DD281185A5 - PROCESS FOR PRODUCING SUBSTITUTED PYROLE - Google Patents

Abstract

The invention relates to a process for the preparation of substituted pyrroles. The preparation includes the reduction of ketones substituted by a pyrrole residue and subsequent saponification; Cyclization or hydrogenation. The compounds prepared according to the invention can be used as active ingredients in medicaments. {Pyrroles, process; manufacture; Reduction of ketones; agents; Drug}

Description

28j j 8

Process for the preparation of substituted pyrroles Field of application of the invention

The invention is applied in the pharmaceutical industry, 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 (HMG-CoA reductase) Mevinolin, EP 22 478; US 4,231,938 * J, In addition, certain indole derivatives or, pyrazole derivatives inhibitors of HMG-CoA reductase [EP-A 1 114 027; U.S. Patent 4,613,610],

Object of the invention

The substituted pyrroles of the invention exhibit a good inhibitory effect on the HMG-CoA reductase and cause a reduction in the cholesterol content in the blood,

Explanation of the essence of the invention

The object of the invention is to provide a process for the preparation of substituted pyrroles.

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

R ⁴

I ^ X-A

R ^ R ^X

in v / elcher

281 18

1 _

10

is 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 _f

wherein

15

R ^5, R ⁶

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

20

30

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 ² and R ³ -

are the same or different and represent - 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

35

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28 | 185

Formula -NR ⁵ R ⁶ may be substituted, 5

where r i η

R ⁵ and R ⁶ are as defined above

have, 10

or

is aryl, which may be substituted identically or differently up to 5 times by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aryl,

alkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl), dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or a group of For

mel -NR ⁵ R ⁶ ,

where r in r5 and R have the meaning given above,

in which

R ^ - can also stand for an alkyl radical,

R ⁴ - for hydrogen or

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

for aminocarbonyl, alkylaminocarbonyl, dialkylarnin-35

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281 (85

nocarbonyl, arylaminocarbonyl or alkoxycarbonyl, or

- is cycloalkyl, or

- represents alkyl which may be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonic acid, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of formula -NR R,

wherein

r5 _t p6 _ 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 and aryl radicals of the last-named substituents are identical or different by halogen, cyano, trifluoromethyl, Trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl may be substituted,

or

- stand for heteroaryl, which is up to 3 times the same

or differently by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a

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28) (f

Group of the formula -NR ^ R ° may be substituted,

wherein

R ⁵ and R ° have the abovementioned meaning,

or

- 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 ⁵ R ⁶ ,

wherein

R and R 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

¹ 8 ^F

-CH-CH ₂ -C-CH ₂ -CUOR ⁸ HO

II or ^{> v} v ^ ^J stands,

OH OH

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28ί

wherein 5

R ^{7 is} hydrogen or alkyl and

• ° R ⁸ - hydrogen,

- alkyl, aryl or aralkyl or

- a cation means

15 found.

Surprisingly, the substituted pyrroles according to the invention exhibit a good inhibitory action on HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) and bring about a reduction in the cholesterol content in the blood,

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

Alkyl is generally a branched hydrocarbon radical having 1 to 12 carbon atoms. Preferred is lower alkyl having 1 to about 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and ^ isooctyl may be mentioned.

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2 8 ί f ö 5

- 7 -

Alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is 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, 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 bound 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. Examples which may be mentioned are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, fentylthio, isopentylthio, hexylthio, isohexylthio, heptylthio, isoheptylthio, octylthio or isooctylthio.

Alkylsulfonyl is generally a g ^ Radkettigen or branched hydrocarbon radical having 1 to 12 carbon atoms, which is bonded via a SC ^ group, Preferred is Niedrigalkylsulfonyl having 1 to about 6 carbon atoms. For example, be mentioned! Methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl ι Isopentyl sul f onyl, hexyl sulfonyl, Iaohexyl s * i 1 f onyl.

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Aryl generally represents an aromatic moiety having 6 to about 12 carbon atoms. Preferred aryl radicals are phenyl, naphthyl and diphenyl.

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

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

Arylsulfonyl is generally an aromatic radical having from 6 to about 12 carbon atoms which is attached via an SC> 2 group. Examples which may be mentioned: phenylsulfonyl, naphthylsulfonyl and biphenylsulfonyl.

Aralky1 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 is generally an aralkyl radical having 7 to 14 carbon atoms, wherein the alkylene chain via

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2 8 ί 18

Aralkoxy radicals having 1 to 6 carbon atoms in the aliphatic radical and 6 to 12 carbon atoms in the aromatic moiety are preferred. The following aralkoxy radicals may be mentioned as examples: benzyloxy, naphthylmethoxy, phenethoxy and phenylpropoxy,

Aralkv-1 thio is generally an aralkyl radical having 7 to about 14 carbon atoms, wherein the alkyl chain is bonded via a sulfur atom, Aralkyl thi oreste having 1 to 6 carbon atoms are preferably irr. The following aralkylthio radicals may be mentioned as examples: benzylthio, naphthylmethylthio, phenethylthio and phenylpropylthio,

Aralkylsulfonyl is generally an aralkyl radical having from 7 to about 14 carbon atoms, the alkyl radicals being bonded via an SO ₂ chain. Preference is given to aralkylsulfonyl radicals having from 1 to 6 carbon atoms in the aliphatic part and from 5 to 12 carbon atoms in the aromatic part. The following aralkylsulfonyl radicals may be mentioned as examples: benzylsulfonyl, naphthylmethylsulfonyl, phenethylsulfonyl and phenylpropylsulfonyl,

Can alkoxycarbonyl beispielsvei te by the Form'1 -C-Oalkyl

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- 10 -

Alkyl is in this case 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. Examples which may be mentioned are the following alkoxycarbyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

Acyl is generally phenyl or straight or branched lower alkyl having 1 to about b carbon atoms attached through a carbonyl group. Preference is given to phenyl and alkyl radicals of up to 4 carbon atoms, for example: benzoyl, acetyl, ethylcarbonyl, propylcarbonyl, isoprcylcarbonyl, butylcarbonyl and isobutylcarbonyl,

Haioqe r. is generally fluorine, chlorine, bromine or iodine, büvo-zugt for fluorine, chlorine or bromine · particularly preferably halogen is fluorine or chlorine,

Heteroaryl represents for the purposes of the definition given above in general represents a 5- to 'j-gl iedrigen aromatic ring which may contain as hetero atoms oxygen, sulfur and / or nitrogen and can be fused to the other aromatic rings. Preference is given to 5- and 6-membered aromatic rings which contain an oxygen, a sulfur and / or up to 2 nitrogen atoms.

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-U-

2 8 j ί 8 5

As particularly preferred heteroaryl radicals may be mentioned: thienyl, furyl, pyrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolyl, thiazolyl, benzothiazolyl, isothiazolyl, oxazolyl , Benzoxazolyi, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl, indolyl and isoindolyl,

R ⁸ is alkyl, aryl or aralkyl and thus preferably forms a physiologically acceptable ester residue which is readily hydrolyzed in vivo to a free carboxyl group and a corresponding physiologically acceptable alcohol. These include, for example, alkyl esters (Cj to C ^) and aralkyl esters (C ₇ to C ^ q), preferably lower alkyl and benzyl esters. Furthermore

20 may be mentioned the following ester radicals:

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

When R is a cation, it is preferred to mean a physiologically acceptable metal or ammonium cation. Preference is given here to alkali metal or alkaline earth metal cations such as, for example, sodium, potassium, magnesium or calcium cations, and also aluminum or ammonium cations, as well as non-toxic substituted ammonium cations from amines such as lower alkylamines, triethylenealkylamines, procaine, dibenzylamine, N, N'-dibenzylethylenediamine , N-benzyl-.beta.-phenylethylamine, N-methylmorpholine or N-ethylmorpholine, 1-ephenamine, dihydroabiethylamine, N, N'-bis-dihydro-ethylenediamine, N-lower-alkylpiperidine and other amines which convert to form salts can be.

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2 8 ί

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In the context of the present invention, the substituted pyrroles (Ia) correspond to the general formula

/ X-A

in which

R, R ι R, R ι X and A have the abovementioned meaning.

In the context of the present invention, the N-substituted pyrroles (Ib) correspond to the general formula

in which 25

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

As part of the more general. Formula (I) compounds are preferred with the general formulas (Ia) and (Ib),

Preferably, such compounds of the general

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Formula (Ia) and (Ib) 5

V, ^ / χ-i

(Ia) or || || (Ib)

ους /

R ⁴ R ³

in which

R * - represents cyclopropyl, cyclopentyl or cyclohexyl,

or

- is lower alkyl which may be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl, by

a group of the formula -NR ^ R ^, 20

wherein

R ⁵ and R ^{6 are the} same or different and

Lower alkyl, phenyl, benzyl, acetyl, Ben-25

zoyl, phenylsulfonyl or lower alkyl sulphone

signify fonyl

or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrryl, indolyl, thien-

yl, furyl, imidazolyl, oxtvol, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenyl

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2 81; 8 5

- 14 -

ethylthio or phenylethylsulfonyl, where said heteroaryl and aryl radicals may be substituted by up to 2-fold identical or different by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl, or trifluoromethoxy,

r2 and R ^ are the same or different and

- represents 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 may be substituted by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy and

20 deralkoxycarbonyl, or

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, Phonylethylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a

30 group of formula -NR ⁵ R ⁶ ,

in which

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2 β f ί 3 5

- 15 -

R ^ and R ° have the abovementioned meaning, where R 1 can also be lower alkyl,

R ⁴ - for hydrogen or

is benzoyl or lower alkylcarbonyl, or

- represents lower alkylsulfonyl, phenylsulfonyl or tolylsulfonyl, or

- represents aminocarbonyl, lower alkylaminocarbonyl, di-lower alkylaminocarbonyl, phenylaminocarbonyl or lower alkoxycarbonyl, or

- represents cyclopropyl, cyclopentyl or cyclohexyl or

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

wor in

R ⁵ 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, pyrrolyl, indolyl, thionyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl,

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2 8 ί ί "β 5

- 16 -

Benzyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, where the heteroaryl and aryl radicals mentioned can be substituted by the same or different substituents by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl, or trifluoromethoxy up to 2 ×,

- represents thionyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which may be may be replaced by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or

2 ° deralkoxycarbonyl, or

represent 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, benzyl-difonyl, phenethyl, phenylethoxy, phenylethylthio, Phenylethylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a

³⁰ group of formula -NR ⁵ F ⁶ ,

in which

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281 t 85

- 17 -

R ^ and R ⁶ are as defined above 5

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

A - for a group of formula 10

TR ⁷ yY °

-CH-CHo-C-CHo-COOR ⁸ or HO "| I stands,

I ² I ² V ⁶

OH OH I

wherein

R is hydrogen or lower alkyl, and

20 ο

R ^ö - hydrogen,

- alkyl (C ₁ -C _4), Ary: (C ₆ -C _12), aralkyl (C ₇ -C ₁ O) or

- a physiologically compatible cation

means 25

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

in which 30

R - represents cyclopropyl, cyclopentyl or cyclohexyl,

or - for methyl, ethyl, propyl, isopropyl, butyl, sec, -

Butyl or tert, butyl, dip substituted 35

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281 i S ₅

- 18 -

may be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propyl-sulfonyl, isopropylsulfonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl,

* 0 Butoxycarbonyl, I sobuioxycarbonyl, tert. Butoxycarbonyl, benzoyl, acetyl, pyridyl, pyrimidyl, thicnyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyl, benzylthio or benzylsulfonyl,

R and R ^ are the same or different and

- represent pyridyl, pyrimidyl, quinolyl or isoquinolyl which are substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl

20 may be tuiert, or

represents phenyl which may be substituted identically or differently up to 3 times by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, * propoxy, isopropoxy, butoxy, isobutoxy,

tert-butoxy, methylthio, ethylthio, propylthic, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenyl, phenoxy, benzyl, benzyloxy, fluoro,

Chlorine, bromine, cyano, trifluoromethyl, triflu

ormethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy

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carbonyl, isobutoxycarbonyl or tert-butoxy ** oxycarbonyl,

where R 1 is also methyl, ethyl, propyl, isopropyl, butyl and isobutyl,

R * - represents hydrogen, cyclopropyl, cyclopentyl or

10 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, tertiarybutoxycarbonyl, benzoyl, acetyl, ethylcarbo-

nyl, or by a group -NR ^ R ⁶ , Zo

I would like to

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,

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2Of \ 35

- 20 -

or by pyridyl, pyrimidyl, pyrazinyl, pyridinyl, quinolinyl, isoquinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, where di &quot; heteroaryl and aryl radicals are substituted by fluorine, chlorine, methyl, Ethyl, propyl, isopropyl, ^ Q isobutyl, tert. Butyl, methoxy, ethoxy, propoxy, isopropoxy, Butoi-.y, Isobut.oxy, tert-butoxy, trifluoromethyl or Tri luoriusthoxy may be substituted, or

for thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isooxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzimidazolyl or benzothiazolyl, where the radicals mentioned are substituted by fluorine, chlorine, Methyl, ethyl, propyl, isopropyl, ethyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iscbutoxy, tert-butoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, Isobutoxycarbonyl or tert, butoxycarbonyl may be substituted, or

- 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,

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8ί 18

- 21 -

Ethylsulfonyi, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert.butylsulfonyl, phenyl ι phenoxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoxycarbonyl, Eth- * 0 oxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl or may be substituted by a group -NR R,

15 being

R and R have the abovementioned meaning,

or 20

represents benzoyl, acetyl, ethylcarbonyl, piopylcarbonyl, isopropylcarbonyl, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, butylsulphonyl, isobutylsulphonyl, tert-butylsulphonyl, phenylsulphonyl or tolylsulphonyl,

for aminocarbonyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl-democarbonyl, dimethyl, di-butyl, dipropyl, diisopropyl, dibutyl or diisobutylaminocarbonyl, Phe-

O-nylaminocarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl oter tert, butoxycarbonyl,

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2 8 ί / β 5

- 22 -

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-COüR ⁸ or HO

o-C-CHo I-2,2

OH OH

stands,

wherein

R ^{7 is} hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert, butyl,

and

R ^{8 represents} hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or benzyl, or denotes a sodium, potassium, calcium, or magnesium or ammonium ion,

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

Depending on the meaning of group X or remainder A

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281

- 23 -

result in different stereoisomers, which should be explained in more detail below!

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

(II) E-shape

R ³ -HR

^RJ

(III) Z-form

(R ¹ to R ⁴ , A have the meaning given above).

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

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

-CH-CH ₇ -C-CHO-COOR

I ² I ² OH OH

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2 8 ί

- 24 -

Thus, the compounds of general formula (I) have at least two asymmetric carbon atoms, namely the two carbon atoms to which the hydroxy groups are bonded. Depending on the relative position of these hydroxy groups to one another, the compounds of the invention in the erythro configuration (IV) or in the Threo configuration (V) are present.

R7

-CH-CH ₂ -CH-CH ₂ -COOr ⁸ erythro-form (IV) OH OH

r -I-r ^ X-CH-CHo-CH-CHo-COOR ⁸ OH OH

R ¹

Threo form (V)

Hwei enantiomers, namely 3R, 5S-isomer or 3S, 5R-isomer (erythro-form) and 3R, 5R-isomer and 3S, 5S-isomer (again) exist in each case of the compounds in erythro and in threo configuration ( threo form).

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

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281 IS

35

- 25 -

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

IO15

R HO

Thus, the substituted pyrroles have at least two asymmetric carbon atoms, namely the carbon atom to which the hydroxy group is bonded, and the carbon atom to which the rest of the formula

202530

R ³ - \

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).

HC

R ³ -Ι

egg s-lactone (VI)

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28 /

- 26 -

R ³ -HR

tr & ns lactone (VII)

In turn, both the cis-lactone and the trans-lactone have two isomers namely the 4R, 6R isomer or the 4S, 6S isomer (cis-lactone), as well as the 4R, 6S isomer or 4S, 6R -Isomers (trans-lactone). Preferred isomers are the trans-lactones, the 4R, 6S isomer (trans) and the 4R, 6S-4S, 6R racemate being particularly preferred.

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

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28ί (35

1015

R ⁷ _Vn \ 0H

OH OH

CH-CH ₂ -CHR ⁷ -C00R ⁸

OH OH CH-CH ₉ -CHR ⁷ -C00R ⁸

OH OH

CH-CH ₂ -CHR ⁷ -COOR ⁸

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2 ß f / 35

- 28 -

OH

OH

CH-CH ₂ -CHR ⁷ -COOR ⁸

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- 29 -

OH OH

CH-CHo-CHR ⁷ -

CH-CH ₂ -CHR'-COOR ^C

OH OH

OH-CH ₂ -6hR ⁷ -COOR ⁸

OH OH

CH-CH ₂ -CHR'- ^C 00 R ^c

OH OH CH-CH ₂ -CHR ⁷ -C00R ⁸

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

in which

? * - for cyclopropyl, methyl, ethyl, propyl, isopropyl,

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2 a ί

- 30 -

Butyl, isobutyl or tert-butyl,

R ² and R ³ -

are identical or different and stand for phenyl which may be substituted identically or differently by methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, phenoxy, benzyloxy, fluorine, chlorine or trifluoromethyl up to twice

where R can also be methyl, ethyl, propyl or iso-propyl,

4 _

is hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or

is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl,

or by pyridyl, pyrimidyl, cholinyl, thienyl, furyl, phenyl, phenoxy, phenylsulfonyl or benzyloxy

or

- is phenyl which is up to 2 times the same or different from methyl, ethyl, methoxy, ethoxy, phenyl, benzyl, fluorine, chlorine, trifluoromethyl,

or Le A 25 164-foreign countries

2 8 I ί Β

- 31 -

X - for a group of the formula

(E-configured) is

and

for a group of the formula -CH-CHo-C-CHo-COOR ⁸ or

I ² I ²

OH OH wherein

iteht,

and

- Hydrogen means I

- means hydrogen, methyl or ethyl or means a sodium or potassium cation.

In addition, a process for producing the substituted pyrroles of the general formula (I)

R ³ H

/ X-A

(I)

in which

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X and A have the abovementioned meaning ^

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- 32 -

2 8 j ί 3 5

10

20 25

found,

which is characterized in that one

Ketones of the general formula (VIII)

⁸ '

= CH-CH-CH ₂ -C-CH ₂ -COOR ^C

OH (VIII)

R ³ -]

R ² "R ^J in which

R ¹ , R ² , R ³ and R ^{4 have} the abovementioned meaning, and R ⁸ '- is alkyl,

reduced,

in the case of production of the acids, the esters are saponified,

in the case of production of the lactones, the carboxylic acids eye 1 is

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

30 35

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 isomers.

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

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2 81 ί 8

- 33 -

CH ₂ COOCH ₃

Reducing ion

OH

CH ₂ COOCH ₃

COO ^e Na®

COOH

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28] j 8S

The reduction can be carried out with the usual reducing agents, preferably with those 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. Preference is given to reduction with complex metal hydrides such as lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylhydridoborates, sodium trialkylhydrido. 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 also possible to use mixtures of the solvents mentioned.

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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i.0 | | ft - 35 -

If the AlKoxycarbonylgruppe are not changed, for this purpose, particularly suitable 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, preferably from -78 ⁰ C to ⁰ ° C.

The process of the invention is generally carried out at ¹ ^ 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 1 to 2 mol, preferably from 1 to 1.5 mol, based on 1 mol of the keto compound,

Under the above-mentioned reaction conditions, in general, the carbonyl group is 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) in which X is an ethylene moiety, the reduction of the ketones (III) can be carried out under conditions in which both the carbonyl group and the double bond are reduced,

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28ί ί 85

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)

j- ^ X-CH-CH-CH-CHo-COOH (Ic) OH OH

R ² R ¹ 15 in which

R ¹ , R ² , R ³ , R ⁴ , R ⁷ and X have the abovementioned meaning,

The carboxylic acid esters in the context of the general formula

(1) correspond to the formula (Id)

R ³

-CH-CH-CH-CHo-COOR ⁸ '(Id) II OH OH

in which 30

R ¹ , R ² , R ³ , R ⁴ , R ⁷ and X have the abovementioned meaning,

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2 8 j 18

and

R ⁸ '- is alkyl,

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

-CH-CK-CH-CH ₂ -COU "

n +

(Ie)

in which

R ¹ , R ² , R ³ , R ⁴ , R ⁷ 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)

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2 8 ί j 8

- 38 -

in which 5

R ¹ , R ² , R ³ , R ⁴ , R ⁷ and X have the abovementioned meaning,

2.On production of the inventive carboxylic acids of the general formula] (Ic) are generally the carboxylic acid ester of the general formula (Id) or the lactones of the general formula (If) saponified by conventional methods. The saponification is generally carried out by treating the esters or lactones in inert solvents with customary bases, which generally initially the salts of 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 überfuhrt.

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 ethanolate, sodium methoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide. Particularly preferred are sodium hydroxide or potassium hydroxide

30 used.

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2 81 ι 8

- 39 -

Suitable solvents for the saponification are water or the usual organic solvents for saponification. These include preferably alcohols such as methanol, ethanol , propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethyl formamide or dimethyl sulfoxide. Particular preference is given to using alcohols, such as methanol, ethanol, propanol or isopropanol. It is likewise possible to use mixtures of the solvents mentioned,

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 normal pressure, but it is also possible to operate at reduced pressure or at overpressure (for example from 0.5 to 5 bar).

When 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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28 y y β 5

Mineral acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid are preferred. In the preparation of dicarboxylic acids (Ic), it has proven to be advantageous to acidify the basic reaction mixture of the saponification in a second step without isolating the salts. The acids can 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 customary methods, for example by heating the corresponding acid in inert organic solvents, if appropriate 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 said solvents. 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 ⁰ C to +200 ⁰ C, preferably from -25 ⁰ 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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2 61 ι 8

- 41 -

at negative pressure or at overpressure (z, B, in a range from 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. Carbodiimides are preferably used as dehydrating agents. Carbodiimides used are preferably Ν, Ν'-dicyclohexylcarbodiimide paratoluene sulfonate, N-cyclohexyl-N'- [2- (N "-methylmorpholiumium) ethyl] carbodiimide or N- (3 Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride id

15 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. Particular preference is given to chlorohydrocarbons, for example methylene chloride, chloroform or carbon tetrachloride, or hydrocarbons, such as benzene, toluene, xylene or petroleum fractions,

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 LO.

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2 81 1 ö 5

- 42 -

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 stereochemically contained components is generally carried out by conventional methods as described, for example, by 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 or esters. Particularly preferred is the racemic mixture of the erythro-esters (I ") by treating with either D - (+) - or L - (-) - a-methylbenzylamine by conventional methods in the diastereomeric dihydroxyamides (Ig)

²⁰ OH CHo

I ^ CH ₂ -CONH-CH-C ₆ H ₅

-_u · ^(Ig)

Then, as usual, it is possible to separate it by chromatography or crystallization in the 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

> Le A 25 164 foreign countries

- 43 -

Si ii) _S

hydroxide in water and / or organic solvents such as alcohols, e.g. Methanol, ethanol, propanol or isopropanol, gives the corresponding enantiomerically pure dihydroxy acids (Ic), i-.ie as described above can be converted by cyclization in the enantioroerenreinen 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:

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- 44 -

2 8 f j 8 5

OH

N-

CH. trans-racemate

f H ₂ N-CH-C ₆ H ₅

OH CH-

CH ₂ -CO-NH-CH-C ₆ H ₅

OH DiasLereomerengemisch

1) SlideLereomefsntrennung

Z) saponification

3) lactonization

OH OH

T ι Τ

CH

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- 45 -

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.

Il

CH = CH-CH-CHo-C-CHO-COOR

I ^{2 2}

OH

(VIII)

in which

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^{6 have} the abovementioned meaning

X - stands for a Gruop * -TieT formula -CH ₂ -CH ₂ "

and R ⁸ '- is alkyl, which is characterized in that

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- 46 -

Aldehydes of the general formula (IX) 5

R ⁴

(IX) 2 ^^

in which

R ₁ R ₁ R and R have the abovementioned meaning, 15

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

j)

HoC-C-CHo-COOR ⁰

in which

R has the meaning given above, 25

in the presence of bases.

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2 β

- 47 -

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

base

H ₃ CC-CH ₂ -COOCH ₃ CH ₂ COOCH ₃

AIb bases here are the usual strong basic compounds in question, These include preferably organolithium compounds such as N-butyl1ithium, sec, butyl 1ithium, tert, butyl 1ithium or phenyllithium, or amides such as lithium diisopropyl

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2 8 f f 8

- 48 -

amide, sodium amide or potassium amide, or lithium hexamethyldisilylamide, or alkali metal hydrides such as N> Atr iumhydr id or potassium hydride, It is also possible to use 3emische of said bases, particularly preferred are N-Butyl1ithium odor sodium hydride or a mixture thereof

used, 10

Suitable solvents here are the customary organic solvents which do not change under the reaction conditions. 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 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,

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,

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28) (85

- 49 -

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 process I according to the invention are:

Ac et acetic acid thy thy, acetoacetyl acetate, acetoacetyl propyl ester, acetoacetic acid isopropyl ester,

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

A process has also been developed for preparing the aldehydes of the general formula (IX) 20

(IX) 25

in which

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

found, which is characterized in that one

Pyrroles of general formula (XI) 35

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- 50 -

_J85

R ³ -HR

(XI)

in which

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

in inert solvents in the presence of auxiliaries with N, N-dimethylaminoacrolein of the formula (XII)

H ₃ C

N-CH = CH-CHO

(XII)

H ₃ C

implements,

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

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28f (85

Suitable solvents include the usual organic solvents which are stable under the reaction conditions, these include preferably hydrocarbons such as benzene, toluene, xylene, hexane, petroleum fractions, chlorobenzene or dichlorobenzene, or ethers such as diethyl ether, dioxane or tetrahydrofuran, or Chlororkohlenwasserstjffe such as methylene chloride, Chloroform or carbon tetrachloride, or acetonitrile. It is also possible to use mixtures of the solvents mentioned]. Particular preference is given to using anhydrous acetonitrile or chloroform,

As auxiliaries acid chlorides are generally used. Preferably, Phosphoroxychlor id or phosgene, particularly preferably Phosphoroxycblor id used,

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 a 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 pyrroles of the general formula (XI) used as starting materials are known or can be prepared by known methods CA, Glossauer "The chemistry of pyrroles", Springer Verlag Berlin, 1974],

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28 | 85

- 52 -

The compounds of general formula (I) according to the invention have valuable pharmacological properties, in particular they are inhibitors of 3-hydroxy-3-methyl-glutarylCcenzym A (HGM-CoA) reductase and, as a result, inhibitors of cholesterol biosynthesis. They can therefore be used for the treatment of hyperlipoproteinemia, lipoproteinemia or atherosclerosis, The active compounds according to the invention also cause a reduction in the Chloester.in content in the blood,

The new active compounds can be converted in a known manner into the 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 in each case be present 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 bind to reach 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 the dissolving solvent.

Examples of excipients which are listed are: water, non-toxic organic solvents, such as

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281 ί 85

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Paraffins (e.g., petroleum fractions), vegetable oils (ζ, Β, peanut / sesame oil), alcohols (e.g., ethyl alcohol, glycerol), carriers such as e.g. ground natural minerals (e.g., kaolins, clays, talc, chalk), ground synthetic minerals (e.g., fumed silica, silicates), sugars (e.g., cane, milk and dextrose), emulsifying agents

¹ ^ medium (for example, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates and arylsulfonates), dispersants (eg, lignin sulfites, methyl cellulose, starch and polyvinyl pyrrolidone) and lubricants (for example, magnesium stearate, talc, stearic acid

15 and sodium lauryl sulfate).

The application is carried out in a customary manner, preferably orally, pcirenteral, perlingual or intravenous. In the case of oral administration, tablets may of course also contain additives, such as sodium citrate, calcium carbonyl 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 may be prepared using appropriate liquid

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Support material are used ieri. 5

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.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on the body weight or the type of application route, 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 manage with less than the aforementioned minimum amount, while in other cases, the above upper limit must be exceeded, In the case of the application of larger quantities, it may be advisable to distribute them in several individual doses over the day ,

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/8th

- 55 ccip. Cc

around Preparation Examples

Example 1

1- (4-Fluorpheny1) -4-methyl-pent-l-en-3-one

Il ^ CH. CH = CH-C-CH

^^ CH.

To 198.4 g (1.6 mol) of freshly distilled 4-fluorobenzaldehyde and 137.6 g (1.6 ncL) Mpthylis'jpropylketon in 300 m ~ methanol is added dropwise 75 ml of 15% potassium hydroxide solution and stirred overnight at room temperature. It is then neutralized with 10 ml of acetic acid, added 1 1 of water and extracted with two 500 ml portions of ether. The combined organic phases are washed with 500 ml of saturated sodium chloride solution and dried over sodium sulfate. After removal of the solvent is distilled in a high vacuum,

Yield: 198.6 C | (65 % of theory) yellowish Dl b.p .: 103 ^° C. (0.3 mbar)

¹ H-NMR _(CDCl3): S = 1.2 (. Ei 6H, CH _3); 2.9 (sec, IH ₁ CH-

(CH ₃ J ₂ ); 6.8 (d, IH ₁ olefin-H); 7.1 (m, 2H, Arcmaten-H); 7.6 (m, 3H, aromatics H + olefin-H).

Example 2

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

- 56 -

O CH-

H ^- CHo ^- C ^- CH ^- CHg

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 riol) fresh disti 11 iertsm 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) was added dropwise in 500 ml of dimethylformamide and stirred for 1 h, the temperature is kept at 35 ° C, After addition of 1 1 of water is extracted four times with J ^ 400 ml of chloroform, the combined organic phases with 1 1 of saturated sodium bicarbonate After concentration in vacuo, the mixture is distilled under reduced pressure until a fraction at 138 - 142 ⁰ C (0.9 tnbar) passes. The distillation residue (132 g) is then chromatographed in twelve portions on a column (1.5 kg of silica gel 230-400 mesh, 1 × 9 cm), with potrol ether / ethyl acetate (10: 1). The product is obtained after 4-71 eluent, After removal of the solvent remain 90.0 g (67% of theory), colorless oil],

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2 NC | j

- 57 -

¹ H-NMR (CDCl ₃ ): δ = 1.08 (d, 3Η, CH ₃ ) J 1.12 (d, 3H _, CH ₃ ) J 2.65 (sept, IH, CH- (CH ₃ ) ₂ );

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, Aromav.en-H); 7.23 (m, 2H, Aromatan-H); 7.4 (m, 3H, aromatic-H); 7.95 (m, 2H, flavor

th-H).

Be it 1 3 15

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

2.98 g (10 mmol) of 2- (4-fluorophenyl) -5-methyl-1-phenyl-he-25

xan-l, 4-dione (Example 2) are heated to 80 ° C in 10 ml 40y.iger aqueous methylamine solution and treated with about 14 ml of ethanol, so that a clear solution. The mixture is refluxed for a further 30 minutes and, after cooling, the precipitate is filtered off with suction. This one comes with little

Ethanol and washed in a vacuum desiccator over phosphorus

dried peroxide,

Yield: 1.8 g (61 '/. Dsr theory) of colorless crystals

ijchmp. : 114 ⁰ C

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28i as

- 58 -

¹ K NMR (CDCl ₃ ): δ = 1.35 (d, 6Η, CH- (CH ₃ J ₂ ); 3.9 (sept.

IH, CH- (CH ₃ J ₂ ); 3.42 (s, 3H, _N-CH3); 6.17 (s, IH, pyrrole-H); 6.8 - 7.4 (m, 9H, aromatics-H).

Example 4

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

1.64 ml (18 mmol) of phosphorus oxychloride are dissolved in 10 ml

submitted anhydrous acetonitrile. Under argon, first dropwise at -10 ⁰ C to ^{0 0} C, a solution of 1.85 g (16.8 mmol) 90Vtiges Dimethylaminoacrolein in 7 ml of acetonitrile and then at -5 ⁰ C to ^{0 0} C, a solution of 1.76 25

g (6 mmcl) of 3- (4-fluorophenyl) -5-isopropyl-1-methyl-2-phenylpyrrole (Example 3) in 7 ml of acetonitrile. The mixture is heated at reflux overnight. The batch is then added at 10 ⁰ C in the suspension of 4.4 g of sodium hydroxide in 65 ml of water and 65 ml of toluene, so that the temperature

3O _n .....

After stirring for 1.5 h at room temperature, it is filtered through kieselguhr and the phases are separated,

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2 8 I 18

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Now, the organic phase is dried over sodium sulfate, concentrated and chromatographed on a column (100 g of silica gel 230 - 400 mesh »0 4 cm, methylene chloride). The purified product is finally boiled in methanol.

Yield: 1.3 g (. 62 '/ of theory) of a yellowish solid m.p .: 215 ⁰ C.

¹ H-NMR (CDCl ₃ ): δ = 1.5 (d, 6H, CH- (CH ₃ J ₂ ); 3.5 (m, 4H, N-CH ₃ ♦ CH- (CH ₃ ) ₂ ) J 5.8 (dd, IH, olefin-H); 6.0-7.3 (m, 9H ₍ aromatics-H); 7.6 (d, IH, olefin-H); 9.4 (d, IH , CHO).

Example 5

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

Under argon, it is added dropwise to a suspension of 0.11 g (3.6 mmol) of sodium sodium hydride in 10 ml of dry tea.

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- 60 -

2 NC | i as

Trahydrofuran at ⁰ ° C. 0.38 g (3.3 mmol) of methyl acetoacetate After 15 minutes, 2.1 ml of 15% strength butyllithium in hexane are added dropwise at the same temperature over the course of 10 minutes and the mixture is stirred for 15 minutes. A solution of 1.04 g (3 mmol) of (E) -3- [3 '- (4''- fluorophenyl) -5'-isopropyl- ¹ -methyl-2 ¹ -phenyl-pyrrole-4' is then added dropwise thereto. -yl] -prop-2-enal (Example 4) in 15 ml of dry tetrahydrofuran at 0 ° C and stirred for a further 15 min at this temperature, Then carefully 15 ml of 0.6 N hydrochloric acid are added, the mixture three times with 15 each ml of ether, the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration in vacuo, the residue is chromatographed in a column (50 g silica gel 230-400 mesh, 0 3 cm) with toluene / ethyl acetate (5: 1)

 Yield: 0.58 g (42% of theory) of yellowish oil.

¹ H-NMR (CDCl _3): δ = 1.45 (d, 6H, CH- (CH _{3) 2);} 2.65 (m,

2H, -CH (OH) -CH ₂ -CO-); 3.45 (m, 5H, N-CH _3, CH ₂ -COCH _3); 3.73 (s, 3H, _0-CH3); 4.58 (m, IH, HO-CH); 5.2 (dd, IH, olefin-H); 6.0 (d, IH, olefin-H);

6.8 - 7.3 (m, 9H, aromatics-H).

Example 6 30

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

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2 81 l (J.

- 61 -

CH ₂ -COOCH ₃

To a solution of 465 mg (1 mmol) of methyl (E) -7- [3 '- (4''- fluorophenyl) -5'-isopropyl-1-methyl-2'-phenylpyrrol-4'-yl] -5-hydroxy-3-oxo-hept-6-enoate (Example 5) in 15 ml of dry tetrahydrofuran is added dropwise at room temperature under argon 1.2 ml (1.2 mmol) of IM triethylborane solution in hexane, passed for 5 min Air through the solution and then cooled to -78 ⁰ C, 47 mg (1.24 mmol) of sodium borohydride and slowly added 0.6 ml of methanol, stirred for 15 min at -78 ⁰ C and 15 min at -30 ⁰ C. , At ⁰ ° C., a solution of 3.3 ml of 30% hydrogen peroxide in 7 ml of water is then added dropwise, the mixture is allowed to warm to room temperature, extracted with 15 ml of ethyl acetate, and the organic phase is washed with 10 ml of 0.5N hydrochloric acid and saturated sodium chloride solution and concentrated under reduced pressure. The residue (450 mg) is chromatographed on 80 g of silica gel 230-400 mesh, in a 4 cm diameter column with petroleum ether / ethyl acetate (1: 1). Yield: 240 mg (52 'of theory) yellowish oil MS: m / e 465 (5%, M ⁺ ), 447 (80X, MH ₂ O)

Le A 25 164-foreign countries

2β f 185

- 62 -

¹ H NMR (CDCl ₃ ): 6 = 1.45 (d, 6H ₁ CH- (CH ₃ J ₂ ); 1.6 (m, 2H, CH (OH) -CH ₂ -CHOH); 2.45 (m, 2H, CH ₂ -

CO ₂ -CH ₃ ); 2,6 (d, IH, OH); 3.4 (sept, IH, CH- (CHg) ₂ ); 3.5 (s, 3H, _N-CH3); 3.6 (d, IH, OH); 3.7 (s, 3H, _0-CH3); 4.2 (m, IH, OH-CH); 4.4 (m, IH, HO-CH); 5.2 (dd, IH, 01efin-H);

6.6 (d, IH, olefin-H); 6.8 - 7.3 (m, 9H, aromatics-H).

15 Example 7

1- (4-fluorophenyl) -4-methyl-pent-2-en-l-on

To 138.1 g (1.0 mol) of 4-fluoroacetophenone is added a solution of 17 g (0.3 mol) of potassium hydroxide in 125 ml of water / 125 ml of methanol, heated to 50 ⁰ C and added dropwise within 1.5 h 80th g (1.1 mol) of 2-methylpropanal, whereby a solid precipitates. After a further 3.5 h stirring at 50 ° C is allowed to cool to 25 ° C, the solid is filtered off with suction, washed with 150 ml of methanol and obtained after drying 132.3 g of dimeric condensation product. The solid is mixed with 5 g of sodium acetate and distilled in a water jet vacuum through a 20 cm Vigreux column. A mixture (1: 1.8) of 1- (4-fluorophenyl) -4-methylpent-2-βη-1-one and 1- (4-fluorophenyl) -4-methyl-pent-3-ene is obtained.

35 1-on.

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2 fi y (85

Yield! 120.2 g (62% of theory) ⁵ Kp.: 132 ⁰ C (14 mbar)

¹ H-NMR _(CDCl3): 6 = 1.15 (d, 6H, CH _3); 1.7 (s, 3H, CH _3);

1.8 (s, 3H, CH _3); 2.6 (sept, IH, CH- (CH ₃ J ₂ ), 3.7 (d, 2H, CH ₂ -CH = C (CH ₃ J ₂ ), 5.4 (m, IH, CH ₂ -CH = C (CH ₃ ) ₂ ), 6.7 (d, IH, olefin-H), 7.1 (dd, IH, olefin

H); 7.2 (m, 4H, aromatics-H); 8.0 (m, 4H, aromatic-H),

At game 8

1- (4-fluorophenyl) -4-methyl-3- (1-nitroethyl) -pentan-1-one 20

To a solution of 50 g (0.26 mol) of the isomer mixture (1: 1.8) from Example 7 and 25 g (0.3 mol) of nitroethane in 150 ml of acetonitrile is added dropwise at ^{0 0} C 18.9 g (0 , 13 mol) of 1,5-diazabicyclo (5,4,0) undec-5-ene in 100 ml of acetonitrile, After 2 h stirring at 25 ° C is treated with 260 ml of 1N hydrochloric acid and extracted three times with dichloromethane, the combined are washed with 130 ml of 1N hydrochloric acid, sodium bicarbonate solution and water, dried over sodium sulfate and concentrated in vacuo, to give 63 g of an oil over

Le A 25 164-foreign countries

2öf ι 85

- 64 -

800 g of silica gel with petroleum ether / ethyl acetate 10: 1 is chromatographed.

Yield: 31 g (445% of theory) of oil as diastereomer mixture.

¹ O Example 9

1- (4-fluorophenyl) -3-isopropyl-pentane-1,4-dione

[ I]

40 ml of 2N sodium hydroxide solution are added to a solution of 18.7 g (70 mmol) of Example 8 in 120 ml of ethanol and this solution is added dropwise at ⁰ ° C. to 64 ml of 3N sulfuric acid. After stirring for 1 hour at room temperature, the ethanol is added Vacuum removed, the residue taken up in water / dichloromethane, extracted three times with dichloromethane, the combined organic phases with! Hydrochloric acid and saturated sodium bicarbonate solution and water. The solution dried over sodium sulfate is concentrated in vacuo and the resulting oil (18.4 g) is chromatographed on silica gel gel with petroleum ether / ethyl acetate (10: 1)

 Exhaustion: 16 g (97X of theory)

¹ H-NIiR (CDCl ₃ ): δ = 0.9 (d, 3H, CH ₃ ); 1.0 (d, 3H, CH _3);

2.1 (sept, IH, CH (CH ₃ J ₂ ), 2.3 (s, 3H, CH ₃ CO), 2.9 (dd, IH, CH ₂ -C = O), 3.1 (m , IH, CH-C = O), 3.5 (dd, IH, CH ₃ -C = O); aromatic H 7.1 (m, 2H,);

8.0 (m, 2H, aromatics-H).

Le A 25 164-foreign countries

EXAMPLE 10 Z- (4-Fluorophenyl) -5-methyl-1-phenyl-4-isopropyl-pyrrole

A solution of 25.3 g (0.11 mol) of Example 9, 70 g (0.75 ._ mol) of aniline and a spatula tip of p-toluenesulfonic acid in toluene are refluxed overnight in a water separator. The solvent is then removed under reduced pressure and the residue (20.2 g) is recrystallised from petroleum ether, yield: 7.1 g (22.5% of theory).

¹ H-NMR (CDCl ₃ ): S = 1.3 (d, 6H, (.CH ₃ J ₂ CH); 2.1 (s, 3H,

CH ₃ ); 2.9 (sept, IH, CH (CH ₃ J ₂ ), 6.3 (s, IH, pyrrole-H), 6.8 (m, 2H, aromatic-H), 7.0 (m, 2H, Aromatic-H); 7.1 (m, 2H, aromatic-H); 7.4 (m, 3H,

Aromatics-H),

Example 1 1

(E) -3- [2- (4-fluorophenyl) -5-methyl-I-phenyl-4-isopropyl-

pyrrol-3-yl] -prop-2-enal

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- 66 -

2 8 f i ö 5

The abovementioned compound is obtained analogously to Example 4 from the compound from Example 10, yield: 82% of theory

¹ H-NMR _(CDCl3): 6 = 1.4 <d, 6H ₁ (CH ₂ CH ₃ J); 2.1 (ε, 3Η,

CH ₃ ); 3.3 (sept, IH, CH (CH ₃ J ₂ ); 6.2 (dd, IH, olefin H) j 6.9 (m, 2H, aromatic H); 7.0 (m, 4H, Aromatic-H); 7.3 (m, 3H, aromatic-H); 7.4 (d, IH, olefin-H); 9.4 (d, IH, CHO).

20 Example

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

enoate

OH

(H ₃ C) ₂ HC

OCH

The abovementioned compound is obtained analogously to Example 5 from the compound from Example 11. Yield: 0.7 g (35X theory)

Le A 25 164-foreign countries

i i 8 5

- 67 -

¹ H-NMR (CDCl ₃ ): 8 =

1.4 (d, 6H ₁ (CHg) ₂ CH); 2.1 (s, 3H, CH _3); 2.7 (m, 2H, CH (OH) CH ₂ ); 3.2 (sept, IH, CH (CH ₃ ) ₂ ); 3.5 (s, 2H, CH ₂ COOCH ₃ ): 3.7 <s, 3H, OCH ₃ ); 4.6 (m, IH, CHOH); 5.4 (dd, IH, olefin-H); 6.5 (d, IH, olefin-H); 6.8 (ro, 2H, aromatics-H); 7.0 (m, 2H, aromatic-H); 7.2 (m, 5H, aromatics-H).

In game

¹⁵ Methyl erythro- (E) -7- LZ- (4-fluorophenyl) 5-methyl-1-phenyl-4-isopropyl-pyrrol-3-yl] -3,5-dihydroxy-hept-6-enoate

OH OH O

OCH ^

The title compound is obtained analogously to Example 6 from the compound from Example 12 Yield: 0.42 g (69 '/ of theory.) ¹ H-NMR _(CDCl3): S = 1.4 (d, 6H, CH (CH ₃ J ₂ ); 1.6 (m, 2H,

CH ₂ -CHOH); 2.1 (s, 3H, CH _3); 2.5 (m, 2H, CH ₂ COOCH ₃ ); 3.2 (sept, IH, CH- (CH ₃ ) ₂ ); 3.7 (s, 3H, OCH ₃ ); 4.2 (m,

Le A 25 164-foreign countries

- 68 -

2 8ί 18

IH, CHOH); 4.4 (m, IH, CHOH); 5.4 (dd, IH, olefin-H); 6.5 (d, IH, olefin-H); 6.8 - 7.3 (m, 9H, aromatics H),

10

Example 14

Methyl erythro- (E) -7- [1- (2,6-din-ethylphenyl) -2- (4-fluorophenyl) -5-methyl-4-isopropylpyrrol-3-yl] -3,5- dihydroxyhept-6-enoate

20 25 30

OH OH O

The compound named obttn is analogous to Example 13

received _;

Yield: 67 '/. the theory

¹ H-NMR _(CDCl3): 6 = 1.4 (d, 6H, (CH _{3) 2)} CH); 1.6 (m, 2H,

CH ₂ -CHOH); 2.0 (m, 9H, CH _3); 2.5 (m, 2 '\, CH ₂ COOCH ₃ ); 3.2 (m, IH, OH- (CH ₃ ) ₂ ); 3.7 (s, 3H, OCH ₃ ); 4.2 (m, IH, CHOH); 4.4 (m, IH ₁ CHOH); 5.5 (dd, IH, olefin-H); 6.5 (d, IH, olefin-H); 6.7-7.3 (m, 7H, aromatic & n-H),

Le A 23 164-foreign countries

2 s ι ι e

- 69 -

Example 15

Methyl erythro- (E) -7- [1-benzyl-2- (4-fluorophenyl) -4-isopropyl-5-methyl-pyrrol-3-yl] -3,5-dihydroxy-hept-6-enoate

HoC

OH OH O

The above compound is analogous to Example 13. receive ι

Yield: 39 '/, of theory

¹ H-NMR (CDCl _3); 6 =!, 3 (d, 6H, (CH ₃ ) ₂ CH) J 1.6 (m, 2H,

CH ₂ CHOH); 2.1 (s, 3H, CH _3); 2.5 (m, 2H, CH ₂ COOCH ₃ ); 3.1 (m, IH, CH (CH ₃ ) ₂ ); 3.7 (ε, 3H, OCH ₃ ); 4.2 (m, IH, CHOH); 4.3 (m, IH, CHOH); 4.9 (s, 2H, CH ₂ Ph); 5.3 (dd, IH,

Olefin-H); 6.5 (d, IH, olefin-H); 6.7 - 7.3 (m, 9H, aromatics-H).

In analogy to Example 15 and the reactions described in Examples 1-5, the Vorbindungen listed in Table 1 were obtained.

Le A 25 164-foreign countries

- 70 -

I η ι ι η η η η χ S η η X η ο κ χ χ χ

ι I ι ι I η O η η η χ a χ X χ

► · "· Ul L-1 ► · * I H" V * J U) η · * I * -. "F * Jt * 0 * 1 ^^ U) ► * * * ~ »U) O- * I-"¹

312 * »XX» »3 W * * · · · · (- 'Di * ·

w w il A ^ Jws / U ^ i -J · »AA UI IO U J * X w U) A

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CJ U) X X - ·

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λ - g .. λ · ~. X '3 ι B λ · 3

σ. - »» · A3 W. cn · Β «·« J · * ·

• UIOONI (TvM-J ··· O KJ Vl> <K> · U-J (J VOU <X · Ν> M T TJ I «MU1X OCD X

- ^, ι / ι - 1 (ι · (tx UIXXw ^

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xrox cTv ^ iK) ax> uixxax

, - W ·· - J - M w · U '·· X - ·· · -. t / l ··

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Le A 25 164-foreign countries

- 71 -

2 8 M 8 5

K) "J

K)

to

I η O χ X η η χ X

ι ι I η η η η χ χ χ χ

η η η χ / χ χ η η η χ X χ

ι ι I η η η χ χ χ

α α UJ Ui xk Vl X '- * Ui K- O ul K- σν K) KJ O 3 O ul vn cn ul cn K) _w ul Ui * W _w X X ul A ln -J xk K) w in ul ln W _ CD "· · ' * ' ch ul K) CO K- * X kl X X - α · * α 3 α * - * 3 19 • cn σ> a cn α α 3 LJ 3 α K) "( VC σν nj • ο χ ι /. Kj K- LP X KJ O _ _ U) X X η ^w OD KJ χ χ X O X X ^w Ln σν • - * 5 * X • - co a I " κ- K- K- * p X μ- Ξ κ- «X X * C * κ- • ο LJ O K) ΓΓ ·. CD K) ln 3 VO VC σν ·, , - " ». ul O • vl M X " · - X ul 3 xk * * -. 2; "_, O xk * ch xk 3 ι 3 O KJ X σ, CQ «« X - σν Ul OD w § ^^ KJ X "° X LJ α W 3 *. W U) X t ~> kl K) ^ j **, cn I 3 ·. "t O W % X O 3 * KJ  »J * ul "t Cfv X ^ * U ¹ " * X KJ _. ln ι K- χ xk KJ B " ul X 00 q5 * t xh σν " • ο w · "· VO U) ul * · , - ^ ^ *. ul χ K) O U · 3 a , ". ~ " ^ - ln KJ KJ NJ -J B α - ' * · 3 kj K) U -. X "- < ul SD W χ X X

X X co UJ xk X  «j 3 α X ^ k xk 3 W X X ul K- ΓΤ xk T W KJ " α ul U * X ch X • ul 2 ·· i " ul K) K) * Z ^ " - ^ O χ X X ~ -, S3 σν xk H" W α W U) 3 α ".χ ch xk Οΐ α " X η _ "· X * * ' " ". 0 ln L ¹ V KJ ^ " σ * B K) ch J> ch K- ¹ CDO κ · Oi ln KJ ·· rr χ Λ * »« KJ X X K- KJ U) χ in • · ** ._ * νΰ ^^ . ^ *  ο ^, » • * ' CD VC * · * · OO "^ 3 α xk Ό α 3 X K- X ch cn U) · κ- α α 00 * _M Γ * ϋ W * _ " χ η X X ff * X w σ> Ui η a: ch ο * _ Λ ln (Λ η • I ·· Ut α "ι O W * 3 ~ * xk X 3 ch xk xk Η · xk Vl ci C * v N ^ " ·. ul K) Ξ * O ul * · K) -J LJ X * K- V • Ο ln X U) O CTV (- · * O ul 8th co ·· " _% UI) * I ul KJ UI) ι "J- O KJ 2 • * J X ν " kW χ  w xk K) X ul (η xk N Ui ·· ln X O * "A * ^ W ^^ k " ^^ * α B 3 a -JMN * 00 K) K * ►J X χ U * α co Γ * C α

Le A 25 164-foreign countries

- 72 -

KJ OO

DJ (Λ Ό

• η ο η η

I I ι η η O η η χ χ χ χ χ η η O η η χ χ X χ χ

η η

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\ X> U) 0 * rr X

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t- »KJ KJ

X · £ »X

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t- ►- X

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Le A 25 164-foreign countries

2 8 I f 8 p

- 73 -

Example 34 5

3- (4-fluorophenyl) -5-isopropyl-l, 2-diphenyl-pyrrole

10.1 g (34 mmol) of 2- (4-fluorophoryl) -5-methyl-1-phenyl-hexane-1,4-dione (Example 2) and 9.3 mmol of aniline (102 mmol) are dissolved in the 150th ml of toluene with the addition of 500 mg of p-toluenesulfonic acid for 24 h under reflux on a water separator

heated. After cooling and dilution with acetic acid-20

ethyl ester is washed with 1N hydrochloric acid and then with sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo, finally chromatographed on silica gel,

Yield: 4.4 g (37 '/, of theory)

1.17 (d, 6H); (s, IH); 6.80 - 7.30 (m, 14H).

25.

¹ H-NMR (CDCl _3): δ = 1.17 (d, 6H); 2,70 (sept., IH) J 6,28

In analogy to Example 6 and in Examples 1, 30

2, 33 4, 5 reactions described the compounds listed in Table 2 were obtained.

Le A 25 164-foreign countries

6 η

- 74 -

η η Γ) η η χ χ X χ η η η η X χ χ χ

Φ Φ Φ

χ> K) M X " W ro " Η • X * H- K) H- H- Uf K) 3 rr H- ci X K) ν Uf LJ X • X X " % -ο κ " O α ·· O X ro X ·· O ro w Xb Η- · K) O H- <* "Μ. * · ln • ° cn ** X H- -J ι UJ) Ul) σ " "t IU) ti CD _ M α " ^Λ (πι * · X α " χ ο 3 ro * O 3 Uf 0 K) t H- H-* O Uf σ * CD V ON ln O K) Uf Uf ZZ α. ι H- X I H" η X X K) X O xk O ^^ U * . · * * ^ * H- «j H- X 3 ro *> X 3 * "· α 3 <· * K) * · * % κ · 3 Xb ul t · H- X H-" Η- · H- K) α 1-· "t % X ii S X W X CC α  * H- ¹ U * <·· lft w W Xb xk OO μ * · Ό O "· «< * > J X 3 ul _ _ * xh . ln » ^, ON Xb "^ • 3 W K) 3 * 3 * * t / 1 3 χ Xb X K) K) » U> H- Ui H- K) O KJ OD QD Ό H- X X X X ο X . ΓΓ K) 3 ,, α ,, t α Uf ln U * K) * X K) V * ro Uf χ xk ^, σ " O OO ul 00 ο O • L " α K) » "J Ul 0 "\ 3 3 3 α • χ ro ro • * u> * - * »J K) ^ " b_l H- X *. Uf X Xb X X ^ * in 3 X W > · a. • * · **  *. a. α •

2 8 I

η ο ο η χ

Le A 25 1G4-foreign countries

Continuation Table Ex. No. R *

¹ H-NMR [f. ppm, CDCl ,, 3OO MHz]

in

42

-CH (CH,)

-CH (CHj) ₁

-CH (CH,) ι

-CH (CH,) j

Cl (ν / V Cl

1.29 (m, 6H); 1.45 (m.lH); 2.47 (m, 2H): 2.92 (sec., LH); 3.72 (s, 3H); 4.18 (m, IH); 4.38 (m, 1H); 5.2 O (dd, IH); 6.69 (d, 1H); 6.80 - 7.30 (m, 12H).

1.25 (m, 6H); 1.45 (m.lH); 1.60 (-, 1H); 2.47 (m, 2H); 2.76 (sept., LH); 3.42 (m, 2H); 3.72 (s, 3K); 4.18 (m, lH); 4.38 (m.lH); 5.19 (ra.lH); 6.70-7.45 (a, 19H).

1.27 (d, 6H); 1.55 (m, 2H); 2.47 (m.2H);

3.02 (sept., IH); 3.72 (s, 3H), 4.2O (ra,

IH); 4.37 (m.lH); 5.05 (s, 2H); 5.16 (dd,

IH); 6.71 (d.lH); 6.8O - 7.30 (m, 14H).

1.23 (d, 6H); 1.55 (m, 2H); 2.47 (m, 2H);

2.93 (sec., LH); 3.72 (3.3H); 4.24 (ra.

IH); 4.41 (m.lH); 5.3O (dd.lH); 6,70-

7.40 ("n, 19H).

281 ί 85

Example 43 2- (4-Fluorophenyl) -1> 5-dimethyl-hexane-1,4-dione

To a solution of 19.2 g (0.1 mol) of 1- (4-fluorophenyl) -4-methyl-pent-1-en-3-one and 8.6 ml (0.12 mol) of nitroethane in 100 ml Acetonitrile pa is added dropwise at ^{0 0} C, a solution of 7.9 g (0.05 mol) of 1,5-Diazabieye Io (5,4,0) undec-5-ene in 50 ml of acetonitrile pa Then, 3 h at room temperature stirred and 100 ml of 0.5 N hydrochloric acid are added. After extraction with methylene chloride, the organic phase is dried with sodium sulfate and concentrated. The oily residue is dissolved in 100 ml of ethanol and treated at room temperature with a solution of 4.8 g (0.12 mol) of sodium hydroxide in 60 ml of water. This reaction solution is then added dropwise with ice-cooling to a solution of 13.3 ml (0.25 mol) of concentrated sulfuric acid in 100 ml of water. After stirring at room temperature for 0.5 h, it is diluted with water and extracted several times with ether. The organic phase is washed twice each with 0.5 N hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulfate, concentrated in vacuo and chromatographed on silica gel

 Yield: 14.7 g (62.3> J of theory)

Le A 25 164-Auslarid

3 (105

- 77 -

¹ H-NMR _(CDCl3): 6 = 1.07 (d, 3H); 1.12 (d, 3H); 2.13 (β,

3H); 2.60 (m, 2H); 3.42 (dd, IH); 4.24 (dd, IH); 7.00 - 7.30 (m, 4H).

In analogy to Example 6 and the reactions described in Examples 1, 43, 3 or 34, 4 and 5, the compounds listed in Table 3 were obtained,

Le A 25 164-foreign countries

- 78 -

281

co

I I O η X X η η X χ

ι ι ι η η η χ χ χ η τ η χ χ · S

ι ι ι η η η χ χ χ

LJ KJ - • 0 H- LJ NJ 3 * NJ 8th UJ CJ - * • H- H- LJ 5 ' K) • LH U " - ^ * cn % Uf -O H- X Ξ O - • Ο • α 3 W 3 X 00 X X • C ^ X X * N) X N) NJ 3 YY -J , I " α I * 3 .. α " H- X · KJ -J O X 3 W • α O U α Ni X " ON H- X 3 N) ·· a • N) LJ U) KJ σ ~ OO α KJ Ni %. X cn X NJ N / U) OD OD W • .. X CJ X σ * X S X α "· O X (t X ·· KJ H* X χ " * ^W ,, ^. (t χ *. α 3 ., ., ΙΛ ,, 3 ΓΓ ^ j XI ΓΓ α ·. * X 1 U) OO cn YY »J ., CD Ln CJ KJ ul Uf LJ ^^ ul <· H- -J " xh ' " H- χ X " ·· X * ln ul " 3 H- X A KJ OD 0Λ · " CJ * co L " CK Ν " , ^. cn X »J X N) ο- 3 • sr N) N) O cn OD 3 NJ KJ 0- OD » Ό cn O cn ? α X · .. H* ^ J M CJ F , ^A NJ α to a X I KJ -. ? H" δ W CD It V K) »KJ C cn ΟΌ X »j Uf N) U) O ^ f 0th X " N) r » X O χ Γ? X * · H- X <M> X ι . * " * t w * ". ι cn * T * JC ·· W 3 " ·· * ·· W ^ ·· ·· α NJ -J * i CJ H- T * * ·. ON xk Η O CO N) cn X ^^ " O • * ν cn * cn * O "1 cc X 00 ί- cn O · " W Ni O ·· O ^ ₁ Ο O α O CJ 10 B U ¹ Lil · - » I α I ca " ^ J ON * α 3 B Cl KJ KJ * CJ • Λ H- ¹ LD U) * U * σ * u> 3; H- * X μ ^ X CJ _ 0 ^^ X X cf> ^ * X X tr, _w ». ^^ O t W W C "· ι >. ·· α

η ο ο η

Le A 25 164 -Autland

- 79 -

2 ti ate

example

Methyl-eryl- (E) -7- [3- (4-fluorophenyl) -5-isopropyl-1-methyl-2-phenyl-pyrrol-4-yl] -3,5-dihydroxy-heptanoate

CH ₂ -COOCH ₃

100 mg of the compound from Example 6 are dissolved in 20 ml of methanol and 10 μl of triethylamine and, after addition of 15 mg of 10% palladium on animal charcoal, hydrogenated at 2.5 bar for 3.5 hours. The catalyst is filtered off and the?

Solution is concentrated in vacuo.

Yield: 91 mg (90% of theory)

¹ H-NMR (CDCl _3); 6 = 1.4b On ₁ 10H); 2.48 (m, 2H); 2.60

(m, 2H>; 2.97 (m, IH); 3.28 (m, IH); 3.4 9 (s, 3H); 3.70 (s, 3H); 4.12 (m, IH ), 6.80 - 7.30 (m, 9H).

Le A 25 164-foreign countries

80 -

21> ί ί

Use Example

At game 50th

Di6 enzyme activity determination was carried out according to G, C, Ness et al., Archives of Biochemistry and Biophysics 197 , 493-499 (1979). Male * Ricor rats (body weight 300-400 g) were treated for 11 days with Altromnpulverfutter, the 40 g colestyramine / kg feed was added. 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 (mixture of K ₂ HPO ₄ and KH ₂ PO ₄ mi L pH 7.2), 0.03 M ethylenediaminetetraacetic acid, 0.002 m dithiothreitol (SPE) buffer (sucrose-phosphate-ethylenediaminetetraacetic acid buffer) pH 7.2, homogenized, followed by centrifuging for 15 minutes and discarding the sediment. The supernatant became Sedimented at 100,000 g for 75 minutes. The pellet is taken up in 1/4 volume SPE buffer, homogenized again and then centrifuged again for 60 minutes. The pellet is taken up with 5 times its volume of SPE-Puffe ·, homogenized, and frozen at -78 ⁰ C and stored (enzyme solution).

Le A 25 164-foreign countries

- 81 -

For testing, the test compounds (or, Mevinolin as Feferenzsubstanz) in dimethylformamide with the addition of 5 vol. Dissolved 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 assay 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 (β-nicotinamide adenine dinucleolide phosphate), 1 unit of glucose-6. phosphate 35 _μΜοΙ Κ χ Η γ-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.

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 mixture was centrifuged and 600 μl of the supernatant were applied to a 0.7 × 4 cm column filled with 5-chloride anion exchanger with a particle size of 100 to 200 mesh. It was distilled with 2 ml. Washed water and pass plus wash water with 3 ml of scintillation fluid and counted in scinti lationzähler. IC ^ g values were determined by applying the percentage inhibition to the concentration of the compound as assayed by intrapolation. To determine the

Le A 25 164-Auslend

2Β

- 82 -

relative inhibitory ί-Otenz the IC ₅ g value of the reference substance mevinolin was set as 100 and compared with the simultaneously determined IC ^ g value of the test compound.

The active compounds according to the invention have a higher inhibitory potency than mevinolin.

Example 51

The subchronic action of the compounds of the invention on the blood cholesterol values of dogs was tested in feeding experiments lasting several weeks, this the matter was under investigation over a period of several weeks einmä ^first given daily in a capsule of healthy beagle dogs along with the food po. The feed was also during the entire experimental period, ie before, during and after the application period of the substance to be examined, mixed colestyramine (4 g / 100 g diet) as GaI Iensäuresequestrant, twice weekly, the dogs venous blood was taken and the serum cholesterol determined enzymatically, Serum cholesterol values during the application period were compared with serum cholesterol values before the application period (control).

Thus, for example, for the active compound according to Example 6 after 2 weeks of daily administration of 2 mg / kg po a reduction in serum cholesterol by 27 %,

Le A 25 164-foreign countries

Claims (5)

281 U claims 1. A process for the preparation of substituted pyrroles of the formula R ⁴ X-A R ² R ^J in which 2 8 f 18 -.33 · A - for a group of the formula R ⁷ R ⁷ -CH-CH ₀ -C-CH ₀ -COOR ⁸ or I ² I ² OH OH wherein r HOW stands, R is hydrogen, methyl, t-butyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, and R - is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert Isobutylj.-Butyl or ^benzyl-1 means or means a sodium, potassium, calcium, or magnesium or ammonium ion. 2 8) ί Chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, MeLhoxycarbonyl, ELho ^ ycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert, butoxycarbonyl or by a group -NR ^ R ^ may be substituted, 10 in which R ⁵ and R 1 have the meaning given above, or R ⁴ - represents benzoyl, acetyl, ethylcarbonyl, propylcarbo, nyl, isopropylcarbonyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, Butylsulfonyl, isobutylsulfonyl, tert.Butylsulfonyl, phenylsulfonyl or To Iy1öu1funy1, for aminocarbonyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, aminocarbonyl, dimethyl, diethyl, dipropyl, diisopropyl ··, dibutyl or diisobutyronecarbonyl, phenylaminocarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy ^^ carbonyl, butoxycarbonyl, isobutoxycarbonyl or tert, butoxycarbonyl, X - for a group of the formula -Ch ^ -CHg "or -CH = CH-stands, 35 Le A 25 164-foreign countries 2 8 ί A - for a group of the formula I ^R -CH-CH-C-CH 2 -COG ^ ⁸ or; HO ^] [stands, Il L .0 OH OH wherein R is hydrogen or lower alkyl, and R - hydrogen, - alkyl (C ₁ to C ₄ ), aryl, (C ₆ to C ₁₂ ), aralkyl (G ₇ to C ₁₀ ) or a physiologically compatible cation means 2 81 alkoxy, trifluoromethyl, or trifluoromethoxy may be substituted, for thionyl, Fury !, thiazolyl, isothiazolyl, xxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, 1-goindolyl, quino-1-yl, 1-bochinolyl, phthalazinyl, CJ-inoxalyl, quinazolinyl, 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 - represent 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, Ben, , Benzyl sulfonyl, phenethyl, phenylethoxy, phenylethylthio. Phenyl ethylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula -NR ⁵ R ⁶ , I would like to r5 _and p6 _d j _eo b _en angugii Lene have meaning X - represents a group of the formula -CHg ^- CHO "or ¹ -CH = CH-, Le A 2E 164-foreign countries 2 81 18
94- R ^ and R ° are the same or different and
for thienyl, furyl, thiazolyl, isothiazolyl, Oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinoyl, isoquinolyl, phthalazinyl, quinoxalinyl,
Quinazolinyl, cinnolinyl, benzothiazolyl, benzene ^ oxazolyl or benzimidazolyl, which may be substituted equally or differently up to twice, may be substituted by fluorine, chlorine, iodine, lower alkyl,
Lower alkoxy, phenyl, phenoxy, trifluoroethyl,
Tr if luorrnethoxy or lower alkoxycorbonyl, or ^ - for phenyl or naphthyl, the bic may be substituted 4-fold, identically or differently
may be represented by lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfony1, benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, Phenylethoxy, Phenyletliyl th io, phenylethyl sul funyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula ²⁵ -NR ⁵ R ⁶ , in which R and R have the abovementioned meaning,
30 I would like to R ^ - for hydrogen or represents benzoyl or lower alkylcarbonyl,
or Le A 25 164-foreign countries 281 I 05 - is lower alkylBulf onyl, phenylsulfonyl or Tolyleulfonyl, or - represents aminocarbonyl, lower alkylaminocarbonyl, diniiderylaminocarbonyl, phenyl aminocarbonyl or lower α-.hoxycarbonyl, or - represents cyclicpropyl, cyclopentyl or cyclohexyl or - represents lower alkyl which may be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoro- * ^V methylsulfopyl, lower, benzoyl, Lower alkylcarbonyl, by a group of the formula -NR ⁵ R ⁶ ,
wherein ^ O R- and R "are the same or different and Lower alkyl, phenyl, benzyl, acetyl, benzene; ^T oyl, Phony 1 sulfonyl or NiederalkylbuI -. "Onyl mean or by pyridyl, pyrimidyl, pyrazinyl, Pyridazinyl, quinolyl, I socliol inolyl, pyrrolyl, indolyl. Thienyl, furyl, idazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethyl- pulfonyl, where the said heteroaryl and aryl radicals are identical or different up to 2 times by fluorine, chlorine, bromine, lower alkyl, lower Le A 25 164 Au5land 2 . Process according to Claim I _1, characterized in that substituted pyrroles are prepared, _ So 2 8 M 8 wor in 5 R ¹ - for cyclopropyl, cyclopentyl or cyclohexyl stands / or
- is lower alkyl which may be substituted can by fluorine, chlorine, bromine, cyano, Niederalk- ^'J oxy "lower alkylthio, lower alkylsulfonyl, trifluoromethyl, Trifluormothoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl, by a group of the formula -NR ⁵ R ⁶ , 15 wor in R ⁵ and R "nlsicn or are different and Lower alkyl, phenyl, benzyl, acetyl, benzoyl. Phenylsulfonyl or lower alkylsul fonyl bodeuten, or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrryl, indolyl, thionyl, furyl, imidazolyl, oxazolyl, thiazolyl, Phenyl, phenoxy, phenylthio, phenylsulfonyl, bengyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, said heteroaryl and aryl radicals being the same or different up to twice may be substituted by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl, or trifluoromethoxy, Le A 25 164-foreign countries 2 81 1 ü -83- 8 * ti - stands for alkyl, reduced, in the case of the production of the acid clay, the esters are pre-soaped, 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-) hydrogenated by conventional methods and optionally isomers. 2 8 ij R ⁷ -CH-CH ₂ -C-CH ₂ -COOR ⁰ or HO II, OH OH where r in ₇ R '- is hydrogen or alkyl and R ⁸ - hydrogen, Alkyl, aryl, aralkyl or - a cation means characterized in that raan Ketones of the general formula R ³ H R ² ^ 'CH = CH-CH-CHo-C-CHc-COOR ⁸ ' OH in we I rather R, R, R and R have the abovementioned meaning, Le A 25 164-foreign countries 2 8 ί j 3 5 fluoromethylthio, alkoxycarbonyl or may be substituted by a group of the formula -NR R, wherein 5 6 R and R have the abovementioned meaning, or - represents 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 ⁵ R ⁶ , wherein R and R have the abovementioned meaning, where R can also be alkyl, R - for hydrogen or - is acyl, alkylsulfonyl or arylsulfonyl, where the aryl radical may be substituted by alkyl or halogen, or 28.18 for aminocarbonyl, alky1aminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl and alkoxy carbonyl, or - represents cycloalkyl, or - is alkyl which may be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, Tr if luormethy lthio, Tri f luormethy. ¹ sulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁵ R ⁶ , 15 in which R, R - are the same or different and are alkyl, aryl, aralkyl, acyl, alky 1sulfonyl or Arylsulfonyl, 20 * or by carbamoyl, di a 1ky1carbamoy1, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryloid aryl radicals of the latter substituents up to 3 times, identically or differently, by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy. Alkylthio or Alky lsul f or.yl may be substituted, or represent heteroaryl which may be identical or different up to 3-fold by halogen, alkyl, alkoxy, Le A 25 164-Edition 28H8 Alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoro- methoxy, trifluoromethylthio, alkoxycarbonyl or may be substituted by a group of the formula -NR R,
wherein
10 R ^ and R "have the meaning given above, or
for Aryl Bteht, which may be substituted equally or differently up to 5 times by alkyl, Alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsilyl onyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluorinolinyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, SuIfamoyl, Di alkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ^ R ^, wor in 25 R and R have the abovementioned meaning X - for a group of the formula -CH ₂ -CH ₂ or -CH = CH- is standing, 30 and A - for a group of formula 35 Le A 2 5 164-Foreign countries 2 81 f a R ¹ - represents cycloalkyl, or
*> - is alkyl which may be substituted by halogen, cyano, alkoxy, Alkyithio, alkylsulfonyl, TrifJuormethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl _} acyl, or by a group of the formula -NR ⁵ R ⁶ , wherein R ⁵ ; R - are the same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or Arylsulfonyl, or by carbamoyl, di alkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkyl thio or aralkylsulfonyl, wherein the heteroaryl or aryl radicals of the latter substituents are up to 3 times the same or different by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, Alkyithio or alkylsulfonyl sub can be stituated, R and R are identical or different and represent heteroaryl which may be up to 3 times the same or different from halogen, Alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, tri- Le A 25 164-foreign countries 3
R and R are the same or different and «Stand for phenyl, which up to 2x ? 8ί t '-too- identical or different by methyl, δ ethyl ι propyl, isopropyl, butyl, isobutylene tyl, tert, butyl, methoxy, ethoxy, propoxy, i-propoxy, phenoxy, benzyloxy, fluoro, chloro, bromo, cyano, trifluoromethyl or trifluoromethoxy may be substituted, R ^ - for hydrogen, cycloprapyl, cyclopentyl or Cyclohexyl is, or
is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert, butyl, pentyl, i-pentyl, hexyl or isohexyl, which may be substituted by fluorine, chlorine, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, methylsulfonyl, Ethylsulfonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or by a group of the formula -NR ⁵ R ⁶ , where 25 R ⁵ and R ^ are the same or different and Hydrogen, methyl, ethyl, propyl, isopropyl, phenyl or benzyl,
30 or by optionally substituted by fluorine, chlorine, M6thyl, methoxy, trifluoromethyl or trifluoromethoxy substituted pyridyl, pyrimidyl, chi Le A 25 164-foreign countries t τι. 404'-28t i nolyl, thionyl, furyl, phenyl, phenoxy, phenylsulfonyl or benzyloxy, or - thionyl optionally substituted by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, phenyl, methoxycarbonyl, ethoxycarbonyl, furyl, pyridyl, pyrimidyl, quinolyl, * 0 isoquinolyl, benzoxazolyl, benzthiazolyl or Benzimidazolyl is, or - is phenyl which is up to 2 times the same or different from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl, phenyl, phenoxy , PhenyleuIfonyl, benzyloxy, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy. Methoxycarbonyl, ethoxycarbonyl or 'a group of the formula -NR R' may be substituted, ';, k where R ⁵ and R have the meaning given above, or R ⁴ - represents acetyl, methylsulfonyl, ethylsulfonyl, phenyl, bufonyl, tolylsulfonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, phenylaminocarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, Le A 25 164-foreign countries 28/185 - AOl- Butoxycarbonyl * isobutoxycarbonyl or tert -butoxycarbonyl *, X - for a group of the formula (E-configured) is A - for a group of the formula R ¹ 8 "CH-CH ₂ -C-CH ₂ -COOR or HO I OH OH stands wherein R - hydrogen means uno R represents hydrogen, methyl or ethyl or represents a sodium or potassium cation; 281 (85 -4B3- Use of substituted pyrroles of the formula X-A tr in which R - represents cycloalkyl>, or 28t - is alkyl which may be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of Formula -NR ⁵ R ⁶ ,
10 wherein R ⁵ , R 1 '- are identical or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfmoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfinyl, where the hateroaryl and aryl radicals of the last-mentioned substituents can be substituted by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, up to three times, identically or differently, R 'and R ^J - are the same or different and - Door heteroaryl stand up to 3 times the same or different by halogen, Alkyl, alkoxy, alkylthio, alkylsulfonyl, Aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or 35 Le A 25 164-foreign countries ** 'λθ5' m- may be substituted by a group of the formula -NR 1 -R " wherein R 1 and R ^{6 have} the abovementioned meaning, or - is aryl which may be substituted by up to 5 times or differently by alkyl, alkoxy, alkylthio, alkyl sulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, di alkyl suifamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁵ R ⁶ , 25 in which R ⁵ and R ^{6 have} the meaning indicated above, 30 R ⁴ - for hydrogen or - is acyl, alkylsulfinyl or arylsulfonyl, where the aryl radical may be substituted by alkyl or halogen, or Le A 25 164-foreign countries A0 <o - for amines ..irbonyl, alkylaminocarbonyl, dialkyl aminocarbonyl, arylaminocarbonyl or alkoxyt carbonyl stent, or I - is cycloalkyl, or * * - is alkyl which may be substituted by halogen, cyano, mkoxy, alkylthio, alkyl * G sulfonyl, trifluoromethyl, trifluoromethoxy, tri- fluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁵ R ⁶ , wherein R, R ° - are the same or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or Arylsulfonyl mean ' or by carbamoyl, dialkylcarbamoyl, sulfamoyl, di-alkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkyl-sulfonyl, the heteroaryl and aryl radicals of the latter substituents being up to 3 times the same or different by halogen, cyano , Trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or represent heteroaryl which may be up to 3 times the same or different from halogen, alkyl, alkoxy, Le A 25 164-foreign countries 28] j 8 Alkylthio, AlkyUulfonyl, ATyI ₁ aryloxy, aryl ^p Lhioi arylsulfonyl, trifluoromethyl, trifluoro- methoxy, trifluoromethylthio, alkoxycarbonyl or may be substituted by a group of formula -NP ⁵ R * ¹ , * ^u where R ⁵ and R ⁶ have the abovementioned meaning _# or 3. The method according to claims 1 and 2, characterized in that dafj be prepared substituted pyrroles, wherein 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, fithoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, methylsulfonyl, tylsulfonyl, propylsulfonyl, isopropylulfonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, gethoxycarbonyl, butoxycarbonyl, ^28M8 Isobutoxycarbonyl, tert -butoxycarbonyl, benzoyl, acetyl, pyridyl, pyrimidyl, thienyl, furyl, phenyl , phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, R ² and R ^{3 are the} same or different and are - for pyridyl, pyrimidyl, quinolyl or Isoquinolyl, which may be substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or - stand for phenyl, which up to 3 times be the same or different substituted may be represented by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert, butoxy, methylthio, ethylthio, propylthiu, 1 i.propylthio, Mtrthylsulf onyl, ethyl sul f onyl, propylsulfonyl, Isopropylsulfuny ^1, phenyl, phenoxy, benzyl, benzyloxy, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, methoxy-arbonyl, ethoxycarbonyl, Propoxycarbonyl> 1, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert-butoxycarbonyl, ^ O R ^ - for hydrogen, cyclopropyl, cyclopentyl or Cyclohexyl is, or - For methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert, butyl, pentyl, isopentyl, hexyl Le A 25 164-foreign countries ^28Μβ5 or iBohexyl, 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 F, I would like to R ⁵ and R 1 are the same or different and are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, phenyl, benzyl, acetyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or phenylsulfonyl, by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylolulfonyl, where the heteroaryl and aryl radicals mentioned are represented by fluorine, chlorine, methyl, ethyl, Le A 25 164-foreign countries f öS Propyl, isopropyl, isobutyl, terL, butyl, ° methoxy, ethoxy, propoxy, isopropoxy, butoxy, IsobuLoxy, * ert, -Butoxy, TrifluormeLhyl or trifluoromethoxy may be substituted, or for thionyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isooxazolyl, ^AU imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Quinolyl, isoquinolyl, benzoxazolyl, benzimidazolyl or benzthiazolyl, where the radicals mentioned are substituted 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 ^cu tert, butoxycarbonyl can be substituted, or - is phenyl, which is up to three times the same or different from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isc-pentyl, hexyl, isohexyl, methoxy, ethoxy, Propoxy, isopropoxy, butoxy, isobutoxy, tert -butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, methylsulfonyl, ethylsulfonyl, propyl 3Q sulfonyl, isopropylsulfonyl, butylsulfonyl, 7sobutylsulfonyl, tert-butylsulfonyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, fluoro, Le A 25 164-foreign countries 4, Process according to claims 1 to 3, characterized in that substituted pyrroles are prepared, wherein R - represents cyclopropyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, which may be substituted by fluorine, chlorine, methoxy, phenyl, or phenoxy, * ⁵ - stands for aryl that is up to 5 times the same or may be substituted by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkyl, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethyl, thio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁵ R 1, wherein R ^ and R ^ have the meaning given above, X - represents a group of the formula -Ch ^ -CHg "or -CH = CH-, and Le A 25 164-foreign countries i 8 A - for a group of the formula R ⁷ -CH-CH ₂ -C-CH ₂ -COOR ⁰ II
OH OH stands', wherein R is hydrogen or A, kyl and R - hydrogen - alkyl ', aryl aralkyl or
Gin cation means d characterized by the fact that they were used for the production of medicaments Use according to claim 5y, characterized in that it is used for the preparation of inhibitors of 3-hydroxy = 3 · methylglutaryl coenzyme A (HMG-CoA) · reductase · '