DD283808A5 - PROCESS FOR PREPARING N-SUBSTITUTED N-AMINO PYRROLES - Google Patents

Abstract

The invention relates to a process for the preparation of N-substituted N-amino-pyrroles having an inhibitory effect on HMG-CoA reductase. According to the invention, compounds of the formula (I) are prepared in which the substituents R 1, R 2, R 3, R 4, R 5, X, A have the meaning given in the description and in the claims. Formula (I) {new N-substituted N-amino-pyrroles; inhibitory effect on HMG-CoA reductase; Application as a medicinal product; hyperlipoproteinemia; lipoproteinaemia; Arteriosclerosis}

Description

283800

Process for the preparation of N-eubetituiorten N-amino-pyrrolene Anwendungsbereich the invention

The invention relates to a process for the preparation of sub-substituted pyrroles, zwiechen compounds for their preparation and their use in medicaments / for example for the treatment of hyperlipoproteinemia, lipoproteinemia or the like. "Arteriosclerosis *

Characteristic of the known state of Techpik

Ee 1st it is known that certain indole derivatives or pyrazole derivatives inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A Reduktaee (HMG-CoA-Reduktaee) ein / EP-A 1,114,027; U.S. Patent 4,613,610 / _e

the invention

The aim of the invention is to provide novel compounds with good inhibitory effect on the 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 methods for their Her etellung ,,

There have now been substituted pyrroles of the general formula (I)

- la -

X-A

(I)

R * R

found,

in which

- represents cycloalkyl, or

- is alkyl which may be substituted by halogen, cyano, hydroxy, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of formula -NR ⁶ R ⁷ ,

wherein

R ⁶ ,

are the same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl,

or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heterocycle, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl · and aryl radicals of the latter substituents are up to 3 times the same or different by halogen, cyano , Trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl,

- represents heteroaryl which is up to 3 times identical or different through halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ⁶ R ⁷ may be substituted, in which

Le A 25 837

283806

R ° and R ^{7 have} the meaning given above ι. 5

or

aryl is "up to 5 times the same or differently substituted by alkyl" hydroxyalkyl, alkoxy, alkylthio, alkylsulfonyl, 10 "aryl, aryloxy, arylthio, arylsulfonyl, aralkyl,

Aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or 15 by a group of the formula -NR ⁶ R ⁷ ,

wherein

R ⁶ and R have the meaning given above 20,

R ³ - for hydrogen or

- represents cycloalkyl, or

- is alkyl which may be substituted by halogen, cyano, hydroxy, alkoxy, alkylthio, alkyl

sulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁶ R ⁷ ,

wherein

R ⁶ , R ⁷ - have the abovementioned meaning,

Le A 25 837

or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals of the last-named substituents are up to 3 times the same or different or halogen, cyano, tri or fluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl may be substituted,

or

represents heteroaryl which is up to 3 times identical or different through 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', 20

wherein

R ⁶ and R ^{7 have} the meaning just given,

or

is aryl which may be substituted identically or differently up to 5 times by alkyl, hydroxyalkyl, 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 ⁶ R ⁷ ,

Le A 25 837

wherein 5

R ⁶ and R ^{7 have} the meaning given above ι

R ⁴ and R ^{5 are the} same or different and for - hydrogen,

- stand for cycloalkyl »or

·· 'represent alkyl »which may be substituted by halogen» hydroxy »alkoxy» alkylthio »acyl or by a group of the formula -NR ⁶ R, 15

wherein

⁷ -

have the meaning given above,

or by carbamoyl, heteroaryl, aryl, aryloxy, arylthio, where the heteroaryl and aryl radicals of the last-mentioned substituents may be substituted by the same or different halogen, trifluoromethyl, alkyl, alkoxy, alkylthio or alkylsulfonyl radicals up to 3 times,

or - represents heteroaryl which may be substituted by Halpgen, alkyl, alkoxy, AlkyUhio, alkylsulfonyl, aryl, trifluoromethyl, alkoxycarbonyl or by a group of formula -NR ⁶ R ^{7 up to} twice

Le A 25 837

v / orin 5

R ° and R are as defined above «

or

- stand for aryl that is up to 2 times the same or ver-10. may be substituted by alkyl, hydroxyalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, alkoxycarbonyl, carbamoyl or by a group of the formula -NR ⁶ R ⁷ ,

wherein

R ⁶ and R 'have the meaning given above "20 or

- R ^ and R ^ together with the N atom form a 4- to 8-

form a hetero-cyclic group which may contain another heteroatom Y, wherein

Y is S, O or NR ⁸ , where R ^{8 is} alkyl, aryl, aralkyl, acyl, alkyl

30 sulfonyl, arylsulfonyl mean

can

wherein this heterocycle may be substituted by R, wherein 35

Le A 25 837

R ⁹ - is cycloalkyl, or

- is alkyl which may be substituted by halogen, hydroxy, alkoxy, alkylthio, acyl or by a group of the formula -NR ⁶ R ⁷ ,

in which.

R ⁶ , R ⁷ - have the abovementioned meaning,

or by carbamoyl, heteroaryl, aryl, aryloxy, arylthio, where the heteroaryl and aryl radicals of the latter substituents may be substituted by the same or different halogen, trifluoromethyl, alkyl, alkoxy, alkylthio or alkylsulfonyl radicals up to twice

or

represents heteroaryl which may be substituted identically or differently by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, trifluoromethyl, alkoxycarbonyl or by a group of formula -NR ⁶ R ^{7 up to} twice

where r i η

R ⁶ and R ^{7 have} the abovementioned meaning, 30

or

is aryl which may be substituted identically or differently up to twice by alkyl, hydroxyalkyl, alkoxy, alkylthio, alkylsulfonyl,

Le A 25 837

Halogen »cyano, nitro, trifluoromethyl, alkoxycarbonyl, carbamoyl or by a group of the formula -NR ⁶ R ⁷ ,

wherein

R ⁶ and R ^{7 have} the abovementioned meaning,

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

and

A - for a group of the formula

_R 10

_R 1O

> rr

-CH-CH ₂ -C-CH ₂ -COOR ¹¹ HO '

I I or T ^ stands,

OH OH wherein

R ^{10 is} hydrogen or alkyl and

R ¹¹ - hydrogen,

an alkyl, aryl or aralkyl radical,

or

- a cation means.

Le A 25 837

Surprisingly, the substituted pyrroles according to the invention exhibit a good inhibitory effect on HMG-CoA raductase <3-hydroxy-3-methylglutaryl coenzyme A reductase).

Cycloalkylene generally represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. The cyclopropyl, cyclopentyl and cyclohexyl rings are preferred. 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 of 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. Preferred is lower alkoxy having 1 to about 6 carbon atoms. Particularly preferred is an alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are methoxy, ELhoxy, propoxy, isopropoxy, Bui.oxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.

Alkylthio is generally a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms bonded via a sulfur atom. loading

Le A 25 837

- 10 -

Preferred is Niedrigalkylthio having 1 to about 6 carbon atoms. Particularly preferred is an alkylthio radical having 1 to 4 carbon atoms. Examples which may be mentioned methylthio »ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, isopentylthio, hexylthio, isohexylthio, heptylthio, isoheptylthio, octylthio or isooctylthio.

Alkisulfonyl generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is bonded via an SC 1 - group. Preferred is lower alkylsulfonyl having 1 to about 6 carbon atoms. Examples which may be mentioned are: 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.

Le A 25 837

- 11 -

Arvlsulfonvl is generally an aromatic radical having from 6 to about 12 carbon atoms "which is bonded via an SC ^ group." Examples include: phenylsulfonyl, naphthylsulfonyl and biphenylsulfonyl.

Aralkvl is generally an alkyne. Chain linked aryl radical having 7 to 14 carbon atoms. Aralkyl 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 aralkyl radicals may be mentioned by way of example! Benzyl, naphthylmethyl, phenethyl and phenylpropyl.

Aralkoxv in general represents an aralkyl radical having 7 to 14 carbon atoms, the alkylene chain being 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 ring are preferred. Part "The following aralkoxy radicals may be mentioned as examples: benzyloxy, naphthylmethoxy, phenethoxy and

Phenylpropoxy, 25

Aralkylthio generally represents an aralkyl radical having from 7 to about 14 carbon atoms, the alkyl chain being bonded 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,

Le A 25 837

- 12 -

AralkvlauIfonvl is generally an aralkyl radical having from 7 to about 14 carbon atoms, the alkyl radicals being bonded via an SC.sup.- chain. Preference is given to aralkylsulfonyl radicals having from 1 to 6 carbon atoms in the aliphatic part and from 6 to 12 carbon atoms in the aromatic part. Examples being the following aralkylsulfonyl radicals named: benzylsulfonyl, naphthylmethylsulfonyl, phenethylsulfonyl and phenylpropylsulfonyl.

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

Il

being represented. Alkyl is in this case a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms, preference is given to lower alkoxycarbonyl having 1 to about 6 carbon atoms in the alkyl part, particular preference is given to an alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl part, for example the following alkoxycarbonyl radicals may be mentioned: methoxycarbonyl, Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

Acyl generally represents phenyl or straight-chain 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, for example: benzoyl, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbo

nyl, butylcarbonyl and isobutylcarbonyl, 35

Le A 25 837

- 13 -

Halogen is in general fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. Particular preference is given to halogen being fluorine or cwlor,

Heteroarvl is in the context of the definition given above in general represents a 5- to 6-membered ring aromatisehen "which may contain hetero-atom" oxygen, sulfur and / or nitrogen and may be ankondensiort to which further aromatic rings. Preference is given to 5- and 6-membered aromatic rings which contain one oxygen, one sulfur and / or up to 2 nitrogen atoms and which are optionally benzocondened. Particularly preferred heteroaryl radicals which may be mentioned are: thionyl, furyl, pyrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinol ·, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolyl, thiazolyl _; Banzothiazolyl, Isothiazolyl, Oxazolyl, Bonzoxazolyl, Isoxazolyl, Imidaaolyl, Benzimidazolyl, Pyrazolyl, Indolyl, and Isoindolyl *

SuIf amovl (Aminosulf onyl) stands for the group SC ^ -N ^.

When R ^{11 is} alkyl, aryl, aralkyl, an ester is formed. In the present invention, physiologically acceptable esters are preferred 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 ₄ ) and aralkyl esters (C ₇ to C ₁₀ ), preferably lower alkyl esters and benzyl esters. In addition, the following ester radicals may be mentioned:

Methyl ester, ethyl ester, propyl ester, benzyl ester.

Le A 25 837

- 14 -

If R ^{11 is} a cation, then it is preferably a physiologically acceptable metal or ammonium cation. Alkaline or alkaline-earth cations, for example sodium cations, potassium cations or calcium cations, as well as aluminum or aluminum cations, nonionic cations and non-toxic substituted aminium cations from amines, such as lower alkylamines, tri-lower alkylamines, dibenzylamine, are preferred here "N" N * dibenzylethylenediamine "N-benzyl -? - phenylethylamine" N-methylmorpholine or N-ethylmorpholine, dihydroabietylamine, N, N ¹ -bis-dihydroabietylethylendiamin "which can be used for formation of salts N-lower alkylpiperidine, and other amines, ,

In the context of the present invention, the N-substituted N-amino-pyrroles correspond to (I) dibrarein-1 in formula 20

(Ia)

,

and

.JUU =

NR ⁴

in which

R ¹ , R ² »R ³ , R ⁴ , R ⁵ , X and A have the abovementioned meaning.

Lq A 25 837

In the general formula (I), compounds having the general formulas (Ia) and (Ib) are preferred.

Preference is given to those compounds of the general formula (I)

· Ίη which

R * represents cyclopropyl, cyclopentyl or cyclohexyl,

or

is lower alkyl which may be substituted by fluorine, chlorine, bromine, cyano, hydroxy, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl, by a group of formula -NR ° R, 20

wherein

R ^ and r '' are the same or different and

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

signify fonyl

or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thionyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, where the heteroaryl and aryl radicals mentioned are identical or different by up to 2 times by fluorine, chlorine, bromine,

Le A 25 837

- 16 -

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

R ² - for thionyl ι furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl «pyrimidyl, pyrazinyl, pyridazinyl, indolyl, Ieoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxal inyl, quinazole in ', 1, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl which may be substituted identically or differently up to two times by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, 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, phenylethylthir, Phenylethylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula -NR ⁶ R ⁷ ,

where 30

R and R have the abovementioned meaning, R ^ - for hydrogen or

- represents cyclopropyl, cyclopentyl or cyclohexyl or

Le A 25 837

- 17 -

or lower alkyl which may be substituted by fluoro, chloro, cyano, hydroxy, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl or by a group of formula -NR ⁶ R ⁷ , _% wherein

R ⁶ and R ^{7 have} the abovementioned meaning,

or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, chinclyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylsulfonyl, benzyloxy, phenylethoxy, said heteroaryl, aryl and aryl radicals bis may be monosubstituted by identical or different substituents by fluorine, chlorine, lower alkyl, lower alkoxy, trifluoromethyl,

for thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl may be substituted equally or differently by 2-fold by fluorine, chlorine, lower alkyl, lower alkoxy, phenyl,

Le A 25 837

Phenoxy, trifluoromethyl or lower alkoxycarbonyl, or

Phenyl or naphthyl which may be substituted identically or differently up to twice by lower alkyl, lower hydroxyalkyl, lower alkoxy, phenyl, phenoxy, benzyl, benzyloxy,

Phenethyl, phenylethoxy, fluorine, chlorine, cyano,

Trifluoromethyl, lower alkoxycarbonyl or by a group of the formula -NR ⁶ R ⁷ ,

where 15

R ⁶ and R have the abovementioned meaning R ^ and R 'may be the same or different and

- for hydrogen,

- stand for cyclopropyl, cyclopentyl or cyclohexyl

or is lower alkyl which may be substituted by fluorine, chlorine, hydroxy, lower alkoxy, trifluoromethyl, benzoyl or by a group of the formula -NR ⁶ R ⁷ , in which

R ⁶ and R ^{7 have} the abovementioned meaning,

or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, benzyloxy, phenylethoxy, said heteroaryl and aryl radicals bis

Le A 25 837

may be substituted equally or differently by fluorine, chlorine, lower alkyl, lower alkoxy or trifluoromethyl,

- represent thionyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, iso-chi, nolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which are bis may be substituted twice or the same by fluorine, chlorine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl or lower alkoxycarbonyl, or

- represent phenyl or naphthyl which may be substituted by up to 2-fold or more by lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, phenethyl, phenylethoxy, fluoro, chloro, cyano, Trifluoromethyl, lower alkoxycarbonyl or by a group of the formula -NR 1 R '',

in which

A 7 ·

R ^D and R 'have the meaning given above or

R ** and R ^ together with the N atom form a 5- to 7-membered heterocycle which may contain another heteroatom Y, where 35

Y is S, O or NR ⁸ , where

Le A 25 837

- 20 -

R ^{8 represents} lower alkyl, phenyl, benzyl, lower alkylsulfonyl, phenylsulfonyl, benzoyl or acetyl,

wherein this heterocycle may be substituted by R, wherein

R ^ - represents cyclopropyl, cyclopentyl or cyclohexyl

or

is lower alkyl which may be substituted by fluorine, chlorine, hydroxy, lower alkoxy, benzoyl, lower alkylcarbonyl or by a group of formula -NR ⁶ R ⁷ ,

wherein

R ⁶ , R ⁷ - have the abovementioned meaning,

or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylsulfonyl, benzyloxy or phenylethoxy,

wherein the genannton heteroaryl and aryl radicals may be substituted equally or differently by fluorine, chlorine, hydroxyalkyl, lower alkyl, lower alkoxy, trifluoromethyl, up to 2-fold,

Le A 25 837

- 21 -

for thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridy.1, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzo-liazolyl, benzoxazolyl or benzimidazolyl, which may be up to May be substituted once or twice by fluorine, chlorine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl or lower alkoxycarbonyl, or

- is phenyl which may be substituted identically or differently up to two times by lower alkyl, lower alkoxy, lower alkylsulfonyl, phenyl, phenyloxy, phenylsulfonyl, benzyl, benzyloxy, phenethyl, phenylethoxy, fluoro, chloro, cyano, trifluoromethyl, lower alkoxycarbonyl or by a

Group of formula -NR ⁶ R ⁷ ,

in which

R and R 'are as defined above 25

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

A - for a group of the formula

Olo

_R l0

-CH-CHo-C-CHo-COOR ¹¹ or HO HI is, ι Δ ι Δ L · A '

OH OH wherein 35

R ^{10 is} hydrogen or lower alkyl, and Le A 25,837

- 22 -

R ¹¹ - a Cj-C ₆ alkyl, a C ₆ -C ₁₂ alkyl radical δ or a C ^ -Cjg alkyl radical or

- a physiologically contractual cation means <

Particular preference is given to compounds of the general formulas (Ia) and (Ib)

in which

R ¹ - represents cyclopropyl, cyclopentyl or cyclohexyl, or

- is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, which may be substituted by fluorine, chlorine, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.Butoxy, tert-butoxy, Methylthio, ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzoyl, acetyl, pyridyl, pyrimidyl, thienyl, furyl, phenyl, phenoxy, phenylsulfonyl, benzyloxy , Benzylthio or benzylsulfonyl,

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

Le A 25 837

- 23 -

- is phenyl, which may be up to twice the same or may be substituted by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy , Methylthio, ethylthio, propylthio, isopropylthio, methylsulfonyl, ethyl

* Sulfonyl, propylsulfonyl, isopropylsulfonyl, phenyl, phenoxy, benzyl, benzyloxy, fluorine, chlorine, bromine, cyano, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert-butoxycarbonyl,

R ^ is hydrogen, cyclopropyl, cyclopentyl or cyclohexyl or

- methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl, which may be substituted by fluorine, chlorine, cyano, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, t-butylsulfonyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarboviyl, butoxycarbonyl, isobutoxycarbonyl , tert, butoxycarbonyl, benzoyl, acetyl, ethylcarbonyl, or by a group -NR ^ R ^,

where 35

Le A 25 837

- 24 -

R and R are the same or different and Methyl, ethyl »propyl, isopropyl, butyl,

iBobi'tyl, tert, butyl, phenyl, benzyl, acetyl, methyl t-butyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or phenylsulfonyl,

R ^ and R ^ may be the same or different and

- represent hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or

represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl, which may be substituted by fluorine, chlorine, hydroxyl, methoxy, ethoxy, methylthio, ethylthio, propylthio, isopropylthio, Butylthio, isobutylthio, tert.Butylthio, benzoyl, acetyl, ethylcarbonyl or by a group -NR ^ R ⁷ ,

in which

R ⁶ and R 'have the abovementioned meaning,

or by pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thionyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, where the said heteroaryl and aryl radicals are represented by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, Isobutyl, tert. Butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, trifluoromethyl may be substituted, or

Le A 25 837

- 25 -

for thionyl, furyl, pyridyl, pyrimidyl, pyrazinyl,

Pyridazinyl, oxazolyl, isooxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzimidazolyl or benzothiazolyl, where the radicals mentioned are represented by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl,

Isobutyl, tert, butyl, methoxy, ethoxy, propoxy,

Isopropoxy, butoxy, isobutoxy, tert-butoxy, phenyl, phenoxy, trifluoromethyl, trifluoromaleoxy, methoxycarbonyl, ethoxycarbonyl, isoproroxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert-butoxycarbonyl, or

- represent phenyl which is up to 2 times the same or different from methyl, ethyl, propyl, isopropyl, butyl, T.sobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy , Isobutoxy, tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert, butylthio, methylsulfonyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, fluoro, chloro, cyano, hydroxy, trifluoromethyl "methoxycarbonyl, ethoxycarbonyl , Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl or

f 7

be substituted by a group -NR R kanr, where

R and R have the abovementioned meaning,

cdar 35

Le A 25 837

R ^ and R ^ together with the N atom form a 5- to 7-membered heterocyclic group

Heteroatom Y can contain «being

Y is S ₁ O or NR ⁸ ,

where R ⁸

Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert, butyl, phenyl, benzyl, acetyl, methylsulfonyl, ethylsulfonyl, Fropylsulfonyl, isopropylsulfonyl or phenylsulfonyl

wherein this heterocycle may be substituted by R ^

g,

where R

- for cyclopropyl, cyclopentyl or cyclohexyl

stands or

represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl, the substituted F; s': n may be substituted by fluorine, chlorine, hydroxyl,

Methoxy, ethoxy, trifluoromethyl, benzoyl, butyl, ethylcarbonyl or by a group -NP ⁶ R ⁷

A 7 ·

where R and R are as defined above

have

- is pyridyl, pyrimidyl or benzimidazolyl, which may be substituted equally or differently by fluorine, chlorine, methyl, ethyl, methoxy, eth

oxy, phenyl, phenoxy or trifluoromethyl

Le A 25 337

- 27 -

- is phenyl, which may be substituted identically or differently up to two times by methyl, ethyl, propyl, tert-butyl, methylsulfonyl * ethylsulfonyl, propylsulfonyl, phenyl, phenyloxy, phenylsulfonyl, benzyl, benzyloxy, phenethyl, phenylethoxy, fluorine , Chlorine, cyano, trifluoromethyl or dur: h is a group of the formula -NR ^ R ^,

in which

R ° and R have the abovementioned meaning,

for a group of the formula - (stands,

for a group of the formula

R is -CH-CH ₂ -C-CH ₂ -COOR ¹¹ or H (

or -CH = CH-

stands,

OH

wherein

OH

R ^{10 is} hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl,

and

R ^{11 represents} hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or benzyl or denotes a sodium, potassium, calcium, or magnesium or ammonium ion

Le A 25

- 28 -

The substituted pyrroles of the general formula (I) according to the invention have a plurality of asymmetric carbon atoms and can therefore exist in different stereochemical forms. Both the individual isomers and their mixtures are the subject of the invention, 10

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

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:

R ³ -HJ] ^ (II) E form R ² Ϊ R ¹

y Π T < * ^

A (III) Z-form

^{In which}

R, R ² , R, R ⁴ , R ^ and A are as defined above

to have.

Preference is given to those compounds of the general formula (I) which are E-configured (II),

b) If the radical -A- is a group of the formula Le A 25 837

- 29 -

_R 1O

11

-CH-CHp-C-CHO-COOR

I ² I ²

OH OH where R * 0 and R ** have the abovementioned meaning,

...

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

Position of these hydroxy groups to each other, can 15

the compounds according to the invention in the erythrocyte

Configuration (IV) or in the threo configuration

(V) are present,

R ¹⁰

, f / X-CH-CHo-C-CHp-COOR ¹¹ Erythro-Form (IV)

«HCT i i

OH OH R ¹ N

R ² IR ¹

_R 10?

^ -OC-CH-CH ₂ -C-Ch ₂ -COOR ¹¹ Threo-Form (V)

.... OH I) HR ² IR ¹ N

In turn, there are two enantiomers of the compounds in both erythro and threo configurations, namely 3R, 5S isomer, 3S, 5R isomer (erythro form) and 3R, 5R isomer and 3S, 5S-

Isomeric (threo-form).

Le A 25 837

- 30 -

Preference is given here to the erythro-configured isomers, particularly preferably the 3R, 5S isomers and the 3R, 5S-3S, 5F racemate,

c) If the fixed -A- stands for a group of the formula

thus, the N-substituted pyrroles 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 rest of the formula

^r 1X

R ² IR ¹

NR ⁴ 'V ⁵

is bound. Depending on the position of the hydroxy group to the free valence on the lactone ring, the substituted pyrroles may be present as cis-lactones (VI) or as trans-lactones (VII).

r ^ X

^{1 year}

N> cis-lactone (VI)

R ² IR ¹

Le A 25 837

- 31 -

HCFC

² I

⁴ '

trans-lactone (VII)

In turn, both the cis-lactone and the trans lactone have two isomers, namely the 4R, 6R isomers or "the 4S, 6S isomer (cis-lactone)" and the 4R, 6S isomer or "4S.6R" Isomers (trans-lactone) "Preferred isomers are the trans-lactones. Particularly preferred here is the 4R.6S isomer (trans) and the 4R, 6S-4S, 6R racemate.

For example, the following isomeric forms of the substituted pyrroles may be mentioned:

Le A 25

- 32 -

HO * .os

R ^ V ^ N ^^ R ¹

OH OH

R ³ XXhC ^ R ¹

Il R ⁴ "^ ⁵

10

OH OH

^ SVCH-CH ₂ -C-CH ₂ -COOR ^{1 X} 1 olO

OH

RSx ¹ N _n X ¹ XrI

_R -% ₅ QH

lO

La A 25

- 33 -

OH OH

CH-CH ₂ -C-CH ₂ -COOR ¹¹ ilO

⁴ '

10

 he ^ o

Le A 25 837

OH OH

H -C-

R ¹⁰

10 · Q "S ^H

CH-CHo-C-CH ₉ -COOR ^{1 X}

OH OH

_R 10

20 _R 4 ^ _r .

OH OH

_R 10

Very particular preference is given to the compounds of all-. common formula (Ia),

in which

R ¹ - for cyclopropyl, methyl, ethyl, propyl, isopropyl, 35

Le A 25 837

- 35 -

Butyl »isobutyl or tert-butyl« which may be substituted by fluorine, chlorine «hydroxy» methoxy »phenyl or phenoxy«

R ² - for phenyl is up to 2 times the same or

differentiated by methyl "ethyl" propyl "isopropyl" butyl "isobutyl" tert -butyl "hydroxymethyl, methoxy" ethoxy "propoxy" phenoxy "benzyloxy" fluorine "chlorine" cyano "trifluoromethyl may be substituted"

R ^{3 is} hydrogen,

- stands for cyclopropyl «

- for methyl "ethyl" propyl "isopropyl" which may be substituted by fluorine "hydroxy" chlorine "cyano or trifluoromethyl"

- is phenyl which may be substituted by fluorine, chlorine, cyano, hydroxy or trifluoromethyl

R ^ and R are the same or different and

- represent methyl, ethyl, propyl, isopropyl, butyl or tert-butyl or

- stand for phenyl which may be the same or different by up to 2-fold by methyl, ethyl, propyl, isopropyl, methoxy, fluorine, chlorine, hydroxy, trifluoromethyl or methoxycarbonyl

or

R ^ and R ^ together with the N atom form a 5- to 7-membered

to form a heterocyclic group »35

Le A 25 837

- 36 -

wherein this heterocycle may be substituted by R 'where

R - for cyclopropyl or

for methyl, ethyl, tert, butyl or

- stands for pyridyl or

- is phenyl which may be substituted identically or differently up to 2 times by methyl, ethyl, propyl, fluorine, chlorine, cyano or trifluoromethyl,

X - for a group of the formula

(E configuration) and A - for a group of the formula

-CH-CH ₀ -C-CH ₀ -COOR ¹¹ or I ² I ^ OH OH '

R is hydrogen

R is hydrogen, methyl or ethyl, or in sodium or potassium cation,

The process according to the invention for the preparation of the substituted pyrroles of the general formula (I)

»37«

X-A

R ² 'R ¹

in which

R, FT ₁ R, R, R <, X and A have the abovementioned meaning,

i3t characterized in that one

Ketones of the general formula (VIII)

12

II CHnCH-CH-CH _o -C-CH _o -Cr> 0R ^J

^dd

R ⁴ ' R ⁵

in which

R, R, R, R, R have the abovementioned meaning, and

R ¹² - for alkyl eteht, reduced,

in the case of the preparation of the acids, saponifying the esters,

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 = ⁵ -CH ₂ -CH ₂ -) hydrogenated the ethene compounds (X = -CH ^ CH-) by conventional methods,

and optionally isomers are separated ·

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

Le A 25

- 39 -

H ₂ COOCH ₃

Reduction

H ₂ COOCH ₃

COO ^e Na® OH

Cyclization OH

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. Reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane, is particularly suitable. Preference is given to reduction with complex metal hydrides such as, for example, lithium borohydride, sodium borane, potassium borohydride, zinc borohydride, lithium trialkylhydridoborates, 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 here are the customary 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 likewise possible to use mixtures of the abovementioned 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

Le A 25 837

- 41 -

If the alkoxycarbonyl group is not changed, the use of sodium borohydride as reducing agent in the presence of triethylborane in inert solvents, such as preferably ethers, is particularly suitable.

The reduction is generally carried out in a temperature range from -90 ⁰ C to room temperature (+30 ⁰ C) ₁ preferably from -80 ⁰ C to ⁰ ° C.

The process according to the invention is generally carried out under normal 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 from 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 the general formula (I), j αΛ which X is an ethylene group, the reduction of the ketones (III) can be carried out under such conditions, under which both the carbonyl group. s also the double bond is reduced,

Le A 25 837

- 42 -

In addition, it is also possible to carry out the reduction of the carbonyl group and the reduction of the double bond in two separate steps. Preferably, the double bond is hydrogenated after reduction of the carbonyl group in the presence of a noble metal catalyst such as palladium or rhodium (J, Med, Chem. 28, 347 (1985),

The carboxylic acids in the context of the general formula (I)

correspond to the formula (Ic)

R ¹⁰

, / X-CH-CH ₂ -C-CH ₂ -COOH (Ic)

~ ΗΠΓ ι ι

YnK oh oh R ² IR ¹

R ³ -

in which

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ and X have the abovementioned meaning,

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

, X-CH-CHo-C-CHo-COOR ¹² (Id)

YUK OH OH

R ² IR ¹ N

in which

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ and X have the abovementioned meaning,

Le A 2 5 837

- 43 -

and

R ¹² - is alkyl.

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

10

HOT R ² IR ¹

Oh oh

Mn ⁺ (Ie)

in which

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ and X have the abovementioned meaning,

and

M ^{n + stands} for a cation.

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

(If)

Le A 25

- 44 -

in which 5

R ¹ , R ^ ₁ r3 _v r4 _{# r} 5 ₄ plO _and χ _d £ _eo b _s have the meaning given to them «

To prepare 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 saponified by customary methods. The saponification is generally carried out by reacting the esters or the lactones in inert solvents ¹ ^ treated with customary bases "which generally initially the salts of general formula (Ie) arise, which can then be converted in a second step by treatment with acid in the free acids of the general formula (Ic), 20

Suitable bases for saponification are the customary inorganic bases. These include preferably alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium bicarbonate, or alkali metal alkoxides such as sodium, sodium, potassium, potassium or potassium tert-butoxide. Sodium hydroxide or potassium hydroxide are particularly preferably used.

Le A 25 837

- 45 -

Suitable solvents are saponification water ** or the usual for saponification organic solvents "These include preferably alcohols such as methanol" ethanol "propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulfoxide." Alko are particularly preferred - ¹ ^ such as methanol, ethanol, propanol or isopropanol used «It is also possible to use mixtures of the said solvents

The hydrolysis is carried out in general 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 "but it is also possible to work at reduced pressure or at overpressure (for example, from 0.5 to 5 bar).

When carrying out the saponification, the base is generally employed in an amount of from 1 to 3 mol, preferably from 1 to 1.5 mol, relative to 1 mol of the ester or of the lactone. It is particularly preferred to use molar quantities of the reactants.

When carrying out the reaction, in the first step, the salts of the compounds (Ii) 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.

Le A 25 837

- 46 -

These include preferably mineral acids such as hydrochloric acid. Hydrobromic acid, sulfuric acid or phosphoric acid. It has proven to be advantageous in the preparation of the carboxylic acids (Ic) to acidify the basic reaction mixture of the saponification in a second step without isolation of the salts. The acids can then be isolated in a customary manner.

To prepare the lactones of the formula (If) according to the invention, the carboxylic acids (Ic) according to the invention are generally cyclized by customary methods, for example by heating the corresponding acid in inert organic solvents, if appropriate in the presence of molecular sieve.

Suitable solvents 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 solvents mentioned. Particular preference is given to using hydrocarbons, in particular toluene, in the presence of molecular sieve.

The cyclization is generally carried out in a temperature range from -40 ° 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

Le A 25 837

- 47 -

to be carried out under reduced pressure or overpressure (2, B, in a range of 0.5 to 5 bar) «

Moreover, the cyclization is also carried out in inert organic solvents "with the aid of cyclizing or" dehydrating agents. "Carbodiimides are preferably used as dehydrating agents here. When carbodiimides are preferably N ₁ N'-Dicyclohexylcarbodi imide paratoluene sulfonate. N-cyclohexyl-N '- [2' - (N '' -methylmorphol inium) ethyl lcarbodi imide or N- (3-dimethylaminopropyl) -N ¹ -ethylcarbodiimid hydrochloride used.

Suitable solvents here are the customary 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, xylene, or petroleum fractions, chlorohydrocarbons such as methylene chloride, chloroform or carbon tetrachloride are particularly preferably used.

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

Le A 25 837

- 48 -

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

The separation of the isomers into the stereoisomerically uniform constituents is generally carried out by customary methods as described, for example, by E, L. Eliel, Steruochemistry of Carbon Compounds, McGraw Hill, 1962. "The separation of the isomers at the stage of the racemic lactones is preferred here. Particular preference is given here to the racemic mixture of trans-lactones (VII) by treating with either D - (+) - or L - (-) - a-methylbenzylamine by conventional methods in the diastereomeric dihydroxyamides (Ig)

CH

H ₂ -CONH-CH-C ₆ H ₅

(Ig)

Then, as usual, can be separated by chromatography or crystallization in the individual diastereomers. Subsequent hydrolysis

the pure diastereomeric amides by conventional methods, for example by treating the diastereomeric amides with inorganic bases such as sodium hydroxide or potassium

Le A 25 837

- 49 -

hydroxide in water and / or organic solvents of alcohols e.g. Methanol, ethanol, propanol or isopropanol, the corresponding enantiomerically pure dihydroxy acids (Ic), which can be converted as described above by cyclization in the enantiomerically pure lactones. In general, for the preparation of the compounds of the general formula (I) according to the invention in enantiomerically pure form, 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:

Le A 25 837

- 50 -

trane-Racemnt

♦ Η, Ν-CH-C.H

CH-

H ₂ -CO-NH-CH C ₆ H ₅

diastereomeric mixture

1) diastereomer separation

2) saponification

3) lactonization

Le A 25 837

- 51 -

83

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

A process for the preparation of the ketones according to the invention of the general formula (VIII)

· I

CH-CH-CH-CH ₂ -C -CH ₂ -COOr ¹²

in which

R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{12 have} the abovementioned meaning

have, 20

found «which is characterized in that one

Aldehydes of the general formula '.IX)

in which

R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the abovementioned meaning,

Le A 2 5 837

- 52 -

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

Il

H ₃ CC-CH ₂ -COOR

12

(X)

in which

R * ^ has the meaning given above »in the presence of bases»

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

base

H ₃ CC-CH ₂ -COOCH ₃

H ₂ COOCH ₃

Le A 25 837

- 53 -

Suitable bases here are the usual strongly basic compounds. These preferably include organolithium compounds such as n-butyl lithium, tert-butyl lithium, butyl lithium or phenyl lithium, or amides such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethyldisilylamide, or alkali hydrides such as sodium hydride or quinium hydride, It is also possible to use mixtures of the abovementioned bases. Particular preference is given to n-butyl-1-lithium or sodium hydride or a mixture thereof

used · 15

Suitable solvents here are the customary 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 halogenated fractions. It is likewise possible to use mixtures of the abovementioned solvents. Particular preference is given to using ethers, such as diethyl ether or tetrahydrofuran,

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

Le A 25 837

In carrying out the process, the acetoacetic ester is generally used in an amount of 1 to 2, preferably from 1 to 1.5, mol, based on 1 mol of the aldehyde.

The acetoacetic esters 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, propyl acetoacetate, isopropyl acetoacetate.

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

It has also been a process for the preparation of

Aldehydes of the general formula (IX) 25

so _VnV

² I

(IX)

_VnV

R ² IR ¹

in which R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the abovementioned meaning,

Le A 2 5 837

- 55 -

found «which is characterized in that one 5

Pyrroles of general formula (XI)

^r2 i

⁴ '

^rl

in which

R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meaning given above

in inert solvents in the presence of acid halides with Ν, Ν-dialkylaminoacrolein of the formula (XII)

alkyl

N-C = CH-CHO (XII)

alkyl

wherein

Alkyl is a straight-chain or branched hydrocarbon radical (C ₁ to C ₄ ),

converts "

Le A 25 837

- 56 -

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

N-CH = CH-CHO

Suitable solvents here are the customary organic solvents which are stable under the reaction conditions. These include preferably hydrocarbons such as benzene, toluene, xylene, hexane, petroleum fractions, halogenated hydrocarbons such as chlorobenzene or dichlorobenzene, or Etb, r 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 the mentioned solvents "Anhydrous acetonitrile or chloroform is particularly preferred"

Le A 25

- 57 - 2 83 β

Ale Hilfestoffe be used in general acid chlorides. Preference is given to using phosphorus oxychloride or phosgene "particular preference to phosphorus oxychloride.

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 under normal pressure. However, it is also possible to carry out the process under reduced pressure or at elevated pressure (for example in a range from 0.5 to 5 bar).

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

The pyrroles of the general formula (XI) used as starting materials are known or can be prepared by known methods. Glossauer "The chemistry of the Pyrrole", Springer publishing house Berlin, 19743.

The N-substituted N-amino-pyrroles according to the invention have valuable pharmacological properties and can be used as active ingredients in medicaments. In particular, they are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HGM-CoA) reductase and inhibitors of cholesterol biosynthesis. They can be used to treat hyperlipoproteinemia, lipoproteinemia or arteriosclerosis. The active compounds according to the invention also cause a reduction in the cholesterol content in the blood.

Le k 25 837

- 58 -

The new active ingredients can in a known manner in the usual. Formulations, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents. In this case, the therapeutically active compound should in each case be at a concentration of about 0, From 5 to 98 parts by weight, preferably from 1 to 90 parts by weight, of the total mixture, d, h, in amounts sufficient to achieve the stated dosage latitude.

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 be used as optional solvents,

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 / sesame oil), alcohols (e.g., ethyl alcohol, glycerin), carriers such as e.g. ground natural minerals (e.g., kaolins, clays, talc, chalk) ground synthetic minerals (e.g., fumed silica, silicates),

Sugar (e.g., cane, milk, and grape sugar), emulsifying agents (e.g., polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates, and aryl sulfonates), dispersing agents (e.g., lignin-sulfite liquors, 35

Le A 25 837

- 59 -

Methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g., B, 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 course, tablets may also contain, in addition to the abovementioned excipients, additives such as sodium citrate, calciumcarborate and dicalcium phosphate together with various adjuvants 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 can be used in addition to the abovementioned excipients with various flavor enhancers or dyes.

be moved.

In the case of parenteral administration, solutions of the active ingredients may be employed using suitable liquid carrier materials.

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 of body weight.

Le A 25 837

- 60 -

Nevertheless, if necessary, it may be necessary to deviate from the stated amounts, depending on the body weight or the type of administration, on the individual behavior towards the drug, the type of formulation and the time or interval at which administration takes place Thus, in some cases, it may be sufficient to manage with less than the above mentioned limit, while in other cases this upper limit must be exceeded. "In the case of the application of larger quantities, it may be advisable to divide these into several single doses throughout the day.

Ausführuncisbeispiel

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

- 61 -

Connections and Installation Example 5

example 1

1- (4-fluorophenyl) -4-methyl-pent-l-en-3-one

I / CH ₃

H = CH-C-CH

\ CH ₃

To 198.4 g (1.6 mol) of freshly distilled 4-fluorobenzaldehyde and 137.6 g (1.6 mol) of methyl isopropyl in 300 ml of methanol is added dropwise 75 ml of 15% potassium hydroxide solution and stirred overnight at room temperature »Then with 10 ml of acetic acid neutralized, 1 1 of water was added and extracted with two 500 ml portions of ether, The combined 2Q organic phases are washed with 500 ml of saturated sodium chloride solution and dried over sodium sulfate, After removal of the solvent is distilled under high vacuum,

Yield: 198.6 g (65X of theory) of yellowish oil Kp. 103 ⁰ C (0.3 mbar)

¹ H-NMR _(CDCl3): S = 1.2 (d, 6H, CH _3); 2.9 (sept, IH, CH-

(CH ₃ ) ₂ ); 6.8 (d, IH, olefin-H); 7.1 (m, 2H, Aromafen-H); 7.6 (m, 3H, aromatics H + olefin K),

Le / 25 837

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Example 2 5

2- (4-fluorophenyl) -5-methyl-1-phenyl-hexane-1,4-dione

H-CH ₂ -C-CH-CH ₃

To a solution of 5.88 g (0.12 mol) of sodium cyanide in

300 ml of dimethylformamide, is added dropwise at 35 ° C, a solution of 63.6 g (0.6 mol) of freshly distilled benzaldehyde in 300 ml of dimethylformamide within 30 min and stirred for a further 5 min at this temperature, then within 1.5 h 86.5 g (0.45 mol) of 1 - (4-fluorophenyl) -4-methyl-pent-l-en-3-one (Example 1) in 500 ml of dimethylformamide was added dropwise and stirred for 1 h, the temperature was always is kept at 35 ° C After addition of 1 1 of water is extracted four times with 400 ml of chloroform, the combined organic phases washed with 1 1 of saturated sodium bicarbonate solution and 1 1 of water and dried over sodium sulfate. After concentration in vacuo, the mixture is distilled under reduced pressure until finally a fraction at 138 - 142 ⁰ C (0.9 mbar) passes. The distillation residue (132 g) is then chromatographed in two portions on a column (1.5 Kg silica gel 230-400 mesh, a 9 cm), with petroleum ether / ethyl acetate (10: 1). The product is obtained after 4-71 elution , After removal of the solvent, 90.0 g (67% of theory) of colorless oil remain.

Le A 2 5 837

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10

¹ H-NMR _(CDCl3) S 6 = 1.08 (d, 3H, CHg); 1.12 (d, 3H,

CH ₃ ); 2.65 (sept, IH, CH (CHg) ₂₎ J 2.7 (dd, IH, -CO-CH ₂ -CH); 3.6 (dd, IH, -CO-CH ₂ -CH); 5.12 (dd, IH, HCC ₆ H ₄ -F); 6.95 (m, 2H, aromatics-H); 7.23 (m, 2H, aromatics-H); 7.4 (m, 3H, aromatic-H); 7.95 (m, 2H, aromatic-H),

15 20 25 30

Example 3

3- (4-fluorophenyl) -5-isopropyl-2-phenyl-l- (1-pyrrolidinyl) pyrrole

15 g (50 mmol) of the compound from Example 2 and 20 g (164 mmol) of N-aminopyrrolidine hydrochloride are dissolved in 150 ml of toluene p.A. and 30 ml of dimethylformamide with 20 g of molecular sieve 3Ä added and boiled for 48 h at reflux. The mixture is cooled, filtered off and washed well with toluene. The toluene solutions are combined and extracted 3 χ with 1 N hydrochloric acid. The orga-

35

Le A 25 837

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nische phase is then washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo, the residue is stirred with a little ethanol, cooled and filtered with suction. After drying in a desiccator to obtain 2.3 g of substance,

Yield: 12.8 Y * of theory, 10

¹ H-NMR _(CDCl3): δ

1.31 (D, 6H) J 1,5- 1.8 (m, 4H); 3.05 (M, IH); 3.23 (M, 4H); 6.03 IH); 6.8 (M, 2H); 7.07 (M, 2H); 7.35 (M, 5H).

Example 4

(E) -3-C3- (4-fluorophenyl) -5-isopropyl-2-phenyl-l- (1-pyrrolidinyl) pyrrole-4-yl] -prop-2-enal

'CHO

Under nitrogen, to 1.8 ml (19.2 mmol) of fresh 3Q distilled phosphoroxychloride in 20 ml of acetonitrile pA at -5 ⁰ C 1.9 g (17.9 mmol) of 90 Xiges 3-dimethylamino-acrolein in 30 ml of acetonitrile pA dripped. The mixture is stirred for 10 minutes and added dropwise at the same temperature 2.3 g (6.4 mmol) of the compound of Example 3

Le A 25 837

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dissolved in 20 ml acetonitrile pA and 30 ml tetrahydrofuran ρ, A. to. The mixture is then refluxed overnight and cooled to room temperature. The mixture is added to a mixture of 4.7 g of sodium hydroxide in 300 ml of toluene / water 1: 1 «so that the temperature does not exceed 10 ⁰ C. The mixture is stirred for a further 10 minutes, the organic phase is separated off and the aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried over magnesium sulfate. After concentration in vacuo, the residue is stirred with ethyl acetate / petroleum ether 1: 1, filtered off with suction and dried in a desiccator. Yield: 2 g (71.4 % of theory),

¹ H-NMR (CDCl ₃ ): 6 =

1.48 (d, 6H); 1.72 (m, 4H); 3.23 (m, 4H); 3.5 (m, IH); 5.75 (dd, IH); 6.85 (m, 2H); 7.05 (m, 2H); 7.25 (m, 5H); 7.55 <d, IH); 9.38 (d, IH).

Example 5

Methyl (E) -7- [3- (4-fluorophenyl) -5-isopropyl] -2-phenyl-1 (1-pyrrolidinyl) -pyrrol-4-yl] ~ 5-hydroxy-3-oxo-hept-6 enoate

OH 0

COCH,

Le A 25 837

Under nitrogen is added dropwise to a suspension of 360 mg (12 mmol) of 80 Xigern sodium hydride in 30 ml of dry tetrahydrofuran at -5 ⁰ C 1.1 ml (10 mmol) of methyl acetoacetate in 5 ml of dry tetrahydrofuran After 15 minutes at the same temperature 6 , 2 ml (10 mmol) of 15 Xiges butyllithium in η-hexane was added dropwise and stirred for 15 minutes. Subsequently, 2 g (5 mmol) of compound aue Example 4, dissolved in 20 ml of dry tetrahydrofuran, added dropwise and stirred at -5 ⁰ C for 30 minutes. The reaction solution is carefully mixed with 3.3 ml of 50 Xiger acetic acid, diluted with 100 ml of water and the mixture extracted three times with 100 ml of ether. The combined organic phases are washed twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column (silica gel 70-230 mesh, with ethyl acetate / petroleum ether 4: 6), yield: 1 g (40 Y. of theory)

¹ H-NMR (CDCl ₃ ): δ = 1.42 (d, 6H) J 1.50 (m, 2H);

1.72 (m, 2H); 2.62 (m, 2H);

3.22 (m, 4H); 3.32 (m, IH);

3.46 (s, 2H); 3.73 (s, 3H);

4.55 (m, IH); 5.12 (dd, IH);

6.62 (d, IH); 6.82 (m, 2H);

7.03 (m, 2H); 7.23 (m, 5H).

Le A 25 837

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35

Example 6

10

Methyl erythro- (E) -7- [3- (4-fluorophenyl) -5-isopropyl-2-phenyl-1- (1-pyrrolidinyl) -pyrrol-4-yl] -3,5-dihydroxyhept-n- enoate

OH OH

0OCH ₃

20 25 30

To a solution of 1 g (1.93 mmol) of the compound from Example 5 in 30 ml of dry tetrahydrofuran is added at room temperature 2.4 ml (2.4 mmol) of a 1 molar triethylborane solution in tetrahydrofuran, passed for 5 minutes Air through the solution and cooled to -30 ° C internal temperature. There are 91 mg (2.4 mmol) of sodium borohydride and slowly added 1.8 ml of methanol, stirred for 30 minutes at -30 ° C and then with a mixture of 8.5 ml 30 '/.igem hydrogen peroxide. and 17 ml of water. The temperature is allowed to rise to ^{0 0} C and stirred for 30 minutes after «The mixture is extracted three times with 50 ml of ethyl acetate, the combined organic phases washed once each with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is concentrated on a column

Le A 25 837

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(Silica gel 230-400 mesh with ethyl acetate / petroleum ether 1: 1) chromatographed

Yield: 400 mg (40 % of theory),

¹ H-NMR (CDCl _3): δ = 1.42 (d, 6H); 1.40-1.80 (m, 6H);

2.47 (m, 2H); 3.22 (m, 4H);

3.32 (m, IH); 3.70 (s, 3H);

4.22 (m, IH) J 4.37 (m, IH); 5.17 (dd, IH); 6.58 (d, IH); 6.80 (m, 2H); 7.03 (m, 2H);

7.23 (m, 5H). 15

Example 7

3- (4-fluorophenyl) -5-isopropyl-2-phenyl-1-piperidinopyrrole 20

22.5 g (75 mmol) of the compound from Example 2 and 25 g (250 mmol) of N-aminopiperidine in 200 ml of toluene p.A, and 30 ml of dimethylformamide are mixed with 7.5 ml. Hydrochloric acid and heated for 48 h at the Wassetabscheider to reflux. The mixture is cooled, diluted with 200 ml of ethyl acetate, washed three times with 1 N hydrochloric acid and twice

Le A 25

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10

extracted with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, concentrated in vacuo and the residue is chromatographed on a column (silica gel 70-230 mesh, with ethyl acetate / petroleum ether 95: 5). Yield: 7.2 g (26.5 % of theory).

¹ H-NMR _(CDCl3): δ

1.0 (m, IH); 1.26 (d, 6H); 1.35-1.6 (m, 5H); 2.88 (m, 2H);

3.1 (m, 3H); 5.95 (s, IH); 6.75 (m, 2H); 7.0 (m, 2H) J 7.31 (m, 5H).

Example 8

(E) -3- [3- (4-fluorophenyl) -S-isopropyl-1-phenyl-1-piperi-dinopyrrol-4-yl] -prop-2-enal

CHO

7.2 g (20 mmol) of the compound from Example 7 are reacted analogously to Example 4

Yield: 7.2 g (86.7 % of theory).

¹ H-NMR (CDCl _3): δ = 0.93 <m, IH); 1.48 (d, 6H);

1.5-1.7 (m, 5H); 2.92 (m, 2H);

Le A 25 837

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3.15 (m, 2H); 3.55 (m, IH); 5.75 (dd, IH); 6.83 (m, 2H);

7.0 (m, 2H); 7.25 (m, 5H); 7.52 (d, IH); 9.37 (d, IH).

• Example 9 10

Methyl (E) -7- [3- (4-fluorophenyl-5-isopropyl-2-phenyl-1-piperidino-pyrrol-4-yl] -5-hydroxy-3-oxo-hept-6-enoate

7.2 g (17.3 mmol) of the compound from Example 8 are reacted analogously to Example 5,

Yield: 6.2 g (67.4 % of theory), 25

¹ H-NMR (CDCl _3): δ = 1.40 (d, 6H) '; 0.90-1.60 (m, 6H);

2.62 (m, 2H); 2.90 (m, 2H);

3.12 (m, 2H); 3.38 (m, IH);

3.47 (s, 2H); 3.73 (s, 3H);

4.33 (m, IH); 5.15 (dd, IH);

6.54 (d, IH); 6.80 (m, 2H);

7.01 (m, 2H); 7.25 (m, 5H).

Le A 25 837

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Example 1 0 5

Methyl-9-triethyl- (E) -7- [3- (4-fluorophenyl) -5-i-propyl-2-phenyl-1-pipero-pyrrol-4-yl] -3,5-dihydroxyhept-6-enoate

6.2 g (11.7 mmol) of Vcroindung from Example 9 are reacted analogously to Example 6, ^u * Yield: 4.3 g (69.4% of theory).

¹ H-NMR _(CDCl3) O = 1.42 (d, 6H); 0.90-1.70 (m, 8H);

2.47 (m, 2H); 2, i2 (m, 2H);

3.13 (m, 2H); 3.41 (m, IH);

3.72 (s, 3H); 4.2C <m, IH);

4.36 (m, IH): 5.19 (dd, IH);

6.52 (d, IH); 6.78 (m, 2H);

7.02 (m, 2H); 7.23 (m, 5H).

Le A 25 837

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28380Ö

Example 5 1- (4-Fluoro-3-phenoxyphenyl) -4-methyl-pent-1-en-3-one

64.8 g (0.3 mol) of 3-phenoxy-4-fluorobenzaldehyde and 51.6 g (0.6 mol) of methyl isopropyl ketone in 90 ml of methanol are mixed with 14.1 ml of 15 Xiger aqueous potassium hydroxide solution and overnight Room temperature stirred. The

Mixture is neutralized with 1.95 ml of glacial acetic acid, with 20

The organic phase is dried over magnesium sulfate, concentrated by evaporation in a vacuum and the residue is chromatographed on a column (silica gel 70-230 mesh, with ethyl acetate / petroleum ether 1: 9). Yield: 41.6 g (48.8 % of theory).

example

2- (4-fluoro-3-phenoxyphenyl) -5-methyl-l-phenyl-hexane-1.4-30

dion

Le A 25

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2Θ3808

12.5 g (44 mmol) of the compound from Example 11 are reacted according to Example 2.

Yield * 9.5 g (55.5 Y, theory) » example

3- (4-Fluoro-3-phenoxyphenyl) -5-isopropyl-2-phenyl-1-pipe · pyrrino-pyrrole

18.45 g (47.4 mmol) of the compound from Example are reacted analogously to Example 7. Yield: 5.1 g (23.7 % of theory),

¹ H-NMR (CDCl _3): δ = 1.0 (m, IH) J 1.28 (d, 6H) J

1.4-1.6 (m, 5H); 2.89 (m, 2H); 3.1 <m, 3H); 5.95 (s, IH); 6.2-7.35 (m, 13H).

Le A 25

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Example 14

(E) -3-C3- (4-fluoro-3-phenoxyphenyl) -5-isopropyl-2-piperidino-phenyll-pyrrol-4-yl] -prop-2-enal

5.1 g (11.2 mmol) of the compound from Example 13 are reacted analogously to Example 4, yield: 5 g (87.7 Y, of theory).

20 ¹ H-NMR _(CDCl3) 6 ί

0.9 (m, IH) J 1.45 (m, 6H); 1.52 (m, 5H) J 2.9 (m, 2H); 3.1 (m, 2H); 3.5 (m, IH);

5.81 (dd, IH); 6.7-7.35 (m, 13H);

7.5 (d, IH); 9.4 (d, IH).

Example 15

Methyl (E) -7- [3- (4-fluoro-3-phenoxyphenyl) -5-isopropyl-2-phenyl-l-piperidino-pyrrol-4-yl] -5-hydroxy-3-oxo-hept- 6-enoate

OH 0

COOCH ₃

Le A 25 837

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ίο

5 g (9.8 mmol) of the compound from Example 14 are reacted analogously to Example 5

Yield: 3.5 g (57.3 Y, theory),

¹ H-NMR (CDCl _3): δ = 1.37 (d, 6H); 0.90-1.60 (m, 6H) j

2.62 (m, 2H); 2.87 (m, 2H);

3.08 (m, 2H); 3.37 (m, IH);

3.45 (s, 2H); 3.73 (s, 3H);

4.54 (m, IH); 5.22 (dd, IH);

6.52 (d, IH); 6.71 (m, 2H);

6.78 (m, IH); 6.92 (m, IH);

7.02 (m, IH); 7.23 (m, 8H).

Example 16

20

Methyl erythro- (E) -7- [3- (4-fluoro-3-phenoxyphenyl) -5-isopropyl-2-phenyl-1-piperidino-pyrrol-4-yl) -3,5-di-hydroxy hept-6-enoate

OH OH

COOCH-

3.5 g (5.6 mmol) of the compound from Example 1 are reacted analogously to Example 6

Yield: 2.3 g (65.5 % of theory),

35

Le A 25 837

¹ H-NMR (CDCl ₃ )! 6 = 1.37 (d, 6H); 0.9-1.7 (m, 8H);

2.47 (m, 2H); 2.90 (m, 2H);

3,12 <m, 2H); 3.38 (m, IH);

3.72 <s, 3H); 4.22 (m, IH);

4.37 (m, IH); 5.26 (dd, IH);

6.51 (d, IH); 6.65-7.10 (m, 5H);

7.25 <m, 8H).

Example 17

3- (4-fluoro-3-phenoxyphenyl) -6-methyl-heptan-2,5-dione

O 20

10 g (35.2 mmol) of the compound from Example 11 in 30 ml of acetonitrile pA are added at ⁰ ° C. with 3 ml (42.2 mmol) of nitroethane. Then 2.77 g (17.6 mmol) are added at the same temperature. 1,8-diazabicyclo (5,4,0) undec-7-en dissolved in 10 ml of acetonitrile pA ,, added dropwise and stirred for 1 hour at room temperature, the mixture is mixed with 35 ml of 0.5 N hydrochloric acid, extracted several times with dichloromethane and the organic phase dried over magnesium sulfate. Concentration in vacuo gives an oily residue, which is taken up in 35 ml of ethanol and treated with a solution of 1.7 g (42.2 mmol) of sodium hydroxide in 21 ml of water. This mixture is added dropwise at 0 ° C to 4.68 ml (88 nunol) conc.

Sulfuric acid in 35 ml of water and allowed to stand for 30 minutes at Jo

Le A 25 837

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Stir room temperature. It is diluted with water and extracted several times with ether. The organic phase is washed twice each with 1 N hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated by evaporation in a vacuum. After chromatography on a column (silica gel 70-230 mesh with ethyl acetate / petroleum ether 2: 8), 4 is obtained. 8 g of substance, yield; 41.5 V. of theory,

¹ H-NMR (CDCl _3): δ = 1.05 (d, 3H); 1,1 (d, 3H);

2.J5 (s, 3H); 2.58 (m, 2H);

¹ S 3.35 (m, IH); 4.15 (m, IH);

6.85-7.38 (m, 8H).

Example 18

3- (4-fluoro-3-phenoxyphenyl) -5-isopropy1-2-methyl-l-piperidino-pyrrole

11.2 g (34 mmol) of the compound from Example 17 are reacted analogously to Example 7, yield: 4.2 g (31.5 Y. of theory).

Le A 25 837

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¹ H-NMR (CDCl _3): δ = 1.22 (d, 6H); 1.30 <m, IH);

1.72 (m, 5H); 2.38 (ε, 3Η);

3.06 (m, IH); 3.15 (m, 2H);

3.30 (rr ,, 2H); 5.77 (ε, IH);

7.0-7.40 (m, 8H).

10 Example 19

(E) -3-E 3- (4-Fluoro-4-phenoxyphenyl) -S-isopropyl-methyl-1-pipericiaminopyrrol-4-yl] -prop-2-enal

CHO

4.15 g (10.6 mmol) of the compound from Example 18 are reacted analogously to Example 4, yield: 2 g (42.6 X of theory).

¹ H-NMR (CDCl _3): δ =

1.30 (m, IH); 1.38 (d, 6H);

1.73 (m, 5H); 2.18 (s, 3H);

3.13 (m, 2H); 3.32 (m, 2H);

3.43 (m, IH); 5.73 (dd, IH);

6.70-7.45 (m, 8H); 7.40 (d, IH); 9.33 (d, IH).

Le A 25 837

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example

Methyl (E) -7- [3- (4-fluoro-3-phenoxyphenyl) -5-isopropyl-2-methyl-1-piperidino-pyrrol-4-yl] -5-hydroxy-3-oxo-hept- 6-enoate

OH O

COOCH-;

2 g (4.5 mmol) of the compound from Example 19 are reacted analogously to Example 5 « ²⁰ yield: 1.7 g (67.2 % of theory).

¹ H-NMR (CDCl _3): δ =

1.32 (d, 6H) j 1.20-1.80 (m, 6H);

2.22 (s, 3H); 2.62 <m, 2H);

3.13 (m, 2H); 3.30 (m, 3H); 3.46 (3, 2H);

3.73 (s, 3H); 4.52 (m, IH); 5.18 (dd, IH); 6.45 (d, IH);

6.90-7.40 (m, 8H).

Le A 25

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example

Methyl erythro- (E) -7- [3- (4-fluoro-3-phenoxyphenyl) -5-isopropyl-2-methyl-l-piperidino-pyrrol-4-yl] -3,5-dihydroxyhept-5- enoate

COOCH ₃

1.7 g (3 mmol) of the compound from Example 20 are reacted analogously to Example 6

Yield: 330 mg (19.5 Y, theory).

¹ H-NMR (CDCl _3): δ =

1.32 (d, 6H); 1.20-1.80 (m, 8H) J 2.20 (s, 3H) J 2.47 (m, 2H) J 3.15 (m, 2H) J 3.30 (m, 3H) J 3 , 71 (s, 3H) J 4,22 (m, IH) J

4.33 (m, IH) J 5.19 (dd, IH) J 6.40 (d, IH) J 6.90-7.20 (m, 6H) J 7.30 (m, 2H).

Le A 25

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Example 22

3- (4-fluorophenyl) -l-hexahydroazepinyl-5-isopropyl-2-phenyl-pyrrole

5 g (16.7 mmol) of the compound from Example 2 and 5.7 g (50.1 mmol) of N-amino-hexahydroazepine in 100 ml of toluene pA and 80 ml of dimethylformamide are treated with 1.7 ml of conc. Hydrochloric acid and boiled for 24 hours on a water separator. The mixture is cooled, diluted with 200 ml of ethyl acetate and extracted three times with 1 N hydrochloric acid and twice with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, concentrated in vacuo and the residue chromatographed on a column (silica gel 70-230 mesh, with ethyl acetate / petroleum ether 1: 9), yield: 560 mg (8.9 Y, of theory).

¹ H-NMR (CDCl _3): δ = 1.32 (d, 6H) 1.35 to 1.7 j <m, 8H); 3.0-3.4 (m, 5H); 6.01 (s, IH);

6.8 (m, 2H); 7.05 (m, 2H); 7.35 (m, 5H).

Le A 25 837

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Example 5 <E) -3- [3- (4-Fluorophenyl) -1-hexahydroazepinyl-5-isopropyl] -2-phenyl-pyrrol-4-yl] -prop-2-enal

'CHO 10

550 mg (1.5 mmol) of the compound from Example 22 are reacted analogously to Example 4,

Yield: 410 mg (63 * 6 Y, theory). 20

¹ H-NMR (CDCl ₃ ): δ = 1.28-1.7 (m, 8H) J 1.5 (d, 6H);

3.08 (m, 2H); 3.28 (m, 2H);

3.58 (m, IH); 5.7 (dd, IH);

6.84 (m, 2H); 7.02 (m, 2H);

7.21 (m, 5H); 7.6 (d, IH);

9.35 (d, IH).

Le A 25

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example Methyl - (E) -7-1- (4-fluorophenyl) -1-hexahydroazepinyl-5-

ieopropyl-2-phenyl-pyrrol-4-yl] -5-hydroxy-3-oxo-hept-6-

enoate

OH O

COOCi -,

400 mg (0.93 mmol) of the compound from Example 23 are reacted analogously to Example 5

Example: 187 mg (36.8 Y, theory).

¹ H-NMR '(CDCl ₃ )!

1.42 (d, 6H); 1.30-1.80 (m, 8H);

2.58 (m, 2H); 3.08 (m, 2H);

3.30 (m, 2H); 3.42 (m, IH);

3.48 (β, 2H); 3.73 (β, 3H);

4.53 <m, IH); 5.08 (dd, IH);

6.68 (d, IH); 6.82 (m, 2H);

7.04 (m, 2H); 7.22 (m, 5H),

Le A 25

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example

Methyl erythro- (E) -7- [3- (4-fluorophenyl) -l-hexahydroazepinyl-5-ieopropyl-2-phenyl-pyrrol-4-yl] -3,5-dihydroxyhept-6-enoate

OH OH

COOCH ₃

180 mg (0.33 nunol) of the compound from Example 24 are reacted analogously to Example 6, ^"20 Yield: 130 mg (72.2 Y, of theory).

¹ H-NMR _(CDCl3): S

1.43 (d, 6H); 1.20-1.80 (m, 10H);

2.74 (m, 2H); 3.10 (m, 2H);

3.31 (m, 2H); 3.41 (m, IH);

3.72 (s, 3H); 4.19 (m, IH);

4.33 <m, IH); 5.12 (dd, IH);

6.62 (d, IH); 6.80 (m, 2H);

7.03 (m, 2H); 7.22 (m, 5H).

Le A 25

Example 5

3- <4-fluorophenyl) -S-isopropyl-l- (4-methylpiperidino) -2-phenyl-pyrrole

10.1 g (34 mmol) of the compound from Example 2 and 11.6 g (102 mmol) of N-amino-4-methyl-piperidine in 100 ml of toluene p.A, and 50 ml of dimethylformamide with 3.4 ml of conc. Hydrochloric acid and boiled for 24 hours on a water. The mixture is cooled, diluted with 200 ml of Eseigester and extracted three times with 1 N hydrochloric acid and twice with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, concentrated in vacuo and the residue is chromatographed on a column (silica gel 70-230 mesh, with ethyl acetate / petroleum ether 5:95). Yield: 1.9 g (14.8% of theory).

Ls A 25

- 86 -

example

E- (3) - [3- (4-Fluorophenyl) -S-isopropyl-1- (4-methylpiperidino) -2-phenyl-pyrrol-4-yl] -prop-2-enal

CHO

1 * 9 g (5.1 mmol) of the compound from Example 26 are reacted analogously to Example 4, yield: 1.2 g (54.5 Y, of theory),

¹ H-NMR (CDCl ₃ ):

0.86 (d, 3H) J 1.0-1.70 (m, 5H); 1.48 (d, 6H); 2.97 (m, 2H); 3.12 (m, 2H); 3.56 (m, IH); 5.77 (dd, IH.); 6.82 (m, 2H); 7.0 (m, 2H); 7.27 (m, 5H); 7.52 (d, IH); 9.38 (d> IH).

Le A 25

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example

Methyl (E) -7-t3- (4-fluorophenyl) -5-isopropyl-1- (4-methylpiperidino) -pyrrol-4-yl] -5-hydroxy-3-oxo-hept-6-enoate

OH 0

COOCH ₃

1.2 g (2.8 mmol) of the compound from Example 27 are reacted analogously to Example 5

 Yield: 850 mg (55.6 K of theory),

¹ H-NMR (CDCl _3): δ =

0.87 (d, 3H); 1.0-1.70 (m, 5H) J

1.42 (d, 6H); 2.62 (m, 2H);

2.91 (m, 2H); 3.09 (m, 2H);

3.40 (m, 1H)> 3.48 (s, 2H);

3.73 (s, 3H); 4.55 (m, IH); 5.18 (dd, IH); 6.52 (d, IH);

6.78 <m, 2H); 6.99 (m, 2H);

7.25 (m, 5H).

Le A 25

- 88 -

example

Methy1-erythro- (E) -7-C3- (4-fluorophenyl) -5-isopropyl-l- (4-methyIpiperidino) -pyrrole-4-yl] -3,5-dihydroxy-hept-6-enoate

OH OH

COOCH-:

830 mg (1.7 mmol) of the compound from Example 28 are reacted analogously to Example 6, yield: 620 mg (66.5 % of theory).

¹ H-NMR (CDCl _3): δ =

0.87 (d, 3H); 1.0-1.7 (m, 7H);

1.39 (d, 6H); 2.47 (m, 2H);

2.90 (m, 2H); 3.12 (m, 2H);

3.39 (m, IH); 3.72 (ε, 3H);

4.22 (m, IH); 4.38 (m, IH); 5.22 (dd, IH); 6.48 (d, IH);

6.76 (m, 2H); 6.98 (m, 2H);

7.25 (m, 5H).

Le A 25

Application Example 5

Example 30

The enzyme activity determination was modified according to G, C, Ness et al., Archives of Biochemistry and Biophysics 197, 493-499 (1979). Male ricot rats (body weight 30 ° - 400 g) were treated for days with Altromin powder feed to which 40 g cholestyramine / kg diet had been added. After decapitation> remove the liver from the animals and place on ice. The livers were minced and mixed in the Potter Elvejem homogenizer 3 times in 3 volumes of 0.1 M sucrose, 0.05 M KCl, 0.04 M K _x Hy 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 5 times the amount of its volume of SPE buffer, homogenized, and frozen at -78 ⁰ C and stored (= enzyme solution).

For palpation, the test compounds (or mevinolin as a reference substance) were dissolved in dimethylformamide with the addition of 5 vol. X 1 η 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 25 837

- 90 -

was 0.380 ml and contained 4 μΜοΙ glucose-6-phosphate, 1.1 mg bovine serum albumin, 2.1 μΜοΙ dithiothreitol, 0.35 μΜοΙ NADP, 1 unit glucose-o-phosphate dehydrogenase, μΜοΙ K _x H _y 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

 10

The mixture was incubated for 60 minutes at 37 ° C and the reaction was stopped by the addition of 300 μΐ 0.24 m HCl. After a subsequent incubation of 60 minutes at 37 ° C., the batch was centrifuged and 600 μl of the supernatant were applied to a 0.7 × 4 cm column filled with Biorex * ^R * 5 chloride 100-200 mesh (anion exchanger). Ee was distilled with 2 ml. Washed water and pass plus Waechwaeeer mixed with 3 ml of Aquasol and counted in the LKB scintillation counter. IC ₅ g values were determined by order of the percentage inhibition against the concentration of the compound in the test by intrapolation. To determine the relative inhibitory potency of ICgQ -Vfort the reference substance mevinolin was as 100 ge

and compared with the simultaneously determined ICgQ value of the test compound.

Le A 25 837

- 91 -

Example 31 p

The subchronic effect of the compounds of the invention on the blood cholesterol levels of dogs was tested in several weeks of feeding experiments. For this purpose, the substance to be examined was given once a day for several weeks in a capsule of healthy beagle dogs together with the food po. The food was also during the entire test period _# ie before "during and after the Applikat ionspe> Riode of the test substance, cholestyramine added (4 g / 100 g diet) as Gallensäuresequestrant. Twice a week venous blood was taken from the dogs and serum cholesterol was determined enzymatically. Serum cholesterol levels during the application period were compared with serum cholesterol levels before the application period (control),

Le A 25 837

Claims (2)

claims Ι »Process for the preparation of N-eubetitulierter N-aminopyrroles of the formula (D in which R ¹ - for cycloalkyl eteht, or - is alkyl which may be substituted by halogen, cyano, hydroxy, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethyleuifonyl, alkoxycarbonyl, acyl or by a group of formula -NR ⁶ R, wherein 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, aryl9-sulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals of the last-mentioned sub-substituents are up to 3-fold identical or different from halogen, cyano, trifluoromethyl, Trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl may be substituted, R ² - represents heteroaryl which may be up to 3 times the same or different from halogen, Alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, Arylsu'lfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a Group of the formula -NR ⁶ R ^{7 be} substituted can, in which ζ 7 · R and R have the abovementioned meaning,
25 or - is aryl which may be substituted identically or differently up to 5 times by alkyl, hydroxyalkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, aryl thio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbunyl, sulfamoyl, dialkylsulfamoyl, carbo- moyl, dialkylcarbamoyl or by a group of the formula -NR ⁶ R ⁷ , Le A 2 5 837 -9 wherein R ^ and R ^ have the meaning given above, R ³ - for hydrogen or
- represents cycloalkyl, or - is alkyl which may be substituted by halogen, cyano, hydroxy, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethyl-sulphonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ^ R, wherein R ^, R ⁷ - the above mentioned meaning have or by carbcimoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, Aryloxy, arylthio, arylsulfonyl, aralkoxy, Aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals of the last-mentioned substituents are up to 3 times identical or different through halogen, cyano, trifluoromethyl, 3U trifluoromethoxy, alkyl, alkoxy, alkylthio or May be substituted alkylBUlfonyl, or represents heteroaryl which is up to 3 times identical or different through halogen, alkyl, alkoxy, Alkylthio, alkylsulfonyl, aryl, aryloxy, aryl Le A 25 837 263808 thio "arylsulfonyl" trifluoromethyl, trifluoromethoxy "trifluoromethylthio, alkoxycarbonyl or may be substituted by a group of the formula -NR ⁶ R '» wherein
10 A 7 R and R are as defined above « or - for Aryl it's up to 5 times the same or may be substituted differently by alkyl «hydroxyalkyl, alkoxy. Alkylthio, alkylsulfonyl "aryl" aryloxy "arylthio" arylsulfonyl "aralkyl, aralkoxy, aralkylthio" aralkylsulfonyl "halogen, cyano, nitro, tri fluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁶ R ⁷ , wherein R ⁶ and E ^{7 have} the abovementioned meaning to have"
30 R and R ^{D are the} same or different and for - hydrogen, - stand for cycloalkyl «or - represent alkyl "which may be substituted by halogen" hydroxy, alkoxy, alkylthio " Le A 25 837 - 36- Acyl or by a group of the formula NR ⁶ R ⁷ , wherein R, R '- have the meaning given above « or by carbamoyl _t heteroaryl aryl, aryloxy, arylthio, wherein the heteroaryl and aryl radicals of the latter substituents are up to 3 times the same or different by Hal, trifluoromethyl, alkyl, alkoxy ₃ alkylthio or alkylsulfonyl may be substituted, or - stand for heteroaryl, which can be up to 2x identical or different by halogen, alkyl, Alkoxy, alkylthio, alkylsulfonyl, aryl, trifluoromethyl, alkoxycarbonyl or may be substituted by a group of the formula -NR R, wherein ~> and R are as defined above to have,
30 or - represent aryl which may be substituted identically or differently up to twice by alkyl, hydroxyalkyl, alkoxy, alkylthio, alkyl Le A 25 837 263808 sulfonyl, halogen, cyano, nitro, trifluoro- 5 methyl, alkoxycarbonyl, carbamoyl or by a group of the formula -NR ⁶ R ⁷ , wherein 10 R and R are as defined above to have, or 15 - R ^ and R together with the N atom form a 4- to form 8-membered heterocycle «another. May contain heteroatom Y, 20 where Y is S, O or NR ⁸ , where 25 R ^{8 is} alkyl, aryl, aralkyl, Acyl, alkylsulfonyl, arylsulfonyl, wherein this heterocycle may be substituted by R ⁹ , wherein R ^{9 is} - fi'-cycloalkyl, or - represents alkyl which may be substituted serine by halogen, hydroxy, alkoxy, A. alkylthio, 35 acyl or by a group of the formula -NR ⁶ R ⁷ , Le A 25 837 wherein
5 R ⁶ , R ⁷ - have the meaning given above « or by Carbarnoyl, Heterctryi _t aryl, aryloxy, arylthio, where the heteroaryl and aryl substituents of the latter up to 2-fold may be the same or different halogen, trifluoromethyl, alkyl, alkoxy, alkylthio or alkylsulphonyl be substituted, or represents heteroaryl which may be identical or different by up to two times by halogen, alkyl, alkoxy, alkylthio, alkylthio, alky) -sulfonyl, aryl, trifluoromethane thyl, alkoxycarbonyl or by a group A 7 * the formula -NR R may be substituted, wherein
25 R and R have the abovementioned meaning, or - stands for aryl that is up to 2 times the same or may be substituted by alkyl, hydroxyalkyl, alkoxy, alkylthio, alkylsulfonyl, Le A 25 837 - Qt- Halogen, cyano, nitro, trifluoromethyl, alkoxy-5 carbonyl, carbamoyl or by a group of Formula -NR ⁶ R ⁷ , wherein 10 R ⁶ and R ⁷ are as defined above to have, X - for a group of the formula -CH ₂ -CH ₂ - or -CH = CH- stands,
15 and A - for a group of the formula _R 10 20 Ί R ¹⁰ ^^^ KX -CH-CH ₂ -C-CH ₂ -COOR ¹¹ HO " I I or \ ^ Pteht, OH OH I wherein
25 R ^{10 is} hydrogen or alkyl and ³⁰ R ¹¹ - hydrogen, an alkyl, aryl or an aralkyl radical or - a cation means ^3, characterized in that ketones of the general formula (VIII) Le A 25 837 -AOQ ' ¹¹ 12 ^ CHeCH-CH-CH ₂ -C-CH ₂ -COOR ¹ 2 ^λ 1 R Λ R ¹ OH P ¹ in which Rr, R, R ν R: "R have the meaning given above", R ^{12 is} alkyl, reduced, in the case of production of the acids, the esters are 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 production of the ethylene compounds (X β -CH ₂ -CH ₂ -) the ethene compounds (X = -CHeCH-) after hydrogenated conventional methods, and optionally separates isomers. 2 «method according to claim 1, characterized in that one carries out the reduction in the temperature range of -90 ⁰ C to +30 ⁰ C.