DD283379A5 - METHOD FOR THE PRODUCTION OF DISUBSTUED PYRIDINES - Google Patents

Abstract

The invention relates to a process for the preparation of disubstituted pyridines of the formula * in the ketones of the general formula (VIII) is reduced, for. For example, in the case of the production of the acids, the esters are saponified or, in the case of the preparation of the lactones, the cyclized carboxylic acids and optionally the isomers are separated. The compounds prepared according to the invention can be used for the preparation of medicaments. {Disubstituted pyridines; Method; manufacture; Drug; Arteriosclerosis; inhibitors; HMG-CoA reductase}

Description

71 561/11

Process for the preparation of disubstituted pyridines

Field of application of the invention

The invention is used in the pharmaceutical industry, especially in drug synthesis

Characteristic of the known state of the art

It is known that lactone derivatives isolated from fungal cultures are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase) (Mevinolin, EP-A 22 478, US 4,231,938). In addition, certain indole derivatives or pyrazole derivatives are also inhibitors of HMG-CoA reductase (EP-A 1 114 027) US Pat. No. 4,613,610) "

Object of the invention

The process according to the invention provides disubstituted pyridines which have a superior inhibitory effect on HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase).

Presentation of the Ess of the invention

The invention has for its object to provide a process for the preparation of new disubstituted pyridines.

There have now been disubstituted pyridines of the general formula (I),

^A - ^X U)

in which

R ^J - heteroaryl, which is up to 3 times the same or different by halogenoalkyl, alkoxy, alkyl

thio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or may be substituted by a group of formula -NR ⁴ R ⁵ , 10

wherein

R ⁴ , R ^{5 are} identical or different and are alkyl, aryl, aralkyl, acyl, alkylsulfonyl or '15 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 30

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

R ^{2 is} cycloalkyl, or 35

Le A 25 738

- 3 - ZfJ J / S

- Alkyl means "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 ⁰

wherein

R, R 1 - are identical or different and denote alkyl "aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl" 15

or by carbamoyl "Dialkylcarb'.moyl, sulfamoyl, dialkylsulfamoyl" heteroaryl "Arvl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, wherein the heteroaryl and aryl radicals of the latter substituents are up to 3 times the same or different halo ^ n , Cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl,

R ^{3 is} hydrogen, or

- Cycloalkyl means, 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 1 R 3,

Le A 25 738

ZiSUS

wherein

R ^, R ^ have the meaning given above,

or by carbamoyl, dialkylcarbamoyl-1-sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy,

Arylthio, arylsulfonyl, aralkoxy, aralkylthio or

Aralkylsulfonyl, where the heteroaryl and aryl groups may be substituted by the same or different halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl groups up to 3 times,

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 * ⁵ , 25

wherein

R ^ and R ^ have the meaning given above, or

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

Le A 25 738

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 ^{5 have} the abovementioned meaning,

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

and

A is a group of the formula

I ₇

-CH-CHo-C-CHo-COOR ⁷ II

R ⁶ HO

or

OH

wherein

OH

R ^{6 is} hydrogen or alkyl,

and

R ⁷ - is hydrogen or

means

Le A 25

- represents alkyl, aryl or aralkyl or - represents a cation,

found"

Surprisingly, the disubstituted pyridines of the invention show a superior inhibitori see

Effect on HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) «

Cycloalkyl in general represents 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 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 a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms bonded via an oxygen atom. Preferred is lower alkoxy having 1 to about 6 carbon atoms. Particular preference is given to an alkoxy radical having 1 to 4 carbon atoms. "Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy,

Le A 25 738

Isopentoxy "hexoxy, isohexoxy, heptoxy. Isoheptoxy, octoxy or isooctoxy called «

Alkylthio is generally a Ubor a sulfur atom-bonded straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Lower alkylthio having 1 to about 6 carbon atoms is preferred. 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, T.sohexylthio, Heptylthio, Isoheptylthio, Octylthio or Isooctylthio called «

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

Sulfamovl (aminosulfonyl) represents the group -SO ₂ -NH ₂ *

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

Le A 25 738

- β - // S3 fS

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

Arylthio 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.

Arvlsulfonv l is generally an aromatic radical having 6 to about 12 carbon atoms! which is bonded via an SO 2 group, for example: phenylsulfonyl, naphthylsulfonyl and biphenylsulfonyl,

Aralkvl is generally an aryl radical having 7 to 14 carbon atoms bonded via an alkylene chain. Aralkyl radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. For example, the following aralkyl radicals may be mentioned; Benzyl, naphthylmethyl, phenethyl and phenylpropyl,

Aralkoxv is generally an aralkyl radical having 7 to 14 carbon atoms! wherein the alkylene chain is bonded via an oxygen atom. Aralkoxy radicals having from t to 6 carbon atoms in the aliphatic part and from 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,

Le A 25 738

Aralkylthio is in general an aralkyl radical having from 7 to about 14 carbon atoms, the alkyl chain being bonded via a sulfur atom. Aralkylthio radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. For example, the following aralkylthio radicals may be mentioned: benzylthio, Naphthylmethylthio, phenethylthio and phenylpropylthio «

Aralkvlsulfonyl generally represents 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 6 to 12 carbon atoms in the aromatic part. For example, the following aralkylsulfonyl radicals may be mentioned: benzylsulfonyl, naphthylmethylsulfonylphenethylsulfonyl and phenylpropylsulfonyl.

Alkoxycarbonyl , for example, by the formula

-C-Oalkyl

H

being represented. Alkyl here stands for a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms.

carbonyl with 1 to about 6 carbon atoms in the alkyl moiety. Particularly preferred is an alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety. For example, the following alkoxycarbonyl radicals may be mentioned: methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl, isopropoxy

oxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

Le A 25 738

- ίο - Μ33Ϊ3

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

Halogen is generally fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. Particular preference is given to halogen being fluorine or chlorine. 15

Heteroarvl is generally a 5- to 6-membered aromatic ring which contains oxygen, sulfur and / or nitrogen as heteroatoms 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 and which are optionally benzo-fused. Particularly preferred heteroaryl radicals which may be mentioned are: thionyl, Fury !, pyrolyl, pyrazolyl, pyridyl, pyrimidyl , Pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolyl, thiazolyl, benzothiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, indolyl, and isoindolyl,

In the context of the present invention, the disubstituted pyridines (Ia) correspond to the general formula

Le A 25 738

- 11 -

A-

OC-A

(Ia)

in which

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

In the context of the present invention, the disubstituted pyridines (Ib) correspond to the general formula 15

(Ib)

20 in which

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

in the context of the general formula (I), compounds having the general formulas (Ia) and (Ib) are preferred »

Preference is given to compounds of the general formula (Ia) and (Ib) 30

(Ia)

(Ib)

Le A 25 738

- 12 -

in which 5

R ^{1 is} - thionyl, 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 Substituted by the same or different substituents 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 ,

in which

R ⁴ and R ^{5 are the} same or different and lower alkyl, phenyl, benzyl, acetyl,

Benzoyl, phenylsulfonyl or lower alkylsulfonyl,

Le A 25 738

- 13 -

R ^ - cyclopropyl, cyclopentyl or cyclohexyl means »or

Lower alkyl which may be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl, by a group of the formula -NR ⁴ R **,

wherein

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

or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thionyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl,

fonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, where the said heteroaryl and aryl radicals are identical or different up to 2-fold by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl, or tri

fluoromethoxy may be substituted,

R ^{3 is} hydrogen, or cyclopropyl, cyclopentyl or cyclohexyl, or

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

Le A 25 738

- 14 - ZfJJts

deralkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl , by a group of the formula -NR ^ F ^,

wherein 10

R ^ and R have the meaning given above «

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 twice

- thionyl, 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 may be the same or different substituted by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or

- Phenyl or naphthyl means up to 4 times 35

Le A 25 738

- 15 -

ZJiStS

may be identically or differently substituted 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 ⁵ R ⁶ ,

where 15

R ⁵ and R ^{6 have} the abovementioned meaning, X - is a group of the formula -CH = CH- and

A - a group of the formula

I 7 ^{R <} U τ

-CH-CHo-C-CH ₂ -COOR 'or HO,

I ² I ²

OH OH

wherein

R ^{6 is} hydrogen or lower alkyl,

Le A 25 738

- 16 -

and 5

R ^{7 is} lower alkyl, phenyl or benzyl,

or - a physiologically acceptable cation

means

 10

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

in which 15

pi _ 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, tertrButoxy, methylthio, ethylthio , Propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenyl, phenoxy, benzyl, benzyloxy, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert-butoxycarbonyl,

R 1 is cyclopropyl, cyclopentyl or cyclohexyl, or

- methyl, ethyl, propyl, isopropyl, butyl, sec-butyl 35

Le A 25 738

Wed 379

or tart.Butyl means «which may be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.Butoxy, tert.butoxy, methylthio, ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl , Propylsulfonyl, isopropylsulfonyl, trifluoromethyl,

Trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl,

Butoxycarbonyl, isobutoxycarbonyl, tert -butoxycarbonyl, benzoyl, acetyl, pyridyl, pyrimidyl, thionyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl,

R ^ is hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or

Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl, which may be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , tert.butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.butylthio, methylaulfonyl, 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

Le A 25 738

- ie -

R ⁴ and R ^{5 are} g'jich or different <=> ind and Methyl, ethyl, propyl, isopropyl, butyl, iso

butyl, tert, butyl, phenyl, benzyl, acetyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or phenylsulfonyl, 10

or by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thionyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, where the 15 heteroaryl and aryl radicals mentioned are replaced by fluorine, chlorine, methyl, ethyl, Propyl, isopropyl, isobutyl, tert. Butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert, butoxy, trifluoromethyl or trifluoromethoxy, or - thionyl, furyl, pyridyl, pyrimidyl, pyrazinyl , pyridazinyl, oxazolyl, isooxazolyl, 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, hethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , tert, butoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxy

carbonyl or tert, butoxycarbonyl, or - phenyl which is up to 3 times the same or different

Le A 25 738

methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, Butylthio, isobutylthio, tert, butylthio, methylsulfonyl,

Ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoxycarbonyl,

Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl or may be substituted by a group -NR 1 R ',

in which

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

and

A - a group of formula 30

f _{R> r} y

-CH-CH ₂ -C-CH ₂ -COOR 'or HOI | means IIS

OH OH

Le A 25 738

- ²⁰ - // yy / s

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.

Very particular preference is given to compounds of the general formulas (Ia) and (Ib) 20

in which

R ^{1 represents} phenyl which may be substituted identically or differently by methyl, ethyl, propyl, isopropyl, phenoxy and / or fluorine up to twice

r 2 - is cyclopropyl or cyclohexyl or is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, which may be substituted by fluorine, chlorine, methoxy, phenyl or phenoxy,

Le A 25 738

- 21 -

r3 is hydrogen, cyclopropyl, cyclopentyl or cyclohexyl or phenyl, or

Methyl, ethyl, propyl, isopropyl, butyl or benzyl,

X - a group of the formula

(E-configured) means

and

A - a group of the formula

R ^{6 is} -CH-CHo-C-CH ₉ -COOR ⁷ or HO

I ² I ²

OH OH

wherein

R ^{6 is} hydrogen

means

and

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

The disubstituted pyridines of the general formula (I) according to the invention have a plurality of asymmetric carbon atoms.

Le A 25

- 22 -

and therefore may exist in various stereochemical forms. "Both the individual isomers and their mixtures are the subject of the invention.

Depending on the meaning of the groups X or "of the radicals A, different stereoisomers are obtained" which should be explained in more detail below!

a) If the group -X- represents a group of the formula CH =CH-, then 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:

A-

A-

(II) E-form (III) Z-form

Le A 25

- 23 -

wherein 5

R ¹ , r3, r3, χ _and d have the meaning given above.

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

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

r6

-CH-CH ₂ -IcH ₂ -COOR ₇

I ² I ²

OH OH

thus, the compounds have the general formula

(I) at least two asymmetric carbon atoms "namely the two carbon atoms to which the hydroxy groups are bonded" Depending on the relative position of these hydroxy groups to each other, the compounds of the invention in the erythro configuration (IV) or in the threo configuration (V) can be present .

R ⁶

-CH-CHo-C-CHo-COOR ⁷ Erythro-Form (IV)

A ² A

OH OH

Le A 25 738

- 24 -

R ⁶

-CH-CH ₂ -C-CH ₂ -COOR ⁷ threo-form (V)

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

The erythro-configured isomers, particularly preferably the 3R, 5S isomers and the SRiSS-SSiSR racemate, are preferred here. C) If the radical -A is a group of the formula

r6

HO

Thus, the disubstituted pyridines 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

Le A 25 738

- 25 - // YY? 9

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

HO

cis-lactone (VI)

trans-lactone (VII) 20

Both cis-lactone and trans-lactone

In turn, two isomers each exist namely the 4R, 6R isomers or, the 4S, 6S isomers (cis-lactone) · and the 4R, 6S isomers or · 4S, 6R isomers (trans-lactone). Preferred isomers are the trans-lactones.

Particularly preferred here is the 4R, 6S isomers

(trans) and the 4R, 6S-4S, 6R racemate.

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

Le A 25 738

- 26 -

10

OH OH ▼ V

CH-CHo-CHR ⁶ -C00R ⁷

OH OH Ti-CHo-C * HR ⁶ -C00R ⁷

Le A 25

- 27 -

/ η ρ 3

A-

OH OH CH-CH ₂ -Cr ⁶ CH ₂ -COOR ⁷

R ¹ OH OH

A-

15 A-

A-

A-

Le A 25 738

- 28 -

W St 3

OH OH

CH-CH ₂ -Cr ⁶ CH ₂ -COOR ⁷

A-

OH OH

^ Ch-CH ₂ -CR ⁰ CH ₂ -COOR

OH OH

^{Ψ Τ}6 7

CH-CH ₂ -CR ⁰ CH ₂ -COOR ⁷

OH OH CH-CH ₂ -Cr ⁶ CH ₂ -COOR ⁷

In addition, further possibilities of isomerization arise, since the disubstituted pyridines according to the invention are substituted by two groups of the formula -XA. The same applies to the second group -XA in the molecule. Likewise, all stereoisors are the subject of the invention produced by the second group of the formula -XA, in particular in connection with the first group -XA.

In addition, a process for the preparation of the disubstituted pyridines of the general formula (I)

Le A 25 73 8

- 29 -

(I)

^ q in which

R, R, R, X and A are as defined above,

, c found,

which is characterized in that one

Ketones of the general formula (VIII)

0

R ⁸ 00C-HoC-C-HoC-HC-HC = HC'O < ^A 5 ^ v ^ CH = CH-CH-CHo-C-CHo-C00R ⁸

OH _> μΛ _ OH

(VIII)

in which

R * R 1 and Br have the abovementioned meaning,

and

Le A 25

- 30 -

R ⁸ - is alkyl, 5

reduced,

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

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

in the case of preparing the salts, either the esters or the lactones are saponified, 15 in the case of preparation of the ethylene compounds (X = -CH ₂ -CH ₂ -) de ethene compounds (X = -CH = CH-) hydrogenated by customary methods,

and optionally isomers are separated ·

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

H ₃ COOCIi ₂ C

₂ COOCH ₃

reduction

Le A 25 73 *

- 31 -

reduction

OH

10

H ₃ COOCH ₂ C

OH

H ₂ COOCH ₃

Versei fung

OH

NaOOCH ₂ C

OH

H ₂ COONa

25

cyclization

30

OH OH

Le A 25

- 32 -

10

OH

OH

NaOOCH ₂ C

H ₂ COONa

OH

HOOCH ₂ C

H ₂ COOH

OH

Le A 25 73fi

- 33 -

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

Le A 25 738

- 34 -

If the alkoxycarbonyl group is not changed, the use of sodium borohydride as the reducing agent is particularly suitable for this purpose! 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 +30 ⁰ C, preferably from -78 ⁰ C to ⁰ ° C.

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

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

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

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

Le A 25 738

- 35 -

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

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

R ⁶ R ⁶

I ¹

OH OH V _n OH OH (Ic) ^{2 3}

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 (Id)

R ⁶ R ⁶

IR ¹ I

R ⁸ 00C-H ₂ CCH ₂ C-CH-XV _| > C% _| ^ X-CH-CH2-C-CH ₂ -C00R ⁸ OH OH OH OH (Id)

in which

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

Le A 25 738

- 36 -

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)

R °

⁰ OOC HoC HoC C-HC-2.2,

HO HO

-CH-CH ₇ -C-CHO-COO ⁹

I ² I ²

OH

ffl

(Ie)

in which

R ¹ , R ² , R ³ , R * and X have the abovementioned meaning ha

ben.

and

M ⁿ ® stands for a cation.

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

(If)

Le A 25

- ³⁷ - zn j 79

in which 5

R *, R ^, R, R ° and X have the abovementioned meaning.

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

Suitable bases for saponification are the customary inorganic bases. Particular preference These preferably include alkali or alkaline earth! Hydroxides such as sodium hydroxide, "potassium hydroxide or barium" or alkali metal such as sodium or potassium carbonate or sodium _t or Alkal! Alcoholates, such as sodium, sodium, Kai iummethanolat ', potassium ethoxide or Kaiium tert "butoxide · Sodium hydroxide or potassium hydroxide used.

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M solvents are suitable for the saponification of 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 dimethylformamide or dimethylsulfoxide. Particular preference is given to using alcohols such as methanol, ethanol, propanol or isopropanol. It is also possible to use mixtures of even solvents.

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

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

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

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Mineral acids such as, for example, hydrochloric acid "hydrobromic acid" sulfuric acid or phosphoric acid have proved to be advantageous in the preparation of the carboxylic acids (Ic) "to acidify the basic reaction mixture of the saponification in a second step without isolating the salts." 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 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 of -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

Le A 25 738

- 40 - ! TiSl3

at negative pressure or boi overpressure (eg in a range from O ₁ S to 5 bar).

Moreover, the cyclization is also carried out in inert organic solvents, with the aid of cyclizing or dehydrating agents. As dehydrating agents, preference is given to using carbodiimides. Preferred carbondiimides are Ν, Ν'-dicyclohexylcarbodiimide paratoluene sulfonate, N-cyclohexyl-N * -C 2 - (N '' -MethylmorpholiniunOethylHarbodiimid or N- (3-dimethylaminopropyl) -N * -ethylcarbamoimid dihydrochloride

• 15 used.

Suitable solvents here 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. Particularly preferred are 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 using chlorohydrocarbons, for example methylene chloride, chloroform or carbon tetrachloride.

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

Le A 25 738

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

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 ι McGraw Hill, 1962. In this case, preference is given to the separation of the isomers at the stage of the racemic lactones. In particular, preference is given to the racemic mixture of the trans-lactones (VII) by treatment either; _t \ it D (+) or L (-) -a-methylbenzylamine. by customary methods into diastereomeric dihydroxyamides (Ig)

HoC HO OH CHo

I I I

HCC ₆ -HC-HNOC-H ₇ C ^ ^ -CHO CONH-CH-C ₆ H .:

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 25 738

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S? S

hydroxide in water and / or organic solvents such as alcohols for example, methanol, ethanol, propanol or isopropanol, give the corresponding enantiomerically pure Oi hydroxy acids (Ic) "which can be converted by cyclization into the enantionerenreinen lactones as described above. 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 is dependent on the configuration of the starting materials.

The isomer separation should be exemplified in the following scheme:

OH

trans-racemate

CHr

HoN-CH-C, H

6 ⁿ 5

Le A 25 738

- 43 -

♦ H ₂ N-CH-C ₆ H ₅

"3?

H ₅ C ₆ -HC-HN-OC-

15

diastereomeric mixture

20

1) diastereomer separation

2) saponification

3) lactonization

30 35

OH

Le A 25 738

- 44 - HSSfS

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

8 " ^R \ ^"

R ^e 00C hoc C hoc HC-HC = HC% _f V> v ^ CH = CH-CH-CHo-C-CHO-C00R ⁸

ι Τι Τ ι

HO V _n ^ ~ OH

R ^z R ³ (VIII)

in which

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

and 20

R ^{8 is} alkyl,

found, which is characterized in that one

Aldehydes of the general formula (IX)

- <ix,

in which 35

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

Le A 25

- 45 -

2t SS79

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

H ₃ CC-CH ₂ -COOE ^

(X)

in which

R ^{8 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:

₃₀ H ₃ COOCH ₂ C

ο Il

+ H ₃ CC-CH ₂ -COOCH ₃

base

H ₂ COOCH ₃

Le A 25

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

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 ⁰ C + '30

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 25 738

- 47 -

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

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

As Acetessigeuter for the process according to the invention are for example called '

Methyl acetoacetate, ethyl acetoacetate «acetoacetic acid propyl ester, acetoacetic acid isopropyl ester ·

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

The preparation of the aldehydes can be exemplified by the following reaction scheme for the compounds of type (Ia):

Le A 25 738

- 48 -

CA] R ⁹ OOCV-ZSnZCOOR ¹⁰

(X) (XI)

CB]

HOH ₂ C

CH ₂ OH

CC]

(XII) (XIII)

0HC \ R ¹ / CHO

CD]

(IX)

R ⁹ , R ¹⁰ = alkyl

Le A 25

- 49 -

Here, in the first step CA], the dihydropyridines of the general formula (X) are oxidized in suitable solvents, with suitable oxidizing agents. Preference is given to the dihydropyridines in chlorinated hydrocarbons such as methylene chloride, with 2,2-dichloro-5,6-dicyano-p-benzoquinone at room temperature; or oxidized with chromium trioxide in glacial acetic acid at elevated temperatures, preferably at reflux temperature, to the pyridines of formula (XI). In the second step CB], the pyridines (XI) are added in inert solvents such as ethers, for example diethyl ether, dioxane or tetrahydrofuran, preferably in tetrahydrofuran, with metal hydrides such as lithium aluminum hydride, sodium cyano borohydride, diisobutylaluminum hydride or sodium bis (2). methoxyethoxy) dihydroaluminate, in a temperature range from -80 ⁰ C to + 40 ⁰ C, preferably from -70 ⁰ C to room temperature to the Hydroxyverb.indungen of the general formula (XII) reduced. In the third step CC] the hydroxy compounds (XII) by known methods with oxidizing agents such as pyridinium chlorochromate, optionally in the presence of alumina, in inert solvents such as chlorinated hydrocarbons, preferably methylene chloride, at room temperature or with trifluoroacetic acid and dimethyl sulfoxide (Swern oxidation) or other For the oxidation of hydroxymethyl compounds to aldehydes usual methods to the aldehydes (XIII) oxidized. In the fourth step CD], the aldehydes (XIII) by reacting with diethyl 2- (cyclohexylamino) vinyl phosphonate in inert solvents such as ethers, preferably in tetrahydrofuran in the presence of sodium hydride, in a

Le A 25 738

- so -

Temperature range from -20 ⁰ C to + 30 ⁰ C, preferably from -5 ⁰ C to room temperature in the compounds (IX) transferred,

The dihydropyridines of the general formula (X) used as starting materials are known or can be prepared by known methods CEP-A 88 276; DE-A 28 47 236].

In particular, they are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HGM-CoA) reductase and, consequently, inhibitors of cholesterol biosynthesis, they can therefore be used for the treatment of hyperlipoproteinemia , Lipoproteinemia or atherosclerosis are used, the erfindungsgeinäßen active ingredients also cause a reduction in the 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 inert, non-toxic, pharmaceutically suitable excipients or solvents. In this case, the therapeutically active compound should be present in each case in a concentration of about 0.5 to 98% by weight, -X, preferably 1 to 90% by weight, -X of the total concentration, i. in amounts sufficient to achieve the stated dosage margin,

The formulations are prepared, for example

Le A 25 738

- ⁵¹ -

by stretching the active compounds with solvents and / or excipients, if appropriate using emulsifiers and / or dispersants, wherein z, B, in the case of using water as a diluent, if appropriate organic solvents can be used as Hi Ifslösungsmittel.

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

The application is carried out in a customary manner, preferably orally, parenterally, perlingually or intravenously. In the case of oral administration, tablets may of course also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatin and the like, in addition to the abovementioned carriers. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tabletting

Le A 25 738

- 52 -

be used. In the case of aqueous suspensions, the active substances may be mixed with various flavor enhancers or colorants in addition to the above-mentioned auxiliary substances. "

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

In general, it has been found to be advantageous to administer amounts of about 0.001 to 1 mg / kg, preferably about U, 01 to 0.5 mg / kg of body weight to achieve effective results when administered intravenously, and when dosed orally 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 administration route, the individual behavior towards the drug, the nature of its 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 said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

Le A 25 738

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Execution examples of production examples

Example 1

(E / Z) -4-Garboxyethyl-5- (4-fluorophenyl) r2-methyl-pent-4-en-3-one

62 g (0.5 mol) of 4-fluorobenzaldehyde and 79 g (0.5 mol) of isobutanoylacetic acid ethyl ester are dissolved in 300 ml of dry isopropano! initially charged and mixed with a mixture of 2.81 ml (28 mmol) of piperidine and 1.66 ml (29 mmol) of acetic acid in 40 ml of isopropanol 43 h at room temperature, concentrated in vacuo and the residue is distilled in a high vacuum _e Kp 0.5 mm: 127 ° 0 Yield: 108.7 g (82.3 % of theory)

Example 2

Diethyl 1,4-dihydro-Z , 6-diisopropyl-4- (4-fluorophenyl) -pyridine-3,5-dicarboxylate

- 54 -

if Ut 9

'2 ^H 5 10

98 g (0.371 mol) of the compound from Example 1 are refluxed for 18 hours with 58.3 g (0.371 mol) of ethyl 3-amino-4-methylpent-2-enoate in 300 ml of ethanol. The mixture is dissolved Cooled room temperature, the solvent evaporated in vacuo and the unreacted Ausgangsierier are distilled off in a high vacuum at 130 ⁰ C, the residual syrup is stirred with η-hexane and the precipitate filtered off, washed with η-hexane and dried in a desiccator, yield : 35 g (23, AY, of theory) ¹ H-NMR _(CDCl3): δ * from 1.1 to 1.3 (m, 18H) J 4.05 to 4.25 (m,

6H); 5.0 <s, IH); 6.13 (s, IH); 6.88

(m, 2H); 7.2 (m, 2H).

Example 3

2,6-diisopropyl-4- (4-fluorophenyl) pyridine-3,5-dicarboxylic acid diethyl ester

Le A 25 738

- 55 -

35

H ₅ C ₂ 00Cs _r iT \ _T ^ C00C ₂ H ₅ 10

To a solution of 6.6 g (16.4 mmol) of the compound from Example 2 in 200 ml of methylene chloride p.a. Are added 3.8 g (16.4 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone and stirred for 1 h at room temperature. Then it is filtered off with suction through diatomaceous earth, the methylene chloride phase extracted three times with 100 ml of water and dried over magnesium sulfate. After concentration in vacuo, the residue is on a

_ ₀ column (100 g of silica gel 70-230 mesh, 0 3,5 cm, with Essigester / petroleum ether (1: 9), chromatographed, yield: 5.8 g (87,9X of theory) ¹ H-NMR (CDCl ₃ ): δ = 0.98 (t, 6H), 1.41 (d, 12H), 3.1 (m,

2H); 4,11 (q, 4H); 7.04 (m, 2H); 7.25 (m, 2H).

Example 4 3,5-Dihydroxymethyl-2,6-diisopropyl-4- (4-fluorophenyl)

30

pyridine

Le A 25 738

- 56 -

HO-Η ₂ (ΤΝ _γί ί ^ ν _ϊ ^ 'αΐ2 - OH 10

Under nitrogen, to a solution of 4.6 g (11.4 mmol) of the compound of Example 3 in 100 ml of dry tetrahydrofuran at -10 ⁰ C to -5 ⁰ C 22.8 ml (80 mmol) of a 3.5 The mixture is stirred overnight at room temperature and then heated to 40 ^° C. for 5 h. After renewed cooling to ⁰ ° C., it is added dropwise.

2Q visually 100 ml of water and extracted three times with 100 ml of ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is applied to a column (100 g of silica gel 70-

2g 230 mesh, 3.5 cm, with ethyl acetate / petroleum ether (6: 4), chromatographed ·

Yield: 2.4 g (66, 7Y, of theory)

¹ H-NMR _(CDCl3): 6 = 1.35 (d, 12H); 3.43 (m, 2H) j 4.47

(d, 4H); 7.05 - 7.3 (m, 4H).

Example 5

2,6-diisopropyl-4- (4-fluorophenyl) -pyridine-3,5-dicarbaldehyde

Le A 25 738

- 57 - inns

OHC 10

To a solution of 3.8 g (12 mmol) of the compound of Example 4 in 100 ml of methylene chloride p.a. are added 10.3 g (48 mmol) of pyridinium chlorochromate and 4.9 g (48 mmol) of neutral alumina and stirred for 1 h at room temperature. It is suctioned off over Kioselgur and washed with 300 ml of methylene chloride to «The methylene chloride phase is concentrated in vacuo and the residue on a column (150 g

2Q Kieselgel 70-230 mesh, 0 3.5 cm, with ethyl acetate / petroleum ether 2: 8), yield: 3.2 g (85.3% of theory) ¹ H-NMR (CDCl ₃ )! δ = 1.33 (d, 12H); 3.85 (m, 2H); 7.1 -

7.32 (m, 4H); 9.8 (s, 2H),

Example 6 '

(E, E) -2,6-diisopropyl-4- (4-fluorophenyl) -3,5-di (prop-2-en-1-al-3-yl) -pyridine

Le A 25 738

- 58 -

CHO

Under nitrogen is added dropwise to a suspension of 0.36 g (12 mmol) 80Xigern sodium hydride in 20 ml of dry tetrahydrofuran at -5 ⁰ C 3.1 g (12 mmol) of diethyl 2- (cyclohexylamino) -vinylphosphonat dissolved in 20 ml of dry tetrahydrofuran. After 30 minutes, 1.6 g (5 mmol) of the compound from Example 5 in 20 ml of dry tetrahydrofuran are added dropwise at the same temperature and the mixture is stirred for 30 minutes

2Q heated to reflux. After cooling to room temperature, the mixture is added to 200 ml of ice-cold water and extracted three times with 100 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate.

₂ c dries. After concentration in vacuo, the residue is taken up in 50 ml of toluene, treated with a solution of 2 g (15 mmol) of qxalic acid dihydrate in 25 ml of water and heated to reflux for 30 min. After cooling to room temperature, the phases are separated, the organic phase washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column (100 g of silica gel 70-230 mesh, a 3.5 cm, with ethyl acetate / petroleum ether 2: 8),

Le A 25 738

- ⁵⁹ - HS HS

Yield: 920 mg (50% of theory)

¹ H-NMR (CDCl ₃ )! 6 = 1.33 <d, 12H); 3.33 (m, 2H); 6.03

(dd, 2H); 7.0 - 7.35 (m, 6H); 9.42

(d, 2H).

Example 7

2,6-diisopropyl-4- (4-fluorophenyl) -3,5-di- (methyl (E) -5-hydroxy-3-oxo-hept-6-enoate-7-yl) pyridine

H ₃ COOC

Under nitrogen is added dropwise to a suspension of 360 _ _c mg (12 mmol) of 80% sodium hydride in 30 ml of dry tetrahydrofuran at -5 ⁰ C 1.16 g (10 mmol) of methyl acetoacetate in 5 ml of dry tetrahydrofuran, After 15 ¹ min At the same temperature 6.2 ml (10 mmol) of 15Xigef »butyl lithium in η-hexane added dropwise and stirred for 15 min». Subsequently, 912 mg (2.5 mmol) of the

The compound of Example 6 dissolved in 20 ml of dry tetrahydrofuran was added dropwise and stirred at -5 ⁰ C for 30 min. The reaction solution is carefully mixed with 3 ml

Le A 25 738

- 60 -

50Xiger acetic acid added diluted with 100 ml of water and the mixture extracted three times with 100 ml of ether. The combined organic phases are washed twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column (80 g of silica gel 70-230 mesh, 0 3 cm, with ethyl acetate / petroleum ether 1: 1),

Yield: 800 mg (53.6X of theory)

¹ H-NMR (CDCl _3): δ = 1.25 (m, 12H); 2.47 (m, 4H); 3.25 (m, 2H); 3.42 (s, 4H); 3.73 (s, 6H);

4.5 (m, 2H); 5.25 (dd, 2H); 6.35 (dd, 2H); 7.0 (m, 4H).

Example 8

2,6-diisopropyl-4- (4-fluorophenyl) -3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoate-7-yl) -pyridine

OH

H ₃ COO

COOCH.

To a solution of 776 mg (1.3 mmol) of the compound from Example 7 in 30 ml of dry tetrahydrofuran is added

Le A 25 738

- 61 - Μ3Ϊ9

at room temperature 3.2 ml (3.2 mmol) of 1 M triethylborane solution in tetrahydrofuran, "conducts during 5 min of air through the solution and cooled to -30 ⁰ C are an inner temperature from" 122 mg (3.2 mmol) of sodium borohydride and slowly added 2.5 ml of methanol, stirred for 30 min at -30 ⁰ C and then treated with a mixture of 10 ml of 30Xigem hydrogen peroxide and 20 ml of water. The temperature is allowed to rise to ^{0 0} C and stirred for a further 30 min. The mixture is extracted three times with 50 ml of ethyl acetate, the combined organic phases are washed once each with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column (50 g silica gel 230-400 mesh, 0 2.5 cm, with ethyl acetate / petroleum ether 1: 1), yield: 400 mg (51.4% of theory) ¹ H-NMR (CDCl ₃ )! S = 12.5 (m, 12H) J 1.4 (m, 4H); 2.42 (m,

4H); 3.3 (m, 2H); 3.72 (s, 6H); 4.1 (m, 2H); 4.3 (m, 2H); 5.25 (dd, 2H); 6.3 (dd, 2H); 7.0 (m, 4H).

Example 9

(E / Z) -4-carboxyethyl-2-methyl-5-phenyl-pent-4-en-3-one 30

COOC ₂ H ₅

Le A 25 738

- 62 -

6 * 9 g (0.44 mol) of isobutanoylacetic acid ethyl ester and 46.3 g (0 * 44 mol) of benzaldehyde are initially charged in 300 ml of isopropanol »with a mixture except 2.5 ml (25 mmol) piperidine and 1.5 ml 126 mmol ) Acetic acid in 40 ml of isopropanol and stirred for 24 h at room temperature. The mixture is concentrated in vacuo and the residue is distilled under high vacuum. Kp 0.5 mm: 130 ⁰ C. Yield: 60.7 g (56.2% of theory)

Example 10

1,4-Dihydro-2,6-diisopropyl-4-phenyl-pyridine-3,5-dicarboxylic acid diethyl ester

29.5 g (120 mmol) of the compound from Example 9 and 18.8 g (120 mmol) 3-amino-4-methyl-pent-2-en-saureethyles ^»i .he in 150 ml of ethanol for 48 hours under reflux overall

cooks. The mixture is cooled * concentrated in vacuo and the residue is chromatographed on a column (500 g of silica gel * 70-230 mesh, 0 5 cm, with ethyl acetate / petroleum ether 1: 9).

Le A 25 738

- 63 -

Yield: 7.2 g (15.1% of theory)

¹ H-NMR (CDCl ₃ )? δ = 1.2 (m, 18H) J 4.1 (m, 4H); 4.21 (m,

2H) J 5.02 (a, IH); 6.13 (β, IH); 7.2 (m, 5H).

example

2,6-diisopropyl-4-pher.yl-pyridine-3,5-dicarboxylic acid di-ethyl ester

7.2 g (18.2 mmol) of the compound from Example 10 are reacted analogously to Example 3. Yield: 6.4 g (88.8 v. Of theory)

Example 12

3,5-dihydroxymethyl-2,6-diisopropyl-4-phenylpyridine 30

Le A 25

- 64 -

Zf i 373

Under nitrogen, to a solution of 6, Ί g (16.2 mmol) of the compound from Example 11 in 100 ml of dry tetrahydrofuran at ^{0 0} C 40.5 ml (40.5 mmol) eir. <* R 1 molar solution of Lithium aluminum hydride is added dropwise in ether. "It is stirred overnight at room temperature, heated for 3 h at 50 ⁰ C and again cooled to ^{0 0} C from. 200 ml of water are carefully added dropwise to the mixture, filtered off with suction through kieselguhr and washed with 250 ml of ether. The organic phase is separated, washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is stirred with petroleum ether, the precipitate is filtered off with suction and dried in a desiccate, yield: 4 g (83.3 × drir theory) ¹ H-NMR (CDCl ₃ ): δ = 1.3 (d, 12H); 3.5 (m, 2H); 4.3 (d,

4H); 7.35 (m, 5H).

Example 13

2,6-diisopropyl-4-phenyl-pyridine-3,5-dicarbaldehyde

CHO

Le A 25 738

- 65 -

4 g (13.3 mmol) of the compound from Example 12 are reacted analogously to Example 5

Yield: 3.4 g (87.2 "of theory)

¹ H-NMR (CDCl ₃ )! 6 = 1.35 (d, 12H); 3.4 <m, 2H) J 7.3 (m,

2H); 7.5 (m, 3H); 9.3 (b, 2H),

example

(E, E) -2,6-Diisopropyl-4-phenyl-3,5-di- (prop-2-en-1-al-3-yl) -pyridine • 15

OHC \ V- ^ / CHO

3.35 g (11.4 mmol) of the compound from Example 13 are reacted analogously to Example 6

Yield: 2.7 g (67.5% of theory)

¹ H-NMR _(CDCl3): S = 1.35 (d, 12H); 3.47 (m, 2H); 6.04

(dd, 2H); 7.0-7.45 (m, 7H); 9.4 (d, 2H).

example

2,6-diisopropyl-4-phenyl-3,5-di- (methyl (E) -5-hydroxy-3-

oxo-hept-6-enoate-7-yl) -pyridine 35

Le A 25

- 66 -

H ₃ COOC

COOCHr

2.7 g (7.8 mmol) of the compound from Example 14

implemented analogously to Example 7.

Yield: 3.2 g (71.1 v. Of theory)

¹ H-NMR (CDCl _3): δ = 1.25 (m, 12H); 2.35 (m, 4H); 3.27

(m, 2H); 3.40 (s, 4H); 3.75 (s, 6H); 4.38 (m, 2H); 5.25 (dd, 2H); 6.37 (dd, 2H); 7.02 (m, 2H); 7.30 (m,

3H).

At ti- -s 1

2,6-diisopropyl-4-phenyl-3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoate-7-yl) pyridine

H ₃ COOC

COUCH,

Le A 25

- 67 - irsin

3.2 g (5.5 mmol) of the compound from Example 15 are reacted analogously to Example 8

Yield: 2 g (62.5K of theory)

¹ H-NMR _(CDCl3) δ J = 1.25 (m, 12H); 1.3-1.7 (m, 4H);

2.39 (m, 4H); 3.2 - 3.4 (m, 2H); 3.71 (s, 6H); 4.02 (m, 2H); 4.27 (m, 2H); 5.3 (m, 2H); 6.32 (m, 2H); 7.0

(m, 2h); 7.25 (m, 3H),

Example 17 .15

(E / Z) -2-ethoxycarbonyl-1- (4-fluorophenyl) -but-2-en-3-one

COOC ₂ H ₅

62 g (0.5 mol) of 4-fluorobenzaldehyde and 53.9 ml (0.5 mol) of methyl acetoacetate are initially charged in 300 ml of isopropanol, with a mixture of 2.81 ml (28 mmol) of piperidine and 1.66 ml (29 mmol) of acetic acid in 40 ml of isopropanol and stirred at room temperature for 48 h »

The mixture is concentrated in vacuo and the residue

distilled under high vacuum «

Kp 0.5 mm: 138 ^° C

Yield: 50.5 g (45.5% of theory)

Le A 25 738

- 68 -

Example 18

1 | 4-dihydro-2,6-dimethyl-4- (4-fluorophenyl) pyridine-3,5-dicarboxylic acid dimethyl ester

H ₃ COOC

COOCHo

33.3 g (0.15 mol) of the compound from Example 17 are refluxed with 17.3 g (0.15 mol) of methyl S-aminocrotonate in 150 ml of ethanol for 4 hours. The mixture is cooled to U ⁰ C, the precipitated precipitate was filtered off, washed with a little petroleum ether and in

Desiccator dried. Yield: 32 g (66.8X of theory)

¹ H-NMR _(CDCl3): 6 = 2.33 (s, 6H); 3.65 (s, 6H); 4.99 (s, IH); 5.77 (s, IH); 6.89 (m, 2H);

7.22 (m, 2H).

Example 19

2,6-dimethyl-4- (4-fluorophenyl) pyridine-3,5-dicarboxylic acid dimethy! Ester

Le A 25 738

- 69 -

H ₃ COO

COOCH-;

32 g (0.1 mol) of the compound from Example 18 are reacted analogously to Example 3. Yield: 27.2 g (87X of theory) ¹ H-NMR (CDCl ₃ )! δ = 2.59 (s, 6H); 3.56 (s, 6H); 7.08 (m,

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

example

3,5-dihydroxymethyl-2,6-dimethyl-4- (4-fluorophenyl) -pyridine

HO-H ₂ C

H ₂ -OH

Under nitrogen, a solution of 7.9 g (25 mmol) of the compound from Example 19 in 100 ml of dry

Le A 25

Tetrahydrofuran at ^{0 °} C 25 ml (87.5 mmol) ^ r a 3.5 molar solution of sodium bis (2-methoxyethoxy) -dihydroaluminate in toluene, is stirred for 6 h at room temperature, cooled again to 0 ° C. and 200 ml of water is slowly added dropwise. The mixture is extracted three times with 150 ml of ethyl acetate, the combined organic phases washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is stirred with ether, filtered off with suction and dried in a desiccator.

Yield: 3.5 g (53.8X of theory)

.15 ¹ H-NMR (CDCl _3): δ = 2.81 (s, 6H); 4.28 (d, 4H); 7.1 (m,

2H); 7.3 (m, 2H).

Example 21 20

2,6-dimethyl-4- (4-fluorophenyl) -pyridine-3,5-carbaldehyde

'CHO

3.5 g (13.4 mmol) of the compound from Example 20 become 30

implemented analogously to Example 5

 Yield: 1.7 g (53% of theory)

¹ H-NMR _(CDCl3): S = 2.88 (s, 6H); 7.28 (m, 4H); 9.82 (s,

2H).

Le A 25 738

- 71 -

i / s 393

Example 22

(E ₁ E) -2,6-Dimethyl-4- (4-fluorophenyl) -3,5-bis (p-nop-en-1 al-3-yl) -pyridine

OHC

CHO

1.7 g (7 mmol) of the compound from Example 21 are reacted analogously to Example 6, yield: 1 g (47.6% of theory) ¹ H-NMR (CDCl ₃ ) J 6 = 2.7 <s, 6H) ; 6.15 (dd, 2H); 7.15 (m,

6H); 9.43 (d, 2H).

Example 23

2,6-Dimethyl-4- (4-fluorophenyl) -3,5-di- (methyl- (E) -5- ₎ -hydroxy-3-oxo-hept-6-enoate-7-yl) -pyridine

H ₃ COOC

COOCH.

Le A 25 738

- 72 -

1 g (3) 2 mmol) of the compound from Example 22 are reacted analogously to Example 7

Yield: 1 g (57 Y, the theory)

¹ H-NMR _(CDCl3): 6 = 2.50 (m, 4H); 2.55 (ε, 6H); 3.45 (s, 4H); 3.73 (s, 6H); 4.52 (m, 2H); 5.35 (dd, 2H); 6.28 (d, 2H); 7.05 (m, 4H) ppm ·

Example 24

2,6-Dimethy1-4- (4-fluorophenyl) -3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoate-7-yl) pyridine

^H 3 ^C0 °

1 g (1.8 mmol) of the compound from Example 23

implemented analogously to Example 8 «'

Yield: 0.7 g (69.9 Y, of theory)

¹ H-NMR (CDCl _3): δ = 1.20-1.60 (m, 4H); 2.43 (m, 4H); 2.54 (s, 6H); 3.72 (s, 6H); 4.09 (m, 2H); 4.33 (m, 2H); 5.37 (dd, 2H);

6.22 (d, 2H); 7.03 (m, 4H) ppm.

Le A 25 738

- 73 -

Example 25 5

1,4-Dihydro-4- (4-fluorophenyl) -2-isopropyl-6-methylpyridine-3,5-dicarboxylic acid 3-ethyl-5-methyl ester

- H

15 g (56.8 mol) of the compound from Example 1 and 6.5 g (56.8 mmol) of S-aminocrotonic acid methyl ester are boiled in 150 2Q ml of ethanol for 20 h at reflux. The mixture is cooled, filtered off and concentrated in vacuo. The residue is chromatographed on a column (250 g silica gel 70-230 mesh, 0 4.5 cm, with ethyl acetate / petroleum ether 3: 7)

 Yield: 13.6 g (66.3X of theory)

¹ H-NMR (CDCl _3): δ = 1.2 (m, 9H); 2.35 (s, 3H); 3.65 (s,

3H); 4.12 (m, 3H); 4.98 (s, IH);

5.75 (s, IH); 6.88 (m, 2H); 7.25 (m,

2H).

Le A 25 738

- 74 -

Example 5 4- (4-Fluorophenyl) -2-1BOpTOPyI-O-HIethylpyridine-3,5 · dicarboxylic acid 3-ethyl-5-methyl ester

13.5 g (37.4 mmol) of the compound from Example 25 are reacted analogously to Example 3

Yield: 9.5 g (70.954 of theory)

¹ H-NMR _(CDCl3): S = 0.98 (t, 3H); 1.31 (d, 6H) J 2.6 (s,

3H); 3.11 (m, IH); 3.56 (s, 3H);

4.03 (q, 2H); 7.07 (ro, 2H); 7.25 (m,

2H).

example

3,5-Dihydroxymathyl-4- (4-fluorophenyl) -2-isopropyl-6-methyl-pyridine

Le A 25

- 75 -

20.7 g (57.7 mmol) of the compound from Example 26 dissolved in 50 ml of absolute tetrahydrofuran are slowly added dropwise under nitrogen to a suspension of 6 g (158 mmol) of lithium aluminum hydride in 200 ml of absolute tetrahydrofuran at 60 ° C. The mixture is Heated to reflux for 1 h, cooled to ^{0 0} C and cautiously mixed with 18 ml of water. It is 6 ml of potassium hydroxide solution to potassium, sucks from the precipitate and the residue is boiled twice with 250 ml of ether aup, the combined mother liquors are dried over magnesium sulfate and concentrated in vacuo · The residue is stirred with petroleum ether, filtered off with suction and dried in a desiccator .

2c, yield: 11.5g (68.9M of theory)

¹ H-NMR _(CDCl3): 6 = 1.3 (d, 6H); 2.69 (s, 3H); 3.51 (m,

IH); 4.3 (m, 4H); 7.1 (m, 2H); 7.3 (m, 2H).

Example 28

4- (4-fluorophenyl) -2-isopropyl-6-methyl-pyridine-3,5-dicarbaldehyde

Le A 25 73Q

- 76 -

if3 J? 9

ii, 5 g '40 nunol) of the compound from Example 27 are reacted analogously to Example ~, yield: 7.3 σ (64X of theory) ¹ H-NMR (CDCl ₃ ): ο = 1.32 (d ₍ 6H); 2.88 (s, 3H); 3.87 (m,

IH); 7.25 (m, 4H); 9.81 (d _f 2H).

example

(E, E) -4- <4-fluorophenyl) -2-isopropyl-6-r.tetrahydro-3,5-di (prop-2-en-1-al-3-yl) -;.; Yi i.din

OHC

CHO

7.3 g (21.7 mmol) of the compound from Example 28 are reacted analogously to Example 6, yield: 6.35 g (86.9 K of theory)

Le A 25

- 77 -

¹ H

H-NMR _(CDCl3):

1.32 (d, 6H); 2.7 (ε, 3H); 3.34 <m, IH); 6.02 (dd, IH); 6.15 (dd, IH); 7.0 - 7.35 (m, 6H); 9.42 (d, IH); 9.43 (d, IH).

10 example

4- (4-fluorophenyl) -4-isopropyl-o-methyl-SiS-di- (methyl (E) -5-hydroxy-3-oxo-hept-6-enoate-7-yl) -pyridine

H ₃ COO

COOCH.

H ₃ C

6.3 g (18.8 mol) of the compound from Example 29 are reacted analogously to Example 7.

Yield: 5.7 g (53.5X of theory)

¹ H-NMR (CDCl _3): δ = 1.25 (d, 6H); 2.42 (m, 2H); 2.53 (m,

2H); 2.57 (s, 3H); 3.28 (m, IH); 3.42 (s, 2H); 3.43 (r, 2H); 3.75 (s, 6H); 4.52 (m, 2H); C, 25 (dd, IH); 5.36 (dd, IH); 6.28 (d, IH); 6.37 (d, IH); 6.90 - 7.20 (m, 4H).

Le A 25

- 78 -

10

Example 31

4- (4-fluorophenyl) -2-isopropyl-6-methyl-3,5-di-methyl-erythro- (E) -SiS-dihydroxy-hept-fe-enoate-Z-yl) -pyridine

OH

H ₃ COOC

COOCH ·:

5.7 g (10 mmol) of the compound bub Example 30 are reacted analogously to Example 8

Yield: 2.9 g (50.8% of theory)

¹ H-NMR (CDCl ₃ )! δ = 1.25 (m, 6H); 1.2-1.5 (m, 4H);

2.41 (m, 4H); 2.57 <s, 3H); 3.3 (m _t IH); 3.72 (b, 6H); 4.1 (m, 2H); 4.3 (m, 2H); 5.15-5.5 (m, 2H); 6.15 6.45 (nt, 2H); 7.0 (m, 4H),

Example 32

Diethyl 1,4-dihydro-2-ethyl-4- (4-fluorophenyl) -6-isoprorylpyridine-3,5-dicarboxylate

^H 5 ^C 2

Le A 25 738

- 79 ~

10

9.5 g (73.6 mmol) of 3-amino-pent-2-enoic acid methyl ester and 19.4 g (73.6 mmol) of the compound from Example 1 are refluxed in 200 ml of n-butanol for 5 hours, The mixture is cooled to room temperature, the solvent is concentrated under reduced pressure and the residue is chromatographed on a column (silica gel 70-230 mesh, with petroleum ether / ethyl acetate 9: 1), yield: 5.3 g (19.3 % of theory)

Example 33

2-ethyl-4- (4-fluorophenyl) -6-isopropy1-3,5-di- (methylerythro- (E) -3,5-dihydroxy-hept-6-enoate-7-yl) -pyririin

20 25

H ₃ COO

^H 5 ^C 2

OH OH

COOCH,

30 35

From the compound of Example 32, in analogy to the reactions of Examples 3, 27, 5, 6, 7, 8, Example 33 was prepared:

¹ H-NMR (CDCl ₃ )! S = 1,? 8 (m, 9H); 1.43 (m, 4H) j 2.42 (m,

4H); 2.82 (q, 2H); 3.32 (m, IH);

3.72 (s, 6H); 4.09 (m, 2H); 4.32 (m,

2H); 5.28 (m, 2H); 6.30 (m, 2H);

7.00 (m, 4H) ppm

Le A 25 738

- 80 -

HS 3 W

Example 34

1! 4-Dihydro-4- (4-fluorophenyl) -2-isopropyl-6-n-propylpyridine-3,5-dicarboxylic acid diethyl ester

H ₅ C ₂ OOC

COOC ₂ H ₅

5.8 g (36.8 mmol) of ethyl 3-amino-hex-2-enoate and 9.7 g (36.8 mmol) of the compound from Example 1 are refluxed in 100 ml of ethanol pA for 48 hours. " The mixture is cooled, the solvent is concentrated under reduced pressure and the residue is chromatographed on a column (silica gel 70-230 mesh, with petroleum ether / ethyl acetate 8: 2),

Yield: 2.6 g (17.7 Y, theory), Example 35

4- (4-fluorophenyl) -2-isopropyl-6-n-propyl-1,3,5-di (methyl erythro (E) -3,5-dihydroxy-hept-6-enoate-7-yl) -pyridine

Le A 25 738

- 81 -

OH OH

H ₃ COOC

OH OH

COOCHr

From the compound of Example 34, Example 35 was prepared analogously to the reactions of Examples 3, 27, 5, 6, 7, 8.

¹ H NMR (CDClO)! 6 =

0.98 (t, 3H); 1.22 (d, 6H); 1.38 (m,

4H); 1.77 (m, 2H); 2.40 (m, 4H);

2.78 (m, 2H); 3.28 (m, IH); 3.70 (s,

6H); 4.05 (m, 2H); 4.28 (m, 2H);

5.25 (in, 2H); 6.28 (m, 2H); 6.95 (m, 4H) ppm,

example

Diethyl 1,4-dihydro-2-n-butyl-4- (4-fluorophenyl) -6-isopropylpyridine-3,5-dicarboxylate,

HoC "HoC-HoC-H

Le A 25

- 82 -

e / sm

6.3 g (36.8 mmol) of ethyl 3-amino-hept-2-enoate and 9.7 g (36.8 mmol) of the compound from Example 1 are reacted analogously to Example 34. Yield; 2.5 g (16.4 X of theory)

example

2-n-Butyl-4- (4-fluorophenyl) -6-isopropyl-3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoate-7-yl) - pyridine

OH OH

H ₃ COOC

COOCHr

From the compound from Example 36, analogously to the reactions of Examples 3, 27, 5, 6, 7, since »Example 37 was prepared,

BeJB c- ' iel

Diethyl 1,4-dihydro-2-benzyl-4- (4-fluorophenyl) -6-isopropylpyridine-S-dicarboxylate

COOC ₂ H ₅

Le A 25

- 83 -

7.4 g (36.8 mmol) of ethyl 3-amino-4-phenylcrotonate and 9.7 g (36.8 mmol) of the compound from Example 1 are reacted analogously to Example 34, yield: 2.1 g (12, 6 % of theory),

Example 39

2-Benzyl-4- (4-fluorophenyl) - ^ - isopropyl-S, -di- (methyl erythro (E) -3,5-dihydroxy-hept-6-enoate-7-yl) -pyridine

OH OH

H ₃ COOC

OH OH

COOCHr

The example 39 was prepared from the compound of Example 38 in analogy to the reactions of Examples 3, 27, 5, 6, 7, 8.

* ¹ H-NMR _(CDCl3): S = 1.10-1.50 (m, 10H); 2.40 (m, 4H);

3.32 (m, IH); 3.72 (s, 3H); 3.73 (s, 3H); 3.98 (m, IH); 4.08 (m, IH); 4.18 (m, IH); 4.21 (s, 2H); 4.28 (m,

IH); 5.13 (dd, IH); 5.27 (dd, IH); 6.25 (d, IH); 6.33 (d, IH); 6.97 (m, 4H); 7.25 (m, 5H) ppm.

Le A 25 738

- 84 - if J St}

Example 5 (E / Z) -2-carboxyethyl-1-cyclopropyl-3- (4-fluorophenyl) prop-2-en-1-one

COOC ₂ H ₅

39 g (0.25 mol) of ethyl cyclopropylcarbonylacetate and 31 g (0.25 mol) of 4-fluorobenzaldehyde are initially charged in 150 ml of dry isopropanol and treated with a mixture of 1.4 ml (14 mmol) of piperidine and 0.83 ml (14, 5 mmol) of acetic acid in 20 ml of isopropanol. The mixture is stirred for hours at room temperature, concentrated in vacuo and the residue is distilled in a high vacuum · Kp 0.5 mm: 14O ⁰ C.

Yield: 52.3 g (79.8 Y, of theory) example

Diethyl 1,4-dihydro-2-cyclopropyl-4- (4-fluorophenyl) -6-isopropylpyridine-3,5-dicarboxylate

Le A 25

- 85 -

H ₅ C ₂ OOCv _ir - v _{; T} ^ cOOC ₂ H ₅ 'H

39.3 g (0.15 mol) of the compound from Example 40 and 23.6 g (0.15 mol) of 3-amino-4-methyl-pent-2-enoic acid

ethyl esters are boiled in 150 ml of ethylene glycol overnight under reflux. After cooling to room temperature is extracted several times with ether, the combined ether phases washed three times with 10 Kiger hydrochloric acid, once each with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue is stirred with petroleum ether / ether, filtered off and dried in a desiccator, yield: 22.8 g (37.9 Y, of theory)

¹ H-NMR (CDCl _3): δ = 0.65 (m, 2H); 1.03 (m, 2H); 1.15 (m,

13H); 2.78 (m, IH); 4.15 (m, 4H) '; 5.03 (s, IH); 5.72 (s, IH); 6.90 (m, 2H); 7.22 (m, 2H) ppm.

Example 42

2-Cyclopropyl-4- (4-fluorophenyl) -6-isopropyl-3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoate-7-yl) -pyridine 35

Le A 25 738

- 86 -

OH OH

Η ₃ σοοο ^ ν ^ Ν ^ Ν ^ y ^ ₍ / '\ ^ \ / cooch ₃

The example 42 was prepared from the compound from Example 41, analogously to the reactions from Examples 3, 27, 5, 6, 7, 8,

¹ H-NMR (CDCl _3): δ = 0.90 (m, 2H); 1.20 (d, 6H); 1, ΙΟΙ, 60 (nt, 6H); 2.25 (m, IH); 2.43 (m, 4H); 3.25 (m, IH); 3.73 (s, 6H); 4.08 (m, 2H); 4.30 (m, 2H); 5.22

(dd, IH); 5.53 <dd, IH); 6.30 (m, 2H); 6.98 (m, 4H) ppm,

Example 43 25

S-amino-S-cyclopropyl-acrylic acid ethyl ester

/ COOCoH ₅ H ₂ N ^

49.9 g (0.32 mol) of cyclopropylcarbonylacetic acid ethyl ester in 200 ml of dry toluene are diluted with 1.1 g of

Toluenesulfonic added and at room temperature below 35

Le A 25 738

- 87 -

Agitation with ammonia gas saturated "After allowing to stand overnight, refluxed for 8 hours using a water while continuously ammonia gas is introduced · allowed to cool overnight, filtered, the toluene solution is concentrated in vacuo and distilled under high vacuum to 65 ⁰ C. from the unreacted starting material. The substance is then in the residue. Yield: 11.9 g (24 × of theory).

Example 44 15

1,4-dihydro-2,6-dicyclopropyl-4- (4-fluorophenyl) -pyridine-3,5-dicarboneäure-diethyleater

H ₅ C ₂ OOC 25

6.2 g (40 mmol) of the compound from Example 43 and 10.5 g (40 mmol) of the compound from Example 40 are dissolved in 100 ml of ethylene glycol and boiled overnight at reflux. After cooling to room temperature, the mixture is treated several times with ether extracted, the organic phase once each with 10 Xiger hydrochloric acid, saturated

Le A 25 738

- 88 -

Sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated in vacuo, yield: 10.4 g (65.1 × of theory)

¹ H-NMR (CDCl ₃ ): 6 = 0.60 (m, 4H); 0.95 (m, 4H); 1.23 (t,

6H); 2.72 <m, 2H); 4,12 (in, 4H);

5.02 (s, IH); 5.40 (s, IH); 6.88 <m,

2H); 7.20 (m, 2H) ppm.

Example 45

2,6-Dicyclopropyl-4- (4-fluorophenyl) -3,5-di- (methylerythro- (E) -3,5-dihydroxy-hept-6-enoate-7-yl) pyridine

<? ^H 9 ^H / **> »QH QH

From the compound of Example 44, Example 45 was prepared analogously to the reactions of Examples 3, 27, 5, 6, 7, 8.

¹ H-NMR _(CDCl3): S = 0.85 (m, 4H); 1.08 (m, 4H); 1,20-

1.60 (m, 4H): 2.20 (m, 2H); 2.43 (m,

4P); 3.70 (s, 6H); 4.12 (m, 2H);

4.30 (m, 2H); 5.52 (dd, 2H); 6.30

(d, 2H); 7.0 (m, 4H) ppm. 35

Le A 25 738

Example 46 5

(E / Z) -4-carboxyethyl-5- (4-fluoro-3-phenoxyphenyl) -2-methyl-pent-4-en-3-one

COOC ₂ H ₅

49 g (0.31 mol) of isobutanoylacetic acid ethyl ester and 67 g (0.31 mol) of 3-phenoxy-4-fluorobenzaldehyde are initially charged in 300 ml of isopropanol and mixed with 1.81 ml (18 mmol) of piperidine and 1.06 ml (18.6 mmol) acetic acid in 30 ml of isopropanol, it is stirred overnight at room temperature, then concentrated in vacuo and dried in a high vacuum. Yield: 110 g (was used without further purification in Example 47).

Example 47

l, 4-dihydro-2,6-diisopropyl-4- (4-fluoro-3-phenoxyphenyl) pyridine-3,5-dicarboxylic acid diethyl ester

Le A 25 738

- 90 -

COOC ₂ H ₅

30 g (84.3 mmol) of the compound from Example 46 and 13.2 g (84.3 mmol) of ethyl 3-amino-4-methylpent-2-enoate are refluxed in 150 ml of ethanol overnight. The mixture is cooled to ⁰ ° C., the precipitate is filtered off with suction, washed with petroleum ether and dried in a desiccator, yield: 18.4 g (44.2 % of theory)

¹ H-NMR (CDCl ₃ ): 6 =

1.05-1.25 (m, 18H); 4.05-4.2 (m, 6H); 4.95 (s, IH); 6.03 (s, IH); 6.85-7.1 (m, 6H); 7.3 (m, 2H),

example

2,6-diisopropyl-4- (4-fluoro-3-phenoxyphenyl) -3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoate-7-yl pyridine 30

Le A 25 738

- 91 -

H ₃ COOC

COOCH ₃

From the compound of Example 47 was prepared in analogy to the reactions of Examples 3, 27 »5, 6» 7, 8, the example of Example 48.

example

(E / Z) -2-carboxyethyl-l- (4-fluorophenyl) -3-phenyl-propen-3-one

COOC ₂ H ₅

38.4 g (0.2 mol) of ethyl benzoylacetate and 24.8 g (0.2 mol) of 4-fluorobenzaldehyde are dissolved in 200 ml of toluene, mixed with 3 ml of piperidine and 3.5 ml of glacial acetic acid

Le A 25

- 92 - 1 / 33ϊ9

and heated overnight under reflux on a water separator. After cooling to room temperature, extracted with saturated sodium bicarbonate solution and water, the organic phase is dried over magnesium sulfate and concentrated in vacuo. The unreacted starting materials are distilled off under high vacuum to give 55.9 g (93 % of theory) of crude product in the distillation residue.

¹ H-NMR _(CDCl3): 6 = 1.15 (t, 3H); 4.21 (q, 2H); 6,85-

7.95 (m, 10H) ppm. 15

Example 50

Diethyl diethyl ester 1,4-dihydro-4- (4-fluorophenyl) -2-isopropyl-6-phenylpyridine-3,5-dicarboxylate 20

29.8 g (0.1 mol) of the compound from Example 49 and

15.7 g (0.1 mol) of ethyl 3-amino-4-methyl-pent-2-enoic acid are dissolved in 150 ml of ethylene glycol and boiled overnight at reflux. After concentration in vacuo 2 g, the residue is dissolved in ethyl acetate, once each with 10 Xiger hydrochloric acid, saturated sodium bicarbonate

Le A 25 738

ass fs

Solution and water, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column (silica gel 70-230 mesh with ethyl acetate / petroleum ether 1: 5). Yield: 8.6 g (19.7 % of theory)

10 ¹ H-NMR (CDCl ₃ ): δ =

0.85 (t, 3H); 1.20 (m, 9H); 3.85 (q,

2H); 4,12 (q, 2H); 4.25 (m, IH);

5.09 (m, IH); 5.93 (m, IH); 6.93 (m,

2H); 7.25-7.50 (m, 7H) ppm,

15 Example 51

4- (4-fluorophenyl) -4-isopropyl-o-phenyl-3,5-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoate-7-yl) -pyridine

H ₃ COOC

OH OH

COOCH ₃

The Example 51 compound was prepared analogously to the reactions of Examples 3, 27, 5, 6, 7, 8,

Le A 25 738

- 94 -

example

(E / Z) -2- (carboxy-2-cyanoethyl) -S-cyclohexyl-l- (4-fluorophenyl) propene-3-one

COO-CH ₂ -CH ₂ -CN

66.9 g (0.3 mol) of cyclohexylcarbonylacetic acid (2-cyanoethyl ester) and 37.2 g (0.3 mol) of 4-fluorobenzaldehyde were reacted analogously to Example 49, yield: 56.7 g (57.4 %). the theory)

example

1,4-Dihydro-2-cyclohexyl-4- (4-fluorophenyl) -6-isopropy1-

pyridine-3,5-dicarboxylic acid-3-cyanethy! ester-5-ethyl-ester

COOC ₂ H ₅

Le A 25

- 95 -

1 / 33Ϊ9

32.9 g (O ₁ l mol) of the compound from Example 52 and 15.7 g (0.1 mol) of 3-amino-4-methyl-pent-2-enoic acid ethyl ester are dissolved in 100 ml of ethanol and overnight cooked at reflux. After concentration in vacuo, the residue is dissolved in ethyl acetate, washed once each with 10 Xiger hydrochloric acid, saturated sodium bicarbonate solution and water, the organic phase dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column (silica gel 70-230 mesh, with oichloromethane), yield: 7.8 g (17.6 % of theory)

example

2-Cyclohexyl-4- (4-fluorophenyl) -6-isopropyl-1-pyridine-3,6-dicarboxylic acid 3-cyano-1-yl-ethyl ester

COOC ₂ H ₅

3.53 g (7.55 mmol) of the compound from Example 53 are reacted analogously to Example 3, yield: 2.96 g (84 % of theory)

Le A 25

- 96 -

¹ H-NMR (CDCl ₃ ): 6 =

0.98 (t, 3H); 1.33 (m, 10H); 1.82

(m, 6H); 2.35 (t, 2H); 2.69 (m, IH);

3.10 (m, IH) J 4.02 (q, 2H); 4.15 (t,

2H); 7.08 (m, 2H); 7.28 (m, 2H) ppm.

example

2-cyclohexyl-3,5-dihydroxymethyl-4- (4-fluorophenyl) -6-isopropyl-pyridin

HO-H ₂ C

H ₂ -OH

2.5 g (5.35 mmol) of the compound from Example 54 dissolved in 50 ml of dry toluene at -78 ⁰ C under nitrogen atmosphere with 35.7 ml (53.5 mmol) of a 1.5 molar solution of diisobutylaluminum hydride in toluene, stirred for 1 hour at -78 ° C and overnight at room temperature «The mixture is added with ice cooling with 20 Kiger potassium hydroxide solution and extracted several times with toluene.

Le A 25 738

- 97 -

The organic phase is washed with water, dried over magnesium sulfate and concentrated in vacuo, yield: 1.64 g (86 54 of theory)

¹ H-NMR (CDCl ₃ ): S =

1.20-1.50 (m, 4H) J 1.35 (d, 6H) j

1.70-1.95 (m, 6H) j 3.05 (m, IH);

3.43 (m, IH) J 4.35 (s, 4H); 7.05-7.25 (m, 4H) ppm ·

example

15 2-Cyclohexyl-4- (4-fluorophenyl) -6-isopropyl-3, o-di- (methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoate-7-yl) pyridine

H ₃ COOC

OH OH

COOCH ₃

From the compound of Example 55, analogously to the reactions of Examples 5, 6, 7, 8, Example 30 was prepared.

¹ H-NMR _(CDCl3): 5 = 1.20-1.85 (m, 20H); 2.41 in, 4H);

2.90 (m, IH); 3.28 (m, IH); 3.70 (s, 6H); 4.08 (m, 2H); 4.30 (m, 2H);

35, 5.25 (dd, 2H); 6.30 (dd, 2H); 7.0

(m, 4H) ppm.

Le A 25

- 98 -

example

(E (2) -3-ethoxycarbonyl-l- (furan-2-yl) -4-methyl-penten-3-

on

[Γ ~ Ί1 ^ COOCH ₂ CH ₃

: C <

The compound was prepared analogously to Example 1 from furan-2-carbaldehyde.

Yield: 93 K dor theory Kp 0.5 mbar: 130 ^° C.

example

4- (furan-2-yl) ^, S-bis-CSjS hex-1-enyl3-2,6-diisopropylpyridine

OH OH

OH OH

CH ₃ OOC

0OCH,

Example 58 was prepared from the compound of Example analogous to the reactions of Examples 2, 3, 5, 6, 7, 8 and 55.

Colorless crystals, melting point 106 ^° C.

Le A 25

¹ H-NMR _(CDCl3) δ = J

in 3? s

1.25 (m, 12H); 1.4 - 1.65 (m, 4H);

2.45 (m, 4H); 2.77 (d, 2H); 3.3 (m,

2H); 3.6 (m, 2H); 3.6 (d, 2H); 3.72

(s, 6H); 4.1 (m, 2H); 4.4 (m, 2H);

5.4 (dd, 2H); 6.12 (m, IC); 6.4 (m,

IH); 6.5 (d, 2H); 7.45 (m, IH)

Example 59

(E (2) -3-ethoxycarbonyl-4-methyl-1 (thiophene-2-yl) penten-3-one

[jj] ^ 0OCH ₂ CH ₃

Example 59 was prepared analogously to Example 1 from thiophene-2-carbaldehyde,

Yield: 86 '/. the theory Kp 1.5 mbar! 145 ⁰ C

Example 60

3,5-Bis- [3,5-dihydroxy-6-methoxycarbonyl-hex-1-enyl] 2,6-diisopropyl-4- (thiophen-2-yl) -pyridine

OH OH

CH ₃ OOC

COOCH-;

Le A 25 738

- 100 -

Example 60 was prepared from the compound from Example 59 5 analogously to Examples 2, 3, 5, 6, 7, 8 and 27.

Colorless crystals "Melting point 62 ° C

¹ H-NMR (CDCl _3): δ =

1.25 (m, 12H); 1.35-1.6 (m, 4H); 2.45 (m, 4H); 2,6 (β, 2H); 3.3 (m, 2H); 3.5 (d, 2H); 3.72 (ε, 6H); 4.1 '• η, 2H) J 4.35 (m, 2H); 5.48 (dd,); 6.4 (d, 2H); 6.74 (m, IH); 6.98

i. IH)! 7.2fl in. IH)

IH); 7.28 (m, IH)

example

Di-sodium 2,6-diisopropyl-4-phenyl-3,5-di (erythro (E) 3,5-dihydroxy-hept-6-enoate-7-yl) -pyridine

OH OH

OH OH

Na 0OC

θ Θ COO Na

583 mg (1 mmol) of the compound from Example 16 are dissolved in 10 ml of tetrahydrofuran. Add 20 ml of 0.1 N NaOH and allow to stand for 1 hour at room temperature, concentrate in vacuo and then lyophilize the aqueous solution,

Yield: 605 mg (96.5% of theory),

Le A 25

APPLICATION 5

Example 6 2

The enzyme activity determination was modified according to G, C, Nese 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 diet. After decapitation the livers were removed from the animals and placed on ice

• 15 livers were minced and Potter Elvejem homogenizer 3 times in 3 volumes of 0.1 M sucrose, 0.05 M KCl, 0.04 ir> _Κ χ Ηγ phosphate, 0.03 M of ethylenediaminetetraacetic acid, 0.002 m dithiothreitol (SPE ) Buffer pH 7.2, homogenized. It was then centrifuged for 15 minutes at 15,000 * g and the sediment was discarded. The supernatant was sedimented at 100,000 g for 75 minutes. The pellet is taken up in 1/4 volume SPE buffer, homogenized again and then again centrifuged for 60 minutes at 100,000 g. The pellet is taken up with 5 times the amount Ihree volume of SPE buffer, homogenized, and frozen at -78 ⁰ C and stored (= EnzymlÖBung).

For testing, the test compounds (or Movinolin as reference substance) were dissolved in dimethylformamide with the addition of 5 vol. X 1 η NaOH and used with 10 ι 1 in various concentrations in the enzyme assay. The test was started after 20 minutes preincubation of the compounds with the enzyme at 37 ° C. The test set 35

Le A 25 738

- 102 -

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 μΝοΙ K _x Hy phosphate pH 7.2 , 20 μΐ enzyme preparation ion and 56 nmol of 3-hydroxy-3-methyl-glutaryl coenzyme A (glutaryl-3- ¹⁴ C) 100 000 dpm

 10

The mixture was incubated at 37 ° C. for 60 minutes and the reaction was stopped by adding 300 μl of 0.24 m HCl. After a subsequent incubation of 60 minutes at 37 ° C., the batch was centrifuged and 600 μl of the supernatant were brought to a 0.7 × 15 χ 4 cm with Biorex * ^R * 5-Chloride 100-200 mesh (anion exchanger) filled column "Washed with 2 ml deet" water and pass plus wash water with 3 ml Aquasol and counted in the LKB scintillation counter, ICgQ values were determined by order of the percentage inhibition against the concentration of the compound in the test by intrapolation. To determine the relative inhibitory potency, the ICgQ value of the reference substance mevinolin was set as 100 and with the simultaneously determined ICgg value of

Test compound compared, Example 63

The subchronic effect of the disubstituted pyridines on the blood cholesterol levels of dogs was tested in several weeks of feeding experiments. "For this purpose, the substance to be examined over a several-week period once a day in a capsule of healthy beagle dogs together with the feed p.o. In addition, during the entire trial period, the food was "h"

Le A 25 738

- 103 - Μ33Ϊ9

Colestyramine (4 g / 100 g diet) was mixed as bile acid sequestrant before, during and after the application period of the substance to be examined. Twice a week venous blood was taken from the dogs and the serum cholesterol was determined enzymatically. The serum cholesterol values during the application period were compared with the serum cholesterol values before the application period (controls),

Thus, for example, for the Na salt of Example 8 (2,6-diisopropyl-4- (4-fluorophenyl) -3,5-di- (sodium erythro- (E) -3,5-dihydroxy) hept-6-enoate-7-yl) -pyridine) after 2 weeks administration of daily 8 mg / kg p, o, a reduction in serum cholesterol by 22.4 'A,

Le A 25

Claims (1)

Ιίϊ Sf3 claims 1t Process for the preparation of disubstituted pyridines of the formula ^A - ^x Sk ^ ^x " ^A (D in which R is heteroaryl which is up to 3 times identical or different through halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or by a group of the formula -NR ^ R · ⁵ can be substituted, wherein R, R 1 - are identical or different and are alkyl, aryl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl, or ZfH ϊ3 - Aryl, which may be substituted up to 5-the same or different 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 ⁵ are as defined above, 20 R ^{2 is} cycloalkyl, 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 , wherein 30 R ⁴ , R ⁵ - are the same or different and Alkyl, aryl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl, Le A 25 in $ 73 or by carbamoyl, dialkylcarbamoyl, Sulfamoyl, dialkyl sulfo amoyl, heLeroaryl, aryl « Aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio or aralkylsulfonyl, where the heteroaryl and aryl radicals of the last-named substituents are up to 3 times identical or different from halogen, cyano, trifluoromethyl, Trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl may be substituted, R ^ is hydrogen, or
- Cycloalkyl means, or - Alkyl means that it may be substituted by halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or by a Group of the formula -NR ⁴ R ⁵ , wherein
R ⁴ , R have the meaning given above, or by carbamoyl, dialkylcarbamoyl, sulfo-methyl, dialkyl-bifluamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, Aralkylthio or Aralkyleulfonyl, wherein the Heteroaryl and aryl radicals up to 3 times the same or different by halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy ,. Alkylthio or alkylsulfonyl substituted leg, Le A 25 738 -40} - ItiSJ3 or Heteroaryl means "up to 3 times the same or different from halogen, alkyl" alkoxy "alkylthio" alkylsulfonyl "aryl" aryloxy "arylthio" arylsulfonyl, trifluoromethyl, trifluoromethoxy "trifluorroethylthio" alkoxycarbonyl or may be substituted by a group of the formula -NR ⁴ R ⁵ wherein
15 R ⁴ and R ^{5 have} the meaning given above or - Aryl means «up to 5 times the same or may be 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 R ⁴ and R ^{5 have} the meaning given above
35 Le A 25 738 X represents a group of the formula -CH ₂ -CH ₂ - or -CH = CH-5, and A - a group of formula 10 R ⁶ -CH-CH ₂ -C-CH ₂ -COOR ⁷ HO ^ T | means I) or ^ y ^ O OH OH .15 in which R ^{6 is} hydrogen or alkyl, and
20 R ⁷ - is hydrogen or - represents alkyl, aryl or aralkyl or - stands for a cation, 25 thereby signifying that one Ketones of the general formula (VIII) 0 Il R ¹ Il 30 R ⁸ OOC-H ₂ CCH ₂ C-HC-HC = HC ^> N _T > C% _R 1 CH = CH-CH-CH ₂ -C-CH ₂ -COOR ⁸ OH Le A 25 738 in which 12 3
R, R and R have the abovementioned meaning, and R ^{8 is} alkyl, reduced, saponified in the case of the production of the acids the Eater, cyclized in the case of the production of lactones the carboxylic acids, in the case of preparation of the salts, either the esters or the lactones are saponified, in the case of production of the ethylene compounds (X = -GH ₂ -CH ₂ -) the ethene compounds (X = -CH = CH-) hydrogenated by conventional methods, and optionally isomers separated A method according to claim 1, characterized in that the reduction carried out in the temperature range from -80 ⁰ C to +30 ⁰ G