DD283604A5 - PROCESS FOR THE PREPARATION OF DISUBSTITUTED PYRROLES - Google Patents

Abstract

The invention relates to a process for the preparation of disubstituted pyrroles of the formula wherein the substituents R 1, R 2, R 3, X and A have the meaning given in the claims and in the description. They are prepared by reducing ketones of the general formula VIII in which R1, R2, R3 have the meaning given in the description and R8 represents alkyl, and in the case of the preparation of the acids, saponifying the esters, in the case of Production of lactones cyclized carboxylic acids or in the case of the preparation of other compounds performs appropriate reactions. Formula (I) and Formula VIII {new disubstituted pyrroles; inhibitory effect on 3-hydroxy-3-methyl-glutaryl coenzyme A reductase; Application as a medicinal product; Treatment of hyperlipoproteinemia; lipoproteinaemia; Arteriosclerosis}

Description

Process for the preparation of disubstituted pyrroles. Field of application of the invention

The invention relates to a process for the preparation of disubstituted pyrroles, intermediates for their preparation and their use in medicaments o

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-A 22 478; US 4,231,933 /. In addition, certain indole derivatives or "pyrazole derivatives inhibitors of HMG-CoA reductase / EP-A 1,114,027; US 4 513 610 /.

Object of the invention

The aim of the invention is to provide novel compounds with a stronger inhibitory effect on Hi-iG-CoA reductase,

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired intrinsic shade and method for their Herstelluno ο

- la

Disubstituted pyrroles of the general formula (I) have now been

in which

A (I) ₁

R ^{1 represents} heteroaryl which may be up to 3 times the same or different by halogen, alkyl, alkoxy, alkyl

thio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or may be substituted by a group of formula -NR ⁴ R 10

wherein

R, R are identical or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl,

or

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

wherein 30

R 1 and R 5 are as defined above, R ^{2 is} - cycloalkyl, or

Le A 25 803

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 ₍

wherein

R, R are identical 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-mentioned substituents are identical or different by halogen, cyano, trifluoromethyl, Trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl may be substituted,

- Hydrogen means, or

- Cycloalkyl means, or

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 1 R 3,

Le A 25 803

wor in

R, R have the meaning given above,

or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals are identical or different by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl Alkoxy, alkylthio or alkylsulfonyl may be substituted,

or

Heteroaryl, which is up to 3 times identical or different through halogen, alkyl, alkoxy, alkylthio,

Alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or may be substituted by a group of the formula -NR ^ R, 25

wherein

R and R have the abovementioned meaning, or

Aryl, which may be substituted equally or differently up to 5 times by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio,

Le A 25 803

Arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ , 10

wherein

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

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

and

A - a group of the formula

^J 2

I OH OH 25

wherein

1 ^ T T ^

-CH-CHo-C-CHo-COOR ⁷ HO '] | means

R ^{6 is} hydrogen or alkyl,

and

R'- is hydrogen or

Le A 25 803

- an alkyl, aryl or aralkyl radical or

- stands for a cation,

found.

Surprisingly, the disubstituted pyrroles of the invention show a superior inhibitory effect on HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase).

Cyc1oalkyl is generally a cyclic hydrocarbon radical having 3 to 8 carbon atoms. The cyclopropyl, cyclopentyl and cyclohexyl rings are preferred. Examples which may be mentioned are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

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

Alkoxy generally represents an acidic

, nitrogen-bonded straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Lower alkoxy having 1 to about 6 carbon atoms is preferred. An alkoxy radical having 1 to 4 carbon atoms is particularly preferred. Examples are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy,

Le A 25 803

Isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy called.

Alkylthio is generally 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. Particular preference is given to an alkylthio radical having 1 to 4 carbon atoms, for example methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, isopentylthio, hexylthio, isohexylthio, heptylthio, isoheptylthio, octylthio or isooctylthio.

Alkylsulfonyl is generally a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms, which is bonded via a S0 ₂ ~ group. Preferred is lower alkylsulfonyl having 1 to about 6 carbon atoms. Examples which may be mentioned are: methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, isopentylsulfonyl, hexylsulfonyl, isohexylsulfonyl.

SuIfamovl (aminosulfonyl) represents the group -SO 2 -NH 2.

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

Le A 25 803

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

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, in particular phenylthio.

Arylsulfonyl generally represents an aromatic moiety having from 6 to about 12 carbon atoms attached via an SC ^ group. Examples which may be mentioned: phenylsulfonyl, naphthylsulfonyl and biphenylsulfonyl, in particular phenylsulfonyl.

Aralkyl 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, for example be

' ^{i: v}

the following aralkyl radicals mentioned: benzyl, naphthylmethyl, phenethyl and phenylpropyl, in particular benzyl.

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

an oxygen atom is bonded. Aralkoxy radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. The following aralkoxy radicals may be mentioned as examples: benzyloxy, naphthylmethoxy, phenethoxy and phenylpropoxy, in particular benzyloxy,

Le A 25 803

Aralkylthio is generally an aralkyl radical having from 7 to about 14 carbon atoms, the alkyl chain being bonded via a sulfur atom. Preference is given to aralkyl thio radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part. The following aralkylthio radicals may be mentioned as examples: benzylthio, naphthylmethylthio, phenethylthio and phenylpropylthio, in particular benzylthio.

Aralkylsulfonyl is generally an aralkyl radical having from 7 to about 14 carbon atoms, the alkyl radicals being bonded via an SC ^ chain. Preference is given to aralkylsulfonyl radicals having from 1 to 6 carbon atoms in the aliphatic part and from 6 to 12 carbon atoms in the aromatic part. Examples which may be mentioned are the following aralkylsulfonyl radicals: benzylsulfonyl, naphthylmethylsulfonyl, phenethylsulfonyl and phenylpropylsulfonyl, in particular benzylsulfonyl.

Alkoxycarbonyl , for example, by the formula

-C-Oalkyl

being represented. Alkyl is in this case a straight-chain or branched hydrocarbon radical

,

1 to 12 carbon atoms. Lower alkoxycarbonyl having 1 to about 6 carbon atoms in the alkyl moiety is preferred. Particularly preferred is an alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety. For example, the following alkoxycarbonyl radicals may be mentioned:

oxycarbonyl, ethoxycarbonyl, propoxycarbonyl , isoprop

oxycarbonyl, butoxycarbonyl or isobutoxycarbonyl. Le A 25 803

2 2 MRZ. 19 δ 9 * ö-ε 4 ^ 51

Acyl is generally phenyl or straight chain or branched lower alkyl of 1 to about 6 carbon atoms attached via a carbonyl group. Preference is given to phenyl and alkyl radicals having up to 4 carbon atoms. Examples which may be mentioned: Benzayl, acetyl, ethylcarbonyl, propylcarbonyl, Isopropylcarbo-I ^ nyl, butylcarbonyl and isobutylcarbonyl, in particular benzyl and acetyl

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

Heteroaryl is generally a 5- to 6-membered aromatic ring which may contain oxygen, sulfur and / or nitrogen as heteroatoms and may be fused _to Cj _6n further 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 and which are optionally benzo-fused. Particularly preferred heteroaryl radicals which may be mentioned are: thienyl, furyl, pyrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinoline, quinazolyl, quinoxalyl, phthalazinyl, cinnolyl, thiazolyl, benzothiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl , Indolyl and isoindolyl,

Le A 25 803

If R ^{7 is} an alkyl, aryl or aralkyl radical, an ester group is formed. Preferred are physiologically acceptable esters which have been readily hydrolyzed in vivo to a free carboxyl group and a corresponding physiologically acceptable alcohol. These include, for example, alkyl esters (C ^ to C ^) and aralkyl esters (C ₇ to C ₁₀ ), preferably lower alkyl esters (C ₁ to C ₄ ) and benzyl esters. Particular preference may be given to the following ester radicals: methyl ester, ethyl ester, propyl ester, benzyl ester.

R may also be a physiologically acceptable metal or ammonium cation for a cation (M ^{n +} , where η is valency), particular preference is given to alkali or alkaline earth cations such as, for example, sodium, potassium, magnesium or calcium cations, and also aluminum cations. or ammonium cations, and non-toxic substituted ammonium cations from amines such as lower alkylamines (C 1 to about C 1), tri-lower alkylamines (C 1 to about C 1), dibenzylamine, N, N'-dibenzylethylenediamine, N -benzyl-β-phenylethylamine, N Methylmorpholine or N-ethylmorpholine, dihydroabiethylamine, N, N'-dihydroabiethylethylenediamine, N-lower alkylpiperidine and other amines which can be used to form salts,

In the context of the present invention, the disubstituted pyrroles can be represented by the general formulas (Ia-f)

Le A 25 803

^RJ

(Ia)

(Ib)

A-:

(Ic)

(Id)

OC-A

(Ie)

-Όί-Α

(If)

20

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

2530

being represented.

Preference is given to compounds of the general formulas (I)

in which

R ^{1 is} - thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which may be up to 2 -fold equal or different

35

Le A 25 803

may be substituted by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, 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, phenylethylsulfonyl , Fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula -NR ⁴ R ⁵ ,

where 20

R and R are the same or different and

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

Kylsulfonyl mean,., .- '' '

R 1 is cyclopropyl, cyclopentyl or cyclohexyl, or

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 ⁴ R ⁵ ,

Le A 25 803

wor in

R and R have the abovementioned meaning,

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

nylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenyl ethylthio or phenylethyl sulfonyl, said heteroaryl and aryl radicals being up to 2 times the same or different by fluorine, chlorine, bromine, lower

alkyl, lower alkoxy, trifluoromethyl,. or trifluoromethoxy can be substituted,

R ^J - hydrogen, or

- Cyclopropyl, cyclopentyl or cyclohexyl, or

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 or by a group of the formula -NR R,

wherein

R and R ^ have the meaning given above,

Le A 25 803

or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thionyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, wherein the said heteroaryl and aryl radicals may be substituted equally or differently by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl, or trifluoromethoxy up to 2-fold, - thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl , Pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, quinolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which may be substituted equally or differently by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl , Phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, 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, benzylsulfuryl, phenethyl, phenylethoxy, phenylethylthio , Phenylethylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or by a group of the formula -NR ^ R ⁵ ,

Le A 25 803

where 5

R and R have the abovementioned meaning, X is a group of the formula -CH = CH- and

A - a group of the formula

-CH-CHp-C-CHo-COOR ⁷ or H0 "||

^X 2

I OH OH

wherein R ^{6 is} hydrogen or lower alkyl, and

R - a C ^ to C ^ alkyl radical, a C ^ to C · ^ aryl radical or a Cy to C ^ q aralkyl radical

means, or

- means a physiologically acceptable cation.

Particular preference is given to compounds of the general formula I.

in which

Le A 25

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

- Phenyl which may be substituted up to 3 times the same or different by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert, butoxy, methylthio , Ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenyl, phenoxy, benzyl, benzyloxy, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert-butoxycarbonyl .

"?

R is cyclopropyl, cyclopentyl or cyclohexyl, or

- methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, which may be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, see.Butoxy, tert. Butoxy, methylthio, ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzoyl, acetyl, pyridyl, pyrimidyl, thienyl, furyl, phenyl, Phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl,

Le A 25 803

R is hydrogen, cyclopropyl, cyclopenyl or cyclohexyl, or

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

in which

R and R are the same or different and methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, phenyl, benzyl, acetyl,

Methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or phenylsulfonyl,

or by pyridyl, pyrimidyl, pyrazinyl,

Pyridazinyl, quinolyl, isoquinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, where the said heteroaryl and aryl radicals are represented by fluorine,

Chloro, methyl, ethyl, propyl, isopropyl, isobutyl, tert. Butyl, methoxy, ethoxy,

Le A 2 5 803

Propoxy, isopropoxy, butoxy, isobutoxy, tert, butoxy, trifluoromethyl or trifluoromethoxy may be substituted, or

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

Phenyl which is up to 3 times the same or different from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert, butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert, butylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert, butylsulfonyl, phenyl, phenoxy, phenylthio, phenylsulfonyl,

** ^ benzyl, benzyloxy, benzylthio, benzylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbo-

Le A 25 803

nyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl or may be substituted by a group -NR R,

in which

R ⁴ and R ^{5 have} the abovementioned meaning, X - is a group of the formula -CH = CH-

and 15

A - a group of the formula

R ⁶

OH OH I

-CH-CH ₂ -C-CH ₂ -COOR ⁷ or HO ^ j | means

I I γο

wherein

R ^{6 is} hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert, butyl

and

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

a sodium, potassium, calcium or magnesium or ammonium ion,

Le A 25 803

Very particular preference is given to compounds of the general formulas I

in which

R is - phenyl which may be substituted by methyl, phenoxy, fluorine or trifluoromethyl up to twice as much or differently,

R is isopropyl, cyclopropyl or tert-butyl,

R ^{3 is} cyclopropyl, isopropyl, tert-butyl or phenyl which may be monosubstituted by identical or different substituents by fluorine, methyl, phenoxy or trifluoromethyl,

χ - a group of the formula

(E-configured) means

and 25

A - a group of the formula

R ⁶

I R

-CH-CH ₂ -C-CH ₂ -COOR ⁷ or HC OH OH

wherein

R ⁶ - hydrogen means 35

and

Le A 25 803

, 7 _

Is hydrogen, methyl or ethyl, or a sodium or potassium cation.

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

Particularly preferred are the isomers of the general formula (I), which are substituted in the 2,5 and 3,5-position with the radical X-A.

Depending on the meaning of the groups X or, the radicals A, different stereoisomers result, 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 stereoisomeric forms which may be E-configured (II) or Z-configured (III) on the double bond!

AX- ]

(II) E-shape

Le A 25 803

Γ \ ο ^^

A-X

(III) Z-form

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

R, R ₁ R, X and A have the meaning given above.

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

-CH-CH ₂ -C-CH ₂ -COOR ⁷

OH

OH

Thus, the compounds of the 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 according to the invention can be present in the erythro configuration (IV) or in the threo configuration (V).

^A ~ ^x ~ i

^RJ

OH

erythro-form (IV)

Le A 25 803

Li Mn / .. 1 J -j ^ ^; -> .- ^

Γ- Γ /, f.

if

threo form (V)

OH

OH

In turn, there are two enantiomers of both the erythro and threo configurator compounds, namely 3R ₁ 5S isomer or 3S, 5R isomer (erythro form) and 3R ₁ 5R isomer and 3S, 5S isomer ( threo-form),

Preference is given here to the erythro-configured isomers, particularly preferably the 3R, 5S isomers and the 3R, 5S-3S, 5R racemate. C) If the radical -A is a group of the formula

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

α-χ-ΓΊ

Le A 25

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

cis-lactone (VI)

R2 R3 HQfe ^ R

^RJ

trans-lactone (VII)

Both of the cis-lactone and of the trans-lactone again exist in each case two isomers namely the 4R, 6R-I sort or the 4S, 6S-isomers (cis-lactone), as well as the 4R, 6S-1-someren or 4S 6R-I sort (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:

Le A 25 803

A-X

A-X-

A-X / \ N

ni

A-X-Z ^ N-

R-

OH OH

-CH-CH ₂ -CR ⁶ -CH ₂ -COOR ⁷

OH OH

• β

H-CH ₂ -CR ⁶ -CH ₂ -COOR ⁷

Le A 25 803

- 27 -

OH OH

CH-CHo-CR ⁶ -

7 -C00R ^/

OH OH

CH-CHo-CR ⁶ -CHO-COOR ⁷

A-X-

Le A 25 2 aaz. rj as * ö s 4i ^ i 5 i

A-X

OH

CH-CHo-CR ⁶ -CHO-COOR ⁷

A-X-

R-

OH

CH-CH ₂ -CR ⁶ -CH ₂ -COOR ⁷

A-X-

OH. _rp6 _f-i-r _Γηηρ7

CH-CHo-CR ⁶ -CHO-COOR

A-X

OH

CH-Ch ₂ -CR 1 -CH ₂ -COOR '

In addition, further possibilities of isomer formation arise because the inventive disubstituted pyrroles are substituted by two groups of the formula -X-A. Also for the second group -X-A in the molecule the above applies. They are all the same

Le A 25

Stereoisomers of the invention, which are formed by the second group of the formula -XA _1, in particular in connection with the first group -XA.

In addition, there are further possibilities, since the disubstituted pyrroles according to the invention are characterized by the variation with respect to the position of the radicals R, R ₀ and R_ ο

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

^R 2 ^R 3

^R l

in which

R ₁ , Rp * i ^ -z ^and d A and X have the abovementioned meaning,

is characterized in that ketones of the general formula (VIII)

3 ^lt

H ⁰ OCC-H ₀ CC-CH ₀ -HC-HC = HC

(VIII)

in 1 rather 5

R, R and R have the abovementioned meaning,

and

r8 _ is alkyl, reduced,

in the case of preparation of the acids, the esters are saponified, 15

in the case of production of the lactones, the carboxylic acids cycli sert,

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

in the case of preparation of the ethylene compounds (X = -CH ₂ -CH ₂ -) the ethene compounds (X = -CH = CH-) are hydrogenated by customary methods, 25

and optionally separating isomers,

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

Le A 25

H ₃ COOCH ₂ C

CH ₂ COOCH ₃

0 OH OH 0

reduction

OH OH

'CHoCOOCH-

OH OH

Verse i test

Na00CH ₂ (

OH OH

CH ₇ COONa

OH OH

Cyclization

OH

Le A 25

or

10

30 35

NaOOCH ₂ C

OH OH

CH ₂ COONa

OH OH

15

HOOCH ₂ C

OH OH

CHoCOOH

OH OH

20

Le A 25

The reduction can be carried out with the customary reducing agents,. preferably with those suitable for the reduction of ketones to hydroxy compounds are carried out. Particularly suitable here is the reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out with complex metal hydrides such as, for example, lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylhydridoboranates, sodium trialkylhydridoboronates, sodium cyano-trihydridoboranate 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

Le A 25 803

LL iiiiU. IJ - 2 * · .. · v .: H ^L i ti i.

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

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

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

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

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

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

Le A 25 803

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 general formula (I) correspond to the formula (Ig) 10

R ⁶ Ro Ro R ⁶

, 2 3.

HOOC-HoC-C-HoC-HC-X-1J-X-CH-CHo-C-CHo-COOH (Ig)

² I ² IWiI

OH OH R ¹ OH OH

in which

R ^1, R ^2, R ^{3, R 6} and X have the abovementioned meaning ·

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

R ⁶ R ² R ³ R ⁶

R ⁸ OOC-HoC-C-HoC-HC-X-ff ^/ f | -X-CH-CHo-C-CHo-COOR ⁸ (Ih)

² I ² I ^ V * ² I ²

OH OH R ¹ OH OH

in which

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

Le A 25 803

22M1U.

and R ⁸ - is alkyl.

The salts of the compound according to the invention in the context of the general formula (I) correspond to the formula (Ii)

I ι

OH OH

0OC-CHo-C-CH ₇ -CH-X-- | '[--X-CH-CH ₇ -C-CHO-COO

² I ² IY ^ I ² I ²

OH

OH

^Μ η (Ii)

in which

Have R ¹ , r ² ,

_R 6 _unc j

_o ^ _en specified meaning

and

fo

25 M ^{n stands} for a η-valent cation.

The lactones in the general formula (I) correspond to the formula (Ij)

^RJ

Le A 25

in weleher 5

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

For the preparation of the carboxylic acids of the general formula (Ig) according to the invention, in general the carboxylic acid esters of the general formula (Ih) or the lactones of the general formula (Ij) are saponified by customary methods. The saponification is generally carried out by treating the esters or lactones in inert solvents _with customary bases, generally the salts of the general formula (Ii) are formed first, which are then treated in a second step by treatment with acid in the free acids general formula (Ig) can be converted. 20

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

Le A 25 803

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

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

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

In carrying out the saponification, the base is generally used in an amount of 1 to 3 mol, preferably from 1 to 1.5 raol, based on 1 mol of the ester or of the lactones. 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 (Ii) according to the invention are formed as intermediates which can be isolated. The acids (Ig) according to the invention are obtained by treating the salts (Ii) with customary inorganic acid.

Le A 25 803

22

These include preferred mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. It has proved advantageous in the preparation of the carboxylic acids (Ig), * the basic reaction mixture from the hydrolysis in a second step without isolation of the I - ¹ acidify salts. The acids can then be isolated in the usual way.

For the preparation of the lactones of the formula (Ij) according to the invention, the carboxylic acids (Ig) 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 the solvents mentioned. Particular preference is given to using hydrocarbons, in particular toluene, in the presence of molecular sieve.

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

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

Le A 25 803

i L ili Π /. I t, ¹ -> i ' ^r tJ O "i " Λ - ·'

at negative or positive pressure (e.g., in a range of 0.5 to 5 bar).

Moreover, the cyclization is also carried out in inert organic solvents, with the aid of eye-lysing or dehydrating agents. As dehydrating agents preferably carbodiimides are used here. Preferred carbodiimides used are N, N'-dicyclohexylcarbodiimide-paratoluenesulfonate, N-cyclohexyl-N '- [2- (N "-methylmorpholinium) ethyl-carbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride.

Suitable solvents are the usual organic solvents. These include preferably ethers such as diethyl ether, tetrahydrofuran or dioxane, or chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride, or hydrocarbons such as benzene, toluene, xylene or petroleum fractions. Particular preference is given to chlorinated hydrocarbons, for example methylene chloride, chloroform or carbon tetrachloride.

·

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

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.

Le A 25 803

22

51

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

The separation of the isomers into the stereoisomerically uniform constituents is generally carried out by conventional methods such as those of E, L, for example. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962 is described here »is preferred here, the separation of the isomers at the stage of the racemic lactones, particularly preferred here is the racemic mixture of trans-lactones (VII) by treating either with D - (+ ) - or L- (-) -cx-methylbenzylamine by customary methods in the diastereomeric Dihydroxyamide (Ik)

H ₃ C HO OH "CH ₃

-H ₂ C / ^. R ² R ³

H ₅ C ₆ -HC-HNOC-H ₂ C / ^. R ² R

HCK ^ X-ff 'If-X'

(Ik)

R ¹ 25

Then, as usual, can be separated by chromatography or crystallization into the individual diastereomers. Subsequent hydrolysis of the pure diastereomeric amides by conventional methods,

...

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

Le A 25 803

10

hydroxide in water and / or organic solvents such as alcohols, e.g. Methanol, ethanol, propanol or isopropanol, give the corresponding enantiomerically pure dihydroxy acids (Ig), which can be converted as described above by cyclization in the enantiomerically pure lactones. In general, for the preparation of the compounds of the general formula (I) according to the invention in enantiomerically pure form, the configuration of the end products according to the method described above is dependent on the configuration of the starting materials.

The isomer separation should be exemplified in the following scheme:

20

30 35

OH

OH

trans-racemate

+ H ₂ N-CH-C ₆ H ₅

Le A 25 803

go -, y \] κ.: q * .-. f. λ λ ^ -t

LL '! MI! .. ι uv ^ - u ι: "A" i V' Ju

HoC

³ I

H ₅ C ₆ -HC-HN-OC-

^CH 3 CH ₂ -CO-NH-CH-C ₆ H ₅

Di astereomerengemi sch

1. Diastereomer separation

2. saponify

3. Lactonization

Le A 25

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.

0 -

R ² R ³

R ⁰ OOC-CH ₂ -C-CH ₂ -CH-CH = 15 OH

= CH-CH-CHo-C-CH ₇ -COOR ⁸

! ^{2 2}

OH

(VIII)

in which

-t ο ο o R, R, R and R have the abovementioned meaning,

which is characterized in that aldehydes of the general formula (IX)

in which

Le A 25 803

(IX)

L lili'i

:} ^ ^f -i 51

A O * 0

R, R and R have the abovementioned meaning,

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

H ₃ CC-CH ₂ -COOR ^C

(X)

in which R has the meaning given above, in the presence of bases.

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

+ H ₃ CC-CH ₂ -COOCH ₃

H ₃ COOCH ₂

CH ₂ COOCH ₃

Le A 25

Suitable bases here are customary strongly basic compounds. The reaction is also carried out in the presence of zinc salts. These include preferably organolithium compounds such as n-Butyl1ithium, sec, butyl 1ithium, tert.Butyl 1ithium or phenyl 1iLhiura, or amides such as lithium diisopropylamide, sodium or potassium amide, or Lithiumhexamethyldisilylamid, or alkali metal hydrides such as sodium or potassium hydride, It is also possible mixtures use the said bases. Particular preference is given to n-butyl-1-lithium, sodium hydride or their mixture in the presence of zinc bromide,

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 likewise possible to use mixtures of the abovementioned solvents. Particular preference is given to using ethers, such as diethyl ether or tetrahydrofuran.

The reaction is generally carried out in a temperature range of -80 ⁰ C to +50 ⁰ C, preferably from -20 ° C to + 30 ° C

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

Le A 25 803

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

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

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

Methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate _t isopropyl acetoacetate.

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

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

in which

R, R ^ and R ^ are as defined above, 35

Le A 25 803

found, which is characterized in that 5

Pyrroles of the general formula (XI) R ² R ³

J ^(XI) '

_R l

in which

R, R and R have the abovementioned meaning, in inert solvents in the presence of auxiliaries with Ν, Ν-dialkylaminoacrolein of the formula (XII)

alkyl ^

N-CH = CH-CHO (XII)

Alkyl '' 20

in which

Alkyl is a straight-chain or branched carbon radical having 1 to 6 carbon atoms, 25

implements.

The inventive method can, for example, by

the following formula scheme are clarified: 30

H ₃ C>

N-CH = CH-CHO

Le A 25 803

IL al iH. 1 -j Q 2 * · -; * .. · I ^c i v> L

Suitable solvents here are the customary organic solvents which are stable under the reaction conditions. These include preferably hydrocarbons such as benzene, toluene, xylene, hexane, petroleum fractions, chlorobenzene or o-dichlorobenzene, or ethers such as diethyl ether, dioxane or tetrahydrofuran, or chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride, or acetonitrile, It is also possible to mixtures of the above Use solvents. Anhydrous acetonitrile or chloroform is particularly preferably used.

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

Le A 25

22i / ia /.

f) S ^. 51

The reaction is carried out in a temperature range from -20 ° C to +150 ⁰ C, preferably of 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 1 to 6, preferably from 1.2 to 3 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 [A. Glossauer "The chemistry of the Pyrrole", Springer publishing house Berlin, 1974].

The disubstituted pyrroles of the invention can be used in medicaments for therapeutic treatment in humans and animals. They may preferably be used as inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and 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 of cholesterol 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

Le A 25 803

Inert, non-toxic, pharmaceutically suitable excipients or solvents. Here, the therapeutically active compound should be present in each case in a concentration of about 0.5 to 98 wt .-%, preferably up to 90 wt .-%, of the total mixture, i. in amounts sufficient to achieve the stated dosage margin.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using 15% of emulsifiers and / or dispersants, e.g. in the case of benzene use of water as a diluent, organic solvents may optionally be used as the heating solvent.

Examples of excipients which may be mentioned are: water, non-toxic organic solvents such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut / sesame oil), alcohols (e.g., ethyl alcohol, glycerol), excipients such as e.g. ground natural minerals (e.g.

Kaolins, clays, talc, chalk), ground synthetic minerals (eg fumed silica, silicates), sugars (eg, cane, milk and dextrose), emulsifying agents (eg polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates and arylsulfonates) , Dispersants (eg lignin-sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

Le A 25 803

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

In general, it has proven to be advantageous, when administered intravenously, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight.

·

To administer weight to achieve effective results, and when administered orally, the dosage is about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg 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 nature of its formulation and the time

Le A 25 803

3 6 O

Thus, in some cases it may be sufficient to manage with less than the minimum amount mentioned above, while in other cases this upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to to distribute these in several single doses throughout the day.

embodiment

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

- 54 output connections and production examples

Example 1

1,2-bis (4-fluorophenyl) -acrylic tri1

A solution of 2.3 g of sodium in 35 ml is added dropwise to a 50 ^° C. solution of 137.7 g (1.11 mol) of 4-fluorobenzaldehyde and 150 g (1.11 mol) of 4-fluorobenzyl cyanide in 900 ml of ethanol ethanol. In this case, a voluminous colorless precipitate falls out of which, after 1 h of stirring, is filtered off without heating. It is washed with water and dried over phosphorus pentoxide in a high vacuum

 Yield: 258 g (96% of theory) mp: 164 ° C.

In game 2, 2-ethoxycarbonyl-3,5-bis- (4-fluorophenyl) -pyrrole

Le A 25 803

ΰδ ^ ^ 51

To a suspension of 5.1 g (0.17 mol) of 80 Y.igem sodium hydride in 125 ml of anhydrous tetrahydrofuran is added dropwise at -15 ⁰ C, a warm solution of 18 g (0.16 mol) of isocyanacetic acid ethyl ester and 29.4 g ( 0.12 mol) of the compound from Example 1 in 15 ml of dimethyl sulfoxide and 125 ml of tetrahydrofuran, stirred for a further hour at -15 ⁰ C and finally for 30 min at room temperature, Now carefully added dropwise water, the aqueous phase separated, extracted three times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. After drying over sodium sulfate, the mixture is concentrated to give a brown oil (48 g), which is filtered through toluene over 200 g of silica gel. From ether crystallize 16.2 g (41 % of theory), almost colorless

Crystals of melting point 138 ^° C. 25

Example 3

2-ethoxycarbonyl-3,4-bis (4-fluorophenyl) -l-isopropyl-

pyrrole 30

Le A 25 803

"· T · Λ / ·· '" S 1

<· Ι · ίι ο ι

Et-O ₂ C

10 g (30.6 mmol) of the compound from Example 2 in 50 ml of tetrahydrofuran are added dropwise at ⁰ ° C. to 5.14 g (45.8 mmol) of potassium tertiary-butoxide in 40 ml of anhydrous tetrahydrofuran, followed by 15.6 g (91, 8 mmol) isopropyl iodide. The mixture is refluxed for 18 h and then poured into 300 ml of ice water. After addition of 300 ml of water, it is extracted three times with 150 ml of ethyl acetate, the organic phase washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated (13 g of brown oil). After filtration through 100 g silica gel (230-400 mesh) using petroleum ether-dichloromethane (3: 1) gives 9.2 g (81 '/ of theory.) Slightly colored oil which solidified in the refrigerator. M.p .: 49 ⁰ C

¹ H-NMR (CDCl ₃ ): δ = 0.95 (t, 3H, CH ₂ -CH ₃ ), 1.53 (d,

6H, CH- (CH ₃ ) ₂ ) j 4.05 (q, 2H, CH ₃ -CH ₃ ) j 5.43 (sept, IH, CH (CH ₃ ) ₂ ; 6.8 7.2 (m, 9H, 5H + aromatics-H).

Le A 25 803

22J ₁ IrI /. i'Jc - ^ *; *) ^ * '* 51

Example 4

3,4-bis (4-fluorophenyl) l-isopropyl-pyrrol-2-carboxylic acid

6.8 g (18.4 mol) of the compound from Example 3 are boiled in 30 ml of ethanol and 3.4 ml of 6 N sodium hydroxide solution for 18 h at reflux. Then it is acidified with 1 N hydrochloric acid and the precipitate is filtered off with suction. The precipitate is redissolved in ethyl acetate, extracted with 1N hydrochloric acid and saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness. Recrystallization from ether / petroleum ether gives 4.35 g (69% of theory) of colorless crystals of melting point 212 ^° C.

Example 5

3,4-bis (4-fluorophenyl) -1-isopropyl-pyrrole

Le A 25 803

4.6 g (13.5 mmol) of the compound from Example 4 are dissolved in 15 ml of acetic acid for 30 min. cooked at reflux. Considering the acetic acid in vacuo, the residue in Di chiormethan dissolves, washed with sodium bicarbonate solution and sodium chloride solution and dried over sodium sulfate, After concentration, 3.9 g (97% of theory) remain colorless crystals of melting point 105 ⁰ C ,

B:

While cooling with ice, 2.27 g (13.2 mmol) of the compound from Example 11 in 15 ml of tetrahydrofuran are added dropwise to 2.22 g (19.8 mmol) of potassium tetrahydrofuran in 15 ml of tetrahydrofuran. At room temperature, then added dropwise (39.6 mmol) of isopropyl iodide and boiled for 3 h at reflux.

After addition of 50 ml of water is extracted three times with methylene chloride, the combined organic phases dried and concentrated to a yellow oil. Filtration over 50 g of silica gel with petroleum ether / methylene chloride (10: 1) gives 2.13 g (54 * /.) Color crystals of mp. 104 ⁰ C (in DC identical to the sample obtained according to method A),

At game 6 30

3,4-bis (4-fluorophenyl) 2-5-bis- (2-formyl-ethenyl) -1-isopropyl-pyrrole

Le A 25 803

LL iiliW .. i i- ¹ ν W "-J -.J. '.' Λ ν- k

OHC - HC = HC '^^ N' ^^ CH = CH-CHO

To 3.82 ml (41.9 mmol) of phosphorus oxychloride in 20 ml of anhydrous acetonitrile is added dropwise at -5 ° C, a solution of 4.3 g (39.1 mmol) of 90% dimethylaminoacrolein in 10 ml of acetonitrile and then in portions 2 , 1 g (7.1 mmol) of the compound from Example 5 to. The mixture is refluxed for 18 hours, then added to a cold emulsion of 200 ml of toluene and 200 ml of water in which 13 g of sodium hydroxide are dissolved and stirred vigorously for 1.5 hours at room temperature. It is suctioned off on diatomaceous earth, the organic phase is dried over sodium sulfate and concentrated to a black oil (3.2 g). Column chromatography on 60 g of silica gel (230,400 mesh) with 300 ml of toluene, toluene / ethyl acetate (10: 1), (5: 1) and (3: 1) yields two fractions. First, 0.88 g (36 ') are eluted. /.) 3, 4-Bi s- (4-f luorphenyl) -2- (2-f.ormyl-ethenyl) -1-i sopropyl-pyrrol as slightly colored crystals of melting point 153 ⁰ C, then the product, 1 , 4 g of yellow foam, which crystallized from ether / petroleum ether gives 1.12 g (39 Y.) of orange crystals of melting point 207 ° C,

Example 7 .

3,4-bis (4-fluorophenyl) -2,5-bis (3-hydroxy-6-methoxycarbonyl-5-oxo-hex-1-enyl) -1-isopropyl-pyrrole

Le A 25 803

H ₃ COOC

COOCH '

OH

Under argon, to a suspension of 107 mg (3.56 mmol) of 80% sodium hydride in 10 ml of anhydrous tetrahydrofuran at -5 ⁰ C slowly 0.35 ml (3.25 mmol) of methyl acetoacetate and then at about ^{0 0} C. slowly 2.72 ml (4.43 mmol) of a 15% solution of butyllithium in hexane, after 15 min. Stirring at ⁰ ° C., a solution of 0.6 g (1.48 ml) of the compound from Example 6 in 5 ml of tetrahydrofuran is added dropwise and the mixture is stirred at the same temperature for a further 15 minutes. Finally, carefully added dropwise 0.58 g (9.67 mmol) of acetic acid and then 50 ml of water, extracted three times with ethyl acetate and the organic phase is dried over sodium sulfate and sodium carbonate. After removal of the solvent, 0.94 g of reddish foam of R 1 value: 0.2 remain with toluene / ethyl acetate (1: 1). The crude product is processed further,

At game 8

3,4-bis (4-fluorophenyl) -2,5-bis (3,5-dihydroxy-6-methoxycarbonyl-hex-1-enyl) -1-isopropylpyrrole

H ₃ COOC

COOCH-

OH OH

OH

Le A 25 803

Under argon is added dropwise at room temperature to a solution of 0.94 g (1.48 mol) of the compound from Example 7 in 10 ml of anhydrous tetrahydrofuran 3.56 ml of a 1 M solution of triethylborane in tetrahydrofuran and 5 minutes air passes through the Solution, After cooling to -78 ⁰ C, 138 mg (3.64 mol) of sodium borohydride curb, then slowly added dropwise 1.96 ml of anhydrous methanol, so that the temperature remains below -65 ⁰ C, 15 min at ca, -75 ⁰ C and 15 min, stirred at -30 ° C, before being added dropwise at ^{0 0} C 9.9 ml of 30% hydrogen peroxide in 30 ml of water. After warming to room temperature, extracted three times with 30 ml of ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and sodium carbonate and concentrated to a reddish brown foam (850 mg). After twice column chromatography on 30 times the amount of silica gel (230-400 mesh) first with toluene / ethyl acetate (1: 1) and ethyl acetate, secondly with dichloromethane / ethyl acetate (1: 1) and (1: 3) to obtain 102 mg (11 V almost colorless amorphous solid. theory)

R _f = 0.3, ethyl acetate

¹ H-NMR _(CDCl3): 8 = 1.3 to 1.6 (m, 1 OH, CH (CHg) ₂ +

CH (OH) -CH ₂ -CH (OH); 2.45 (m, 4H, CH ₂ -COOCH ₃ ); 3.18 (d, 2H, OH); 3.62 (d, 2H, OH); 3.7 (s, 6H, COOCH ₃ ); 4.13 (m, 2H, CH-OH); 4.38 (m, 2H, CH-OH);

4.7 (m, 2H, CH (CH ₃ ) ₂ ); 5.32 (dd, 2H, olefin-H); 6.1 (d, 2H, olefin-H); 6.85 (m, 4H, 3'-H); 7.0 (m, 4H, 2'- H)

 35

Le A 25 803

1 J - j ^v <-) ν) -l · 'I (J

15 20

- 62 -

Example 9

3,4-Bis- (4-fluoro-1-phenyl) -1-isopropyl-2,5-pyrrolebis (3,5-dihydroxy-hept-6-enoic acid di-sodium salt

NaCOOC

COONa

OH

86 mg (0.13 mmol) of the compound from Example 8 are stirred in 2 ml of tetrahydrofuran with 0.25 ml of 1 M aqueous sodium hydroxide solution at room temperature for 1.5 h »It is concentrated by rotary evaporation and dried over phosphorus pentoxide under high vacuum.

Yield: 72 mg (81% of theory) of amorphous yellowish solid

Dec. from 200 ° C

30

¹ H-NMR (CD ₃ OD): δ = 1.25-1.6 (m, 1 OH, CH- (CH ₃ J ₂ +

CH (OH) CH ₂ -CH (OH)); 2.25 (m, 4H, CH ₂ -COOCH ₃ ) J 3.85 (m, 2H, CH-OH); 4.25 (m, 2H, CH-OH); 5.35 (m, 2H, olefin-H); 6.6 (d, 2H, olefin-H); 6.8 - 7.1 (m, 8H, aromatic-H),

35

Le A 25 803

Example 5 4-Cyano-3,4-bis (4-fluorophenyl) -3H-4,5-dihydropyrrole-2-carboxylic acid sodium salt

To a suspension of 17.7 g (0.59 mol) of 80% sodium hydride in 450 ml of anhydrous tetrahydrofuran is added dropwise at -15 ⁰ C, a warm solution of 62 g (0.55 mol) of ethyl isocyanurate and 101 g (0.42 mol) of the compound from Example 1 in 50 ml of dimethyl sulfate.

foxid and 450 ml of tetrahydrofuran and stirred for one hour at -15 ⁰ C. At this temperature, 500 ml of water are carefully added dropwise, then allowed to warm to room temperature with stirring. Extract four times with ethyl acetate and discard the org. Phases. From the water

phase falls a voluminous colored precipitate, which is filtered off and dried in vacuo over phosphorus pentoxide.

Yield 95 g (62 %) . Recrystallization from water gives colorless crystals, which decompose at 193-194 ⁰ C, then fixed and melt again at 252-253 ⁰ C with decomposition.

Le A 25

C ₁₈ H ₁₁ F ₂ NaNO ₃ * H ₂ O (366.3) 5

C H F Na N

Re: 59.0 3.6 10.4 6.3 7.6

Gef. : 58.9 3.3 10.5 6.0 7.5

¹ H NMR (D ₆ -DMSO): δ = 4.5 (m, 2Η, CH ₂ )

4.7 (ξ, IH, 3-Η) 7.1-7.9 (m, 8H, Ar-H)

In game 15 3,4-bis (4-fluorophenyl) -pyrrole

1.63 g (4.45 mmol) of the compound from Example 10 and 3 g of ethanolamine are heated at 100 ^° C. for 3 hours. The solution is mixed with 50 g of ice water and extracted three times with ethyl acetate. The united org. Phases are washed with 1N hydrochloric acid, saturated bicarbonate solution and brine, brine, dried over sodium sulfate and

concentrated. The residue (1.7 g of brown oil) is filtered through 50 g of silica gel with petroleum ether-methylene chloride (2: 1).

Yield: 0.77 g (68 % of theory)

colored crystals of mp 142 ⁰ C. 35

Le A 25

Applicationξbe i spi e1

Example 12

The enzyme activity determination was carried out according to G _t C _t Ness et al., Archives of Biochemistry and Biophysics 197 , 493-499 (1979). Male ricot rats (body weight 300-400 g) were treated for 11 days with Altromin powder feed supplemented with 40 g cholestyramine / kg feed. After decapitation the animals were taken from the liver and placed on ice. Livers were minced and homogenized in a homogenizer times in 3 volumes of 0.1 M sucrose, 0.05 M KCl, 0.04 m _Κ χ Η phosphate (a mixture of K ₂ HPO ₄ and KH ₂ PO _4, pH 7.2) , 0.03 M ethylenediaminetetraacetic acid, 0.002 m dithiothreitol (SPE) buffer (sucrose-phosphate-ethylenediaminetetraacetic acid buffer) pH 7.2 homogenized. The mixture was then centrifuged for 15 minutes and the sediment was discarded. The supernatant was sedimented for 75 minutes, the pellet is taken up in 1/4 volume SPE buffer, homogenized again and then

again centrifuged for 60 minutes. The pellet is taken up with 5 times its volume SPE buffer, homogenized and frozen at -78 ° C and stored (= enzyme solution)

 30

For testing, the test compounds (or, mevinolin as a reference substance) in dimethylformamide with the addition of 5 vol-y. Dissolved 1 η NaOH and used with 10 μΐ in various concentrations in the enzyme assay. The 35th

Le A 25 803

2 2 f,!; I.7.1 ¹ J.} -J - fi 5 α Λ 5

Assay 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, 1 unit glucose-6-phosphate dehydrogenase 35, μΜοΙ Κ _χ Η phosphate PH 7 , 2, 20 μΐ enzyme preparation and 56 nmol 3xHydroxy-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 having a particle size of 100-200 mesh (anion exchanger). It was distilled with 2 ml. Rinse with water and pass through plus wash water with 3 ml of a Scint i 1 lation ratio and count in the scintillation counter. IC ^ Q values were determined by order of the percent inhibition against the concentration of the compound as assayed by intrapolation. To determine the relative inhibitory potency, the ICrjQ value of the reference substance mevinolin was set to 1 and compared to the simultaneously determined IC.sub.i.sup.Q value of the test compound.

The active compounds according to the invention show a higher activity than mevinolin,

Example No .: relative activity (mevinolin = 1)

9 40

[Δ Example 9 is 40 χ better than mevinolin] Le A 25 803

Example 13 5

The subchronic effect of the compounds according to the invention on the blood cholesterol values of dogs was tested in several-week fasting experiments. For this purpose, the substance to be examined over a multi-weekly period once a day in a capsule of healthy beagle dogs together with the feed p.o. given. The feed was also throughout the experimental period, i. before, during and after the application period of the substance to be examined, colestyramine (4 g / 100 g diet) mixed as bile acid sequestrant. Twice a week venous blood was taken from the dogs and serum cholesterol was determined enzymatically. Serum cholesterol values during the application period were compared with serum cholesterol values before the application period (control).

Le A 25 803

Claims (3)

(& Fatentansprüche 1, Process for the preparation of disubstituted pyrroles of the formula 2. The method according to claim 1, characterized in that it la temperature range of -90 to +30 ⁰ C is performed. "2 ^1V 3 A-X- -I ·! H X-A (I) ^R l in which
5 R ^{1 represents} heteroaryl which may be identical or different up to three times by halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, Alkoxycarbonyl or may be substituted by a group of the formula -NR ⁴ R " ⁵ , wherein R ⁴ , R 1 '- are identical or different and denote alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, or Aryl, which may be substituted equally or differently up to 5 times by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, Halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ , wherein R ⁴ and R 1 have the abovementioned meaning, R ^{2 is} cycloalkyl, or Le A 25 803 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, where r i η R ⁴ , R ⁵ - are identical 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-mentioned substituents are identical or different by halogen, cyano, trifluoromethyl, Trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl may be substituted, R ³ - is hydrogen, or _, .. · .. - Cycloalkyl means, or Alkyl, which may be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethyl sulfonyl, alkoxycarbonyl, acyl or by a group of the formula -NR ⁴ R ⁵ , Le A 25 803 wor in R, R have the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl wherein the heteroaryl and aryl radicals are the same or different by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl up to 3-fold Alkoxy, alkylthio or alkylsulfonyl may be substituted, or Heteroaryl, which is up to 3 times identical or different through halogen, alkyl, alkoxy, alkylthio, Alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or may be substituted by a group of formula -NR ⁴ R ⁵ , 25 wherein R and R have the abovementioned meaning, or Aryl, which may be substituted equally or differently up to 5 times by alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, Le A 25 803 -fl- Arylsulfonyl, aralkyl, aralkoxy, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethyl, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbaraoyl, dialkylcarbamoyl or by a group of the formula -NR ⁴ R ⁵ ,
10 wherein R and R have the abovementioned meaning, X- is a group of the formula -CH ₂ -CH ₂ "or -CH = CH-, and A- a group of the formula R ⁶ I R ^^ -CH-CH ₂ -C-CH ₂ -COOR ⁷ HO ^ I | means! j or ° OH OH
25 where r i η R ^b - is hydrogen or alkyl, and R is hydrogen or Le A 25 803 an alkyl, aryl or aralkyl radical or stands for a cation, characterized in that ketones of the general formula (VIII) 0 R ₂ R ₃ H ⁸ OOC-H ₂ CC-CH ₂ -HC-Hc = HC- [T "! J-CH = CH-CH-Ch ₂ -C-CH ₂ COOR ⁸ OH R ¹ OH in which R, R and R have the meaning indicated above, 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 carbon acidic cyclized, in the case of preparation of the salts, either the esters or the lactones are saponified, Le A 25 XQ Case of preparation of the ethylene compounds (X = -CK ₀ -CrU-) the iron compounds (X = -CH = CH-) hydrogenated by conventional methods, and optionally separating isomers 3 "use of disubstituted pyrroles according to claim I _1, characterized in that they are used for the production of medicaments.für the treatment of diseases»