrum: (M + H) ⁺ = 328

Example 10 N-ethoxycarbonylmethyl- [4- (4-amidino-phenoxy) -6-methyl-pyrimi din-2-yl] cyclopentanecarboxamide hydrochloride a. N-ethoxycarbonylmethyl- [4- (4-cyano-phenoxy) -6-methyl-pyri midin-2-yl] cyclopentane carboxamide hydrochloride

A solution of 0.45 g (0.004 mol) of potassium tert-butoxide in 20 ml of dimethylformamide is treated under nitrogen at room temperature with 1 g (0.00031 mol) of N- [4- (4-cyano-phenoxy) -6 -methyl pyrimidin-2-yl] -cyclopentanecarboxamide and stirred for half an hour. Then 0.47 ml (0.004 mol) of ethyl iodoacetate are added dropwise. After stirring overnight, the reaction mixture is extracted with dichloromethane and 1N hydrochloric acid. The organic phases are dried over sodium sulfate and the solvent is removed. The purification is carried out by column chromatography on silica gel (cyclohexane / ethyl acetate = 2: 1).
Yield: 0.8 g (63.2% of theory),
Melting point: 112 ° C
C ₂₂ H ₂₄ N ₄ O ₄ (408.45)
Calculated: C 64.69 H 5.92 N 13.72
Found: C 64.90 H 5.81 N 13.46

b. N-ethoxycarbonylmethyl- [4- (4-amidino-phenoxy) -6-methyl- pyrimidin-2-yl] cyclopentanecarboxamide hydrochloride

Prepared analogously to Example 1c from N-ethoxycarbonylmethyl- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] -cyclopentane carboxamide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.57 g (56% of theory),
Melting point: 148 ° C
C ₂₂ H ₂₇ N ₅ O ₄ (425.49)
Mass spectrum: (M + H) ⁺ = 426

Example 11 1- (2-chlorophenyl) -3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidine- 2-yl] urea hydrochloride hydrate a. 1- (2-chlorophenyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimi din-2-yl] urea

A mixture of 2.3 g (0.01 mol) of 2-amino-4- (4-cyano-phenoxy) - 6-methyl-pyrimidine, 50 ml of anhydrous dioxane and 2.3 g (0.015 mol) of 2-chlorophenyl isocyanate is added stirred for three hours in the microwave at 170 ° C. After the reaction mixture has cooled, the precipitated crystals are filtered off and washed with diethyl ether and ethyl acetate.
Yield: 1.35 g (35.5% of theory),
Melting point: 232 ° C

a. 1- (2-chlorophenyl) -3- [4- (4-amidino-phenoxy) -6-methyl-pyrimi din-2-yl] urea hydrochloride hydrate

Prepared analogously to Example 1c from 1- (2-chlorophenyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 0.3 g (20.1% of theory),
Melting point: 252-254 ° C
C ₁₉ H ₁₇ ClN ₆ O ₂ (396.83)
Mass spectrum: (M + H) ⁺ = 397/399

Example 12 1-cyclohexyl-3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidine- 2-yl] urea hydrochloride hydrate a. 1-cyclohexyl-3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidine- 2-yl] urea

Prepared analogously to Example 11a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, cyclohexyl isocyanate and dioxane.
Yield: 2.9 g (82.5% of theory),
Melting point: 206 ° C

b. 1-cyclohexyl-3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidine- 2-yl] urea hydrochloride hydrate

Prepared analogously to Example 1c from 1-cyclohexyl-3- [4- (4-cyano phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.5 g (44.1% of theory),
Melting point: 255 ° C (decomposition)
C ₁₉ H ₂₄ N ₆ O ₂ (668.44)
Mass spectrum: (M + H) ⁺ = 369

Example 13 1- (2-methoxyphenyl) -3- [4- (4-amidino-phenoxy) -6-methyl-pyrimi din-2-yl] urea dihydrochloride dihydrate a. 1- (2-methoxyphenyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyri midin-2-yl] urea

Prepared analogously to Example 11a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, 2-methoxyphenyl isocyanate and dioxane.
Yield: 2.3 g (79.7% of theory),
Melting point: 215 ° C

b. 1- (2-methoxyphenyl) -3- [4- (4-amidino-phenoxy) -6-methyl-pyri midin-2-yl] urea dihydrochloride dihydrate

Prepared analogously to Example 1c from 1- (2-methoxyphenyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1 g (31.6% of theory),
Melting point: from 243 ° C (decomposition)
C ₂₀ H ₂₄ N ₆ O ₃ (392.42)
Mass spectrum: (M + H) ⁺ = 393

Example 14 1-isopropyl-3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate a. 1-isopropyl-3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidine- 2-yl] urea

0.96 g (0.022 mol) of 55% strength is added to a suspension of 1.8 g (0.008 mol) of 2-amino-4- (4-cyano phenoxy) -6-methyl-pyrimidin-4-ylamine in 100 ml of toluene Added sodium hydride and heated to reflux for two hours. 1 ml (0.01 mol) of isopropyl isocyanate in 20 ml of toluene is then added dropwise. After the reaction has subsided, the mixture is heated under reflux for one hour. 10% citric acid solution is added and the precipitate is filtered off, taken up in dichloromethane and purified by column chromatography on silica gel (dichloromethane / acetone = 10: 1).
Yield: 1.55 g (62% of theory),
Melting point: 224 ° C

b. 1-isopropyl-3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidine- 2-yl] urea hydrochloride hydrate

Prepared analogously to Example 1c from 1-isopropyl-3- [4- (4-cyano phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.7 g (92.5% of theory),
Melting point: foams from 212 ° C
C ₁₆ H ₂₀ N ₆ O ₂ (328.37)
Mass spectrum: (M + H) ⁺ = 329

Example 15 1-ethyl-3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urine hydrochloride hydrate a. 1-ethyl-3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 14a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, sodium hydride, ethyl isocyanate and toluene.
Yield: 1.7 g (71.5% of theory),
Melting point: 242 ° C

b. 1-ethyl-3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate

Prepared analogously to Example 1c from 1-ethyl-3- [4- (4-cyano-phen oxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.6 g (68% of theory),
Melting point: from 220 ° C
C ₁₅ H ₁₈ N ₆ O ₂ (314.34)
Mass spectrum: (M + H) ⁺ = 315

Example 16 1- (2,6-dichlorophenyl) -3- [4- (4-amidino-phenoxy) -6-methyl-pyri midin-2-yl] urea hydrochloride dihydrate a. 1- (2,6-dichlorophenyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyri midin-2-yl] urea

Prepared analogously to Example 14a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, sodium hydride, 2, 6-dichlorophenyl isocyanate and toluene.
Yield: 0.25 g (23% of theory),
Melting point: 197-200 ° C

b. 1- (2,6-dichlorophenyl) -3- [4- (4-amidino-phenoxy) -6-methyl- pyrimidin-2-yl] urea hydrochloride dihydrate

Prepared analogously to Example 1c from 1- (2,6-dichlorophenyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.13 g (50% of theory),
Melting point: foams from 108 ° C
C ₁₉ H ₁₆ Cl ₂ N ₆ O ₂ (431, 28)
Mass spectrum: (M + H) ⁺ = 431/433/435

Example 17 1 - [(R) -1-phenylethyl] -3- [4- (4-amidino-phenoxy) -6-methyl-pyri midin-2-yl] urea dihydrochloride tetrahydrate a. 1 - [(R) -1-phenylethyl] -3- [4- (4-cyano-phenoxy) -6-methyl-pyri midin-2-yl] urea

Prepared analogously to Example 11a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, (R) -1-phenylethyl isocyanate and dioxane.
Yield: 0.6 g (52% of theory),
Melting point: 154-155 ° C

b. 1 - [(R) -1-phenylethyl] -3- [4- (4-amidino-phenoxy) -6-methyl pyrimidin-2-yl] urea dihydrochloride tetrahydrate

Prepared analogously to Example 1c from 1 - [(R) -1-phenylethyl] - 3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.2 g (32% of theory),
Melting point: from 146 ° C
C ₂₁ H ₂₂ N ₆ O ₂ (390.44)
Mass spectrum: (M + H) ⁺ = 391

Example 18 1- (2-Methylpropyl) -3- [4- (4-amidino-phenoxy) -6-methyl-pyrimi din-2-yl] urea hydrochloride hydrate a. 2-methyl propyl isocyanate

A solution of 9 g (0.082 mol) of 2-methylpropylamine hydrochloride in 200 ml of dichloromethane and 26.6 ml of pyridine is mixed with 58.4 ml (0.11 mol) of a 20% phosgene solution in toluene under a nitrogen atmosphere at 0 ° C. The mixture is stirred at 0 ° C. for two hours and then extracted with 0.5 N hydrochloric acid and water. The aqueous phases are re-extracted with dichloromethane and the combined organic phases are concentrated. The residue is mixed with diethyl ether, filtered and the filtrate is concentrated.
Yield: 1.2 g (14.8% of theory),

b. 1- (2-methylpropyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyri midin-2-yl] urea

Prepared analogously to Example 14a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, sodium hydride, 2-methylpropyliso cyanate and toluene.
Yield: 0.46 g (14.2% of theory),
Melting point: 209 ° C

c. 1- (2-Methylpropyl) -3- [4- (4-amidino-phenoxy) -6-methyl-pyri midin-2-yl] urea hydrochloride hydrate

Prepared analogously to Example 1c from 1- (2-methylpropyl) - 3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.35 g (82.5% of theory),
Melting point: from 258 ° C (decomposition)
C ₁₇ H ₂₂ N ₆ O ₂ (342.40)
Mass spectrum: (M + H) ⁺ = 343

Example 19 1- (1-Methylcyclohexyl) -3- [4- (4-amidino-phenoxy) -6-methyl-py rimidin-2-yl] urea hydrochloride hydrate a. 1- (1-Methylcyclohexyl) -3- [4- (4-amidino-phenoxy) -6-methyl-py rimidin-2-yl] urea hydrochloride hydrate

10 g (0.07 mol) of 1-methylcyclohexane carboxylic acid are mixed with 50 ml of thionyl chloride and heated to reflux for three hours. The excess thionyl chloride is distilled off, the oily residue is taken up in toluene and concentrated. The residue is dissolved in dichloromethane and mixed with 19.2 g (0.2 mol) ammonium carbonate. The mixture is then stirred at room temperature for twelve hours, the inorganic salts are filtered off, washed with dichloromethane and the filtrate is concentrated. The residue is recrystallized from petroleum ether.
Yield: 1.8 g (15.6% of theory),
Melting point: 67 ° C

b. 1-methylcyclohexyl isocyanate

A mixture of 4 g (0.031 mol) of 1-methylcyclohexylamide in 80 ml dichloromethane and 16.1 g (0.403 mol) sodium hydroxide in 25 ml of water is added after adding 0.53 g (0.0016 mol) of tetra n-butylammonium hydrogen sulfate with vigorous stirring at 5 ° C 3.2 ml (0.062 mol) of bromine were added dropwise. You stir one hour under ice cooling, the organic phase separates and extracted it with ice water. The organic phase will dried and the solvent removed. Yield: 3.6 g (83.5% of theory),

c. 1- (1-methylcyclohexyl) -3- [4- (4-cyano-phenoxy) -6-methyl- pyrimidin-2-yl] urea

Prepared analogously to Example 14a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, sodium hydride, 1-methylcyclohexyl isocyanate and toluene.
Yield: 1.2 g (41% of theory),
Melting point: 222-224 ° C

d. 1- (1-methylcyclohexyl) -3- [4- (4-amidino-phenoxy) -6-methyl- pyrimidin-2-yl] urea hydrochloride hydrate

Prepared analogously to Example 1c from 1- (1-methylcyclohexyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.95 g (72.5% of theory),
Melting point: from 247 ° C (decomposition)
C ₂₀ H ₂₆ N ₆ O ₂ (382.46)
Mass spectrum: (M + H) ⁺ = 383

Example 20

1- (1,1-Dimethylpropyl) -3- [4- (4-amidino-phenoxy) -6-methyl-pyri midin-2-yl] urea hydrochloride dihydrate

a. 1,1-dimethylpropyl isocyanate

10.5 g (0.085 mol) of 1,1-dimethylpropylamine hydrochloride are dissolved in 200 ml of dichloromethane and 28 ml (0.35 mol) of pyridine and under nitrogen at 0 ° C. with 60 ml (0.113 mol) of a 20% phosgene solution in toluene transferred. The mixture is stirred for two hours at 0 ° C., the aqueous phase is washed with ice-cold 1N hydrochloric acid and the aqueous phase is re-extracted with dichloromethane. The combined organic phases are extracted with saturated sodium chloride solution, dried and concentrated. The residue is distilled.
Yield: 33 g of a solution of 1,1-dimethylpropyl isocyanate in toluene.
Boiling point: 25-28 ° C at 15 mbar

b. 1- (1,1-dimethylpropyl) -3- [4- (4-cyano-phenoxy) -6-methyl- pyrimidin-2-yl] urea

Prepared analogously to Example 14a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, sodium hydride, 1, 1-dimethylpropyl isocyanate and toluene.
Yield: 2.35 g (84% of theory),
Melting point: 203 ° C
C ₁₈ H ₂₁ N ₅ O ₂ (339.39)
Calculated: C 63.70 H 6.24 N 20.63
Found: C 63.62 H 6.26 N 20.63

c. 1- (1,1-dimethylpropyl) -3- [4- (4-amidino-phenoxy) -6-methyl- pyrimidin-2-yl] urea hydrochloride dihydrate

Prepared analogously to Example 1c from 1- (1,1-dimethylpropyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 0.95 g (63.3% of theory),
Melting point: foams from 223 ° C
C ₁₈ H ₂₄ N ₆ O ₂ (356.43)
Mass spectrum: (M + H) ⁺ = 357

Example 21 1- (1-Ethylpropyl) -3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidine- 2-yl] urea hydrochloride a. 1-ethyl propyl isocyanate

Prepared analogously to Example 20a from 1,1-dimethylpropylamine hydrochloride, phosgene and pyridine.
Yield: 93.5 g of a solution of 1-ethylpropyl isocyanate in toluene.
Boiling point: 28-32 ° C at 15 mbar

b. 1- (1-Ethylpropyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimi din-2-yl] urea

Prepared analogously to Example 14a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, sodium hydride, 1-ethylpropyl isocyanate and toluene.
Yield: 2.8 g (71.1% of theory),
Melting point: 168 ° C
C ₁₈ H ₂₁ N ₅ O ₂ (339.39)
Calculated: C 63.70 H 6.24 N 20.63
Found: C 63.69 H 6.31 N 20.22

c. 1- (1-Ethylpropyl) -3- [4- (4-amidino-phenoxy) -6-methyl-pyrimi din-2-yl] urea hydrochloride

Prepared analogously to Example 1c from 1- (1-ethylpropyl) - 3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.35 g (68.7% of theory),
Melting point: foams from 225 ° C
C ₁₈ H ₂₄ N ₆ O ₂ (356.43)
Mass spectrum: (M + H) ⁺ = 357

Example 22 1- [1- (R, S) -ethoxycarbonyl-ethyl-3- [4- (4-amidino-phenoxy) - 6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate a. 1- [1- (R, S) -ethoxycarbonyl-ethyl-3- [4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-2-yl] urea

A solution of 1.8 g (0.008 mol) of 2-amino-4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-4-ylamine and 1.4 ml (0.01 mol) of 2- (R, S) -Iso cyanato-propionic acid ethyl ester in 50 ml of dimethylformamide is stirred at 120 ° C for five hours. The dimethylformamide is then distilled off and the residue is purified by column chromatography on silica gel (cyclohexane / ethyl acetate = 2: 1).
Yield: 2 g (67.6% of theory),
Melting point: from 148 ° C

b. 1- [1- (R, S) -ethoxycarbonyl-ethyl-3- [4- (4-amidino-phenoxy) - 6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate

Prepared analogously to Example 1c from 1- [1- (R, S) -ethoxycarbonylethyl] -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.55 g (65.1% of theory),
Melting point: foams from 215 ° C
C ₁₈ H ₂₂ N ₆ O ₄ (386.41)
Mass spectrum: (M + H) ⁺ = 387

Example 23 1- [1- (R, S) -carboxy-ethyl] -3- [4- (4-amidino-phenoxy) -6-methyl- pyrimidin-2-yl] urea dihydrochloride dihydrate a. 1- [1- (R, S) -carboxy-ethyl] -3- [4- (4-amidino-phenoxy) -6-me thyl-pyrimidin-2-yl] urea dihydrochloride dihydrate

To a solution of 0.5 g (0.001 mol) of 1- [1- (R, S) -ethoxycar bonyl-ethyl] -3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidine-2- yl] urea hydrochloride hydrate in 20 ml of dioxane, 4 ml of 1 N sodium hydroxide solution are added. The solution is stirred for two hours at room temperature. 4 ml of 1N hydrochloric acid are then added dropwise and the solution is concentrated.
Yield: 0.29 g (62.1% of theory),
Melting point: 200-210 ° C
C ₁₆ H ₁₈ N ₆ O ₄ (358.35)
Mass spectrum: (M + H) ⁺ = 359

Example 24 1- [1- (R, S) -ethoxycarbonyl-2-methyl-propyl] -3- [4- (4-amidino- phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate a. 1- [1- (R, S) -ethoxycarbonyl-2-methyl-propyl] -3- [4- (4-cyano- phenoxy) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 22a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, 2- (R, S) -isocyanato-3-methylbutter acid ethyl ester and dimethylformamide.
Yield: 1.4 g (44% of theory),
Melting point: 167 ° C

b. 1- [1- (R, S) -ethoxycarbonyl-2-methyl-propyl] -3- [4- (4-cyano- phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate

Prepared analogously to Example 1c from 1- [1- (R, S) -ethoxycarbonyl-2-methyl-propyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.1 g (71.1% of theory),
Melting point: foams from 205 ° C
C ₂₀ H ₂₆ N ₆ O ₄ (414.46)
Mass spectrum: (M + H) ⁺ = 415

Example 25 1- [1- (R, S) -carboxy-2-methyl-propyl-3- [4- (4-amidino-phenoxy) - 6-methyl-pyrimidin-2-yl] urea dihydrochloride dihydrate a. 1- [1- (R, S) -carboxyl-2-methyl-propyl-3- [4- (4-amidino-phen oxy) -6-methyl-pyrimidin-2-yl] urea dihydrochloride dihydrate

Prepared analogously to Example 23a from 1- [1- (R, S) -ethoxycarbonyl-2-methyl-propyl] -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea- hydrochloride hydrate, sodium hydroxide solution and dioxane.
Yield: 0.2 g (45% of theory),
Melting point: from 170 ° C
C ₁₈ H ₂₂ N ₆ O ₄ (386.41)
Mass spectrum: (M + H) ⁺ = 387

Example 26 1- [1- (R, S) -ethoxycarbonyl-2-phenyl-ethyl] -3- [4- (4-amidino- phenoxy) -6-methyl-pyridin-2-yl] urea hydrochloride hydrate

a. 1- [1- (R, S) -ethoxycarbonyl-2-phenyl-ethyl] -3- [4- (4-amidino- phenoxy) -6-methyl-pyridin-2-yl] urea

Prepared analogously to Example 14a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, 2- (R, S) -isocyanato-3-phenylpropionic acid ethyl ester, sodium hydride and dimethylformamide.
Yield: 0.4 g (30% of theory),
Melting point: 137-140 ° C

b. 1- [1- (R, S) -ethoxycarbonyl-2-phenyl-ethyl] -3- [4- (4-amidino phenoxy) -6-methyl-pyridin-2-yl] urea hydrochloride hydrate

Prepared analogously to Example 1c from 1- [1- (R, S) -ethoxycarbonyl-2-phenyl-ethyl] -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.22 g (52.4% of theory),
Melting point: from 125 ° C
C ₂₄ H ₂₆ N ₆ O ₄ (462.51)
Mass spectrum: (M + H) ⁺ = 463

Example 27 1- [1- (R, S) -ethoxycarbonyl-3-methyl-butyl-3- [4- (4-amidino- phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate

a. 1- [1- (R, S) -ethoxycarbonyl-3-methyl-butyl-3- [4- (4-cyano- phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate

A solution of 1.13 g (0.005 mol) of 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidin-4-yl-amine and 1 g (0.0052 mol) of 2- (R. , S) -Isocyanato-4-methyl-pentanoic acid ethyl ester in 25 ml of dimethylformamide is heated in the steel bomb at 180 ° C for three hours. The solvent is then removed on a rotary evaporator and the residue is purified by column chromatography on silica gel (cyclohexane / ethyl acetate = 2: 1).
Yield: 0.45 g (21.8% of theory),
Melting point: resin

b. 1- [1- (R, S) -ethoxycarbonyl-3-methyl-butyl-3- [4- (4-amidino- phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate

Prepared analogously to Example 1c from 1- [1- (R, S) -ethoxycarbonyl- 3-methyl-butyl] -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidine- 2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.

Yield: 0.3 g (56.5% of theory),
Melting point: sinters from 130 ° C
C ₂₁ H ₂₈ N ₆ O ₄ (428.49)
Mass spectrum: (M + H) ⁺ = 429

Example 28 1- [1- (R) -methoxycarbonyl-2-methyl-propyl] -3- [4- (4-amidino- phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride di hydrate a. 1- [1- (R) -methoxycarbonyl-2-methyl-propyl] -3- [4- (4-cyano- phenoxy) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 18a from (R) -valin methyl ester, phosgene solution, pyridine and toluene.
Yield: 8.6 g (91.2% of theory),
Boiling point: 78-85 ° C at 15 mbar

b. 1- [1- (R) -methoxycarbonyl-2-methyl-propyl] -3- [4- (4-cyano- phenoxy) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 22a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, 2- (R) -isocyanato-3-methylbutter acidic methyl ester and dimethylformamide.
Yield: 6.4 g (66.8% of theory),
Melting point: 135 ° C

c. 1- [1- (R) -methoxycarbonyl-2-methyl-propyl] -3- [4- (4-amidino- phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride di hydrate

Prepared analogously to Example 1c from 1- [1- (R) -methoxycarbonyl-2-methyl-propyl] -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid , Ethanol and ammonium carbonate.
Yield: 0.67 g (74.6% of theory),
Melting point: foams from 215 ° C
C ₁₉ H ₂₄ N ₆ O ₄ (400.44)
Mass spectrum: (M + H) ⁺ = 401

Example 29 1- [1- (R) -methoxycarbonylmethylcarbamoyl-2-methyl-propyl] - 3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride a. 1- [1- (R) -carboxy-2-methyl-propyl] -3- [4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-2-yl] urea

A solution of 10 g (0.026 mol) of 1- [1- (R) -methyloxycarbonyl-2-methyl-propyl] -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea and 100 ml of 0.5 N sodium hydroxide solution in 100 ml of methanol are stirred for 15 hours at room temperature. After acidifying with citric acid, it is extracted with dichloromethane. The purification is carried out by column chromatography on silica gel (cyclohexane / ethyl acetate = 1: 1). The crude product obtained is subjected to a further chromatography on silica gel (dichloromethane / methanol = 20: 1).
Yield: 3.6 g (37.5% of theory),
Melting point: from 232 ° C

b. 1- [1- (R) -methoxycarbonylmethylcarbamoyl-2-methyl-propyl] - 3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea

A solution of 1 g (0.0027 mol) of 1- [1- (R) -carboxy-2-methyl-propyl] -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidine-2- yl] urea in 30 ml of dimethylformamide and 30 ml of tetrahydrofuran is successively mixed with 1 g (0.003 mol) of TBTU, 0.41 g (0.003 mol) of HOBT, 0.38 g (0.003 mol) of glycine methyl ester hydrochloride and 3.1 ml (0.013 mol ) Ethyldiisopropylamine was added and the mixture was stirred under nitrogen at room temperature for 15 hours. The solution is concentrated and the residue is extracted with 2N sodium hydroxide solution and dichloromethane. The organic phase is extracted with 2 N hydrochloric acid. After removing the solvent, an oil remains.
Yield: 0.5 g (40% of theory).

c. 1- [1- (R) -methoxycarbonylmethylcarbamoyl-2-methyl-propyl] - 3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride

Prepared analogously to Example 1c from 1- [1- (R) -methoxycarbonylmethylcarbamoyl-2-methyl-propyl] -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.22 g (55.6% of theory),
Melting point: foams from 90 ° C
C ₂₁ H ₂₇ N ₇ O ₅ (457.49)
Mass spectrum: (M + H) ⁺ = 458

Example 30 1- [1- (R) -carboxymethylcarbamoyl-2-methyl-propyl] -3- [4- (4-ami dino-phenoxy) -6-methyl-pyrimidin-2-yl] urea a. 1- [1- (R) -carboxymethylcarbamoyl-2-methyl-propyl] - 3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 29a from 1- [1- (R) -methyloxycarbonylmethycarbamoyl-2-methyl-propyl] -3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea, Sodium hydroxide solution and methanol.
Yield: 0.09 g (40.6% of theory),
Melting point: from 220 ° C
C ₂₀ H ₂₅ N ₇ O ₅ (443.46)
Mass spectrum: (M + H) ⁺ = 444

Example 31 1- [1- (R) -morpholinocarbonyl-2-methyl-propyl] -3- [4- (4-amidino- phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride a. 1- [1- (R) -carboxy-2-methyl-propyl] -3- [4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 29b from TBTU, HOBT, N, N-diisopropylethylamine, morpholine, dimethylformamide and tetrahydrofuran.
Yield: 0.9 g (40% of theory).

b. 1- [1- (R) -morpholinocarbonyl-2-methyl-propyl] -3- [4- (4-ami dino-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride

Prepared analogously to Example 1c from 1- [1- (R) -morpholinocarbonyl-2-methyl-propyl] -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidine-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.15 g (20.3% of theory),
Melting point: sinters from 60 ° C
C ₂₂ H ₂₉ N ₇ O ₄ (455.52)
Mass spectrum: (M + H) ⁺ = 456

Example 32 1- [1- (S) -Methoxycarbonyl-2-methyl-propyl-3- [4- (4-amidino- phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate a. 1- [1- (S) -methoxycarbonylmethylcarbamoyl-2-methyl-propyl] - 3- [4- (4-cyanophenoxy) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 22a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, 2- (S) -isocyanato-3-methylbutter acidic acid methyl ester and dimethylformamide.
Yield: 2.4 g (62.6% of theory),
Melting point: 135 ° C

b. 1- [1- (S) -methoxycarbonylmethylcarbamoyl-2-methyl-propyl) - 3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate

Prepared analogously to Example 1c from 1- [1- (S) -methoxycarbonylmethylcarbamoyl-2-methyl-propyl] -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1 g (64.6% of theory),
Melting point: sinters from 110 ° C
C ₁₉ H ₂₄ N ₆ O ₄ (400.44)
Mass spectrum: (M + H) ⁺ = 401

Example 33 1- (pyrrolidinylcarbamoylmethyl) -3- [4- (4-amidino-phenoxy) -6-me thyl-pyrimidin-2-yl] urea dihydrochloride pentahydrate a. 1-ethoxycarbonylmethyl-3- [4- (4-cyano-phenoxy) -6-methyl- pyrimidin-2-yl] urea

Prepared analogously 42023 00070 552 001000280000000200012000285914191200040 0002019851421 00004 41904g Example 11a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, isocyanatoacetic acid ethyl ester and dioxane.
Yield: 2.37 g (75.7% of theory),
Melting point: 165-170 ° C

b. 1-carboxymethyl-3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidine- 2-yl] urea

Prepared analogously to Example 2% from 1-ethoxycarbonylmethyl-3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, 1 N sodium hydroxide solution and ethanol.
Yield: 2 g (68.9% of theory),
Melting point: decomposes from 220 ° C

c. 1- (pyrrolidinylcarbamoylmethyl) -3- [4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 29b from 1-carboxymethyl-3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, pyrrolidine, TBTU, HOBT, triethylamine and dimethylformamide.
Yield: 0.2 g (29.4% of theory),
Melting point: decomposes from 224 ° C

d. 1- (pyrrolidinylcarbamoylmethyl) -3- [4- (4-amidino-phenoxy) - 6-methyl-pyrimidin-2-yl] urea dihydrochloride pentahydrate

Prepared analogously to Example 1c from 1- (pyrrolidinylcarbamoylme ~ ethyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.17 g (53.2% of theory),
Melting point: foams from 105 ° C
C ₁₉ H ₂₃ N ₇ O ₃ (397.44)
Mass spectrum: (M + H) ⁺ = 398

Example 34 1-dimethylcarbamoylmethyl-3- [4- (4-amidino-phenoxy) -6-methyl- pyrimidin-2-yl] urea dihydrochloride trihydrate a. 1-dimethylcarbamoylmethyl-3- [4- (4-cyano-phenoxy) -6-methyl- pyrimidin-2-yl] urea

A solution of 0.8 g (0.0024 mol) of 1-carboxymethyl-3- [4- (4-cy ano-phenoxy) -6-methyl-pyrimidin-2-yl] urea in 40 ml of tetrahydrofuran is 20 ° C with 0.4 ml (0.0029 mol) of triethylamine and then with 0.25 ml (0.0026 mol) of ethyl chloroformate in 6 ml of tetrahydrofuran. After 30 minutes, 0.39 g (0.004 mol) of dimethylamine hydrochloride are added and the mixture is stirred for three hours. The reaction mixture is slowly thawed and stirred for two days at room temperature. The solvent is distilled off and the residue is taken up in dichloromethane and extracted with water and saturated sodium carbonate solution. The organic phases are dried over sodium sulfate.
Yield: 0.25 g (29.4% of theory),
Melting point: decomposes from 180 ° C

b. 1-Dimethylcarbamoylmethyl-3- [4- (4-amidino-phenoxy) -6-me thyl-pyrimidin-2-yl] urea dihydrochloride trihydrate

Prepared analogously to Example 1c from 1-dimethylcarbamoyl-3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.19 g (53.7% of theory),
Melting point: foams from 105 ° C
C ₁₇ H ₂₁ N ₇ O ₃ (371.40)
Mass spectrum: (M + H) ⁺ = 372

Example 35 1-isopropylmethylcarbamoylmethyl-3- [4- (4-amidino-phenoxy) - 6-methyl-pyrimidin-2-yl] urea dihydrochloride trihydrate a. 1-isopropylmethylcarbamoylmethyl-3- [4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 34a from 1-carboxymethyl-3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethyl chloroformate, N-methylisopropylamine and tetrahydrofuran.
Yield: 0.11 g (15.7% of theory),
Melting point: 174-179 ° C

b. 1-isopropylmethylcarbamoylmethyl-3- [4- (4-amidino-phenoxy) - 6-methyl-pyrimidin-2-yl] urea dihydrochloride trihydrate

Prepared analogously to Example 1c from 1-isopropylmethylcarbamoyl-3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.08 g (80.2% of theory),
C ₁₉ H ₂₅ N ₇ O ₃ (399.45)
Mass spectrum: (M + H) ⁺ = 400

Example 36 1- (1-Ethoxycarbonylcyclohexyl) -3- [4- (4-amidino-phenoxy) -6-me thyl-pyrimidin-2-yl] urea dihydrochloride hydrate a. 1-Isocyanato-cyclohexane carboxylic acid ethyl ester

Prepared analogously to Example 18a from 1-amino-cyclohexane carbonate, ethyl ester hydrochloride, phosgene, pyridine and dichloromethane.
Yield: 22.5 g (81.5% of theory),
Boiling point: 113-115 ° C at 15 mbar

b. 1- (1-Ethoxycarbonylcyclohexyl) -3- [4- (4-cyano-phenoxy) -6-me thyl-pyrimidin-2-yl] urea

Prepared analogously to Example 22a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, 1-isocyanato-cyclohexane carboxylic acid, ethyl ester and dimethylformamide.
Yield: 2.65 g (62.5% of theory),
Melting point: 188 ° C

c. 1- (1-ethoxycarbonylcyclohexyl) -3- [4- (4-amidino-phenoxy) - 6-methyl-pyrimidin-2-yl] urea dihydrochloride hydrate

Prepared analogously to Example 1c from 1- (1-ethoxycarbonylcyclohexyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.7 g (76.3% of theory),
Melting point: foams from 150 ° C
C ₂₂ H ₂₈ N ₆ O ₄ (440.50)
Mass spectrum: (M + H) ⁺ = 441

Example 37 1- (1-carboxycyclohexyl) -3- [4- (4-amidino-phenoxy) -6-methyl- pyrimidin-2-yl] urea hydrate a. 1- (1-Carboxycyclohexyl) -3- [4- (4-amidino-phenoxy) -6-methyl pyrimidin-2-yl] urea hydrate

The reaction mixture of 0.47 g (0.001 mol) of 1- (1-ethoxycarbonylcyclohexyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate and 3 ml (0.003 mol) of lithium hydroxide in 10 ml of ethanol is stirred for 15 hours at room temperature. The pH is then adjusted to 6.9 using 3 N hydrochloric acid, the precipitate is filtered off and washed with isopropanol and ethyl acetate.
Yield: 0.35 g (81% of theory),
Melting point: decomposes from 214 ° C
C ₂₀ H ₂₄ N ₆ O ₄ (412.45)
Mass spectrum: (M + H) ⁺ = 413

Example 38 1- (1-Ethoxycarbonylcyclopentyl) -3- [4- (4-amidino-phenoxy) -6-me thyl-pyrimidin-2-yl] urea hydrochloride hydrate a. 1-Isocyanato-cyclopentenecarboxylic acid ethyl ester

Prepared analogously to Example 18a from 1-amino-cyclopentane carbonate, ethyl ester hydrochloride, phosgene, pyridine and dichloromethane.
Yield: 28.7 g (82% of theory),
Boiling point: 104-106 ° C at 15 mbar

b. 1- (1-ethoxycarbonylcyclopentyl) -3- [4- (4-cyano-phenoxy) - 6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 22a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, 1-isocyanato-cyclopentanecarboxylic acid ethyl ester and dimethylformamide.
Yield: 11.1 g (90.8% of theory),
Melting point: 153-155 ° C

c. 1- (1-ethoxycarbonylcyclopentyl) -3- [4- (4-amidino-phenoxy) - 6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate

Prepared analogously to Example 1c from 1- (1-ethoxycarbonylcyclopentyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.65 g (73.5% of theory),
Melting point: foams from 90 ° C
C ₂₁ H ₂₆ N ₆ O ₄ (426.47)
Mass spectrum: (M + H) ⁺ = 427

Example 39 1- (1-carboxycyclopentyl) -3- [4- (4-amidino-phenoxy) -6-methyl- pyrimidin-2-yl] urea hydrate a. 1- (1-carboxycyclopentyl) -3- [4- (4-amidino-phenoxy) -6-methyl- pyrimidin-2-yl] urea hydrate

Prepared analogously to Example 37a from 1- (1-ethoxycarbonylcyclopentyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate, lithium hydroxide and ethanol.
Yield: 0.3 g (72% of theory),
Melting point: decomposes from 237 ° C
C ₁₉ H ₂₂ N ₆ O ₄ (398.42)
Mass spectrum: (M + H) ⁺ = 399

Example 40 1- (1-Methoxycarbonylmethylcarbamoylcyclohexyl) -3- [4- (4-ami dino-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate a. 1- (1-carboxy-cyclohexyl) -3- [4- (4-cyano-phenoxy) -6-methyl- pyrimidin-2-yl] urea

Prepared analogously to Example 29a from 1- (1-ethoxycarbonylcyclohexyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, sodium hydroxide solution and ethanol. A mixture is obtained with 1- (1-ethoxycarbonylcyclohexyl) -3- [4- (ethoxy) -6-methyl-pyrimidin-2-yl] urea.
Yield: 4.76 g (83.5% of theory),
Melting point: decomposes from 184 ° C

b. 1- (1-methoxycarbonylmethylcarbamoyl) cyclohexyl] - 3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 29b from the mixture of 1- (1-ethoxycarbonylcyclohexyl) -3- [4- (4-cyano-phenoxy) -6-methylpyrimidine-2-yl] urea and 1- (1-ethoxycarbonylcyclohexyl) - 3 - [(4-ethoxy-6-methyl-pyrimidin-2-yl] urea, glycine methyl ester hydrochloride, TBTU, HOBT, N-diisopropylethylamine and dimethylformamide. The purification is carried out by column chromatography on silica gel (dichloromethane / ethyl acetate = 1: 2).
Yield: 2.2 g (43% of theory),
Melting point: decomposes from 180 ° C

c. 1- (1-methoxycarbonylmethylcarbamoyl-cyclohexyl) - 3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate

Prepared analogously to Example 1c from 1- (1-methoxycarbonylmethyl carbamoyl-cyclohexyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidine-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.8 g (74.3% of theory),
Melting point: foams from 170 ° C
C ₂₃ H ₂₉ N ₇ O ₅ (483.53)
Mass spectrum: (M + H) ⁺ = 484

Example 41 1- (1-carboxycyclohexyl) -3- [4- (4-amidino-phenoxy) -6-methyl- pyrimidin-2-yl] urea hydrochloride a. 1- (1-carboxymethylcarbamoylcyclohexyl) -3- [4- (4-amidino- phenoxy) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 23a from 1- (1-methoxycarbonylmethylcarbamoyl-cyclohexyl) -3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate, sodium hydroxide solution and dioxane. The crude product is dissolved in a mixture of 10 ml (dichloromethane / methanol = 4: 1) and 0.3 ml of 2N hydrochloric acid. The purification is carried out by column chromatography on silica gel (dichloromethane / methanol = 4: 1).
Yield: 0.09 g (28% of theory),
Melting point: foams from 130 ° C
C ₂₂ H ₂₇ N ₇ O ₅ (469.50)
Mass spectrum: (M + H) ⁺ = 470

Example 42 1- (1-Methoxycarbonylmethylcarbamoylcyclopentyl) -3- [4- (4-ami dino-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate a. 1- (1-carboxycyclopentyl) -3- [4- (4-cyano-phenoxy) -6-methyl- pyrimidin-2-yl] urea

Prepared analogously to Example 29a from 1- (1-ethoxycarbonylcyclopentyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, sodium hydroxide solution and ethanol.
Yield: 2.4 g (63% of theory),
Melting point: decomposes from 214 ° C

b. 1- (1-methoxycarbonylmethylcarbamoyl-cyclopentyl) - 3- [4- (4-cyano-phenoxy) -6-methylpyrimidin-2-yl] urea

Prepared analogously to Example 29b from 1- (1-ethoxycarbonylcyclohexyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidin-2-yl] urea, glycine methyl ester hydrochloride, TBTU, HOBT, N, N- Diiso propyl-ethylamine and dimethylformamide.
Yield: 1.6 g (58.9% of theory),
Melting point: 140 ° C

c. 1- (1-methoxycarbonylmethylcarbamoyl-cyclopentyl) - 3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea hydrochloride hydrate

Prepared analogously to Example 1c from 1- (1-methoxycarbonylmethyl carbamoyl-cyclopentyl) -3- [4- (4-cyano-phenoxy) -6-methyl-pyrimidine-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.2 g (74% of theory),
Melting point: foams from 160 ° C
C ₂₂ H ₂₇ N ₇ O (469.50)
Mass spectrum: (M + H) ⁺ = 470

Example 43 1-cyclohexyl-3- [4- (4-amidino-phenylamino) -6-methyl-pyrimidine- 2-yl] urea dihydrochloride a. 2.-Amino-4- (cyano-phenylamino) -6-methyl-pyrimidine

13.2 g (0.11 mol) of 4-aminobenzonitrile and 14.8 g (0.1 mol) are added in succession to a solution of 13.5 g (0.12 mol) of potassium tert-butoxide in 150 ml of dimethylformamide. Given 2-amino-4-chloro-6-me thylpyrimidine. The reaction solution is heated to reflux for two hours and then the solvent is distilled off in vacuo. Ice water is added to the residue, acidified with citric acid and the precipitate is filtered off. The precipitate is washed with water, isopropanol and ethyl acetate and recrystallized from dioxane / dimethylformamide.
Yield: 13.3 g (59% of theory),
Melting point: decomposes from 220 ° C

b. 1-cyclohexyl-3- [4- (4-cyano-phenylamino) -6-methyl-pyrimidine- 2-yl] urea

Prepared analogously to Example 11a from 2-amino-4- (4-cyano-phenylamino) -6-methyl-pyrimidine, cyclohexyl isocyanate and dioxane.
Yield: 1.2 g (51.7% of theory),
Melting point: 218 ° C

c. 1-cyclohexyl-3- [4- (4-amidino-phenylamino) -6-methyl-pyrimi- din-2-yl] urea dihydrochloride

Prepared analogously to Example 1c from 1-cyclohexyl-3- [4- (4-cyanophenylamino) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.38 g (23% of theory),
C ₁₉ H ₂₅ N ₇ O (667.45)
Mass spectrum: (M + H) ⁺ = 368

Example 44 1-benzyl-3- [4- (4-amidino-phenylamino) -6-methyl-pyrimidine- 2-yl] urea dihydrochloride a. 1-benzyl-3- [4- (4-cyano-phenylamino) -6-methyl-pyrimidine- 2-yl] urea

Prepared analogously to Example 11a from 2-amino-4- (4-cyano-phen oxy) -6-methyl-pyrimidine, benzyl isocyanate and dioxane.
Yield: 0.32 g (15% of theory),
Melting point: 207 ° C

b. 1-benzyl-3- [4- (4-amidino-phenylamino) -6-methyl-pyrimidine- 2-yl] urea dihydrochloride

Prepared analogously to Example 1c from 1-benzyl-3- [4- (4-cyano phenylamino) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.12 g (44.1% of theory),
Melting point: from 261 ° C (decomposition)
C ₂₀ H ₂₁ N ₇ O (375.43)
Mass spectrum: (M + H) ⁺ = 376

Example 45 1- [1- (R, S) -ethoxycarbonyl-2-methyl-propyl] -3- [4- (4-amidino- phenylamino) -6-methyl-pyrimidin-2-yl] urea dihydrochloride a. 1- [1- (R, S) -ethoxycarbonyl-2-methyl-propyl] -3- [4- (4-cyano phenylamino) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 22a from 2-amino-4- (4-cyano-phen ylamino) -6-methyl-pyrimidine, 2- (R, S) -isocyanato-3-methylbutyric acid ethyl ester and dimethylformamide.
Yield: 0.96 g (39% of theory),
Melting point: decomposes from 248 ° C

b. 1- [1- (R, S) -ethoxycarbonyl-2-methyl-propyl] -3- [4- (4-amidino- phenylamino) -6-methyl-pyrimidin-2-yl] urea dihydrochloride

Prepared analogously to Example 1c from 1- [1- (R, S) -ethoxycarbonyl-2-methyl-propyl] -3- [4- (4-cyano-phenylamino) -6-methyl-pyrimidine-2-yl] urea , ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.36 g (67% of theory),
Melting point: decomposition from 268 ° C
C ₂₀ H ₂₇ N ₇ O ₃ (413.48)
Mass spectrum: (M + H) ⁺ = 414

Example 46 1- [1- (R) -methoxycarbonyl-2-methyl-propyl] -3- [4- (4-amidino-phe nylamino} -6-methyl-pyrimidin-2-yl] urea dihydrochloride a. 1- [1- (R, S) -ethoxycarbonyl-2-methyl-propyl] -3- [4- (4-cyano phenylamino) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 22a from 2-amino-4- (4-cyano-phenylamino) -6-methyl-pyrimidine, 2- (R) -isocyanato-3-methylbutter acidic acid methyl ester and dimethylformamide.
Yield: 0.4 g (18.6% of theory),
Melting point: 188 ° C

b. 1- [1- (R) -methoxycarbonyl-2-methyl-propyl] -3- [4- (4-amidino- phenylamino} -6-methyl-pyrimidin-2-yl] urea dihydrochloride

Prepared analogously to Example 1c from 1- [1- (R) -methoxycarbonyl-2-methyl-propyl] -3- [4- (4-cyano-phenylamino) -6-methyl-pyrimidine-2-yl] urea, ethanolic Hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.11 g (20% of theory),
Melting point: 148 ° C
C ₁₉ H ₂₅ N ₇ O ₃ (399.45)
Mass spectrum: (M + H) ⁺ = 400

Example 47 1- (1,1-Dimethylpropyl) -3- [4- (4-amidino-phenylamino) -6-methyl pyrimidin-2-yl] urea dihydrochloride hydrate a. 1- (1,1-Dimethylpropyl) -3- [4- (4-cyano-phenylamino) -6-methyl pyrimidin-2-yl] urea

Prepared analogously to Example 22a from 2-amino-4- (4-cyano-phenylamino) -6-methyl-pyrimidine, 1,1-dimethylpropyl isocyanate and dimethylformamide.
Yield: 0.92 g (34% of theory).

b. 1- (1,1-Dimethylpropyl) -3- [4- (4-amidino-phenylamino) -6-me thylpyrimidin-2-yl] urea dihydrochloride hydrate

Prepared analogously to Example 1c from 1- (1,1-dimethylpropyl) -3- [4- (4-cyano-phenylamino) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.12 g (13.3% of theory),
Melting point: decomposes from 248 ° C
C ₁₈ H ₂₅ N ₇ O (355.44)
Mass spectrum: (M + H) ⁺ = 356

Example 48 1- (1-Ethylpropyl) -3- [4- (4-amidino-phenylamino) -6-methyl-pyri midin-2-yl] urea dihydrochloride a. 1- (1-Ethylpropyl) -3- [4- (4-cyano-phenylamino) -6-methyl-pyri midin-2-yl] urea

Prepared analogously to Example 22a from 2-amino-4- (4-cyano-phenylamino) -6-methyl-pyrimidine, 1-ethylpropyl isocyanate and dimethylformamide.
Yield: 0.42 g (28.2% of theory),
Melting point: 203-204 ° C

b. 1- (1-Ethylpropyl) -3- [4- (4-amidino-phenylamino) -6-methyl- pyrimidin-2-yl] urea hydrochloride

Prepared analogously to Example 1c from 1- (1-ethylpropyl) - 3- [4- (4-cyano-phenylamino) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.28 g (27.4% of theory),
Melting point: decomposition from 277 ° C
C ₁₈ H ₂₅ N ₇ O (355.44)
Mass spectrum: (M + H) ⁺ = 356

Example 49 1- (1-Methoxycarbonylmethylcarbamoylcyclohexyl] -3- [4- (4-ami dino-phenylamino) -6-methyl-pyrimidin-2-yl] urea- hydrochloride a. 1- (1-Etoxycarbonyl-cyclohexyl] -3- [4- (4-cyano-phenylamino) - 6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 22a from 2-amino-4- (4-cyano-phenylamino) -6-methyl-pyrimidine, 1-isocyanato-cyclohexane carboxylic acid, ethyl ester and dimethylformamide.
Yield: 1.8 g (19.2% of theory),
Melting point: 198 ° C

b. 1- (1-carboxy-cyclohexyl] -3- [4- (4-cyano-phenylamino) -6-me thyl-pyrimidin-2-yl] urea

Prepared analogously to Example 37a from 1- (1-ethoxycarbonylcyclohexyl] -3- [4- (4-cyano-phenylamino) -6-methyl-pyrimidin-2-yl] urea, 1 N lithium hydroxide solution and methanol.
Yield: 1.6 g (74.5% theory).

c. 1- (1-Methoxycarbonylmethylcarbamoylcyclohexyl] -3- [4- (4-cy ano-phenylamino) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 29b from 1- (1-ethoxycarbonylcyclohexyl] -3- [4- (4-cyano-phenylamino) -6-methyl-pyrimidin-2-yl] urea, glycine methyl ester hydrochloride, TBTU, HOBT, N, N- Di isopropylethylamine and dimethylformamide.
Yield: 1.1 g (58.3% of theory),
Melting point: 148 ° C

d. 1- (1-methoxycarbonylmethylcarbamoylcyclohexyl] - 3- [4- (4-amidino-phenylamino) -6-methyl-pyrimidin-2-yl] urine fabric hydrochloride

Prepared analogously to Example 1c from 1- (1-methoxycarbonylmethyl carbamoyl-cyclohexyl] -3- [4- (4-cyano-phenylamino) -6-methyl-py rimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.08 g (5.2% of theory),
C ₂₃ H ₃₀ N ₈ O ₄ (482.54)
Mass spectrum: (M + H) ⁺ = 483

Example 50 1- (1-Ethoxycarbonylcyclohexyl) -3- [4- (4-amidino-N-methyl-ami no) -6-methyl-pyrimidin-2-yl] urea trihydrochloride dihydrate a. 2-amino-4- (4-cyano-N-methyl-anilino) -6-methyl-pyrimidine

A solution of 1.45 g (0.011 mol) of 4- (N-methylamino) -benzoni tril and 1.45 g (0.01 mol) of 2-amino-4-chloro-6-methylpyrimidine in 20 ml of water, 10 ml Acetone and 0.3 ml of concentrated hydrochloric acid dissolved and heated to reflux for 5 hours. The solvent is distilled off, the residue is suspended in water and neutralized with saturated sodium bicarbonate solution. The precipitate is filtered off and washed with water and diethyl ether.
Yield: 2.2 g (92% of theory),
Melting point: 215 ° C

b. 1- (1-Ethoxycarbonylcyclohexyl] -3- [4- (4-cyano-N-methyl-ani lino) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 22a from 2-amino-4- (4-cyano-N-methyl-anilino) -6-methyl-pyrimidine, 1-isocyanato-cyclohexane carboxylic acid ethyl ester and dimethylformamide.
Yield: 5.45 g (83% of theory),
Melting point: 194 ° C
C ₂₃ H ₂₈ N ₆ O ₃ (436.52)
Calculated: C 63.28 H 6.46 N 19.25
Found: C 63.16 H 6.49 N 19.29

c. 1- (1-Ethoxycarbonylcyclohexyl] -3- [4- (4-amidino-phenyl-N-me thyl-amino) -6-methyl-pyrimidin-2-yl] urea trihydrochloride dihydrate

Prepared analogously to Example 1c from 1- (1-ethoxycarbonylcyclohexyl] -3- [4- (4-cyano-N-methyl-anilino) -6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate .
Yield: 1.4 g (99% of theory),
Melting point: foams from 223 ° C
C ₂₃ H ₃₁ N ₇ O ₃ (453.54)
Mass spectrum: (M + H) ⁺ = 454

Example 51 1- (1-Methoxycarbonylmethylcarbamoylcyclohexyl] -3- [4- (4-ami dino-phenyl-N-methyl-amino) -6-methyl-pyrimidin-2-yl] urea- trihydrochloride dihydrate a. 1- (1-Carboxy-cyclohexyl] -3- [4- (4-cyano-phenyl-N-methyl amino) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 37a from 1- (1-ethoxycarbonylcyclohexyl] -3- [4- (4-cyano-phenyl-N-methylamino) -6-methylpyrimidine-2-yl] urea, 1 N lithium hydroxide solution and Methanol.
Yield: 2.9 g (71% of theory),
Melting point: foams from 237 ° C

b. 1- (1-Methoxycarbonylmethylcarbamoylcyclohexyl] -3- [4- (4-cy ano-phenyl-N-methylamino) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 29b from 1- (1-ethoxycarbonylcyclohexyl] -3- [4- (4-cyano-phenyl-N-methylamino) -6-methylpyrimidine-2-yl] urea glycine methyl ester hydrochloride, TBTU, HOBT , N, N-Diisopropyl-ethylamine and dimethylformamide.
Yield: 2.8 g (75% of theory),
Melting point: from 130 ° C

c. 1- (1-methoxycarbonylmethylcarbamoylcyclohexyl] - 3- [4- (4-amidino-phenyl-N-methylamino) -6-methyl-pyrimidine- 2-yl] urea trihydrochloride dihydrate

Prepared analogously to Example 1c from 1- (1-methoxycarbonylmethyl carbamoyl-cyclohexyl] -3- [4- (4-cyano-phenyl-N-methyl-amino) - 6-methyl-pyrimidin-2-yl] urea, ethanolic hydrochloric acid, Ethanol and ammonium carbonate.
Yield: 1.85 g (64.3% of theory),
Melting point: foams from 185 ° C
C ₂₄ H ₃₂ N ₈ O ₄ (496.57)
Mass spectrum: (M + H) ⁺ = 497

Example 52 1- (1-Carboxycyclohexyl] -3- [4- (4-amidino-phenyl-N-methyl-ami no) -6-methyl-pyrimidin-2-yl] urea a. 1- (1-Carboxymethylcarbamoylcyclohexyl] -3- [4- (4-amidino phenyl-N-methyl-amino) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 37a from 1- (1-methoxycarbonylmethylcarbamoyl-cyclohexyl] -3- [4- (4-amidino-phenyl-N-methylamino) -6-methyl-pyrimidin-2-yl] urea trihydrochloride dihydrate, 1 N lithium hydroxide solution and dioxane.
Yield: 0.22 g (28.5% of theory),
Melting point: decomposes from 233 ° C
C ₂₃ H ₃₀ N ₈ O ₄ (482.54)
Mass spectrum: (M + H) ⁺ = 483

Example 53 1- (1-Ethoxycarbonylcyclopentyl] -3- [4- (4-amidino-phenyl-N-me thylamino) -6-methyl-pyrimidin-2-yl] urea dihydrochloride- hydrate a. 1- (1-Ethoxycarbonylcyclopentyl] -3- [4- (4-cyano-phenyl-N-me thylamino) -6-methyl-pyrimidin-2-yl] urea

Prepared analogously to Example 22a from 2-amino-4- (4-cyano-phenyl-N-methyl-amino) -6-methyl-pyrimidine, 1-isocyanato-cyclopentane carboxylic acid ethyl ester and dimethylformamide.
Yield: 13.8 g (81.6% of theory),
Melting point: 204 ° C

b. 1- (1-Ethoxycarbonylcyclopentyl] -3- [4- (4-amidino-phenyl- N-methyl-amino) -6-methyl-pyrimidin-2-yl] urea dihy hydrochloride hydrate

Prepared analogously to Example 1c from 1- (1-ethoxycarbonylcyclopentyl] -3- [4- (4-cyano-phenyl-N-methylamino) -6-methylpyrimidin-2-yl] urea, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 2 g (94.3% of theory),
Melting point: foams from 228 ° C
C ₂₂ H ₂₉ N ₇ O ₃ (439.52)
Mass spectrum: (M + H) ⁺ = 440

Example 54 4- [2- (cyclohexylmethylamino) -6-methyl-pyrimidin-4-yloxy] benz amidine hydrochloride hydrate a. 6-methyl-2-thioxo-2,3-dihydro-1-H-pyrimidin-4-one

A solution of 23 g (1 mol) of sodium in one liter of absolute ethanol is mixed at room temperature with 128 ml (1 mol) of acetoacetic ester and 76.8 g (1 mol) of thiourea. The mixture is heated to reflux for 5 hours and stirred at room temperature for 15 hours. The ethanol is then distilled off, the residue is mixed with 500 ml of ice water and acidified with 100 ml of concentrated hydrochloric acid. The precipitate is filtered off, washed with water, isopropanol and diethyl ether and dried.
Yield: 121 g (85% of theory),
Melting point: <300 ° C

b. 4-hydroxy-6-methyl-2-methylsulfanyl-pyrimidine

14.2 g (0.1 mol) of 6-methyl-2-thioxo-2,3-dihydro are added to a solution of 11.5 g (0.1 mol) of potassium tert-butoxide in 100 ml of dimethylformamide at room temperature Given -1-H-pyrimidin-4-one. After 30 minutes, 6.6 ml (0.105 mol) of methyl iodide are added dropwise and the solution is stirred for 15 hours. The reaction mixture is then diluted with ice water and acidified with 10% citric acid solution. The precipitate is filtered off, washed with water and dried.
Yield: 12.2 g (78.5% of theory),
Melting point: 227 ° C
C ₆ H ₈ N ₂ OS (156.22)
Calculated: C 46.13 H 5.20 N 17.94 O 10.24 S 20.53
Found: C 46.20 H 5.14 N 17.90 O 10.41 S 20.35

c. 4-hydroxy-6-methyl-2-cyclohexylmethylamino-pyrimidine

The mixture of 7.8 g (0.05 mol) of 4-hydroxy-6-methyl-2-methylsulfanyl-pyrimidine and 7.3 ml (0.055 mol) of cyclohexyl methylamine is stirred at 150 ° C. under nitrogen for two hours. After the development of methyl mercaptan has ended, the clear resinous residue is triturated with ethyl acetate. The colorless crystals obtained are filtered off and washed with ethyl acetate and diethyl ether.
Yield: 8 g (72.4% of theory),
Melting point: 140 ° C

d. 2-cyclohexylmethylamino-4-chloro-6-methyl-pyrimidine

The mixture of 5.5 g (0.025 mol) of 4-hydroxy-6-methyl-2-cyclohexylmethylamino-pyrimidine, 20 ml of phosphorus oxychloride and 3 ml of triethylamine is stirred at 80 ° C. for three hours. The clear reaction solution is poured onto ice water and extracted with dichloromethane. The organic phase is washed with water and concentrated. The purification is carried out by column chromatography on silica gel (cyclohexane / dichloromethane = 1: 3). The product obtained is recrystallized from petroleum ether.
Yield: 4.1 g (68.5% of theory),
Melting point: 88 ° C
C ₁₂ H ₁₈ ClN ₃ (239.75)
Calculated: C 60.12 H 7.57 N 17.53 O
Found: C 60.19 H 7.59 N 17.35 O 9.17

e. 4- [2- (cyclohexylmethylamino) -6-methyl-pyrimidin-4-yloxy] - benzonitrile

3.15 g (0.0265 mol) of 4-hydroxybenzonitrile and 5.5 g (0.024 mol) of 2-cyclohexylmethylamino are added to a solution of 3 g (0.0265 mol) of potassium tert-butoxide in 40 ml of dimethylformamide. Given 4-chloro-6-methyl-pyrimidine. The clear solution is heated to 160 ° C. in a microwave oven for two hours and, after cooling, is diluted with ice water. The precipitate is filtered off and washed with water. The purification is carried out by column chromatography on silica gel (cyclohexane / ethyl acetate = 3: 1).
Yield: 5.7 g (73.8% of theory),
Melting point: 146 ° C

f. 4- [2- (cyclohexylmethylamino) -6-methyl-pyrimidin-4-yloxy] - benzamidine hydrochloride hydrate

Prepared analogously to Example 1c from 4- [2- (cyclohexylmethyl amino) -6-methyl-pyrimidin-4-yloxy] benzonitrile, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1.2 g (57.5% of theory),
Melting point: 217 ° C
C ₁₉ H ₂₅ N ₅ O (339.44)
Mass spectrum: (M + H) ⁺ = 340

Example 55 4- (2-cyclohexylamino-6-methyl-pyrimidin-4-yloxy) benzamidine hydrochloride hydrate a. 4-hydroxy-6-methyl-2-cyclohexylamino-pyrimidine

Prepared analogously to Example 54c from 4-hydroxy-6-methyl-2-methylsulfanyl-pyrimidine and cyclohexylamine.
Yield: 5.2 g (93.4% of theory),
Melting point: 102 ° C

b. 2-cyclohexylamino-4-chloro-6-methyl-pyrimidine

Prepared analogously to Example 54d from 4-hydroxy-6-methyl-2-cyclohexylamino-pyrimidine, phosphorus oxychloride and triethylamine.
Yield: 4.7 g (86.3% of theory),
Melting point: resin

c. 4- (2-cyclohexylamino-6-methyl-pyrimidin-4-yloxy) benzo nitrile

Prepared analogously to Example 54e from 2-cyclohexylamino-4-chloro-6-methyl-pyrimidine, 4-hydroxybenzonitrile, potassium tert-butoxide and dimethylformamide.
Yield: 0.9 g (33% of theory).

d. 4- (2-cyclohexylamino-6-methyl-pyrimidin-4-yloxy) benzami din hydrochloride hydrate

Prepared analogously to Example 1c from 4- (2-cyclohexylamino-6-methyl-pyrimidin-4-yloxy) benzonitrile, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.25 g (26.3% of theory),
Melting point: 198 ° C
C ₁₈ H ₂₃ N ₅ O (325.41)
Mass spectrum: M ⁺ = 325

Example 56 4- [2- (2, 3-Dimethyl-cyclohexylamino) -6-methyl-pyrimidin-4-yl oxy] benzamidine dihydrochloride hydrate a. 4-hydroxy-6-methyl-2- (2,3-dimethyl-cyclohexylamino) pyrimi din

Prepared analogously to Example 54c from 4-hydroxy-6-methyl-2-methylsulfanyl-pyrimidine and 2,3-dimethyl-cyclohexylamine at 180 ° C.
Yield: 5.4 g (99% of theory).

b. 2 .- (2,3-Dimethylcyclohexylamino) -4-chloro-6-methyl-pyrimidine

Prepared analogously to Example 54d from 4-hydroxy-6-methyl-2- (2,3-dimethyl-cyclohexylamino) pyrimidine, phosphorus oxychloride and triethylamine.
Yield: 4 g (74% of theory),
Melting point: resin

c. 4- [2- (2,3-dimethyl-cyclohexylamino) -6-methyl-pyrimidine- 4-yloxyl benzonitrile

Prepared analogously to Example 54e from 2- (2,3-dimethyl-cyclohexylamino) -4-chloro-6-methyl-pyrimidine, 4-hydroxybenzonitrile, potassium tert-butoxide and dimethylformamide.
Yield: 1.7 g (64% of theory),
Melting point: 112-117 ° C

d. 4- [2- (2,3-dimethyl-cyclohexylamino) -6-methyl-pyrimidine- 4-yloxyl-benzamidine dihydrochloride hydrate

Prepared analogously to Example 1c from 4- [2- (2,3-dimethyl-cyclohexylamino) -6-methyl-pyrimidin-4-yloxy] benzonitrile, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.65 g (50% of theory),
Melting point: from 170 ° C
C ₂₀ H ₂₇ N ₅ O (353.47)
Mass spectrum: (M + H) ⁺ = 354

Example 57 4- [2- (4-methyl-cyclohexylamino) -6-methyl-pyrimidin-4-yloxy] - benzamidine hydrochloride a. 4-hydroxy-6-methyl-2- (4-methyl-cyclohexylamino) pyrimidine

Prepared analogously to Example 54c from 4-hydroxy-6-methyl-2-methylsulfanyl-pyrimidine and 4-methyl-cyclohexylamine at 180 ° C.
Yield: 3.4 g (68.6% of theory),
Melting point: 95-96 ° C

b. 2- (4-methyl-cyclohexylamino) -4-chloro-6-methylpyrimidine

Prepared analogously to Example 54d from 4-hydroxy-6-methyl-2- (4-methyl-cyclohexylamino) pyrimidine, phosphorus oxychloride and triethylamine.
Yield: 1.9 g (52% of theory),
Melting point: resin

c. 4- [2- (4-methyl-cyclohexylamino) -6-methyl-pyrimidin-4-yl oxyl] benzonitrile

Prepared analogously to Example 54e from 2- (4-methyl-cyclohexylamino) -4-chloro-6-methyl-pyrimidine, 4-hydroxybenzonitrile, potassium tert-butoxide and dimethylformamide.
Yield: 1.7 g (66.1% of theory),
Melting point: 130-136 ° C

d. 4- [2- (4-methyl-cyclohexylamino) -6-methyl-pyrimidin-4-yl oxy] benzamidine hydrochloride

Prepared analogously to Example 1c from 4- [2- (4-methyl-cyclohexylamino) -6-methyl-pyrimidin-4-yloxy] benzonitrile, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.6 g (47.6% of theory),
Melting point: 225-230 ° C
C ₁₉ H ₂₅ N ₅ O (339.44)
Mass spectrum: (M + H) ⁺ = 340

Example 58 4- [2- (3-methyl-cyclohexylamino) -6-methyl-pyrimidin-4-yloxy] - benzamidine hydrochloride hydrate a. 4-hydroxy-6-methyl-2- (3-methyl-cyclohexylamino) pyrimidine

Prepared analogously to Example 54c from 4-hydroxy-6-methyl-2-methylsulfanyl-pyrimidine and 3-methyl-cyclohexylamine at 180 ° C.
Yield: 5.5 g (97% of theory),
Melting point: from 60 ° C

b. 2- (3-methylcyclohexylamino) -4-chloro-6-methyl-pyrimidine

Prepared analogously to Example 54d from 4-hydroxy-6-methyl-2- (3-methyl-cyclohexylamino) pyrimidine, phosphorus oxychloride and triethylamine.
Yield: 4.1 g (70.7% of theory),
Melting point: resin

c. 4- [2- (3-methyl-cyclohexylamino) -6-methyl-pyrimidin-4-yl oxyl] benzonitrile

Prepared analogously to Example 54e from 2- (3-methyl-cyclohexylamino) -4-chloro-6-methyl-pyrimidine, 4-hydroxybenzonitrile, potassium tert-butoxide and dimethylformamide.
Yield: 3 g (62.5% of theory),
Melting point: from 106 ° C

d. 4- [2- (3-methyl-cyclohexylamino) -6-methyl-pyrimidin-4-yl oxyl] benzamidine hydrochloride hydrate

Prepared analogously to Example 1c from 4- [2- (3-methyl-cyclohexylamino) -6-methyl-pyrimidin-4-yloxy] benzonitrile, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 1 g (62.5% of theory),
Melting point: 223-225 ° C
C ₁₉ H ₂₅ N ₅ O (339.44)
Mass spectrum: (M + H) ⁺ = 340

Example 59 4- [2- (N-ethyl-cyclohexylamino) -6-methyl-pyrimidin-4-yloxy] - benzamidine hydrochloride a. 2-methylsulfanyl-4-chloro-6-methyl-pyrimidine

A solution of 3.12 g (0.02 mol) of 4-hydroxy-6-methyl-2-methylsulfanyl-pyrimidine, 30 ml of phosphorus oxychloride and 3 ml of triethylamine is stirred at 100 ° C. for 1.5 hours. The phosphorus oxychloride is then distilled off and the residue is poured onto ice water. The aqueous phase is neutralized with ammonia and extracted with dichloromethane. The organic phase is dried over sodium sulfate and filtered over activated carbon.
Yield: 3.2 g (91.6% of theory),
Melting point: from 60 ° C
C ₆ H ₇ ClN ₂ S (174.68)
Calculated: C 41.26 H 4.04 N 16.04 S 18.36 Cl 20.30
Found: C 41.23 H 4.04 N 15.81 S 18.21 Cl 20.22

b. 4- (2-methylsulfanyl-6-methyl-pyrimidin-4-yloxy) benzonitrile

Prepared analogously to Example 54e from 2-methylsulfanyl-4-chloro-6-methyl-pyrimidine, 4-hydroxybenzonitrile, potassium tert-butoxide and dimethylformamide.
Yield: 3.65 g (83.5% of theory),
Melting point: 125 ° C

c. 4- [2- (N-ethyl-cyclohexylamino) -6-methyl-pyrimidin-4-yloxy] - benzonitrile

To a solution of 0.9 g (0.0035 mol) of 4- (2-methylsulfanyl-6-methyl-pyrimidin-4-yloxy] benzonitrile in 50 ml of chloroform are added 6.3 ml (0.01 mol) of 12% added sodium hypochlorite solution and stirred for two hours at 0 ° C. Then 3 ml of acetic acid are added dropwise and the mixture is stirred for one hour at 0 ° C. The organic phase is separated off and washed with water and sodium bicarbonate solution. The solution is dried over sodium sulfate and the solvent The crystalline residue is refluxed for one hour with 10 ml of N-ethyl-cyclohexylamine. The excess N-ethyl-cyclohexylamine is distilled off and the residue is dissolved in dichloromethane. The organic phase is washed with 10% citric acid solution The purification is carried out by column chromatography on silica gel (cyclohexane / ethyl acetate = 6: 1). The product is recrystallized from petroleum ether.
Yield: 0.4 g (34% of theory),
Melting point: 88 ° C
C ₂₀ H ₂₄ N ₄ O (336.4)
Calculated: C 71.40 H 7.19 N 16.65 O 4.76
Found: C 71.31 H 7.19 N 16.52 O 4.98

d. 4- [2- (N-ethyl-cyclohexylamino) -6-methyl-pyrimidin-4-yloxy] - benzamidine hydrochloride

Prepared analogously to Example 1c from 4- [2- (N-ethylcyclohexyl amino) -6-methyl-pyrimidin-4-yloxy] benzonitrile, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Yield: 0.3 g (43.2% of theory),
Melting point: 245 ° C
C ₂₀ H ₂₇ N ₅ O (353.47)
Mass spectrum: (M + H) ⁺ = 354

Example 60 Dry ampoule with 75 mg active ingredient per 10 ml composition

Active ingredient 75.0mg Mannitol 50.0mg Water for injections ad 10.0ml

Manufacturing

Active ingredient and mannitol are dissolved in water. After bottling is freeze-dried. The resolution for ready to use Solution is done with water for injections.  

Example 61 Dry ampoule with 35 mg of active ingredient per 2 ml composition

Active ingredient 35.0 mg Mannitol 100.0 mg Water for injections ad 2.0 ml

Manufacturing

Active ingredient and mannitol are dissolved in water. After bottling is freeze-dried.

The ready-to-use solution is dissolved with water for injections.

Example 62 Tablet with 50 mg of active ingredient composition

(1) Active ingredient 50.0 mg (2) milk sugar 98.0 mg (3) corn starch 50.0 mg (4) polyvinyl pyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg           215.0 mg         

Manufacturing

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are mixed (5). Tablets are pressed from this mixture, biplan with facets on both sides and partial notch on one side.
Tablet diameter: 9 mm.

Example 63 Tablet with 350 mg of active ingredient composition

(1) Active ingredient 350.0 mg (2) milk sugar 136.0 mg (3) corn starch 80.0 mg (4) polyvinyl pyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg           600.0 mg         

Manufacturing

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are mixed (5). Tablets are pressed from this mixture, biplan with facets on both sides and partial notch on one side.
Tablet diameter: 12 mm.

Example 64 Capsules with 50 mg of active ingredient composition

(1) Active ingredient 50.0 mg (2) Dried corn starch 58.0 mg (3) powdered milk sugar 50.0 mg (4) Magnesium stearate 2.0 mg           160.0 mg         

Manufacturing

(1) is triturated with (3). This trituration becomes the mixture from (2) and (4) added with intensive mixing.

This powder mixture is in a capsule filling machine Bottled hard gelatin capsules size 3.  

Example 65 Capsules with 350 mg active ingredient composition

(1) Active ingredient 350.0 mg 350 mg (2) Dried corn starch 46.0 mg (3) powdered milk sugar 30.0 mg (4) Magnesium stearate 4.0 mg           430.0 mg         

Manufacturing

(1) is triturated with (3). This trituration becomes the mixture from (2) and (4) added with intensive mixing.

This powder mixture is in a capsule filling machine Bottled hard gelatin capsules size 0.

1 suppository contains:

Example 66 Suppository with 100 mg of active ingredient

Active ingredient 100.0 mg Polyethylene glycol (M.G. 1500) 600.0 mg Polyethylene glycol (M.G. 6000) 460.0 mg Polyethylene sorbitan monostearate 840.0 mg           2000.0 mg         

Manufacturing

The polyethylene glycol is used together with polyethylene sorbi tan monostearate melted. At 40 ° C the ground effect substance homogeneously dispersed in the melt. It gets to 38 ° C cooled and into weakly pre-cooled suppository forms poured.

Claims (10)

1. Pyrimidines of the general formula
in the
R _a is a hydrogen atom, optionally substituted by a carboxy or C _1-3 alkoxycarbonyl C _1-3 substituted alkyl group or a trifluoromethyl group,
R _{b is} a C _1-3 alkyl group optionally substituted by a phenyl or C _5-7 cycloalkyl group, a C _4-7 alkyl group or a C _5-7 cycloalkyl group, the above-mentioned cycloalkyl groups being represented by 1 or 2 C _1-3 alkyl groups, by a carboxy, C _1-3 alkoxycarbonyl, carboxyC _1-3 alkylaminocarbonyl or C _1-3 alkoxycarbonylC _1-3 alkylaminocarbonyl group and the above-mentioned phenyl group by fluorine -, chlorine or bromine atoms, by trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy groups mono- or disubstituted and the substituents may be the same or different,
a carbonyl group substituted by a C _1-6 alkyl or C _5-7 cycloalkyl group, a C _2-4 alkanoyl group substituted by 1 or 2 phenyl groups, one by a phenyl, thienyl, oxazole or thiazole -, imidazole, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl group substituted carbonyl group, the heteroaromatic groups mentioned above by C ₁₃ alkyl or phenyl groups and the above-mentioned phenyl group by fluorine, chlorine or bromine atoms, by trifluoromethyl -, C _1-3 alkyl or C _1-3 alkoxy groups mono- or disubstituted and the substituents can each be the same or different,
a C _1-6 alkylaminocarbonyl, phenyl-C _1-3 alkylaminocarbonyl or C _5-7 cycloalkylaminocarbonyl group, in each of which the alkyl, cycloalkyl and cycloalkenyl parts are substituted by R ₂ and additionally the alkyl and Cyclo alkyl parts can be substituted by 1 or 2 C _1-3 alkyl groups, or a phenylaminocarbonyl group, in the phenyl part by fluorine, chlorine or bromine atoms, by trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy groups mono- or disubstituted and the substituents can each be the same or different, in which
R _{2 is} a hydrogen atom,
a carboxy or C _1-3 alkoxycarbonyl group,
a C _1-3 -alkylaminocarbonyl-, di- (C _1-3 -alkyl) -aminocarbonyl-, N- (phenyl-C _1-3 -alkyl) -N- (C _1-3 -alkyl) -aminocarbonyl-, C _4-6 -cycloalkyleniminocarbonyl, morpholinocarbonyl, piperazinocarbonyl or N- (C _1-3 -alkyl) -piperazinocarbonyl group, in addition in each of the groups mentioned above the alkyl part by a carboxy or C _1-3 - Alkoxycarbonyl group can be substituted,
R _{c is} a cyano, amino, (2-amino-1H-imidazol-4-yl) - or an R ₁ NH-C (= NH) group in which
R _{1 represents} a hydrogen atom, a hydroxy group, a C _1-3 alkyl group or a radical which can be split off in vivo,
R _{d is} a hydrogen atom or a C _1-3 alkyl group,
A is a phenylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy group, a C _3-7 cycloalkylene group or one optionally in the carbon skeleton a C _1-3 alkyl group substituted thienylene, oxazolylene, thiazolylene, imidazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group and
X represents an oxygen or sulfur atom, a methylene or --NH group optionally substituted by a C _1-3 alkyl group,
their tautomers, their stereoisomers and their salts. 2. pyrimidine derivatives of the general formula according to claim 1, in which R _a to R _d , and A are defined as mentioned in claim 1 and
X represents an oxygen or sulfur atom or an --NH group which is optionally substituted by a C _1-3 alkyl group,
their tautomers, their stereoisomers and their salts. 3. pyrimidine derivatives of the general formula according to claim 1, in which
R _a is a hydrogen atom, optionally substituted by a carboxy or C _1-3 alkoxycarbonyl C _1-3 alkyl group substituted,
R _{b is} a C _1-5 alkyl group, a C _1-3 alkyl group substituted by a phenyl or cyclohexyl group, a cyclohexyl, methylcyclohexyl or dimethylcyclohexyl group,
a carbonyl group substituted by a C _1-4 alkyl, cyclopentyl or cyclohexyl group, an acetyl group substituted by 1 or 2 phenyl groups, a carbonyl group substituted by a phenyl or oxazole group, the above-mentioned heteroaromatic group by methyl or Phe nyl groups and the above-mentioned phenyl group are mono- or disubstituted by C _1-3 alkyl or C _1-3 alkoxy groups and the substituents can each be the same or different,
a C _1-5 alkylaminocarbonyl, phenyl-C _1-3 alkylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl or methylcyclohexylaminocarbonyl group in which the alkyl and cycloalkyl parts are each substituted by R ₂ , or a phenylaminocarbonyl group in the phenyl part by Fluorine, chlorine or bromine atoms, mono- or disubstituted by methyl or methoxy groups and the substituents can each be the same or different, in which
R _{2 is} a hydrogen atom,
a carboxy or C _1-3 alkoxycarbonyl group,
a C _1-3 -alkylaminocarbonyl-, di- (C _1-3 -alkyl) -amino-, N- (phenyl-C13-alkyl) -N- (C ₁₃ -alkyl) -aminocarbonyl-, C _4-6 - Represents cycloalkyleniminocarbonyl, morpholinocarbonyl, piperazinocarbonyl or N- (C _1-3 -alkyl) -piperazinocarbonyl group, in which case the alkyl part in each of the above-mentioned groups may additionally be substituted by a carboxy or C _1-3 -alkoxycarbonyl group,
R _{c is} a cyano or an R ₁ NH-C (= NH) group in which
R _{1 represents} a hydrogen atom, a hydroxyl group, a C _1-3 alkyl group,
R _{d is} a C _1-3 alkyl group,
A is a phenylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy group and
X represents an oxygen or sulfur atom or an --NH group which is optionally substituted by a C _1-3 alkyl group,
their tautomers, their stereoisomers and their salts. 4. pyrimidine derivatives of the general formula according to claim 1, in which
R _{a is} a hydrogen atom,
R _{b is} a C _1-5 alkylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl or methylcyclohexylaminocarbonyl group, in which the alkyl and cycloalkyl parts are each substituted by R ₂ , in which
R _{2 is} a hydrogen atom,
a carboxy or C _1-3 alkoxycarbonyl group,
a C _1-3 -alkylaminocarbonyl-, di- (C _1-3 -alkyl) -amino-, N- (phenyl-C _1-3 -alkyl) -N- (C _1-3 -alkyl) -aminocarbonyl-, C _4-6 cycloalkyleneiminocarbonyl, morpholinocarbonyl, piperazinocarbonyl or N- (C _1-3 alkyl) piperazinocar bonyl group, in addition in each of the groups mentioned above the alkyl part by a carboxy or C _1-3 alkoxycarbonyl group can be substituted
R _{c is} a cyano or an R ₁ NH-C (= NH) group in which R _{1 represents} a hydrogen atom, a hydroxy group, a C _1-3 alkyl group,
R _{d is} a C _1-3 alkyl group,
A is a phenylene group optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl or C _1-3 alkoxy group and
X represents an oxygen atom or an -NH group optionally substituted by a C _1-3 alkyl group,
their tautomers, their stereoisomers and their salts. 5. The following pyrimidine derivatives of the general formula according to claim 1:

• a) N- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] -cyclopentanecarboxamide,
• b) 1-cyclohexyl-3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea,
• c) 1- (1, 1-dimethylpropyl) -3- [4- (4-amidino-phenylamino) - 6-methyl-pyrimidin-2-yl] urea,
• d) 1- [1- (R, S) -ethoxycarbonyl-2-methyl-propyl-3- [4- (4-aminodinophenoxy) -6-methyl-pyrimidin-2-yl] urea,
• e) 1- (1-methoxycarbonylmethylcarbamoylcyclopentyl) - 3- [4- (4-amidino-phenoxy) -6-methyl-pyrimidin-2-yl] urea and
• f) 1- (1-Methoxycarbonylmethylcarbamoylcyclohexyl] -3- [4- (4-amidino-phenylamino) -6-methyl-pyrimidin-2-yl] urea
  as well as their stereoisomers and their salts.

6. Physiologically acceptable salts of the compounds according to claims 1 to 5, in which R _{b represents} one of the amidino groups mentioned in claims 1 to 5. 7. Medicament containing a compound according to at least one of claims 1 to 5, in which R _{b represents} one of the amidino groups mentioned in claims 1 to 5, or a salt according to claim 6, optionally together with one or more inert carriers and / or diluents . 8. Use of a compound according to at least one of claims 1 to 5, in which R _{b represents} one of the amidino groups mentioned in claims 1 to 5, or a salt according to claim 6 for the manufacture of a medicament with an effect which prolongs the thrombin time, one antithrombin activity and an inhibitory effect on related serine proteases. 9. A process for the manufacture of a medicament according to claim 7, characterized in that a compound according to at least one of claims 1 to 5, in which R _{b represents} one of the amino groups mentioned in claims 1 to 5, or a salt by non-chemical means according to claim 6 is incorporated into one or more inert carriers and / or diluents. 10. A process for the preparation of the compounds according to claims 1 to 6, characterized in that

• a) for the preparation of a compound of general formula I, in which R _{c represents} an R ₁ NH-C (= NH) group, a given compound of the general formula, if any, formed in the reaction mixture
  in the
  A, X, R _a , R _b and R _{d are defined} as in claims 1 to 5 and
  Z _{1 represents} an alkoxy or alkylthio group optionally substituted by an aryl group, with an amine, with an amine of the general formula
  R ₁ -NH ₂ , (III)
  in the
  R _{1 is} as defined in claims 1 to 5, or its salts are reacted or
• b) for the preparation of a compound of the general formula I in which R _{b represents} one of the acyl groups mentioned for R _b in claims 1 to 5, a compound of the general formula
  in the
  A, X and R _{a are} as defined in claims 1 to 5 and
  R _c 'is a cyano group or one of the amidino groups mentioned for R _c in claims 1 to 5, which are protected by a protective radical, with a compound of the general formula
  HO-R _b ', (V)
  in the
  R _b 'represents one of the acyl groups mentioned for R _b in claims 1 to 5, or reacted with their reactive derivatives and, if necessary, a protective radical used is then split off from a compound obtained in this way or
• c) for the preparation of a compound of the general formula I, in which R _{b represents} one of the aminocarbonyl groups mentioned for R _b in claims 1 to 5, a compound of the general formula
  in the
  A, X and R _{a are} as defined in claims 1 to 5 and
  R _c 'is a cyano group or one of the amidino groups mentioned for R _c in claims 1 to 5, which are protected by a protective radical, means with a compound of the general formula
  Z ₂ -R _b ", (VI)
  in the
  R _b "is one of the amino carbonyl groups mentioned for R _b in claims 1 to 5 and
  Z _{2 is} a leaving group or
  Z ₂ together with a hydrogen atom of the adjacent -CONH group mean a further carbon-nitrogen bond, reacted and, if necessary, a protective radical used is subsequently split off from a compound obtained in this way or
• d) for the preparation of a compound of general formula I, in which X represents an oxygen or sulfur atom or a -NH group optionally substituted by a C _1-3 alkyl group and R _{c represents} a cyano group, a compound of the general formula
  in the
  R _a , R _b and R _{d are} as defined in claims 1 to 5 and
  Z _{3 represents} a leaving group with a compound of the general formula
  H-X'-A-CN, (VIII)
  in the
  A is defined as mentioned in claims 1 to 5 and
  X 'represents an oxygen or sulfur atom or an -NH group optionally substituted by a C _1-3 alkyl group, is reacted or
• e) for the preparation of a compound of the general formula I in which R _{b represents} one of the optionally substituted alkyl and cycloalkyl radicals mentioned for R _b in claims 1 to 5 and R _{c represents} a cyano group, a compound of the general formula
  in the
  A, X, R _a and R _{d are} as defined in claims 1 to 5, with a compound of the general formula
  Z ₄ -R _b ''', (X)
  in the
  R _b '''represents one of the optionally substituted alkyl and cycloalkyl radicals mentioned for R _b in claims 1 to 5 and
  Z _{4 represents} a leaving group, is implemented or
• f) for the preparation of a compound of the general formula I in which R _{1 is} one of the acyl radicals mentioned in the definition of the radical R ₁ in claims 1 to 5 or those which can be split off in vivo, a compound of the general formula
  in the
  A, X, R _a , R _b and R _{d are defined} as in claims 1 to 5, with a compound of the general formula
  Z ₅ -R ₆ , (XII)
  in the
  R _{6 is} one of the acyl radicals mentioned in the definition of the radical R ₁ in claims 1 to 5 or in vivo cleavable radicals and
  Z _{5 is} a nucleofugic leaving group, is implemented or
• g) a guanidine of the general formula for the preparation of a compound of the general formula I in which R _{d is} in the 4-position and X is a methylene group which is optionally substituted by a C _1-3 -alkyl group
  (R _a NR _b ) - (HN =) C-NH ₂ , (XIII)
  in the
  R _a and R _{b are} as defined in claims 1 to 5, with a 1,3-diketone of the general formula
  R _d CO-CH ₂ -CO-X "-AR _C , (XIV)
  in the
  A, R _c and R _{d are} as defined in claims 1 to 5 and
  X "denotes a methylene group optionally substituted by a C _1-3 alkyl group, is reacted and
  if desired, a compound of the general formula I, which contains an alkoxycarbonyl group, is then converted into a corresponding compound of the general formula I, which contains a carboxy group, by hydrolysis or
  a compound of the general formula I thus obtained, which contains a carboxy group, is converted by esterification or amidation into a corresponding compound of the general formula I, which contains one of the alkoxycarbonyl or aminocarbonyl groups mentioned in claims 1 to 5, or
  a protective residue which may be used during the reactions mentioned above is split off from a compound thus obtained or
  a compound of the general formula I thus obtained is separated into its stereoisomers or
  a compound of the general formula I thus obtained is converted into its salts, in particular into its physiologically tolerable salts.