DD283612A5 - PROCESS FOR PREPARING SUBSTITUTED IMIDAZOLINONES AND IMIDAZOLINTHIONES - Google Patents

Abstract

The invention relates to a process for the preparation of substituted imidazolinones and imidazoline thiones having valuable pharmacological properties, in particular having an inhibitory effect on HMG-CoA reductase for the treatment of hyperlipoproteinemia, lipoproteinemia, arteriosclerosis. According to the invention, there are prepared novel substituted imidazolinones and imidazolinethiones of general formula (I) wherein the substituents R 1, R 2, R 3, A, B and X have the meaning given in the description and in the claims. Formula (I) {new substituted imidazolinones and imidazoline-thiones; inhibitory effect on HMG-CoA reductase; Drug; hyperlipoproteinemia; lipoproteinaemia; Arteriosclerosis}

Description

Process for the preparation of substituted imidazolinones and imidazolinethiones

Field of application of the invention

The invention relates to a process for the preparation of substituted imidazolinones and Imidazolininthionen, Zvvischenverbindungen for their preparation and their use in medicaments.zur treatment of hyperlipoproteinemia, lipoproteinemia or arteriosclerosis »

Characteristic of the known state of the art

It is known that lactone derivatives isolated from fungal cultures are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hi-iG-CoA reductase) are A'ievinolin, EP-PS 22 478; US Pat. No. 4,231,938 /, In addition, certain indole derivatives or pyrazole derivatives are also inhibitors of HMG-CoA reductase / EP-A 1,114,027; US-PS 4,613,610 / known »

Object of the invention

The aim of the invention is the provision of novel compounds with a strong inhibitory effect on 3-hydroxy-3-methyl-glutaryic coenzyme A reductase (HMG-CoA reductase).

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

-Ia-

There have been substituted imidazolinones and imidazolinethiones of the general formula (I)

9 2

l · '

in which

E * - represents cycloalkyl, or

- is alkyl »which may be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl

or by a group of the formula -NR * R, 10

wherein

R 1, R 2 'are identical or different and denote alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl,

or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals of the last-mentioned substituents are identical or different by halogen, cyano, trifluoromethyl, Trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl may be substituted,

R - is heteroaryl which may be up to 3 times the same or different from halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of formula -NR R ^ can be substituted,

wherein r4 _and jbb have the meaning given

Le A 25 813

or

r 2 _ aryl »which may be substituted identically or differently up to 5 times by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, Trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ ,

wherein

R and R have the abovementioned meaning,

R ³ - is hydrogen or - is acyl, alkylsulfonyl or arylsulfonyl, where the aryl radical may be substituted by alkyl or halogen, or

- stands for aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl or alkoxycarbonyl, or

- represents cycloalkyl, or

- is alkyl which may be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁴ R ⁵ ,

wherein

R ⁴ and R have the abovementioned meaning,

Le A 25 813

or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals of the last-mentioned substituents are identical or different by halogen, cyano, trifluoromethyl, Trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl may be substituted,

or R 1 - represents heteroaryl which is up to 3 times the same or different from halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁴ R may be substituted,

wherein

R ⁴ and R 1 have the abovementioned meaning,

or

R - is aryl which may be substituted identically or differently up to 5 times by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl , Trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ ,

Le A 25 813

wherein 5

R ^ and R ^ have the abovementioned meaning, B - represents oxygen or sulfur,

X - represents a group of the formula -CH ₂ -CH ₂ "or -CH = CH,

and

A is a group of the formula

I ^

-CH-CH ₂ -C-CH ₂ -COOR ⁷ HO II or ^ Y ^,

OH OH 20

wherein

R ^{6 is} hydrogen or alkyl and

R ⁷ - hydrogen,

an alkyl, aralkyl or aryl radical or

- a cation means

found. 30

Surprisingly, the substituted imidazolinones and imidazolinethiones according to the invention have a significant pharmacological action, in particular a good inhibitory action on HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase),

Le A 25

Cycloalkyl is generally a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Preferred is the cyclopropyl, cyclopentyl and the cyclohexyl ring. Examples which may be mentioned are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl

Alkyl is generally a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Preferred is lower alkyl having 1 to about 6 carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.

Alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms bonded via an oxygen atom. Lower alkoxy having 1 to about 6 carbon atoms is preferred. Particularly preferred is an alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.

Alkylthio generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms bonded via a sulfur atom. Preferred is lower alkylthio having 1 to about 6 carbon atoms. Particularly preferred is an alkylthio radical having 1 to 4 carbon atoms, for example Me-35

Le A 25 813

thylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, isopentylthio, hexylthio, isohexylthio, heptylthio, isoheptylthio, octylthio or isooctylthio.

Alkvlsulfonyl is generally a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms, which is bonded via an SC ^ group. Preferred is lower alkylsulfonyl having 1 to about 6 carbon atoms. Examples which may be mentioned: methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, isopentylsulfonyl, hexylsulfonyl, isohexylsulfonyl.

Aryl is generally an aromatic radical having from 6 to about 12 carbon atoms. Preferred aryl radicals are phenyl, naphthyl and biphenyl.

Aryloxy is generally an aromatic radical having from 6 to about 12 carbon atoms which is bonded via an oxygen atom. Preferred aryloxy radicals are phenoxy or naphthyloxy.

Arylthio is generally an aromatic radical having 6 to about 12 carbon atoms, which is bonded via a sulfur atom. Preferred arylthio radicals are phenylthio or naphthylthio.

Aryl sulfonyl is generally an aromatic pest having 6 to about 12 carbon atoms, which has a

Le A 25 813

- ft -

For example: phenylsulfonyl, naphthylsulfonyl and biphenylsulfonyl.

Aralkvl is generally an aryl radical having 7 to 14 carbon atoms attached via an alkylene chain. Preference is given to aralkyl radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part. The following aralkyl radicals may be mentioned as examples: benzyl, naphthylmethyl, phenethyl and phenylpropyl.

Aralkoxy in general represents an aralkyl radical having 7 to 14 carbon atoms "wherein the alkylene chain is bonded via an oxygen atom. Aralkoxy radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. The following aralkoxy radicals may be mentioned as examples: benzyloxy, naphthylmethoxy, phenethoxy and phenylpropoxy.

Aralkylthio in general represents an aralkyl _w ith 7 to about 14 carbon atoms wherein the alkyl chain is attached via a sulfur atom. Preference is given to aralkylthio radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part. The following aralkylthio radicals may be mentioned as examples: benzylthio, naphthylmethylthio, phenethylthio and phenylpropylthio.

Aralkvlsulfonyl is generally an aralkyl radical having from 7 to about 14 carbon atoms, where the alkyl

Le A 25 813

kylreste is bound via an SC ^ chain. Aralkylsulfonyl radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. The following aralkylsulfonyl radicals may be mentioned by way of example: benzylsulfonyl, naphthylmethylsulfonyl, phenethylsulfonyl and phenylpropylsulfonyl.

Alkoxycarbonyl , for example, by the formula -C-OAlkyl

Il

being represented. Alkyl here stands for a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Preferred is lower alkoxycarbonyl having 1 to about 6 carbon atoms in the alkyl moiety. Particularly preferred is an alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety. For example, the following alkoxycarbonyl radicals may be mentioned: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

Acyl generally represents phenyl or straight or branched lower alkyl having 1 to about 6 carbon atoms which are bonded via a carbonyl group. Preference is given to phenyl and alkyl radicals having up to 4 carbon atoms. Examples include: benzoyl, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl,

Halogen is generally fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. Halogen is particularly preferably fluorine or chlorine.

Le A 25 813

Heteroaryl represents for the purposes of the given above definition in general represents a 5- to 6-membered aromatic ring "may contain as hetero atoms of oxygen," Sulfur and / or nitrogen and can be fused to the other aromatic rings "are preferably 5- and 6 aromatic rings containing one oxygen, one sulfur and / or up to two nitrogen atoms and optionally benzo-fused. Particularly preferred heteroaryl radicals which may be mentioned are: thienyl, furyl, pyrolyl, 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 radical, an ester group forms ·

Preferred are physiologically acceptable esters which are readily hydrolyzed in vivo to a free carboxyl group and a corresponding physiologically acceptable alcohol. These include, for example, alkyl esters (C ₁ to C ₆ ) and aralkyl esters (C ₇ to C ₁₀ ), preferably lower alkyl esters and benzyl esters. Especially preferred are methyl esters, ethyl esters, propyl esters and benzyl esters.

If R ^{7 is} a cation, it is preferably a physiologically acceptable metal or ammonium cation. Preference is given here alkali or. Alkaline earth cures like 35

Le A 25 813

For example, sodium, potassium, magnesium or calcium cations, and aluminum or ammonium cations, and non-toxic substituted ammonium cations from amines such as di-lower alkylamines, Triniederalkylamine, dibenzylamine, N, N'-dibenzylethylenediamine, N-benzyl-ßphenylethylamin, N- Methylmorpholine or N-ethylmorpholine, dihydroabiethylamine, Ν, Ν ^1- bis-dihydroabiethylethylenediamine, N-lower alkylpiperidine and other amines that can be used to form salts «

In the context of the present invention, the substituted imidazolinones and imidazoline thiones preferably correspond to the general formula

_R 2>

s "^ 1 ^(Ia)

ff

in which

R ¹ , R ² , R ³ , X, A and B are as defined above

to have,

and the general formula el.

3 2 ^(Ib)

R ³ -N \ ^ NR ²

-NVj ^ N-

B in which

Le A 2 5 813

R *, r2, r3, χ, α and B are as defined above «

Preference is given to imidazolinones and imidazolinethiones of the formula (I)

in which

R - is cyclopropyl, cyclopentyl or cyclohexyl, or lower alkyl which may be substituted by fluoro, chloro, bromo, cyano, loweralkoxy, loweralkylthio, loweralkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, loweralkoxycarbonyl, benzoyl, loweralkylcarbonyl, by a group of Formula -NR ^ R,

wherein

R and R are the same or different and

Lower alkyl, phenyl, benzyl, acetyl, benzoyl, phenylsulfonyl or lower alkylsulfonyl,

or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrryl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, ^ O phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, wherein said heteroaryl and aryl groups are up to 2-fold

identical or different by fluorine, chlorine, bromine, 35

Le A 25 813

Lower alkyl, lower alkoxy, trifluoromethyl, or trifluoromethoxy may be substituted,

R ² - is 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 up to May be substituted once or twice by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl,

Phenoxy, trifluoromethyl, trifluoromethoxy or

deralkoxycarbonyl, or

represents phenyl or naphthyl which may be substituted identically or differently up to four times by 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 by a group of the formula -NR 1 R 2,

where r4 _{un (} j p5 jj _{e e} Qben given meaning,

R ³ - for hydrogen or

is benzoyl or lower alkylcarbonyl, or

is lower alkylsulfonyl, phenylsulfonyl or tolyl sulfonyl, or

Le A 25 813

for aminocarbonyl, lower alkylaminocarbonyl, di-lower alkylaminocarbonyl, phenylaminocarbonyl or

Lower alkoxycarbonyl is »or

- represents cyclopropyl, cyclopentyl or cyclohexyl or

- is lower alkyl which may be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy,

deralkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl, by a group of the formula -NR ⁴ R ⁵ , 15

in which .._._

R ⁴ and R 1 have the abovementioned meaning,

or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, wherein the said heteroaryl and aryl radicals may be substituted equally or differently by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl, or trifluoromethoxy up to 2 times, or

R ³ - represents thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, 35

Le A 25 813

Cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which may be up to 2 times the same or different substituted by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or

R 1 is phenyl or naphthyl, which may be substituted identically or differently up to 4 times by lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethyl, phenylethoxy, Phenylethylthio, phenylethylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula -NR ⁴ R ⁵ ,

in which

R ⁴ and R ^{5 have} the abovementioned meaning B is a group of the formula 0 or S,

X - represents a group of the formula -CH ₂ -CH ₂ - or -CH = CH-,

A - for a group of the formula

R ^{6 is} -CH-CH ₂ -C-CH ₂ -COOR ⁷ or HO ^ T,

OH OH I

Le A 25 813

wherein

R 1 represents hydrogen or lower alkyl, and

R ^{7 is} alkyl (C ₁ to C ₆ ), aryl (C ₆ to C ₁₂ ) or

Aralkyl (C ₇ to C ₁ Q), or

- a physiologically contractual cation

means.

Particularly preferred are compounds of the general

Formulas (I) 15

in which

R * - represents cyclopropyl, cyclopentyl or cyclohexyl, or

- is 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 ₄ 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 ^ - is pyridyl, pyrimidyl, quinolyl or isoquinolyl represented by fluoro, chloro, methyl, methoxy or

Le A 25 813

Trifluoromethyl may be substituted by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy , Isobutoxy, tert-butoxy, methylthio, ethyl

* 0 thio, 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,

R ^ - represents hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or

is 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 by a group -NR ^ R ^,

Le A 25 813

in which

R ^ and R ^ are the same or different and

Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, phenyl, benzyl, acetyl, methylsulfonyl, ethylsulfonyl,

Propylsulfonyl, isopropylsulfonyl or Phenylsulfonyl,

or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinoline, isoquinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, where the said heteroaryl and aryl radicals are represented by fluorine, chlorine, methyl, ethyl, Propol, isopropyl, isobutyl, tert. Butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert -butoxy, trifluoromethyl or trifluoromethoxy may be substituted, or

R ³ - is thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isooxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolinyl, benzoxazolyl, benzimidazolyl or benzothiazolyl, where the radicals mentioned are replaced by 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 35

Le A 25 813

   , ; ί

R ³ - is phenyl which is up to 3 times the same or different from 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, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert, butoxycarbonyl or may be substituted by a group -NR ^ Fr,

in which

R ^ and Fr have the abovementioned meaning, 25

or

R ³ - represents benzoyl, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, phenylsulfonyl or tolylsulfonyl,

for aminocarbonyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butylaminocarbonyl, dimethyl, diethyl, dipropyl, diisopro-35

Le A 25 813

pyl-, dibutyl- or Dilsobutylaminocarbonyl, phenylaminocarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert.Butoxycarbonyl,

B- stands for oxygen or sulfur,

X - represents a group of the formula -CH 2 -CH 2 - or -CH = CH,

a - for a group of the formula

-CH-CHo-C-CHo-COOR ⁷ or HO ^ TT,

I ² I ² V ⁶

OH OH

wherein

R ^{6 is} hydrogen, methyl, ethyl, propyl, isopropyl,

Butyl, isobutyl or tert-butyl, and 25

R ^{7 is} hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or benzyl, or a sodium, potassium, calcium or magnesium or ammonium cation.

The substituted imidazolinones and imidazolinethiones of the general formula (I) according to the invention have several asymmetric carbon atoms and can therefore exist in different stereochemical forms.

Le A 25 813

Both the individual isomers and their mixtures are the subject of the invention.

Depending on the meaning of the group X or of the radical A, different stereoisomers result, which in the

should be explained in more detail below: 10

a) If the group -X- represents a group of the formula -CH = CH-, the compounds according to the invention may exist in two stereoisomeric forms which may be E-configured (II) or Z-configured (III) on the double bond:

ZA / A (II)

(E-configured)

I (IH)

(Z-configured) where

ζ for the rest

or I | stands. R ¹ R ^ Nv ^ ²

B B

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

Le A 25

b) If the radical -A- is a group of the formula

OH OH

thus, the compounds have the general formula

(I) 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 to each other, the

erf erfndungsgemäßen compounds in the erythro configuration (IV) or in the threo configuration (V) are present.

ZR ⁶

X-CH-CH ₂ -C-CH ₂ -COOR ⁷ erythro-form (IV) OH OH

¹ 'X-CH-CH ₂ -C-CH ₂ -COOR ⁷ threo-form (V).

OH OH

Both of the compounds in erythro and in threo configuration again each have two

Enantiomers, namely 3R, 5S isomer or 3S, 5R isomer (erythro form) and 3R, 5R isomer and 3S, 5S isomer (threo form).

Preference is given here to the erythro-configured isomers, more preferably the 3R, 5S isomers and the 3R, 5S-3S, 5R racemic ♦

Le A 25 813

c) If the radical -A- is a group of formula 5

RS HO

IQ thus possess the substituted imidazolinones and

Imidazolinthione at least two asymmetric carbon atoms, namely the carbon atom to which the hydroxy group is bonded, and the carbon atom to which the radical of the formula Z-X- is bound,

Depending on the position of the hydroxy group to. free

Valence on the lactone ring, the substituted imidazolinones and imidazolinethiones may be present as cis-lactones (VI) or as trans-lactones (VII):

HQ

cis-lactone (VI)

ζ-:

trans-lactone (VII). Z]

Both cis-lactone and trans-lactone

in turn there are two isomers, namely the 30th

4R, 6R isomers or the 4S, 6S isomer (cis-lactone), and the 4R, 6S isomer or 4S, 6R isomer (trans-lactone). Preferred isomers are the trans-lactones. Particularly preferred here is the 4R, 6S isomer (trans) and the 4R, 6S-4S, 6R racemate.

Le A 25

10

For example, the following isomeric forms of the substituted imidazolinones and imidazolinethiones may be mentioned:

15 20

30

35

Le A 25 813

Γ!

? ^2v > Y ^ _{== Y} ^% ^ CH- CH ₂ - C

«OH

- ₂ -CR ⁶ -CH ₂

R ⁶ -CHo-COOR ⁷

10

R ^d -

τ ·

OH OH 'CH-CH ₂ -CR ⁶ -CH ₂ -C00R ⁷

1520 OH OH 'CH-CH ₂ -CR ⁶ -CH ₂ -C00R ⁷

-ΝγΝ-

OH 25 OH

ch- CHo - c;

₂ -CR ⁶ -CH ₂ -C00R ⁷

30

35 H0V..R ⁶

R ^]

Le A 25 813

10 15

20

OH OH 'CH-CHo-CF

⁶ -

-C00R

R ^J -

30 OH OH 'CH-CH ₂ -CR ⁶ -CH ₂ -COOR ⁷

35

Le A 25 813

OH OH CH-CH ₂ -CR ⁶ -CH ₂ -C00R ⁷

9 ^H

H-CH ₂ -CR ⁶ -CH ₂ -COOR ⁷

Very particular preference is given to the compounds of the general formula (Ia) and (Ib)

in which 20

R * - represents cyclopropyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.

R ^ - is phenyl, which is up to 2 times the same

or may be substituted differently by methyl or trifluoromethyl,

r3 - is methyl, isopropyl, tert-butyl or - is phenyl, which is up to 2 times the same or

may be different from methyl, methoxy, fluorine or chlorine,

B - is oxygen or sulfur, X - is a group of the formula

Le A 25

- 23 -

(T-configured) is

and

A - for a group of the formula

-CH-CH ₂ -C-CH ₂ -COOR

or

OH

OH

HO

stands,

wherein

R is hydrogen and

R represents hydrogen, methyl or ethyl or denotes a sodium or potassium cation.

The erfindungsgernäßa process for the preparation of animal- substituted imidazolinones and imidazolinethiones of the general formula (I)

X-A

(D

in which 12 3

R, R, R _t A ₁ 3 and X dia have the abovementioned meaning,

is characterized in that one

Ketones of the general formula (VIII) 5

R ² S

7 · OH (VIII)

J = U ₁ ZCH = CH-CH-CH ₂ -C-CH ₂ -COOR '

I. fR ¹ I

R ^B

in which

R *, R, R ^ and B are as defined above, and

R ⁷ '- is alkyl (C ₁ to C ₆ ), aryl (C ₆ to C ₁₂ ) or aralkyl (C ₇ to C ₁₀ ),

reduced, ₂ q in the case of the preparation of the acids the esters saponified,

cyclized in the case of the production of lactones the carboxylic acids,

in the case of preparation of the salts, either the esters or the lactones are saponified,

in the case of preparation of the ethylene compounds (X = -CH ₂ -CH ₂ -) the ethene compounds (X = -CH = CH-) are hydrogenated by customary methods 3Q,

and, if appropriate, separating isomers «

The inventive method can be explained by the following equation scheme!

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H ₂ COOCH ₃

reduction

HC00 ^e Na®

H ₂ COOCH ₃

HCOOH

Le A 25

The reduction can be carried out with the customary reducing agents, preferably with those which are suitable for the reduction of ketones to hydroxy compounds. Particularly suitable here is the reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. Preferably, the reduction is carried out with complex metal hydrides such as lithium borohydride "sodium borohydride" potassium borate "zinc borohydride" lithium trialkylhydrido borate "sodium trialkyl hydrido boronates" sodium cyano trihydrido borate or lithium aluminum hydride. Most preferably, the reduction is carried out with sodium borohydride, in the presence of triethylborane »

Suitable solvents include the usual organic solvents which do not change under the reaction conditions. These include, preferably, ethers such as diethyl ether, dioxane, tetrahydrofuran or dimethoxyethane, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, or Hydrocarbons such as benzene, toluene or xylene. It is also possible to use mixtures of the said solvents.

The reduction of the ketone group to the hydroxy group is particularly preferably carried out under conditions in which the other functional groups, such as

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As the alkoxycarbonyl group are not changed. Particularly suitable for this purpose is the use of sodium borohydride as a reducing agent, in the presence of triethylborane in inert solvents such as preferably ethers.

* ^ The reduction is generally carried out in a temperature range of -80 ⁰ C to room temperature (30 ⁰ C), preferably from -78 ⁰ C to ⁰ ° C.

The process of the invention is generally carried out at atmospheric pressure. However, it is also possible to carry out the process under reduced pressure or overpressure (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, preferably from 1 to 1.5 mol, based on 1 mol of the keto compound.

Under the reaction conditions given above, the carbonyl group is generally reduced to the hydroxy group without reduction at the double bond to the single bond.

For the preparation of compounds of general formula (I) in which X is an ethylene moiety, the reduction of ketones (III) can be carried out under such conditions that both the carbonyl group and the double bond are reduced.

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Moreover, 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 acids in the context of the general formula (I) correspond to the formula (Ic) 10

R ²

R ⁶

-CH-CH ₇ -C-CH ₇ -COOH (Ic) 11I

OH OH

^B

in which

R ¹ , R ² , R ³ , R ⁶ , B and X are as defined above

Have 2Q.

The carboxylic acid esters in the context of the general formula (I) correspond to the formula (Id)

(Id)

25 in which one ι-: R ² OH R ⁶ Γ B * ² T OH 30

R ¹ , R ² , R ³ , R ⁶ , B and X have the abovementioned meaning, and

R ⁷ 'is alkyl, aralkyl or aryl

 35

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The salts of the compounds according to the invention in the context of the general formula (I) correspond to the formula (Ie)

, COO "

OH OH

* N +

(Ie)

in which

R ¹ , R ² , R ³ , R ⁶ , B and X have the abovementioned meaning,

and

M ^{n + is} an n-valent cation, where η is 1 or 2 «

The lactones in the context of the general formula (I) correspond to the formula (If)

HCL · JR

(If)

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in which 5

R ¹ , R ² , R ³ , R ⁶ , B and X have the meaning given above

For the preparation of the carboxylic acids of the general formula (Ic) according to the invention, the carboxylic acid esters of the general formula (Id) or the lactones of the general formula (If) are generally saponified by customary methods. The saponification is generally carried out by treating the esters or lactones in inert solvents with customary bases "wherein in general first the salts of the general formula (Ie) arise, which are then in a second step by treatment with acid in the free acids of the general Formula (Ic) can be transferred «20

Suitable bases for saponification are the customary inorganic bases. These include preferably alkali metal hydroxides or alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium bicarbonate, or alkali metal alcoholates such as sodium ethoxide, sodium methoxide, potassium methoxide, potassium ethanolate or potassium tert-butoxide. Particular preference is given to using sodium hydroxide or potassium hydroxide. «

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Suitable solvents are water or the usual organic solvents for saponification. These preferably include alcohols such as methanol, ethanol, propanols isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulfoxide. Alkali hole are particularly preferred such as methanol, ethanol, propanol or isopropanol used. It is also possible to use mixtures of said solvents.

The hydrolysis is in general carried out in a temperature range from ⁰ ° C to +100 ⁰ C, preferably +20 ⁰ C to +80 ⁰ C.

In general, the saponification is carried out at atmospheric pressure. However, it is also possible to operate at reduced pressure or at overpressure (for example from 0.5 to 5 bar).

In carrying out the saponification, the base is generally used in an amount of 1 to 3 mol, preferably from 1 to 1.5 mol, based on 1 mol of the ester or of the lactone. Particular preference is given to using molar amounts of the reactants.

When carrying out the reaction, in the first step the salts of the compounds (Ie) according to the invention are formed as intermediates which can be isolated. The acids (Ic) according to the invention are obtained by treating the salts (Ie) with customary inorganic acid.

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Mineral acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, have proven to be advantageous in the preparation of carboxylic acids (Ic). The basic reaction mixture of saponification can be acidified in a second step without isolation of the salts then be isolated in the usual way «

For the preparation of the lactones of the formula (If) according to the invention the carboxylic acids (Ic) according to the invention are generally cyclized by conventional methods, for example by heating the corresponding acid in inert organic Losemitteln «optionally in the presence of molecular sieve.

Suitable solvents here are hydrocarbons

such as benzene, toluene, xylene, petroleum fractions, or tetralin or diglyme or triglyme. Benzene, toluene or xylene are preferably used. It is also possible to use mixtures of the said solvents. It is particularly preferred to use hydrocarbons, in particular toluene, in the presence of molecular sieve.

The cyclization is generally carried out in a temperature range from -40 ⁰ C to +200 ⁰ C, preferably from -25 ° C to +50 ⁰ C.

The cyclization is generally carried out at atmospheric pressure, but it is also possible, the process

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to be carried out under reduced pressure or overpressure (ζ.Β »in a range of 0.5 to 5 bar).

In addition, the cyclization is also carried out in inert organic solvents, with the aid of cyclizing or dehydrating agents. "Dehydrating agents used here are preferably carbodiimides. As the carbodiimides, there are preferably used N, N'-dicyclohexylcarbodiimide paratoluene sulfonate, N-cyclohexyl-N ¹ - [2- (N "-methylmorpholinium) ethyl] carbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride "

Suitable solvents include the usual organic solvents. These include preferably 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 chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride, or hydrocarbons such as benzene, toluene, xy lol, or petroleum fractions. Particular preference is given to using chlorinated hydrocarbons, for example methylene chloride, chloroform or carbon tetrachloride

 30

The reaction is generally carried out in a temperature range from ⁰ C to +80 ⁰ C, preferably +10 ⁰ C to +50 ⁰ C. "

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In carrying out the cyclization, it has proved to be advantageous to use the cyclization method with the aid of carbodiimides as dehydrating agents.

The separation of the isomers into the stereoisomerically uniform constituents chen ^ ¹ is generally carried out by conventional methods such as, for example, of E, L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962. Preference is given here to the separation of the isomers at the stage of the racemic lactones. Particularly preferred is the racemic mixture of trans-lactones (VII) by treatment with either D - (+) -

or L - (-) - <x-methylbenzylamine by conventional methods in

the diastereomeric dihydroxyamides (Ig) 20

OH CH ₃

JL I

^ -CH ₂ -CONH-CH-C ₆ H ₅ (Ig)

Z-X- ^ M) H 25

in which

Z and X have the meaning given above,

Then, as usual, can be separated by chromatography or crystallization into the individual diastereomers. Subsequent hydrolysis of the pure diastereomeric amides by conventional methods, for example by treating the diastereomeric amides with inorganic bases such as sodium hydroxide or potassium

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hydroxide in water and / or organic solvents such as alcohols z "B" methanol, ethanol, propanol or isopropanol, give the corresponding enantiomerically pure dihydroxy acids (Ic), which can be converted by cyclization into the enantiomerically pure lactones as described above Preparation of the compounds of general formula (I) according to the invention in enantiomerically pure form, that the configuration of the end product according to the method described above depends on the configuration of the starting materials.

The isomer separation should be exemplified in the following scheme:

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trans-racemate

CH-;

H ₂ -CO-NH-CH-C ₆ H ₅

diastereomeric mixture

1) diastereomer separation

2) saponification

3) lactonization

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· ;. ρ.-. ο

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

A process for the preparation of the ketones of the general formula (VIII) according to the invention has been disclosed.

R ² Il ₇ .

H = CH-CH-Ch ₂ -C-CH ₂ -CQQR ⁷

¹ I

I , t ³ T

V OH (VIII)

R ³ T

in which

R, R ² , R ³ and R have the abovementioned meaning,

found, which is characterized in that 20

Aldehydes of the general formula (IX)

(IX)

in which 30

R, R, R and B are as defined above,

in inert solvents with acetoacetic ester of the general formula (X)

S ₇ .

H ₃ CC-CH ₂ -COOR ⁷

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in which

R ⁷ 'has the meaning given above

in the presence of bases «

The process according to the invention can be explained, for example, by the following formula scheme:

+ H ₃ CC-CH ₂ -COOCH ₃

base

H ₂ COOCH ₃

Suitable bases here are the usual strongly basic compounds. These preferably include organolithium compounds such as, for example, n-butyllithium, sec-butyl lithium, tert-butyl lithium or phenyl lithium, or amides such as, for example, lithium diisopropyl

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amide, sodium amide or potassium amide, or Lithiumhexamethyldisilylamid, or alkali metal hydrides such as sodium hydride or potassium hydride, It is also possible to use mixtures of said bases. Particular preference is given to using n-butyllithium or sodium hydride or a mixture thereof

Eventually, additives of metal halides, e.g. Magnesium chloride or zinc bromide advantageous. Particularly preferred is the addition of zinc bromide.

Suitable solvents here are the usual organic solvents which do not change under the Reaktiorisbedingungen. These include, preferably, ethers, such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, or hydrocarbons, such as benzene, toluene, xylene, cyclohexane, hexane or halogenated fractions. It is also possible to use mixtures of said solvents. Particular preference is given to using ethers, such as diethyl ether or tetrahydrofuran,

The reaction is generally carried out in a temperature range from -80 ° C to + 50 ⁰ C, preferably from -20 ° C to room temperature.

The process is generally carried out at atmospheric pressure, but it is also possible to carry out the process under reduced pressure or at elevated pressure, e.g. in a range of 0.5 to 5 bar.

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In carrying out the process, the acetoacetic ester is generally used in an amount of from 1 to 2, preferably from 1 to 1, 5 mol, based on 1 mol of the aldehyde.

The ethyl acetoacetates of the formula (X) used as starting materials are known or can be prepared by known methods [Beilstein's Handbook of Organic Chemistry III . 632; 438],

Examples of suitable acetoacetic esters for the process according to the invention are:

Methyl acetoacetate, ethyl acetoacetate, acetoacetate, ethyl acetoacetate «

The aldehydes of the general formula (IX) used as starting materials are new.

In addition, a process for the preparation of the aldehydes of the general formula (IX) 25

AET

I. fR ¹ (IX)

in which R ¹ , R ² , R ³ and B have the abovementioned meaning,

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- 46 -

which is characterized in that imidazolinones and imidazolinethiones of the general formula (XI)

rhi '

in which 15

R ¹ , R, R ° and B have the abovementioned meaning,

in inert solvents in the presence of auxiliaries

with N, N-dialkylaminoacrolein of the formula (XII) 20

AlkyU,

^ N-CH = CH-CHO (XII), alkyl

in which

Le A 25

Alkyl represents a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms »

implements ·

The process according to the invention can be illustrated, for example, by the following formula scheme:

H ₃ C

H ₃ C

Suitable solvents are the usual organic solvents which are stable under the reaction conditions. These include, preferably, hydrocarbons, such as benzene, toluene, xylene, hexane, petroleum fractions,

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2 η 3

Chlorobenzene or dichlorobenzene, or ethers such as diethyl ether, dioxane or tetrahydrofuran, or chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride or acetonitrile "It is also possible to use mixtures of said solvents." Anhydrous acetonitrile or chloroform is particularly preferably used.

As auxiliaries acid chlorides are generally used. Preference is given to phosphorus oxychloride or phosgene,

particularly preferably used phosphorus oxychloride «15

The reaction is carried out in a temperature range from -20 ⁰ C to +150 ⁰ C, preferably from ⁰ ° C to +100 ⁰ C.

The process is generally carried out at atmospheric pressure. However, it is also possible to carry out the process under reduced pressure or overpressure (for example in the range from 0.5 to 5 bar).

In carrying out the process, the Dimethylaminoacrolein is generally used in an amount of 2 to 6, preferably from 3 to 4 mol, based on 1 mol of the pyrrole.

The imidazolinones used as starting materials and Imidazolinthione the general formula (XI) are known or can be prepared by known methods starting from aminoketones CEP-A-222 664].

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The aminoketones used as starting materials are known or can be prepared by known methods [Methods of Organic Chemistry, Vo. 7 / 2c, 2251 ff (1977); J. Org. Chem. 33, 494 (1968)].

The compounds of the general formula (I) according to the invention have valuable pharmacological properties.

IQ and can be used in pharmaceuticals. In particular, they are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and, as a result, inhibitors of cholesterol biosynthesis. They can therefore be used to treat hyperlipoproteinemia,

Lipoproteinamie or atherosclerosis are used.

The new active compounds can be converted in known manner into customary formulations, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. In this case, the therapeutically active compound should be present in each case in a concentration of about 0.5 to 98% by weight, preferably 1 to 90% by weight, of the total mixture, i. in amounts sufficient to achieve the stated dosage margin.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of using water as a diluent, organic solvents may optionally be used as auxiliary solvents.

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Examples of excipients which may be mentioned are: water, non-toxic organic solvents such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut / sesamol), alcohols (e.g., ethyl alcohol, glycerin), excipients such as e.g. ground natural minerals (eg kaolins, clays, talc, chalk), ground synthetic minerals (eg fumed silica, silicates), sugars (eg cane, milk and dextrose), emulsifying agents (eg polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, Alkylsulfonates and arylsulfonates), dispersants (eg lignin, sulfite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application is carried out in a customary manner, preferably orally, parenterally, perlingually or intravenously. In the case of oral administration, tablets may, of course, besides the abovementioned excipients, also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. Further, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting. In the case of aqueous suspensions, the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.

In the case of parenteral administration, solutions of the active ingredients using appropriate liquid

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Carrier materials are used »

In general, it has proved to be advantageous to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight to achieve effective results when administered intravenously, and for oral administration, the dosage is about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weights

Nevertheless, it may be necessary to deviate from the stated amounts, depending on the body weight or the nature of the application, the individual behavior towards the drug, the type of formulation and the time or interval at which it is administered "Thus, in some cases, it may be sufficient to make do with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. When administering large amounts it may be advisable this individual gave several to distribute over dan day.

Working Example

The invention will be explained in more detail below with reference to some examples.

Example 1 5

2- (Benzyl-methylamino) -l- (4-fluorophenyl) -l-oxo-ethane hydrochloride

0 CH, II I ^W I II * HCl

jg To a solution of 81.8 g (0.68 mol) of N-methylbenzylamine in 220 ml of diethyl ether is added dropwise at ^{0 0} C, a solution of a-bromo-4-fluoroacetophenone (70.9 g, 0.33 mol) in 310 ml of diethyl ether and stirred overnight. The precipitate is separated, the filtrate with hydrochloric acid gas

2Q added, the remaining methylbenzylamine hydrochloride separated, the filtrate is stirred with acetone, the product precipitates.

Yield: 52.8 g 55 % of theory ¹ H-NMR (DMSO): δ = 2.85 (s, 3H, CH ₃ ); 4.5 (br, 2H, CH ₂ );

5.1 (br, 2H, CH ₂ C = O); 7.3-8.2 (m, 9H, aromatics-H) ppm.

Example 2

1- (4-fluorophenyl) -2-methylamino-I-oxo-ethane hydrochloride

HCl

I "II

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1.2 g of 10% palladium on carbon are added to a solution of 10 g (31 mmol) of the compound from Example 1 in 200 ml of glacial acetic acid under a nitrogen atmosphere. After hydrogenation in a shaking apparatus (hydrogen uptake approx. 700 ml), the catalyst is filtered off »Distilled off the solvent, the product washed with water and dried.

Yield: 7.2 g of ¹ H-NMR (DMSO): δ

97% of theory

2.6 (s, 3H, CH _3); 4.75 (s, 2H, CH ₂ ); 7.3-8.2 (m, 4H, aromatics H); 9.5 (br, 2H, NH) ppm.

Example 3

N-C2- (4-fluorophenyl) -2-oxo-ethyl] -N-methyl-N'-phenylurea

To a suspension of 3 g (12.5 mmol) of the compound from Example 2 in 30 ml of toluene are added 1.26 g (12.5 mmol) of phenyl isocyanate and slowly added dropwise at ^{0 0} C 1.5 g (12.5 mmol ) Triethylamine added. It is stirred overnight at 25 ° C. The toluene phase is washed with water, whereby the product precipitates. After drying, 3.54 g.

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Yield: 98.9 % of theory

¹ H-NMR (DMSO): 6 = 2.8 (s, 2H, CH ₂ ); 3.35 (s, 3H, CH _3);

3.6 (s, IH, NH); 6.9-7.6 (m, 9H, aromatic

mate-H) ppm.

10 15 20

Example 4

4- (4-fluorophenyl) -1-methyl-3-phenyl-4-imidazoIiη-2-one

-CH-

In 50 ml of glacial acetic acid, 3.5 g (12.2 mmol) of the compound from Example 3 is refluxed for 24 hours, the solvent is removed and the residue is washed with water. After drying, 3.12 g are obtained.

25

Yield: 95.3% of theory

¹ H-NMR (DMSO): δ = 3.3 (s, 3H, CHg); 6.9 (s, IH,

Imidazole-H); 7.0-7.5 (m, 9H, aromatic-H) ppm.

Example 5

(E) -3- [4- (4-Fluorophenyl) -1-methyl-3-phenyl-4-imidazoline 2-one-5-yl3-prop-2-enal

35

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To 1.37 ml (15 mmol) of phosphorus oxychloride in 8.5 ml of acetonitrile is added dropwise at 0 ° -5 ° C within 10 min under nitrogen atmosphere 1.54 ml (14 mmol) of N, N-dimethylaminoacrolein in 5.3 ml of acetonitrile. After 10 minutes, a solution of 1.3 g (5 mmol) of the compound of Example 4 in 10 ml of acetonitrile is added and the mixture is heated to boiling overnight. At 10 ⁰ C are added 3.7 g of sodium hydroxide in 50 ml of water / 50 ml of toluene, wash the aqueous phase again with toluene, the organic phases are dried and obtained after crystallization from ether 0.85 g.

Yield: 51.2 % of theory.

¹ H-NMR (CDCl _3): δ = 3.6 (s, 3H, CH _3); 6.5 (dd, IH,

CH-CHO); 7.0-7.5 (m, 1OH, aromatics H, CH); 9.5 (d, IH, CHO) ppm.

Example 6

Methyl (E) -7- [4- (4-fluorophenyl) -l-methyl-3-phenyl-4-imidazolin-2-on-5-yl] -5-hydΓoxy-3-oxo-hept-6- enoat 25

OH 0

Under nitrogen is added dropwise to a suspension of 135 mg (5.6 mmol) of sodium hydride in 14 ml of tetrahydrofuran at -5 ⁰ C 0.59 ml (5.4 mmol) of methyl acetoacetate. 35

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After 15 min, added dropwise at -5 ⁰ C 4.0 ml (5.6 mmol) ** 15% n-butyl lithium in η-hexane, stirred for 15 min, a solution of 1.3 g (5.9 mmol ) Zinc bromide in 20 ml of THF, stirred for 15 min and added a solution of 0.6 g (1.8 mmol) of the compound from Example 5 in 6 ml of tetrahydrofuran. After 30 min at -5 ⁰ C is hydrolyzed with saturated ammonium chloride solution, washed three times with dichloromethane, the organic phase is dried and after removal of the solvent and washing the residue with petroleum ether 380 mg.

Yield! 48 X of the theory

¹ H-NMR (CDCl ₃₎ S 8 = 2.7; 3.0 (2d, 2H, CH _2); 3.5 (s, 5H,

NCH ₃ , CH ₂ C = O) J 3.7 (s, 3H, OCH ₃ ); 4.65 (br, IH, CHOH); 5.9 (dd, IH, CHCHO); 6.4 (d, IH, CH); 6.9-7.4 (m, 9H, aromatic-H) ppm.

Example 7

Methyl erythro- (E) -3,5-dihydroxy-7-C4- (4-fluorophenyl) -1-methyl-3-phenyl-4-imidazolin-2-on-5-YL3-hept-6-enoate

By a solution of 350 mg (0.8 mmol) of the compound from Example 6 and 1.12 ml (1.12 mmol) of triethylborane (1 m in tetrahydrofuran) in 7 ml of tetrahydrofuran blast

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Man 5 min air, are added at -30 ⁰ C 42.3 mg (1.12 mmol) of sodium borohydride and slowly 0.76 ml of methanol, stirred for 30 min at -30 ⁰ C, gives a mixture of 3 ml 30 Kiger hydrogen peroxide solution and 6.5 ml of water that the temperature does not exceed ^{0 0} C, diluted after 30 min with water, washed three times with ethyl acetate, the organic phase is washed with sodium bicarbonate solution, dried, the solvent is removed in vacuo and after chromatography on silica gel (ethyl acetate ) 60 mg. ·

Yield: 17 % of theory

¹ H-NMR _(CDCl3): S = 1.6 (m, 2H, CH _2); 2.5 (m, 2H,

CH ₂ C = O); 3,4 (s, 3H, NCH ₃ ); 3.7 (s, 3H, CH _3); 4.2 (br, IH, CHOH); 4.4 (br, IH, CHOH); 5.9 (dd, IH, CH 2 CH 2 OH); 6.3 (d, IH, CH); 6.8-7.5

(m, 9H, aromatic-H) ppm.

Example 8

2- (benzyl-isopropylamino) -l- (4-fluorophenyl) -l-oxo-lethan hydrochloride

HCl

Il I Γ Il 30

Analogously to Example 1, 55 g (0.25 mol) of oc-bromo-4-fluoroacetophenone and 78 g (0.52 mol) of isopropylbenzylamine, 46.9 g of 2- (benzyl-isopropylamino) -l- ( 4-fluorophenyl) -l-oxo-l-ethane hydrochloride.

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- 58 -

Yield: 57.5 % of theory

¹ H NMR (DMSO): S = 1.4 (dd, 6H, CHg) J 3.8 (m, IH, CH) J

4.4 (m, 2H, CH ₂ ) J 5.0 (m, 2H, CH ₂ C = O) J 7.2-8.0 (m, 9H, aromatics H) ppm.

Example 9

1- (4-fluorophenyl) -2-isopropylamino-1-oxo-ethane-hydro-chloride

I ^ Ί · 1

HCl

Analogously to Example 2, from 44.8 g (0.14 mol) of the compound from Example 8, 25.7 g of 1- (4-fluorophenyl) -2-isopropylamino-1-oxo-ethane hydrochloride are obtained.

Yield: 79.8 Y, the theory

¹ H-NMR (DMSO): S = 1.3 (d, 6H, CH ₃₎ J 3.4 (m, IH, CH) J 4.8 (br, 2H, CH ₂₎ J 7.4-8 , 3 (m, 4H,

Aromatics-H) ppm «

Example 10

N -C 2 (4-fluorophenyl) -2-oxo-ethyl] -N-isopropyl-N ¹ -phenylurea

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Analogously to Example 3 is obtained from 7.0 g (30.2 mmol) of the compound from Example 9 and 3.05 g (30.2 mmol) of phenyl isocyanate 6.3 g of N-C2- (4-fluorophenyl) -2 Ethyl 3-oxo-N-isopropyl-N'-phenyl urea.

Yield: 66.4% of theory

¹ H-NMR _(CDCl3): 5 = 1.2 (dd, 6H, CH _3); 2.9 (s, IH, NH);

3.5 (dd, 2H, CH ₂ ); 4.35 (m, IH, CH); 6.9-7.6 (m, 9H, aromatic-H) ppm.

Example 11 15

4- (4-fluorophenyl) -l-isopropyl-3-phenyl-4-imidazolin-2-one

Analogously to Example 4, 5.3 g (16.9 mmol) of the compound from Example 10 give 4.6 g of 4- (4-fluorophenyl) -1-isopropyl-3-phenyl-4-imidazolin-2-one.

Yield: 91.9 * A of theory

¹ H-NMR (CDCl ₃ )! & = 1.4 (d, 6H, CH _3); 4.5 (m, IH, CH); 6.45 (s, IH, CH); 6.8-7.4 (m, 9H,

Aromatic-H) ppm.

Example 12

(E) -3- [4- (4-fluorophenyl) -1-isopropyl-S-phenyl-imidazolin-2-one-5-yl] -prop-2-enal

Le A 2 5 813

Analogously to Example 5, 2.0 g (6.8 mmol) of the compound from Example 11 are used to obtain 1.6 g of (E) -3- [4- (4-fluorophenyl) -1-isopropyl-3-phenyl-4-. imidazolin-2-on-5-YL3-prop-2-enal.

Yield: 67.7 Ji of theory ¹ H-NMR _(CDCl3): 5 = 1.6 (d, 6H, CHg) 4.6 J (m, IH, CH) J

6.2 (dd, IH, CHCHO) J 6.9-7.4 (m, 1OH, aromatic H, CH) J 9.4 (d, IH, CHO) ppm.

Example 13

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

OH

0.8 g (2.3 mmol) of the compound from Example 12 gives 1.1 g of crude product analogously to Example 6, and after chromatography on silica gel (dichloromethane / methanol 10: 1), 0.8 g of methyl (E) are obtained. -7- [4- (4-fluorophenyl) -l-isopropyl-3-phenyl-4-imidazolin-2-on-5-yl] -5-hydroxy-3-oxo-hept-6-enoate.

Le A 25 813

Yield: 75 * / · of theory

¹ H-NMR (CDCl _3): δ = 1.6 (d, 6H, CH _3); 2.7; 3.0 (2d, 2H ₁

CH ₂ ); 3,4 (s, 2H, CH ₂ ); 3.75 (s, 3H, CH _3); 4.4 (m, IH, CH); 4.6 (m, IH, CH-OH); 5.6 (dd, IH, CH); 6.4 (d, IH, CH); 6.8-7.4 (m, 9H, aromatic-H) ppm «

example

Methyl erythro- (E) -3,5-dihydroxy-7-C4- (4-fluorophenyl) -1-isopropy1-3-phenyl-4-imidazolin-2-on-5-yl] hept-6-enoate

OH OH 0

Analogously to Example 7, from 0.8 g (1.7 mol) of the compound from Example 13, 320 mg of methyl erythro- (E) 3,5-dihydroxy-7- [4- (4-fluorophenyl) -l- isopropyl-3-phenyl-4-imidazolin-2-one-5-yl] -hept-6-enoate «

Yield: 40% of theory

¹ H-NMR (CDCl _3): δ = 1.5 (m, 8H, CH _3, CH _2); 2.5 (m, 2H,

CH ₂ ); 3.7 (s, 3H, CH _3); 4.2; 4.4 (2m, 2H, CH); 4.5 (m, IH, CH); 5.6 (dd, IH, CH); 6.4 (d, IH, CH); 6.8-7.3 (m, 9H, aromatic-H) ppm.

Le A 25

example

N- [2- (4-fluorophenyl) -2-oxo-ethyl-N-methyl-N, ¹ -phenylthiourea

Analogously to Example 3 is obtained from 3 g (12.5 mmol) of the compound from Example 2 and 1.6 g (12.5 mmol) of phenyl isothiocyanate 3.67 g of the above compound, yield: 97.2% of theory ¹ H -NMR (DMSO) S S = 2.3 (s, IH); 3.35 (s, 3H); 4.0

(q, IH); 7.0-7.6 (m, 5H) ppm.

example

4- (4-fluorophenyl) -1-methyl-3-phenyl-4-imidazo1in-2-thione

CHR

Analogously to Example 4, 3.5 g (11.6 mmol) of the compound from Example 15 give 2.99 g of the abovementioned compound. Yield: 91 V, of the theory ¹ H-NMR (CDCl ₃ ): S = 3.7 (s, 3H); 6.8-7.5 (m, 10H) ppm.

Le A 25

example

(E) -3- [4- (4-fluorophenyl) -1-methy1-3-pheny1-4-imidazo1in-2-thion-5-yl] -prop-2-enal

Analogously to Example 5, 2.4 g (8.45 mmol) of the compound from Example 16 are used to obtain 1.8 g of product.

Yield: 61.1% of theory ¹ H-NMR (CDCl _3): δ = 4.0 (s, 3H) 6.5 J (dd, IH);

6.9 (d, IH); 6.95-7.5 (m, 9H);

9.5 <d, IH) ppm.

example

Methyl (E) -7- [4- (4-fluorophenyl) -1-methyl-3-pheny1-4-imidazolin-2-thione-5-yl] -5-hydroxy-3-oxo-hept-6- enoate

OH

Analogously to Example 6 is obtained from 1.8 g (5.3 mmol) of the compound from Example 17 3.0 g of crude product. Yield: 100 Y, the theory

¹ H-NMR _(CDCl3): S = 2.3 (s, 2H); 3.5 (s, 3H);

3.7 (s, 3H); 3.75 (s, 2H):

Le A 25

4.65 (m, IH); 5.85 (dd, IH); 5.9 (d, IH); 6.8-7.5 (m, 9H);

example

Methyl erythro- (E) -3,5-dihydroxy-7- [4- (4-fluorophenyl) -1-methyl-3-phenyl-4-imidazolinyl-2-thion-5-yl] -hept-6- enoate

OH OH

Analogously to Example 7, from 2.11 g (4.6 mmol) of the compound from Example 18, 0.3 g of product, yield: 14.2 V. of theory ¹ H-NMR (CDCl ₃ ): δ = 1.6 (m, 2H); 2.5 (d, 2H);

3.7 (s, 3H); 3.8 (s, 3H);

4.2 (m, IH); 4.5 (m, IH);

5.85 (dd, IH); 5.9 (d, IH);

6.9-7.4 (m, 9H) ppm.

example

Methyl erythro (E) -3,5-dihydroxy-7- [4- (4-fluorophenyl) -1-isopropyl-3-phenyl-4-imidazolinyl-2-thion-5-yl] -hept-6-enoate

OH OH 0

The compound from Example 20 can be obtained in analogy to Example 19.

Le A 25

Application Examples 5

example 1

The enzyme activity determination was modified according to GC ₄ Ness et al., Archives of Biochemistry and Biophysics 197 . 493-499 (1979). Male Ricor rats (body weight 300-400 g) were supplemented for 11 days with Altromin powder feed supplemented with 40 g cholestyramine / kg feed. treated. After decapitation the animals were taken from the liver and placed on ice. The livers were minced and ground in the Potter-Elvejem homogenizer 3 times in 3 volumes of 0.1 M sucrose, 0.05 M KCl, 0.04 M K _x H _y phosphate, 0.03 M ethylenediaminetetraacetic acid, 0.002 M dithiothreitol (SPE). Buffer pH 7.2, homogenized. It was then centrifuged for 15 minutes at 15,000 * g and the sediment was discarded. The supernatant was sedimented at 100,000 g for 75 minutes. The pellet is taken up in 1/4 volume SPE buffer, homogenized again and then again centrifuged for 60 minutes at 100,000 g. The pellet is taken up with the 5-fold amount of its volume with the SPE buffer, homogenized and frozen at -78 ° C and stored (= enzyme solution).

For testing, the test compounds (or mevinolin as reference substance) were dissolved in dimethylformamide with the addition of 5% by volume of 1 N NaOH and used with 10 μΐ in various concentrations in the enzyme assay. The test was started after 20 minutes preincubation of the compounds with the enzyme at 37 ° C. The test batch 35

Le A 25 813

was 0.380 ml and contained 4 μΜΜ glucose-6-phosphate, 1.1 mg bovine serum albumin, 2.1 μΜοΙ dithiothreitol, 0.35 μΜοΙ NADP, 1 unit glucose-6-phosphate dehydrogenase, μΜοΙ K "H _V phosphate pH 7.2 , 20 μΐ enzyme preparation ion and 56 nmol of 3-hydroxy-3-methyl-glutaryl coenzyme A (glutaryl-3- ¹⁴ C) 100 000 dpm.

After incubation at 37 ° C. for 60 minutes, the batch was centrifuged and 600 μl of the supernatant were applied to a 0.7 × 4 cm column filled with a 5-chloride 100-200 mesh (anion exchanger). It was distilled with 2 ml. Rinse water and pass plus wash water with 3 mL of scintillation solvent and count in the LKB scintillation counter. ICgg values were determined by applying the percentage inhibition to compound concentration in the test by intrapolation. To determine the relative inhibitory potency, the ICgg value of the reference substance mevinolin was set as 100 and compared with the simultaneously determined ICgQ value of the test compound.

The active compounds of Examples 1 to 14 show a higher activity compared to mevinolin.

Example 2

The serum cholesterol-lowering effect of the compounds according to the invention on the blood cholesterol values of dogs and guinea pigs was found in several weeks feeding experiments. This was the zu

Le A 25 813

In the case of dog trials over a period of several weeks once a day in a capsule of healthy beagle dogs together with the feed p.o., given "The feed was also during the whole experimental period". Before and during the period of application of the substance to be tested, colestyramine (4 g / 100 g diet) was added as bile acid sequestrant.

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

The guinea pig was mixed with the substance in the feed. After two weeks, the animals were bled and serum cholesterol determined.

Le A 25 813

Claims (2)

; 3 3 ' claims 1. A process for the preparation of substituted imidazolinones and Imidazolinthionen the general formula NN in which R is cycloalkyl, or is alkyl which may be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl, odor 4 5 by a group of the formula -NR ii , wherein 3 ί R ^, R ^ - are the same or different and are alkyl, aryl, aralkyl, acyl, Alkylsulfonyl or arylsulfonyl, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, Aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl or aryl radicals of the last-mentioned substituents are up to 3 times identical or different from halogen, cyano, trifluoromethyl, Trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl may be substituted, _r 2 - is heteroaryl which is up to 3 times the same or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ^ R ^ can be substituted, wherein R ^ and R ^ have the meaning given above, or Le A 25 813 - is aryl which may be substituted identically or differently up to 5 times by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, - halogen, cyano, nitro, Trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, Sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ , wherein R and R have the abovementioned meaning, R ³ - for hydrogen or - is acyl, alkylsulfonyl or arylsulfonyl, where the aryl radical may be substituted by alkyl or halogen, or for aminocarbonyl, alkylaminocarbonyl, Dialkylaminocarbonyl, arylaminocarbonyl or Alkoxycarbonyl, or - represents cycloalkyl, or - is alkyl which may be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoro- methoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁴ R ⁵ , Le A 25 813 wherein
5 R ^ and R 'have the meaning given above ι or by carbamoyl, dialkylcarbamoyl, Sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, Aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl or aryl radicals of the latter substituents are up to 3 times the same or different from halogen, cyano, trifluoro- methyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or R ^ - stands for heteroaryl, which is up to 3 times identical or different by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, Alkoxycarbonyl or may be substituted by a group of the formula -NR ^ R ^,
wherein R ^ and r5 are as defined above to have, Le A 25 813 -η- or R ³ - is aryl which may be substituted identically or differently up to 5 times by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halo, cyano, nitro, Trifluoromethyl, trifluoro- methoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of Formula -NR ⁴ R ⁵ ,
15 wherein R ⁴ and R ⁵ are as defined above have 20 B - stands for oxygen or sulfur, X - for a group of the formula -CH ₂ -CH ₂ or -CH = CH-stands, and
25 and A - for a group of the formula 30? -CH-CH ₂ -C-CH ₂ -COOR ⁷ or Η <τ [J, OH OH wherein 35 Le A 25 813 -η- R ⁶ - hydrogen or alkyl means 5 and R ⁷ - hydrogen, an alkyl, aryl or aralkyl radical or a cation, characterized in that ketones of the general formula (VIII) R ² ? ⁷ ' OH ..___. (VIII) P = L ^ _n CH = CH-CH-CH ₂ -C-CH ₂ -COOR ' R B in which 4 O R ¹ , R ⁶ , R ° and B have the abovementioned meaning, and R ⁷ '- is alkyl (C ₁ to C ₆ ) aryl (C ₆ to C ₁₂ ) or aralkyl (C ₇ to C ₁₀ ), reduced, in the case of production of the acids, the esters are saponified, Le A 25 336 cyclized in the case of the production of lactones the carboxylic acids , in the case of preparation of the salts, either the esters or the lactones are saponified, in the case of preparation of the ethylene compounds (X = -CH ₂ -CH ₂ -) the ethene compounds (X = -CH = CH-) are hydrogenated by customary methods, and optionally separating isomers 2. The method according to claim 1, characterized in that the reduction in the temperature range of -SO C to +30 C is performed. -FS- Use of substituted imidazolinones and imidazoline thiones according to claim 1, characterized in that they are used for the preparation of medicaments.