NO890521L - SUBSTITUTED PYRIMIDINES. - Google Patents

Abstract

Substituted pyrlaldins of formula there. K, X and A can have different meanings. The compounds are reported to have, among other things, a serum-cholesterol-lowering effect. The preparation of the compounds is described.

Description

The present invention relates to substituted pyrimidines, intermediate compounds for their preparation, their preparation and their use in pharmaceuticals.

Lactone derivatives isolated from fungal cultures are known to be inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) [EP-A 22 478; US PS

4,231,938]. In addition to this, certain indole derivatives or pyrazole derivatives are also inhibitors of HMG-CoA reductase [EP-A 1 114 027; US-PS 4,613,610]. Substituted pyrimidines with the general formula (I) have now been found

there

R<1>- means cycloalkyl, or

- means alkyl which may be substituted with halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or a group of the formula -NR4R^, where

R<4>, r<5>- are the same or different and mean aryl,

aralkyl, acyl, alkylsulfonyl or arylsulfonyl,

or may be substituted with carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyloxy, aralkylthio or aralkylsulfonyl, whereby heteroaryl- and

the aryl residues in the last-mentioned substituents can be substituted up to three times, identically or differently, with halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl,

r<2>means heteroaryl which may be substituted up to three times, identically or differently, with halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or with a group of the formula -NR<4>R^, where R<4>and R<5> have the meaning indicated above, or

R<2>- means aryl which can be substituted up to five times,

the same or different, with alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkyl, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or with a group of the formula -NR<4>R<5>, where R<4>and R<5> have the meaning indicated above,

R<3>- means hydrogen, or

- means cycloalkyl, or

- means alkyl which may be substituted with halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or a group of the formula -NR<4>R<5>, where R<4>and R<5> has the meaning given above,

or with carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkylthio, aralkylthio or aralkylsulfonyl, whereby the heteroaryl and aryl residues in the latter substituents may be substituted up to three

times, equally or differently, with halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or

R<3>- means heteroaryl which may be substituted up to three times, identically or differently, with halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or with a group of the formula -NR<4>R<5>, where R<4>and R<5> have the above meaning, or

R<3>- means aryl which can be substituted up to five times,

the same or different, with alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkyl, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or with a group of the formula -NR<4>R<5>, where R<4>and R<5> have the above meaning, or

R<3>- means alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio,

aralkylthio or a group with the formula -NR<4>R^, where R<4> and r<5> have the meaning indicated above,

X - means a group with the formula -CH2-CH2- or -CH=CH- and A - means a group with the formula

there

r<6>- means hydrogen or alkyl and

R<7>- means hydrogen,

- an alkyl, aryl or aralkyl residue, or

- means a cation.

Surprisingly, the substituted pyrimidines of the invention show a good inhibitory effect on HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme-A-reductase).

C<y>chloalk<y>l generally means a cyclic hydrocarbon residue of 3 to 8 carbon atoms. Preferred are the cyclopropyl, cyclopentyl and cyclohexyl rings. Examples include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Alkyl generally means a straight-chain or branched hydrocarbon residue with 1 to 12 carbon atoms and is preferably lower alkyl with 1 to approx. 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.

Alkoxy generally means a straight-chain or branched hydrocarbon residue with 1 to 12 carbon atoms attached via an oxygen atom. Preferred is low alcohol with 1 to approx. 6 carbon atoms. Particularly preferred is an carboxylic acid residue with 1 to 4 carbon atoms. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy and isooctoxy.

Alkylthio generally means a straight-chain or branched hydrocarbon residue with 1 to 12 carbon atoms attached via a sulfur atom. Preferred is lower alkylthio with 1 to approx. 6 carbon atoms. Particularly preferred is an alkylthio residue with 1 to 4 carbon atoms. Examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, isopentylthio, hexylthio, isohexylthio, heptylthio, isoheptylthio, octylthio and isooctylthio.

Alk<y>lsulfonyl generally means a straight-chain or branched hydrocarbon residue with 1 to 12 carbon atoms which is attached via a SO2~ group. Preferred is lower alkylsulfonyl with 1 to approx. 6 carbon atoms. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, isopentylsulfonyl, hexylsulfonyl, isohexylsulfonyl.

Ar<y>l generally means an aromatic residue with 6 to about 12 carbon atoms. Preferred aryl radicals are phenyl, naphthyl and biphenyl.

Aryloxy generally means an aromatic residue with 6 to approx. 12 carbon atoms which are bound via an oxygen atom. Preferred aryloxy radicals are phenoxy and naphthyloxy.

Ar<y>ltio generally means an aromatic residue with 6 to about 12 carbon atoms which are bound via a sulfur atom. Preferred arylthio residues are phenylthio or naphthylthio.

Arylsulfonyl generally means an aromatic residue with 6 to about 12 carbon atoms which are bound via a SO2 group. Examples are phenylsulfonyl, naphthylsulfonyl and biphenylsulfonyl.

Aralk<y>1 generally means an aryl residue with 7 to 14 carbon atoms attached via an alkylene chain. Preferred are aralkyl residues with 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part. Examples include benzyl, naphthylmethyl, phenethyl and phenylpropyl.

Aralkyl generally means an aralkyl residue with 7 to 14 carbon atoms whereby the alkylene chain is bound via an oxygen atom. Aralkoc acid residues with 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. Examples include benzyloxy, naphthylmethoxy, phenethoxy and phenylpropoxy.

Aralk<y>ltio generally means an aralkyl residue with 7 to about 14 carbon atoms whereby the alkyl chain is bound via a sulfur atom. Preferred are aralkylthio residues with 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part. Examples include benzylthio, naphthylmethylthio, phenethylthio and phenylpropylthio.

Aralkylsulfon<y>1 generally means an aralkyl radical with 7 to about 14 carbon atoms whereby the alkyl residue is bound via an S0£ chain. Preferred are aralkylsulfonyl residues with 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part. Examples include benzylsulfonyl, naphthylmethylsulfonyl, phenethylsulfonyl and phenylpropylsulfonyl. Alkoxycarbonyl can, for example, be described by the formula

Alkyl here means a straight-chain or branched hydrocarbon residue with 1 to 12 carbon atoms. Preferred is lower alkoxycarbonyl with 1 to approx. 6 carbon atoms in the alkyl part. Particularly preferred is an alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part and particular mention should be made of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

Acyl generally means phenyl or straight-chain or branched lower alkyl with 1 to about 6 carbon atoms which are bound via a carbonyl group. Preference is given to phenyl and alkyl residues with up to 4 carbon atoms. Particular mention should be made of benzoyl, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.

Halogen generally means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine. Particularly preferred are fluorine and chlorine.

Heteroaryl within the framework of the definition given above generally means a 5- to 6-membered aromatic ring which as heteroatoms can contain oxygen, sulfur and/or nitrogen and which can be condensed onto the further aromatic rings. Preferred are 5- and 6-membered aromatic rings which contain one oxygen, one sulfur and/or up to two nitrogen atoms and which are optionally benzo-condensed. Particularly preferred heteroaryl residues are thienyl, furyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolyl, thiazolyl, benzothiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl, indolyl and isoindolyl.

If R<7> is an alkyl, aryl or aralkyl residue, an ester group is formed.

Physiologically acceptable esters are preferred which are easily hydrolyzed in vivo to a free carboxyl group and a correspondingly acceptable alcohol. These include, for example, alkyl esters (C1-6~aryl (C^j^)' and aralkyl esters (C7-1Q), preferably lower alkyl esters such as benzyl ester. Particularly preferred are methyl ester, ethyl ester, propyl ester, benzyl ester.

If R<7> is a cation, a physiologically acceptable metal or ammonium cation is particularly preferred. Preferred here are alkali or alkaline earth metal cations such as sodium, potassium, magnesium or calcium cations as well as aluminum or ammonium cations, further non-toxic substituted ammonium cations from amines such as di-lower alkyl amines (Cg to approx. C^,), tri-lower alkyl amines ( C^ to about C5), dibenzylamine, N,N'-dibenzylethylenediamine, N-benzyl-P-phenyl-ethylamine, N-methylmorpholine or N-ethylmorpholine, dihydro-abiethylamine, N,N'-bis-dihydroabiethylethylenediamine, N— lower alkyl piperidine and other amines, which can be used to form salts.

Preferred are substituted pyrimidines of formula (I), in which

r! - is cyclopropyl, cyclopentyl or cyclohexyl or

- is lower alkyl which may be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl with a group of the formula -NR4R5, where

R<4> and R<5> can be the same or different and mean lower alkyl, phenyl, benzyl, acetyl, benzoyl, phenylsulfonyl or lower alkylsulfonyl,

or with pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrryl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, whereby they said heteroaryl and aryl residues may be substituted up to twice, identically or differently, with fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy,

R<2>- means thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl,

isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which may be substituted up to twice, identically or differently, with fluorine, chlorine, bromine , lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or

means phenyl or naphthyl, which may be substituted up to four times, identically or differently, with lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, phenylethoxy, phenylethylthio, phenylethylsulfonyl, fluoride,

chlorine, bromine or cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or with a group of the formula —NR<4>R^, where R<4> and R^ have the above meaning,

R<3>- means hydrogen, or

- means cyclopropyl, cyclopentyl or cyclohexyl, or - means lower alkyl which may be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl with a group of the formula -NR< 4>R^, where R<4>and R^ have the meaning indicated above,

or with pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, whereby they said heteroaryl and aryl residues may be substituted up to twice, identically or differently, by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy, or

R<3>- means thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl,

isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which may be substituted up to twice, identically or differently, with fluorine, chlorine, bromine , lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or

R<3>- means phenyl or naphthyl which may be substituted up to four times, identically or differently, with lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfony1, phenethyl, phenylethoxy, phenylethylthio, phenylethylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or with a group of the formula

-NR<4>R<5>, where R<4>and R<5> have the meaning stated above, or

R<3>- means alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio,

aralkylthio or a group with the formula -NR<4>R<5>, where R<4> and R<5> have the meaning stated above,

X - means a group with the formula -CH2-CH2- or -CH=CH- and A - means a group with the formula

there

R^ - means hydrogen or lower alkyl and

R<7>- means alkyl C1-alkyl, C6-12-aryl or C7-10-aralkyl, or - means a physiologically acceptable cation thereof.

Particularly preferred are compounds of the general formula (I) where: R<1>- means cyclopropyl, cyclopentyl or cyclohexyl, or - means methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, which may be substituted with fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, methylthio, ethyltlo, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzoyl, acetyl, pyridyl, pyrimidyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl,

R<2>- means pyridyl, pyrimidyl, quinolyl or isoquinolyl, which may be substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or

- means phenyl, which may be substituted up to three times, identically or differently, by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio , ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenyl, phenoxy, benzyl, benzyloxy, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert-butoxycarbonyl , or

R<3>- means hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or

- means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl, which may be substituted with fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl , isobutoxycarbonyl, tert-butoxycarbonyl, benzoyl, acetyl, ethylcarbonyl or substituted with a group -NR<4>R<5>, where

R<4>and R<5>are the same or different and

means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,,phenyl, benzyl, acetyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or phenylsulfonyl,

or with pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, whereby the aforementioned heteroaryl and aryl residues can be substituted with fluorine, chlorine, methyl, ethyl , propyl, isopropyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,

tert-butoxy, trifluoromethyl or trifluoromethoxy, or - means thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzimidazolyl or benzthiazolyl, whereby the said residues can be substituted with fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl , isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert.butoxycarbonyl , or - means phenyl which may be substituted up to three times, identically or differently, with methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, me tylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, phenyl, phenoxy, phentylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl,

trifluoromethoxy, trifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, or may be substituted with a group of the formula -NR<4>R^, where R<4> and R^ have the above meaning . the formula -CH2-CH2- or -CH=CH- and A - means a group with the formula

there

R^ - means hydrogen, methyl, ethyl, propyl, isopropyl,

butyl, isobutyl or tert-butyl, and

R<7>- means hydrogen, methyl, ethyl, propyl, isopropyl,

butyl, isobutyl, tert-butyl or benzyl, or a sodium, potassium, calcium or magnesium or ammonium ion.

The substituted pyrimidines of the invention with the general formula (I) have several asymmetric carbon atoms and can therefore exist in several stereochemical forms. Both the individual isomers and their mixtures are objects of the invention.

Depending on the meaning of the group X or the residue A, different stereoisomers result, which will be explained in more detail below:

a) If the group -X- means a group with the formula -CH=CH-, the compounds of the invention can exist in two stereoisomeric forms which on the double bond are E-configured (II) or Z-configured (III)

Preferred are those compounds of the general formula (I) which are E-configured (II).

b) Denote the remainder -A- for a group with the formula

the compounds with the general formula (I) have at least two asymmetric carbon atoms, namely the two carbon atoms to which the hydroxy groups are attached. Depending on the relative position of these hydroxy groups in relation to each other, the compounds of the invention can exist in erythro-configuration (IV) or in threo-configuration (V)

Of the compounds in both the erythro and threo configurations, there are in turn two enantiomers, namely 3R,5S isomers respectively 3S,5R isomers (erythro form) such as 3R,5R isomers and 3S,5S isomers ( treo form).

Preference is hereby given to the erythro-configured isomers, particularly preferred is the 3R,5S isomer and the 3R,5S-3S,5R racemate.

c) Does the residue -A- mean a group with the formula

the substituted pyrimidines have at least two asymmetric carbon atoms, namely the carbon atom to which the hydroxy group is attached and the carbon atom to which the residue with the formula is attached. Depending on the position of the hydroxy group of the free valence on the lactone ring, the substituted pyrimidines can exist as cis-lactones (VI) or as trans-lactones (VII).

Of both the cis-lactone and the trans-lactone, there are in turn two isomers, namely the 4R,6R-isomer respectively the 4S,6S-isomer (cis-lactone) and the 4R,6S-isomer respectively the 4S,6R-isomer (trans- lactone). Preferred isomers are the trans-lactones. Particular preference is hereby given to the 4R,6S isomer (trans) and the 4R,6S-4S,6R racemate.

For example, the following isomeric forms of the substituted pyrimidines should be mentioned:

Particularly preferred are the compounds of the general formula (I) there

R<1>- means cyclopropyl, methyl, ethyl, propyl, isopropyl,

butyl, isobutyl or tert-butyl,

R<2>- means phenyl, which may be substituted up to twice,

the same or different, with methyl, methoxy, phenoxy, fluorine, chlorine or trifluoromethyl,

R<3>- means methyl, isopropyl, tert-butyl or

- means phenyl, which may be substituted up to twice, identically or differently, by methyl, methoxy, fluorine or chlorine, 18

X - means a group with the formula

(E-configured) and A - means a group with the formula

there

R<k>_ means hydrogen and

R<7>- means hydrogen, methyl or ethyl or

means a sodium or potassium cation.

In addition, a method has been found for the preparation of the substituted pyrimidines with the general formula (I)

there

R<*>, R<2>, R<3>, X and A have the above meaning, and this method is characterized by reducing ketones with the general formula (VIII)

there

R<1>, R<2> and R<3> have the above meaning and R<7>' - means alkyl, aryl or aralkyl,

saponifies the esters to produce the acids,

ring-closes the carboxylic acids to produce the lactones,

saponifies the esters or lactones to produce the salts,

hydrogenates according to usual methods the ethylene compounds (X = -CH=CH-) to produce the ethylene compound (X = -CH2-CH2-) and

optionally separates the isomers.

The method of the invention can be explained by the following formula:

The reduction can be carried out with the usual reducing agents and preferably with those which are suitable for the reduction of ketones to hydroxy compounds. Particularly suitable is reduction with metal hydrides or complex metal hydrides in inert solvents, possibly in the presence of a trialkyl borane. The reduction with complex metal hydrides such as lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoborates, sodium trialkylhydridoborates, sodium cyanotrihydridoborate or lithium aluminum hydride is preferred. Particularly preferred is reduction with sodium borohydride in the presence of triethylborane.

Suitable solvents are the usual organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran or dimethoxyethane or halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane or hydrocarbons such as benzene, toluene or xylene. Likewise, it is possible to use mixtures of the mentioned solvents.

It is particularly preferred to carry out the reduction of the ketone group to a hydroxy group under conditions where the other functional groups, such as the alkoxycarbonyl group for example, are not changed. Particularly suitable for this purpose is the use of sodium borohydride as reducing agent in the presence of triethylborane in an inert solvent such as preferably ether.

The reduction generally takes place in a temperature range from -80°C to room temperature, i.e. approx. 30°C, preferably from -78" C to CC.

The method of the invention is usually carried out by ordinary pressure. However, it is also possible to carry out the method under negative or positive pressure (for example in a range from 0.5 to 5 bar).

In general, the reducing agent is used in an amount of 1 to 2 mol and preferably 1 to 1.5 mol, calculated on 1 mol of keto compound.

Among the reaction conditions stated above, the carbonyl group is reduced to a hydroxy group without any reduction of the double bond to a single bond.

For the preparation of compounds of the general formula (I), where X means an ethylene group, the reduction of the ketones (III) can take place under such conditions where both the carbonyl group and the double bond are reduced.

In addition to this, it is also possible to carry out the reduction of the carbonyl group and the reduction of the double bond in two separate steps.

The carboxylic acid within the framework of the general formula (I) corresponds to formula (Ic)

The carboxylic acid ester within the framework of formula (I) corresponds to the formula (Id) The salts of the compounds of the invention within the framework of the general formula (I) correspond to formula (le)

in which

M<n+>means a cation, with valence n. The preferred valence

is 1 or 2.

The lactones within the framework of the general formula (I) correspond to formula (If)

For the production of the carboxylic acids of the invention with the general formula (Ic), the carboxylic acid esters with the general formula (Id) or the lactone with the general formula (If) are generally saponified according to known methods. The saponification generally occurs when the ester or lactone is treated in inert solvents with common bases, whereby salts with the general formula (le) are generally first formed, which can then in a second step be transferred to the free acids with the general formula (Ic) by treatment with acid.

The usual inorganic bases are suitable as a base for the saponification. These preferably include alkali or alkaline earth hydroxides such as sodium, potassium or barium hydroxide, or alkali carbonates such as sodium or potassium carbonate, or sodium bicarbonate, or alkali alcoholates such as sodium ethanolate, sodium methanolate, potassium methanolate, potassium ethanolate or potassium tert-butanolate. Sodium or potassium hydroxide is particularly preferably used.

Suitable solvents for the saponification are water or the organic solvents usually used for saponification. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethylsulfoxide. Particularly preferred are alcohols such as methanol, ethanol, propanol or isopropanol. Likewise, it is possible to use mixtures of these solvents.

The saponification usually takes place at a temperature from 0°C to +10°C, and preferably from +20°C to +80°C.

In general, the saponification is carried out at normal pressure. However, it is also possible to work at under or over pressure, for example from 0.5 to 5 bar.

When carrying out the saponification, the base is generally used in an amount of from 1 to 3 mol and preferably from 1 to 1.5 mol, calculated on 1 mol of ester, respectively lactone. It is particularly preferred to use molar amounts of the reactants. When carrying out the reaction, the salts of the compounds of the invention (le) are produced in the first step as intermediate products and these can be isolated. The acids (Ic) of the invention are obtained by treating the salts (le) with common inorganic acids. These preferably include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. In the preparation of the carboxylic acids (Ic), it has proven advantageous to anacidify the basic reaction mixture for the saponification in a second step without isolating the salts. The acids can then be isolated in a manner known per se.

For the production of the invention's lactones with formula (If), the invention's carboxylic acids (Ic) are generally ring-closed according to common methods, for example by heating the corresponding acid in inert organic solvents, possibly in the presence of molecular sieves.

Suitable solvents are hydrocarbons such as benzene, toluene, xylene, petroleum fractions or tetralin or diglyme or triglyme. In particular, benzene, toluene or xylene are used. Likewise, it is possible to use mixtures of the mentioned solvents. It is particularly preferred to use hydrocarbons and most preferably to use toluene, in the presence of molecular sieves.

The ring closure usually takes place within a temperature range from -40°C to +200°C, preferably from -25°C to +50°C. The cyclization is usually carried out at normal pressure, but it is also possible to carry out the reaction at under or over pressure, for example within the range of 0.5 to 5 bar.

In addition to this, the ring closure is also carried out in inert organic solvents using ring-closing or water-splitting agents. Carbodiimides are preferably used as such. As carbodiimide, N,N'-dicyclohexylcarbodiimide-paratoluenesulfonate, N-cyclohexyl-N'-[2-(N''-methylmorpholinium)ethyl]carbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride are preferred.

As a solvent, the usual organic solvents are suitable. These preferably include ethers such as diethyl ether, tetrahydrofuran or dioxane, or chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride or hydrocarbons such as benzene, toluene, xylene or petroleum fractions. Particularly preferred are chlorohydrocarbons such as methylene chloride, chloroform or carbon tetrachloride. The reaction is generally carried out within a temperature range from 0 to +80°C and preferably from +10 to +50°C.

When carrying out the ring closure, it has proven advantageous to carry out the ring closure method using carbodiimides as dehydrating agents.

The separation of the isomers into the stereoisomeric unitary components generally takes place according to common methods as described, for example, by E.L. Eliel, "Stereochemistry of Carbon Compounds", McGraw Hill, 1962. Hereby, separation of the isomers at the racemic lactone step is preferred. It is particularly preferred here to transfer the racemic mixture of the trans-lactone (VII) by treatment either with D-( + )- or L-(-)-α-methylbenzylamine according to usual methods to the diastereomeric dihydroxyamides (Ig) which so in the usual way by chromatography or crystallization can be separated into the individual diastereomers. Then the following hydrolysis of the diastereomeric amides according to conventional methods, for example by treating the diastereomeric amides with inorganic bases such as sodium hydroxide or potassium hydroxide in water and/or organic solvents such as alcohols such as methanol, ethanol, propanol or isopropanol, gives the corresponding enantiomers -pure dihydroxy acids (Ic) which, as described above, by ring closure can be transferred to the enantiomerically pure lactones. In general, it applies to the preparation of the compounds of the invention with the general formula (I) in enantiomerically pure form that the configurations of the final product according to the method described above are dependent on the configuration of the starting materials.

The isomer separation must be explained in more detail in the following form:

The ketones (VIII) used as starting materials are new.

A method has been found for the production of the invention's ketones with the general formula (VIII)

there

R<1>, R<2>, R<3> and R<7>' have the meaning given above,

and this method is characterized by

aldehydes of the general formula (IX)

there

R<1>, R<2> and R<3> have the above meaning,

in inert solvents is reacted with acetic acid esters of the general formula (X)

there

R<7>' has the meaning given above,

in the presence of bases.

The method of the invention can be explained, for example, by the following reaction scheme:

As bases, the usual strongly basic compounds come into consideration. These preferably include lithium-organic compounds such as N-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium or amides such as lithium diisopropylamide, sodium amide or potassium amide or lithium hexamethyldisilamide or alkali hydrides such as sodium or potassium hydride. Likewise, it is possible to use mixtures of the aforementioned bases. Particularly preferred is N-butyllithium or sodium hydride or mixtures thereof.

Suitable solvents are the usual organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, or hydrocarbons such as benzene, toluene, xylene, cyclohexane, hexane or petroleum fractions. Likewise, it is possible to use mixtures of the mentioned solvents. Particularly preferred are ethers such as diethyl ether or tetrahydrofuran.

The reaction is generally carried out within a temperature range from -80 to +50°C, and preferably from -20°C to room temperature.

The procedure is usually carried out at normal pressure, but it is also possible to work at low or high pressure, for example within the range from 0.5 to 5 bar.

When carrying out the method, the acetic acid ester is usually used in an amount of from 1 to 2 mol, and preferably 1 to 1.5 mol, calculated on 1 mol of aldehyde.

The acetic acid esters of formula (X) used as starting materials are known or can be prepared by known methods ["Beilstein's Handbuch der organischen Chemie", III. 632; 438].

Examples of acetoacetic esters for the method of the invention are: acetoacetic acid methyl ester, acetoacetic acid ethyl ester, acetoacetic acid propyl ester, acetoacetic acid isopropyl ester. The aldehydes with the general formula (IX) used as starting materials are new. A method for the production of aldehydes with the general formula (IX) has also been found

there

R<1>, R<2> and R<3> have the above meaning,

and this is characterized by reducing pyrimidines with the general formula (XI) in the temperature range -70°C to +100°C to hydroxymethyl compounds with formula (XII), then oxidizing these to the corresponding aldehydes (XIII) and reacting these with dialkyl (C1-4)-aminovinylphosphonates in the presence of sodium hydride in inert solvents such as ethers, for example diethyl ether, tetrahydrofuran or dioxane, preferably tetrahydrofuran, in a temperature range from -20°C to +40°C and preferably -5°C to room temperature, to aldehydes (IX).

The preparation will be explained in the following with an example in compounds of type (I).

Hereby, according to scheme A, pyrimidines of formula (XI ) are there

R<8> is alkyl of up to 6 carbon atoms, C^_12~aryl or C7_12-aralkyl, and

r! and R<2> has the above meaning,

in the first step (1) in inert solvents such as ethers, for example diethyl ether, tetrahydrofuran or dioxane, preferably tetrahydrofuran, reduced with metal hydrides, for example 1 lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, diisobutylaluminum hydride or sodium bis-(2-methoxyethoxy)-dihydroaluminate which reducing agent, in the temperature range from -70 to +100°C, preferably -70°C to room temperature, respectively from room temperature to +70°C, depending on the reducing agent used, to the hydroxymethyl compounds (XII). Preferably, the reduction with 1 lithium aluminum hydride in tetrahydrofuran takes place in a temperature range from room temperature to 80°C.

The hydroxymethyl compounds (XII) are oxidized in the second step (2) to the aldehydes (VII) according to usual methods. The oxidation can, for example, take place with pyridinium chlorochromate, optionally in the presence of aluminum oxide, in inert solvents such as chlorinated hydrocarbons, preferably methylene chloride, in a temperature range from 0 to +60°C, and preferably at room temperature, or carried out with trifluoroacetic acid/dimethyl sulfoxide according to the usual methods of Swern oxidation.

In the third step (3), the aldehydes (XIII) are preferably reacted with diethyl-2-(cyclohexylamino)-vinylphosphonate in the presence of sodium hydroxide in inert solvents such as ethers, for example diethyl ether, tetrahydrofuran or dioxane, and preferably in tetrahydrofuran, within a temperature range from

-20 to +40°C and preferably from -5°C to room temperature, to the aldehydes (IX). The pyrimidines of formula (XI) used here as starting materials are generally obtained according to scheme B by oxidation of dihydropyrimidines (XIV). dihydropyrimidines used as starting materials are prepared according to methods known from the literature, see DE-A 103 796. The oxidation of the dihydropyrimidines (XIV) to the pyrimidines (XI) can for example take place with chromium oxide in glacial acetic acid at a temperature from -20 to +150 °C, and preferably at reflux temperature, or with 2,3-dichloro-5,6-dicyan-p-benzoquinone as oxidizing agent in inert solvents such as chlorohydrocarbons, and preferably methylene chloride in a temperature range from 0 to +100"C, and preferably at room temperature.

The compounds of the invention with the general formula (I) have valuable pharmacological properties and can be used as an active ingredient in pharmaceuticals. In particular, they are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase and, consequently, inhibitors of cholesterol biosynthesis. They can therefore be used for the treatment of hyperlipoproteinaemia, lipoproteinaemia or arteriosclerosis.

The new active substances can be transferred in a known manner to the usual formulations such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions or solutions using inert, non-toxic, pharmaceutically suitable carriers or solvents. Hereby, the therapeutically active compound should be present in a concentration of approx. 0.5 to 98 wt-#, preferably 1 to 90 wt-# of the total mixture, that is, in amounts sufficient to achieve the indicated dosage range.

The formulations are prepared, for example, by diluting the active agent with solvents and/or carriers, possibly using emulsifiers and/or dispersants, whereby, for example, using water as a diluent, organic solvents can also be used as auxiliary solvents.

Examples of excipients include water, non-toxic organic solvents such as: paraffins such as petroleum fractions; vegetable oils such as peanut/sesame oil; alcohols such as ethyl alcohol or glycerol; carriers such as natural stone flour in the form of kaolin, clay, talc or chalk, or synthetic stone flour such as highly dispersed silicon dioxide or silicates; sugars such as cane, milk or dextrose; emulsifiers such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkylsulfonates and arylsulfonates; dispersing agent such as lignin sulphite liquor, methyl cellulose, starch or polyvinylpyrrolidone; or lubricants such as magnesium stearate, talc, stearic acid or sodium lauryl sulfate.

Administration takes place in the usual way, preferably orally, parenterally, perlingually or intravenously. When it comes to oral use, in addition to the carriers mentioned, the tablets can of course also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various aggregates such as starch, preferably potato starch, gelatin and the like. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used during tableting. In the case of aqueous suspensions, the active ingredient can also be used in addition to the above-mentioned substances together with various flavor enhancers or coloring agents.

As regards the parenteral application, solutions of the active ingredient can be used using suitable liquid carriers.

In general, for intravenous administration, it has proven advantageous to use amounts of approx. 0.001 to 1 mg/kg and preferably approx. 0.01 to 0.5 mg/kg body weight of the active ingredient to achieve effective results, at the time of administration, and for oral use the dosage amounts to approx. 0.01 to 20 mg/kg and preferably 0.1 to 10 mg/kg body weight.

Despite this, it may be necessary to deviate from the amounts mentioned, depending on body weight or the method of administration, the individual conditions in relation to the drug used, the type of formulation and the time or the interval for the administration.

Thus, in some cases it may be sufficient to use less than the minimum amount specified above, while the maximum limit must occasionally be exceeded. When it comes to the administration of larger quantities, it may be advisable to spread these over 1 several single administrations during the day.

Example 1

(E/Z )-4-ethoxycarbonyl-4-(4-fluorophenyl)-but-3-en-2-one

62 g (0.5 mol) 4-fluorobenzaldehyde and 53.9 ml (0.5 mol) ethyl acetate are added to 300 ml isopropanol, to which is added a mixture of 2.81 ml (28 mmol) piperidine and 1.66 ml ( 29 mmol) of acetic acid in 40 ml of isopropanol and the whole is stirred for 48 hours at room temperature. The mixture is evaporated under vacuum and the residue is distilled under high vacuum.

Boiling point 0.5 mm: 138°C

Yield: 50.5 g ($45.5 of the theoretical).

Example 2

1,4-dihydro-2,6-dimethyl-4-(4-fluorophenyl)-pyrimidine-5-carboxylic acid ethyl ester

In 230 ml of ethanol, 23.6 g (0.1 mol) of the compound from example 1, 10.5 g (0.11 mol) acetamidine hydrochloride and 9.85 g (0.12 mol) sodium acetate are heated under reflux overnight, the solvent is removed under vacuum, ethyl acetate and 180 ml 1N hydrochloric acid are added to the residue, the organic phase is washed twice more with 100 ml 1N hydrochloric acid, the combined aqueous phases are washed with ether, made alkaline with concentrated caustic soda and extracted three times with acetic acid. The acetate phase is washed with water, dried over Na2SC>4 and evaporated under vacuum.

Yield: 12.4 g corresponding to 44.9$ of the theoretical.

<i>H-NMR (CDCl 3 ): S = 1.15 (tr, 3H, CH 3 ); 1.9 (s, 3H, CH3);

2.3 (s, 3H, CH3); 4.05 (m, 2H, CH2);

5.3, 5.5 (2s, 1H, CH); 6.9-7.4 (m, 4H, aromatics-H) ppm.

Example 3

2,6-dimethyl-4-(4-fluorophenyl)-pyrimidine-5-carboxylic acid ethyl ester

In 70 ml of acetic acid, 12.4 g (45.1 mol) of the compound from example 2 is heated to boiling and 4.6 g (46 mmol) chromium trioxide is added portionwise. After one hour, the whole is allowed to cool to 25°C, it is poured onto ice/25% aqueous ammonia solution, the whole is made alkaline with ammonia solution, extracted with dichloromethane, the organic phase is washed with water and obtained after drying over NaCl^ , evaporation in vacuo and filtration over silica gel (dichloromethane:methanol 10:1) 7.14 g.

Dividend: 57.7$ of the theoretical.

1 H NMR (CDCl 3 ): S = 1.2 (tr, 3H, CH 3 ); 2.65 (s, 3H, CH3);

2.85 (s, 3H, CH3); 4.3 (q, 2H, CH2);

7.1-7.8 (m, 4H, aromatics-H) ppm.

Example 4

2,6-dimethyl-4-(4-fluorophenyl)-5-hydroxymethyl-pyrimidine

To 5.66 g (20.6 mmol) of the compound from example 3 in 100 ml of toluene, 27 ml (40 mmol) of diisobutylaluminum hydride (1.5 m in toluene) is added dropwise under nitrogen at -78°C. After heating to 25°C, it is hydrolysed with 20% aqueous potassium hydroxide solution, the aqueous phase is washed with ethyl acetate, the combined organic phases are dried over Na 2 SO 4 and the solvent is removed under vacuum.

Yield: 4.1 g corresponding to 85.9$ of the theoretical.

<1->H-NMR (CDCl3): δ = 1.8 (tr, 1H, OH); 2.7 (2s, 6H, CH3);

4.65 (d, 2H, CH2); 7.1-7.7 (m, 4H, aromatics-H) ppm.

Example 5

2,6-dimethyl-4-(4-fluorophenyl)-pyrimidine-5-carbaldehyde

To a solution of 4.1 g (17.7 mol) of the compound from example 4 in 100 ml of dichloromethane, 6.06 g (28.1 mmol) of pyrimidinium chlorochromate are added in portions at room temperature and stirred for two hours. The solvent is removed under vacuum and the residue is filtered over silica gel (dichloromethane:methanol 3:1).

Yield: 3.8 g corresponding to 93.4% of the theoretical.

1-H-NMR (CDCl 3 ): S = 2.8 (2s, 6H, CH 3 ); 7.1-7.7 (m, 4H,

aromatics-H); 10.0 (s, 1H, CHO) ppm.

Example 6

(E)-3-[2,6-dimethyl-4-(4-fluorophenyl)-pyrimid-5-yl]-prop-2-enal

To a suspension of 0.5 g (20.8 mmol) sodium hydride in 20 ml

tetrahydrofuran, a solution of 0.81 g of [2-(cyclohexylamino)vinyl]-phosphonic acid diethyl ester in 20 ml of THF is added dropwise at 0°C, stirred for 15 minutes and then added dropwise to a solution of 0.63 g (2.72 mmol) of the compound from example 5 in 15 ml

THF, stir for one hour at 0°C, one hour at 25°C, hydrolyze with 20 ml of water, wash with diethyl ether, remove the solvent under vacuum, take up the residue in 40 ml of toluene and heat the solution with 2 g of oxalic acid and 40 ml of water for one hour at 60°C, washing with diethyl ether, drying over Na 2 SO 4 and obtaining 0.5 g after removal of the solvent.

Dividend: 71.7$ of the theoretical.

1-H NMR (CDCl 3 ): S - 2.7 (s, 3H, CH 3 ); 2.8 (s, 3H, CH3); 6.4 (dd, 1H, CHCH0); 7.2 (d, 1H, CH); 7.1-7.7 (m, 4H, aromatics-H); 9.6 (d, 1H, CHO) ppm. Example 7 Methyl (E)-7-[2,6-dimethyl-4-(4-fluorophenyl)-pyrimid-5-yl]-5-hydroxy-3-oxo-hept-6-enoate

To a suspension of 256 mg (10.7 mmol) of sodium hydride in 25 ml of THF, 1.11 ml (10.3 mmol) of acetoacetic acid methyl ester is added dropwise at 0°C. After 15 minutes, 7.3 ml (10.7 mmol of n-butyllithium (1.5 m in hexane) are added dropwise over 10 minutes, stirred for 15 minutes at 0°C, added dropwise to a solution of 2.4 g (3.8 mmol) of the compound from example 6 in 10 ml THF, stir for 15 minutes at 0°C, hydrolyze with 30 ml saturated aqueous ammonium chloride solution, wash three times with dichloromethane, dry over Na 2 SO 4 , remove the solvent under vacuum and obtains 2.47 g of oil after chromatography over silica gel with ethyl acetate as eluent.

Dividend: $73.00 of the theoretical.

<1>H-NMR (CDCl 3 ): S - 2.55 (s, 3H, CH 3 ); 2.7 (d, 2H, CH2-CHOH); 2.75 (s, 3H, CH3); 3.1 (br, s, 1H, OH); 3.5 (s, 2H, CH2); 3.75 (s, 3H, 0CH3); 4.65 (m, 1H, CHOH); 5.6 (dd, 1H, CHCHOH); 6.6 (d, 1H, CH); 7.0-7.6 (m, 4H, aromatics-H) ppm.

Example 8

Methyl erythro-(E)-3,5-dihydroxy-7-[2,6-dimethyl-4-(4-fluoro-phenyl)-pyrimid-5-yl]-hept-6-enoate

Through a solution of 1.69 g (4.55 mmol) of the compound from example 7 and 5.7 ml (5.7 mmol) of triethylborane (1 m, THF) in 45 ml of THF, air is blown for 5 minutes, cooled to -30°C, add 215 mg (5.7 mmol) sodium borohydride and slowly 3.8 ml methanol, stir for 30 minutes at -30°C, slowly add 15.2 ml 30 µg hydrogen peroxide in 33.4 ml water below 0°C, stir for 30 minutes at 0°C, take up the whole in acetic acid ester, wash with water, IN hydrochloric acid, aqueous sodium bicarbonate solution, dry over Na2SC>4 , remove the solvent under vacuum and obtain after chromatography over silica gel (ethyl acetate ) 1.08 g.

Dividend: 63$ of the theoretical.

<i>H-NMR (CDCl 3 ): δ = 1.8 (br, s, 2H, OH); 2.5 (m, 2H, CH2);

2.55 (s, 3H, CH3); 2.7 (s, 3H, CH3);

3.7 (s, 3H, 0CH3); 4.2 (m, 1H, CHOH);

4.45 (m, 1H, CHOH); 5.6 (dd, 1H, CH, CHOH); 6.5 (d, 1H, CH); 7.0-7.6 (m, 4H, aromatics-H) ppm.

Example 9

1,4-dihydro-4-(4-fluorophenyl)-6-methyl-2-phenyl-pyrimidine-5-carboxylic acid ethyl ester

Analogous to example 2, 87.5 g is obtained from 103.6 g (0.56 mol) of benzamidine hydrochloride, 121.5 g (0.5 mol) of the compound from example 1 and 49.2 g (0.6 mol) of sodium acetate.

Dividend: 25.9$ of the theoretical.

1 H-NMR (CDCl 3 ): S = 1.15 (tr, 2H, CH 3 ); 2.15 (br, s, NH);

2.6 (s, 3H, CH3); 4.1 (q, 2H, CH2); 5.8 (s, 1H, CH); 7.1-8.0 (9H, aromatics-H) ppm.

Example 10

4-(4-Fluorophenyl)-6-methyl-2-phenyl-pyrimidine-5-carboxylic acid ethyl ester

Analogous to example 3, 34.9 g is obtained from 40 g (0.12 mol) of the compound from example 9 and 11.8 g (0.12 mol) chromium trioxide.

Dividend: 87.9$ of the theoretical.

<1>H-NMR (CDCl 3 ): S = 1.15 (tr, 2H, CH 3 ); 2.7 (s, 3H, CH3);

4.25 (q, 2H, CH2); 7.1-8.6 (9H, aromatics-H) ppm.

Example 11

4-(4-fluorophenyl)-5-hydroxymethyl-6-methyl-2-phenylpyrimidine

Analogous to example 2, 23.1 g is obtained from 30 g (0.09 mol) of the compound from example 10.

Dividend: 87.3$ of the theoretical.

<i>H-NMR (CDCl 3 ): S = 2.8 (s, 3H, CH 3 ); 4.5 (br, OH); 4.65

(s, 2H, CH2); 7.1-8.5 (9H, aromatics-H) ppm.

Example 12

4-(4-fluorophenyl)-6-methyl-2-phenyl-pyrimidine-5-carbaldehyde

Analogously to example 5, 11.9 g of pyrimidine chlorochromate is obtained from 12.9 g (44 mmol) of the compound from example 11 and 14.2 g (66 mmol).

Yield: 93% of the theoretical.

1-H-NMR (CDCl 3 ): S = 2.9 (s, 3H, CH 3 ); 7.2-8.7 (9H, aromatics-H); 10.1 (s, 1H, CHO) ppm.

Example 13

E-3-[4-(4-fluorophenyl)-6-methyl-2-phenyl-pyrimid-5-yl]-prop-2-enal

Analogous to example 6, one obtains from 8.0 g (27 mmol) of the compound from example 12, 0.8 g (33.6 mmol) sodium hydride and 8.0 g (32.4 mmol) [2-(cyclohexylamino)vinyl] phosphonic acid diethyl ester 5.9 g.

Dividend: 68.7$ of the theoretical.

<1>H-NMR (CDCl 3 ): S = 2.8 (s, 3H, CH 3 ); 6.45 (dd, 1H, CHCHO);

7.1-8.6 (m, 10H, aromatics-H, CH); 9.65 (d, 1H, CHO) ppm.

Example 14

Methyl-(E)-7-[4-(4-fluorophenyl)-6-methyl-2-phenyl-pyrimid-5-yl]-5-hydroxy-3-oxo-hept-6-enoate

Analogous to example 7, 5.18 g of crude product is obtained from 3.4 g (10.7 mmol) of the compound from example 13.

Raw yield: 100$

<1>H-NMR (CDCl 2 ): S = 2.65 (s, 3H, CH 2 ); 2.7 (d, 2H,

2.9 (br, 1H, OH); 3.5 (s, 3H,

CH3); 3.75 (s, 3H, 0CH3); 4.7 (m, 1H, CHOH); 6.65 (d, 1H, CH-Ar); 7.1-8.6 (m, 9H, aromatics-H) ppm.

Example 15

Methyl erythro-(E)-3,5-dlhydroxy-7-[4-(4-fluorophenyl)-6-methyl-2-phenyl-pyrimid-5-yl]-hept-6-enoate

Analogously to example 8, 4.03 g is obtained from 8.26 g (16 mmol) of the compound from example 14.

Dividend: 57.7$ of the theoretical.

<1>H-NMR (CDCl 3 ): δ = 1.6 (m, 2H, CH 2 ); 2.5 (m, 2H, CH2C=0):

2.7 (s, 3H, CH3); 3.7 (s, 3H, CH 3 O); 4.2 (m, 1H, CHOH); 4.5 (m, 1H, CHOH); 5.7 (dd, 1H, CH-CHOH); 6.6 (d, 1H, CH-Ar); 7.0-8.6 (m, 9H, aromatics-H) ppm. Example 16 (E/Z)-4-ethoxycarbonyl-5-(4-fluorophenyl)-2-methyl-pent-4-en-3-one 62 g (0.5 mol) of 4-fluorobenzaldehyde and 79 g (0. 5 mol) of iso-butyryl acetic acid ethyl ester is added to 300 ml of dry isopropanol and to this is added a mixture of 2.81 ml (28 mmol) of piperidine and 1.66 ml (29 mmol) of acetic acid in 40 ml of isopropanol. The whole is stirred for 48 hours at room temperature, evaporated under vacuum and the residue distilled under high vacuum.

Boiling point 0.5 mm: 127°C

Yield: 108.7 g corresponding to 82.3$ of the theoretical.

Example 17

1,4-dihydro-4-(4-fluorophenyl)-6-isopropyl-2-phenylpyrimidin-S-carboxylic acid ethyl ester

Analogous to example 2, one obtains from 59.5 g (0.2 mol) benzamidine hydrochloride, 79.2 g (0.3 mol) of the compound from example 16 and 28.7 g (0.35 mol) sodium acetate in 500 ml ethanol 39 g.

Dividend: 35.5$ of the theoretical.

1-H-NMR (CDCl 3 ): S = 1.2 (m, 9H, CH 3 ); 2.8 (m, 1H; CH); 4.1

(q, 2H, CH2); 4.2 (br, 1H, NH); 5.75 (s, 1H, CHAr); 6.9-8.1 (m, 9H, aromatics-H) ppm.

Example 18

4-(4-Fluorophenyl)-6-isopropyl-2-phenyl-pyrimidine-5-carboxylic acid ethyl ester

Analogous to example 3, 20.6 g is obtained from 39.0 g (0.11 mol) of the compound from example 17.

Dividend: 56.6$ of the theoretical.

<1>H-NMR (CDCl 3 ): S = 1.15 (tr, 3H, CH 3 ); 1.4 (d, 6H, CH3);

3.3 (m, 1H, CH); 4.2 (q, 2H, CH2); 7.0-8.6 (m, 9H, aromatics-H) ppm.

Example 19

4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-2-phenylpyrimidine

Analogous to example 4, 16.7 g of the title compound is obtained from 20.0 g (55 mmol) of the compound from example 18.

Dividend: 94$ of the theoretical.

<1>H-NMR (CDCl 3 ): S = 1.4 (d, 6H, CH 3 ); 1.7 (br, 1H, OH);

3.55 (m, 1H, CH): 4.7 (s, 2H, CH2);

7.1-8.7 (m, 9H, aromatics-H) ppm.

Example 20

4-(4-fluorophenyl)-6-isopropyl-2-phenyl-pyrimidine-5-carbaldehyde

Analogous to example 5, 7.9 g of the title compound is obtained from 16.3 g (50 mmol) of the compound from example 19.

Dividend: 49.4$ of the theoretical.

<1>H-NMR (CDCl 3 ): S = 1.4 (d, 6H, CH 3 ); 4.0 (m, 1H, CH); 7.2-8.7 (m, 9H, aromatics-H); 10.1 (s, 1H, CHO) ppm.

Example 21

(E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-phenyl-pyrimid-5-yl]-prop-2-enal

Analogous to example 6, 6.9 g of example 21 is obtained from 7.9 g (25 mmol) of the compound from example 20.

Yield: 0% of the theoretical.

1-H-NMR (CDCl 3 ): S 1.4 (d, 6H, CH 3 ); 3.4 (m, 1H, CH); 6.3

(dd, 1H, CHCHO); 7.1-8.7 (m, 9H, aromatics-H); 7.6 (d, 1H, CHAr) ppm.

Example 22

Methyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-phenylpyrimid-5-yl]-5-hydroxy-3-oxo-hept-6-enoate

Analogous to example 7, 0.8 g of example 22 is obtained from 1.9 g (5.5 mmol) of the compound from example 21.

Yield: 30.2%

1-H-NMR (CDCl 3 ): S = 1.35 (d, 6H, CH 3 ); 2.65 (d, 2H, CH2);

3.4 (m, 1H, CH); 3.5 (s, 2H, CH2); 3.75 (s, 3H, CH 3 O); 4.65 (m, 1H, CHOH); 5.5 (dd, 1H, CH CHOH); 6.75 (d, 1H, CHAr);

7.1-8.6 (m, 9H, aromatics-H) ppm.

Example 23

Methyl erythro-(E)-3, 5-dihydroxy-7-[4-(4-fluorophenyl)-6-isopropyl-2-phenyl-pyrimid-5-yl]-hept-6-enoate

Analogously to example 8, 0.8 g (1.75 mmol) of the compound from example 22 yields 0.5 g of example 23.

Dividend: $62

1-H-NMR (CDCl 3 )<:>S = 1.3 (d, 6H, CH 3 ); 1.6 (m, 2H, CH2 ); 2.5

(m, 2H, CH2C=O); 3.45 (m, 1H, CH); 3.7

(s, 3H, CH3O); 4.2 (m, 1H, CHOH); 4.5 (m, 1H, CHOH); 5.5 (dd, 1H, CH-CHOH);

6.7 (d, 1H, CHAr); 7.1-8.6 (m, 9H, aromatics-H) ppm.

Application examples

Example 1

The enzyme activity assays were modified according to G.C. Ness et al. in "Archives of Biochemistry and Biophysics", 197. 493-499 (1979). Male Rico rats with a body weight of 300-400 g were treated for 11 days with altromin powder to which 40 g of cholestyramine had been added per kg for. After decapitation, the liver was removed from the animals and placed on ice. The liver was minced and homogenized in a Potter-Elvejem homogenizer three times in 3 volumes of 0.1 m sucrose, 0.05 m KC1, 0.04 m KxHy- phosphate, 0.03 m ethylenediaminetetraacetic acid, 0.002 m dithiothreitol (SPE)- buffer, pH 7.2. It was then centrifuged for 15 minutes at 15,000 x g and the sediment was discarded. The supernatant was pelleted for 75 minutes at 100,000 x g. This pellet was taken up in a quarter volume of SPE buffer, homogenized once more and then centrifuged for 60 minutes at 1,000,000 x g. The resulting pellet was taken up in the five-fold volume of SPE buffer, homogenized and frozen and stored at -78°C (= enzyme solution).

For testing, the test compounds (or Mevinolin as a reference substance) were dissolved in dimethylformamide with the addition of 5% by volume IN NaOH and used in an amount of 10 µl in different concentrations in the enzyme test. This started after 20 minutes of pre-incubation of the compound with the enzyme at 37°C. The sample batch was 0.380 ml and contained 4 pmol glucose-6-phosphate, 1.1 mg bovine albumin, 2.1 pmol dithiothreitol, 0.35 pmol NADP, 1 unit glucose-6-phosphate dehydrogenase, 35 jjmol KxHy-phosphate pH 7.2, 20 pl enzyme preparation and 56 nmol 3-hydroxy-3-methyl-glutaryl-coenzyme A (glutaryl-3-<14>C) 1,000,000 ppm.

It was incubated for 60 minutes at 37°C and the reaction was stopped by the addition of 300 µl of 0.24 m HCl. After a post-incubation of 60 minutes at 37°C, the whole was centrifuged and 600 µl of supernatant was applied to a 0.7 cm x 4 cm column filled with "Biorex" 5-chloride 100-200 mesh (anion exchanger). One then washed with 2 ml of distilled water and the flow-through plus the wash water was added to 3 ml of aquasol and counted in an LKB scintillation counter. The IC5Q values were determined by plotting the percentage inhibition against the concentration of the compound in the sample by interpolation. To determine the relative inhibitory potency, the ICsQ value for the reference substance Mevinolin was set to 1 and compared with the simultaneously determined IC5Q value of the test compound.

The active substances in examples 1 to 23 showed a higher effect compared to Mevinolin.

Example 2

The serum-cholesterol-lowering effect of the compounds according to the invention on the blood cholesterol values in dogs and guinea pigs was found in a feeding experiment lasting several weeks. For this purpose, the substances to be examined in the case of dogs were given to healthy Beagles during several weeks, once a day, in a capsule together with the feed, orally. Cholestyramine (4 g/100 g of feed as a bile acid sequestering agent) was also added to the feed during the entire experimental period, that is before, during and after the administration period.

Twice a week, venous blood was drawn from the dogs and serum cholesterol was determined enzymatically with a commercially available test kit. The serum cholesterol values during the administration period were compared with the serum cholesterol values before the administration period (controls).

The guinea pigs received the test substance in their feed. After two weeks, blood was drawn and the serum cholesterol content was determined.

Claims (9)

1. Substituted pyrimidines of the general formula (I) there R<1> - means cycloalkyl, or - means alkyl which may be substituted with halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or a group with the formula -NR4R^, where R <4> , R <5> - are the same or different and mean aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or may be substituted with carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyloxy, aralkylthio or aralkylsulfonyl, whereby the heteroaryl and aryl residues in the latter substituents may be substituted up to three times, identically or differently, with halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, R <2> - means heteroaryl which may be substituted up to three times, equally or differently, with halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or with a group of the formula -NR <4>R<5> , where R <4> and R <5> have the meaning stated above, or R <2> - means aryl which may be substituted up to five times, the same or different, with alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkyl, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or with a group of the formula -NR<4>R^, where R <4> and R^ have the meaning indicated above, R <3> - means hydrogen, or - means cycloalkyl, or - means alkyl which may be substituted with halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or a group with the formula -NR<4>R 5, where R <4> and R^ have the meaning indicated above, or with carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkylthio or aralkylsulfonyl, whereby the heteroaryl and aryl residues in the latter substituents can be substituted up to three times, equally or differently, with halogen, cyano , trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or R <3> - means heteroaryl which may be substituted up to three times, the same or different, with halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or with a group of the formula -NR <4> R^, where R<4> and R^ have the meaning indicated above, or R <3> - means aryl which may be substituted up to five times, the same or different, with alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkyl, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or with a group of the formula -NR <4>R ^, where R <4> and R <5> have the meaning stated above, or R <3> - means alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, aralkylthio or a group of the formula -NR <4> R <5> , where R <4> and R <5> have the above meaning, X - means a group with the formula -CH2 -CH2 - or -CH=CH- and A - means a group with the formula there r<6> - means hydrogen or alkyl andR<7> - means hydrogen, - an alkyl, aryl or aralkyl residue, or - means a cation. 2. Substituted pyrimidines according to claim 1, characterized in that R<1> - is cyclopropyl, cyclopentyl or cyclohexyl or - is lower alkyl which may be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl with a group of the formula -NR4R^ , where R <4> and r <5> may be the same or different and mean lower alkyl, phenyl, benzyl, acetyl, benzoyl, phenylsulfonyl or lower alkylsulfonyl, or with pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrryl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, whereby they said heteroaryl and aryl residues may be substituted up to twice, identically or differently, with fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy, R <2> - means thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which may be substituted up to twice, identically or differently, with fluorine, chlorine, bromine , lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or - means phenyl or naphthyl, which may be substituted up to four times, identically or differently, by lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, phenylethoxy, phenylethylthio, phenylethylsulfonyl, fluorine, chlorine, bromine or cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or with a group of the formula —NR<4> R<5> , where R <4> and R^ have the meaning indicated above, R <3> - means hydrogen, or - means cyclopropyl, cyclopentyl or cyclohexyl, or - means lower alkyl which may be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl with a group of the formula -NR <4>R<5> , where R <4> and R <5> have the above meaning, or with pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, whereby they said heteroaryl and aryl residues may be substituted up to twice, identically or differently, by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy, or R <3> - means thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which may be substituted up to twice, identically or differently, with fluorine, chlorine, bromine , lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or R <3> - means phenyl or naphthyl which may be substituted up to four times, the same or different, with lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, phenylethoxy, phenylethylthio, phenylethylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or with a group of the formula -NR <4> R <5> , where R <4> and r <5> have the meaning stated above, or R <3> - means alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, aralkylthio or a group of the formula -NR <4> R^, where R<4> and r <5> have the meaning indicated above, X - means a group with the formula -CH2 -CH2 - or -CH=CH- and A - means a group with the formula there R<k> - means hydrogen or lower alkyl and R<7> - means alkyl C₁-alkyl, C6 _12 -aryl or C7 _10 - aralkyl, or - means a physiologically acceptable cation thereof. 3. Substituted pyrimidines according to claims 1 and 2, characterized in that R<1> - means cyclopropyl, cyclopentyl or cyclohexyl, or - means methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, which may be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy , methylthio, ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzoyl, acetyl, pyridyl, pyrimidyl, thienyl, furyl, phenyl, phenoxy, phenylthio , phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, R <2> - means pyridyl, pyrimidyl, quinolyl or isoquinolyl, which may be substituted with fluorine, chlorine, methyl, methoxy or trifluoromethyl, or - means phenyl, which may be substituted up to three times, identically or differently, by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenyl, phenoxy, benzyl, benzyloxy, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert-butoxycarbonyl, or R <3> - means hydrogen, cyclopropyl, cyclopentyl or cyclo hexyl, or - means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl, which may be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl , trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzoyl, acetyl, ethylcarbonyl or substituted with a group -NR <4> R <5> , where R<4> and R<5> are the same or different and means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, phenyl, benzyl, acetyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or phenylsulfonyl, or with pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, whereby the aforementioned heteroaryl and aryl residues can be substituted with fluorine, chlorine, methyl, ethyl , propyl, isopropyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, trifluoromethyl or trifluoromethoxy, or - means thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzimidazolyl or benzthiazolyl, whereby the said residues may be substituted with fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, Isopropoxy, butoxy, isobutoxy, tert-butoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert.butoxycarbonyl, or - means phenyl which may be substituted up to three times, identically or differently, by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, phenyl, phenoxy, phentylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, or may be substituted with a group of the formula -NR<4>R<5>, where R <4> and R <5> have the meaning stated above, or - means alkoxy, aryloxy, aralkylthio, alkylthio, arylthio, aralkylthio or a group of the formula -NR <4> R <5> , where R <4> and R <5> have the above meaning, X - means a group with the formula -CH2 -CH2 - or -CH=CH- and A - means a group with the formula there R^ - means hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, and R <7> - means hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or benzyl, or a sodium, potassium, calcium or magnesium or ammonium ion. 4. Process for the preparation of substituted pyrimidines of the general formula there Ri - means cycloalkyl, or - means alkyl which may be substituted with halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or a group of the formula -NR <4> R <5> , where R <4> , R <5> - are the same or different and mean aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or may be substituted with carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyloxy, aralkylthio or aralkylsulfonyl, whereby the heteroaryl and aryl residues in the latter substituents may be substituted up to three times, identically or differently, with halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, R <2> - means heteroaryl which may be substituted up to three times, the same or different, with halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or with a group of the formula -NR<4>R ^, where R <4> and R <5> have the meaning stated above, or R <2> - means aryl which may be substituted up to five times, the same or different, with alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkyl, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or with a group of the formula -NR <4> R <5> , where R <4> and R <5> have the above meaning, R <3> - means hydrogen, or - means cycloalkyl, or - means alkyl which may be substituted with halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or a group of the formula -NR<4>R^, where R <4> and R^ have the meaning indicated above, or with carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkylthio or aralkylsulfonyl, whereby the heteroaryl and aryl residues in the latter substituents can be substituted up to three times, equally or differently, with halogen, cyano , trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or R <3> - means heteroaryl which may be substituted up to three times, equally or differently, with halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or with a group of the formula -NR<4>R<5> , where R<4> and R^ have the meaning indicated above, or R <3> - means aryl which may be substituted up to five times, the same or different, with alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkyl, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or with a group of the formula -NR<4>R<5> , where R<4> and R^ have the meaning indicated above, or R <3> - means alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, aralkylthio or a group of the formula -NR <4> R <5> , where R <4> and R <5> have the above meaning, X - means a group with the formula -CH2 -CH2 - or -CH=CH- and A - means a group with the formula there R <6> - means hydrogen or alkyl and R<7> - means hydrogen, - an alkyl, aryl or aralkyl residue, or - means a cation, characterized by reducing ketones with the general formula (VIII) there R<1> , R<2> and R<3> have the above meaning and R <7> ' - means alkyl, aryl or aralkyl, saponifies the esters to produce the acids, ring-closes the carboxylic acids to produce the lactones, saponifies the esters or lactones to produce the salts, hydrates according to usual methods the ethylene compounds (X = -CH=CH-) to produce the ethylene compound (X = -CH2 -CH2 -) and optionally separates the isomers. 5. Method according to claim 4, characterized in that the reduction is carried out in the temperature range -80 to +30"C. 6. Medicine, characterized in that it contains substituted pyrimidines according to claim 1. 7. Use of substituted pyrimidines according to claim 1 for the production of pharmaceuticals. 8. Aldehydes, characterized by the general formula (IX) there R<1> - means cycloalkyl, or - means alkyl which may be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or a group of the formula -NR <4> R^, where R<4> , R <5> - are the same or different and mean aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or may be substituted with carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyloxy, aralkylthio or aralkylsulfonyl, whereby the heteroaryl and aryl residues in the latter substituents may be substituted up to three times, identically or differently, with halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, R <2> - means heteroaryl which may be substituted up to three times, the same or different, with halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or with a group of the formula -NR <4>R<5> , where R <4> and R <5> have the meaning stated above, or R <2> - means aryl which may be substituted up to five times, the same or different, with alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkyl, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or with a group of the formula -NR <4> R <5> , where R <4> and R^ have the meaning indicated above, R <3> - means hydrogen, or - means cycloalkyl, or - means alkyl which may be substituted with halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or a group with the formula -NR<4>R<5>, where R <4> and R <5> have the above meaning, or with carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkylthio, aralkylthio or aralkylsulfonyl, whereby the heteroaryl and aryl residues in the latter substituents may be substituted up to three times, equally or differently, with halogen, cyano , trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or R <3> - means heteroaryl which may be substituted up to three times, the same or different, with halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or with a group of the formula -NR <4>R<5> , where R <4> and R <5> have the meaning stated above, or R <3> - means aryl which may be substituted up to five times, the same or different, with alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkyl, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or with a group of the formula -NR <4> R <5> , whereR<4> and R<5> have the meaning stated above, or R <3> - means alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, aralkylthio or a group of the formula -NR <4> R^, where R <4> and R <5> have the meaning given above. 9. Process for the preparation of aldehydes with the general formula there R<1> - means cycloalkyl, or - means alkyl which may be substituted with halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or a group of the formula -NR <4> R <5> , where R <4> , R <5> - are the same or different and mean aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or may be substituted with carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyloxy, aralkylthio or aralkylsulfonyl, whereby the heteroaryl and aryl residues in the latter substituents may be substituted up to three times, identically or differently, with halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, R <2> - means heteroaryl which may be substituted up to three times, the same or different, with halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or with a group of the formula -NR<4>R ^, where R<4> and R^ have the meaning indicated above, or R <2> - means aryl which may be substituted up to five times, the same or different, with alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkyl, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkyl sulfamoyl, carbamoyl, dialkylcarbamoyl or with a group of the formula -NR<4>R<5> , where R <4> and R^ have the meaning indicated above, R <3> - means hydrogen, or - means cycloalkyl, or - means alkyl which may be substituted with halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or a group with the formula -NR<4>R<5>, where R <4> and R <5> have the above meaning, or with carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkylthio or aralkylsulfonyl, whereby the heteroaryl and aryl residues in the latter substituents can be substituted up to three times, equally or differently, with halogen, cyano , trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or R <3> - means heteroaryl which may be substituted up to three times, equally or differently, with halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or with a group of the formula -NR <4>R<5> , where R <4> and R <5> have the meaning stated above, or R <3> - means aryl which may be substituted up to five times, the same or different, with alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkyl, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or with a group of the formula -NR <4>R<5> , where R<4> and R^ have the meaning indicated above, or R <3> - means alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, aralkylthio or a group of the formula -NR <4> R <5> , where R <4> and R <5> have the above meaning, characterized in that pyrimidines of the general formula (XI) there R<1> , R <2> and R <3> have the meaning given above, and R <8> - means C^^-alkyl, C6 _1Q -aryl or C7 _1Q -aralkyl, is reduced in the temperature range -70°C to +100°C to hydroxy-methylene compounds with the formula: there R<1>, R<2> and R<3> have the above meaning, and are then oxidized to the corresponding aldehydes with the formula: there R<1> ,R<2> ,R<3> have the above "meaning, after which these are reacted with C1_4 -dialkylaminovinylphosphonates in the presence of sodium hydride in inert solvents within the temperature range -20°C to +40°C.