DD290008A5 - PROCESS FOR PREPARING SUBSTITUTED 2-PYRIDONE AND PYRID-2-THIONE - Google Patents

Abstract

The invention relates to processes for the preparation of substituted 2-pyridones and pyrid-2-thiones of the general formula * in which the substituents A, B, D, G, E, X and R have the meaning given in the description. The compounds prepared according to the invention can be used as active ingredients in medicaments for the treatment of hyperlipoproteinemia, lipoproteinemia or atherosclerosis. Formula (I) {2-pyridones; Pyrid-2-thiones production; pharmaceuticals; hyperlipoproteinemia; lipoproteinaemia; Arteriosclerosis}

Description

¹¹

CH = CH-CH-CHo-C-CHp-COOR ^1u

I ^{Δ Δ} (viii)

OH E

in which

A, B, D, E and G are as defined above,

R ^{10 is} alkyl,

reduced,

in the case of the preparation of the acids, saponifying the esters, in the case of the preparation of the lactones cyclizing the carboxylic acids, in the case of preparation of the salts, saponifying either the esters or the lactones, in the case of the preparation of the ethylene compounds (X = -CH ₂ -CH ₂ -) the ethene compounds (X = -CH = CH-) are hydrogenated by customary methods, and optionally isomers are separated.

Field of application of the invention

The invention relates to processes for the preparation of novel substituted 2-pyridones and pyrid-2-thiones which are used in medicaments.

Characteristic of the known state of the art

It is known that lactone derivatives isolated from fungal cultures are inhibitors of S-hydroxy-S-methyl-glutarly-coenzyme A reductase (HMG-CoA reductase) (Mevinolin, EP-A 22478, US 4231 938). In addition, certain indole derivatives or pyrazole derivatives are also inhibitors of HMG-CoA reductase (EP-A 1114027; US Pat. No. 4,613,610).

Object of the invention

By the method according to the invention new 2-pyridones and pyrid-2-thiones are provided which exert a superior inhibitory effect on the S-hydroxy-S-methylglutaryl-coenzyme A reductase.

Explanation of the essence of the invention

The present invention has for its object to provide processes for the preparation of new pharmaceutically active compounds.

According to the invention, new substituted 2-pyridones and pyrid-2-thiones of the general formula (I) have now been prepared,

in which

A - represents a 3- to 7-membered heterocyclic which may contain up to 4 heteroatoms from the series sulfur, oxygen or nitrogen and optionally up to 5 times the same or different by halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, straight-chain or branched Alky I , Alkylthio, alkylsulfonyl, alkoxy or alkoxycarbonyl each having up to 8 carbon atoms, by aryl, arylthio or arylsulfonyl having from 6 to 10 carbon atoms or by a group of the formula -NR ¹ R ² , wherein R ¹ and R ^{2 are the} same or are different and

Hydrogen, aryl or arylsulfonyl having 6 to 10 carbon atoms, straight-chain or branched alkyl or alkylsulfonyl having up to 8 carbon atoms, the last-mentioned radicals being optionally substituted by aryl having 6 to 10 carbon atoms,

a group of the formula -COR ^{3 is} in which

R ³ denotes straight-chain or branched alkyl or alkoxy having up to 8 carbon atoms or phenyl,

R ¹ and R ² together with the nitrogen atom form a 5- to 7-membered ring which may be substituted by straight-chain or branched alkyl having up to 8 carbon atoms,

- represents aryl of 6 to 10 carbon atoms, optionally substituted by identical or different substituents, by straight-chain or branched alkyl, alkylthio, alkylsulfonyl, alkoxy or alkoxycarbonyl of up to 10 carbon atoms, each of which is hydroxy, alkoxy of up to 6 carbon atoms, phenyl or by a group of formula NR ¹ R ² , or by aryl, aryloxy, arylthio or arylsulfonyl having 6 to 10 carbon atoms, or by halogen, nitro, cyano, Trifluormethy I, trifluoromethoxy, Trif Iu romet hy Ithio , Benzyloxy or a group of the formula -NR'R ² , in which

R ¹ and R ^{2 are as} defined above, B - is cycloalkyl of 3 to 8 carbon atoms,

- is straight-chain or branched alkyl having up to 12 carbon atoms, optionally substituted by halogen, cyano, azido, trifluoromethyl, trifluoromethoxy, Trifluormethy Ithio, trifluoromethylsulfonyl, alkoxy having up to 10 carbon atoms, aryl, aryloxy or arylthio having 6 to 10 carbon atoms or by a 5-to 7-membered heterocycle having up to 4 heteroatoms from the series sulfur, oxygen or nitrogen is substituted, this and the aryl radicals optionally up to 3 times the same or different by halogen, cyano, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, alkoxy, Alkylthio or alkylsulfonyl may be substituted with in each case up to 8 carbon atoms, or substituted by a group of the formula -NR ^ or-COR ³ , wherein

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

- is aryl of 6 to 10 carbon atoms, optionally substituted by the same or different substituents, by halogen, cyano, nitro, trifluoromethyl, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 8 carbon atoms or amino,

D and E are the same or different and have the abovementioned meaning of A and are identical or different, or

- stand for hydrogen, nitro or cyano,

- represent cycloalkyl having 3 to 8 carbon atoms,

- represent straight-chain or branched alkyl or alkenyl having in each case up to 12 carbon atoms or imino, which is optionally substituted by halogen, azido, 2,5-dioxo-tetrahydropyrry I, aryl having 6 to 10 carbon atoms, by a 5- to 7-membered heterocycle having up to 4 heteroatoms from the series nitrogen, oxygen or sulfur and the corresponding N-oxides or by a group of formula-NR ¹ R ² , -OR ⁴ , -COR ⁵ or -S (O) _n -R ^{6 are} substituted, wherein

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

R ⁴ -hydrogen or

straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by hydroxy, trialkylsilyl having up to 10 carbon atoms in the entire alkyl portion, halogen or aryl having 6 to 10 carbon atoms, which in turn by halogen, cyano, nitro, hydroxy, straight chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 8 carbon atoms or amino may be substituted, trialkylsilyl having up to 10 carbon atoms in the entire alkyl moiety, tetrahydropyranyl or 2,5-dioxo-tetrahydropyrryl,

Cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms, which in turn may be substituted by halogen, cyano, nitro or amino, or

a group of the formula -COR ⁷ means

wherein

R ⁷ denotes straight-chain or branched alkyl having up to 8 carbon atoms, aryl having 6 to 10 carbon atoms or the group -NR'R ² ,

R ⁵ -hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by hydroxy, phenyl, halogen or cyano, -aryl having 6 to 10 carbon atoms or a 5-membered heterocycle having up to 4 heteroatoms from the series Sulfur, nitrogen or oxygen, which in turn may be substituted by halogen, amino, hydroxy, nitro or cyano, or

a group of the formula -NR ¹ R ² or -OR ⁴ means

η-a number 0,1 or 2 means

R ^{6 is} straight-chain or branched alkyl having up to 10 carbon atoms, which may be substituted by halogen, hydroxy, phenyl or a group of the formula -NR ¹ R ² .

- aryl having 6 to 10 carbon atoms, which may be substituted by halogen, hydroxy, cyano, nitro or amino, or

a group of the FoTmCl-NR ¹ R ² , if η is the number 2, or

D and E are the same or different and are - for a group of the formula-NR ¹ R ⁴ -OR ⁴ OdCr-COR ⁵ , in which R ¹ , R ² , R ⁴ and R ^{5 have} the abovementioned meaning,

or D or E together with B form a 5- to 7-membered saturated or unsaturated ring optionally substituted by

straight chain or branched alkyl of up to 8 carbon atoms or phenyl, G - represents an oxygen or sulfur atom, X - represents a group of the formula -CH 2 -CH 2 - or -CH = CH-, and R - represents a group of the formula

R ⁸

I HO T

-CH-CHo-C-CFU-COOR ^ or> ^ 0,

Ii T.

OH OH

wherein R ^{8 is} hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms

R ^{9 is} hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which may be substituted by phenyl, or

- aryl having 6 to 10 carbon atoms or a cation, or

D - represents the group -X-R, wherein

X and R have the abovementioned meaning and found their salts.

If R ⁹ with the carboxy group forms an ester radical, this is preferably a physiologically compatible ester radical which is easily hydrolyzed in vivo to give a free carboxyl group and a corresponding physiologically compatible alcohol. These include, for example, alkyl esters (C ₁ to C ₆ ) and aralkyl esters (C ₇ to Сю), preferably (C ₁ -C ₄ ) alkyl esters and benzyl esters. In addition, the following ester radicals may be mentioned: methyl ester, ethyl ester, propyl ester, benzyl ester. If R ^{9 is} a cation, then a physiologically compatible metal or ammonium cation is preferably meant. Alkali or alkaline earth cations, such as, for example, sodium, potassium, magnesium or calcium cations, as well as aluminum or ammonium cations, and non-toxic substituted ammonium cations from amines, such as (C ₁ -C ₄ ) -dialkylamines, (C ₁ -C ₄ ) -Trialkylamine, procaine, dibenzylamine, Ν, Ν'-dibenzylethylenediamine, N-benzyl-ß-phenylethylamine, N-methylmorpholine or N-ethylmorpholine, 1-ephenamine, dihydroabietylamine, Ν, Ν'-bis-dihydroabietylethylenediamine, N-lower alkylpiperidine and other amines that can be used to form salts. Surprisingly, the substituted 2-pyridones and pyrid-2-thiones according to the invention exhibit a superior inhibitory effect on the HMG-CoA reductase β-hydroxy-S-methyl-glutaryl-coenzyme A reductase). In the context of the general formula (I), compounds of the general formula (Ia) and (Ib) ₍

A B

in which A, B, D, E, G, X and R have the abovementioned meaning, is preferred. Preference is given to compounds of the general formula (Ia) and (Ib) in which

A - is oxiranyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, indolyl, quinolyl, isoquinolyl, benzothiazolyl or benzimidazolyl, which are optionally identical or different up to 4 times by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, straight-chain or branched Alkyl, Alklythio, alkylsulfonyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, phenyl, phenylthio, phenylsulfonyl or substituted by a group of the formula-NR ¹ R ² , wherein R ¹ and R ^{2 are the} same or different and

Hydrogen, phenyl, phenylsulfonyl, straight-chain or branched alkyl or alkylsulphonyl having up to 6 carbon atoms, benzyl or benzylsulphonyl, or

a group of the formula COR ³ , in which R ³ denotes straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms or phenyl,

R ¹ and R ² together with the nitrogen atom form a 5- to 7-membered ring which may be substituted by straight-chain or branched alkyl having up to 6 carbon atoms,

is phenyl or naphthyl, which is optionally substituted identically or differently up to four times by straight-chain or branched alkyl, alkylthio, alkylsulfonyl, alkoxy or alkoxycarbonyl of up to 8 carbon atoms, which are in turn represented by hydroxy, alkoxy having up to 4 carbon atoms, phenyl or by a Group of the formula NR ¹ R ² can be substituted,

or is substituted by phenyl, phenyloxy, phenylthio, phenylsulfonyl, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, benzyloxy or by a group of the formula -NR ¹ R ² , B - represents cyclopropyl, cyclobutyl, cyclopentylo or cyclohexyl,

represents straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, cyano, azido, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxy having up to 8 carbon atoms or by phenyl, phenyloxy or phenylthio, Thienyl, furyl, pyridyl, pyrimidyl or quinolyl, which in turn may be identically or differently up to two times substituted by fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, straight or branched alkyl, alkoxy, alkylthio or alkylsulfonyl each having up to 6 carbon atoms, or is substituted by a group of formula NR ¹ R ² or COR ³ ,

- is phenyl, optionally up to twice the same or different, substituted by fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms or amino,

D and E are the same or different and the above-mentioned meaning of Ahabenund are the same or different, or

- stand for hydrogen, nitro or cyano,

- represent cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

- represent straight-chain or branched alkyl or alkenyl having in each case up to 10 carbon atoms or imino which is optionally substituted by fluorine, chlorine, bromine, azido, 2,5-dioxo-tetrahydropyrryl, phenyl, pyrimidyl, pyrryl, pyrrolidinyl, morpholino or morpholino-N-oxide is substituted by a group of formula NR ¹ R ^ -OR ⁴ , -COR ⁵ or -S (O) _n -R ⁶ wherein R ¹ and R ^{2 have} the meaning given above, R ⁴ - hydrogen or

represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxy, trialkylsilyl having up to 8 carbon atoms in the entire alkyl moiety, fluorine, chlorine, bromine or phenyl, which in turn is substituted by fluorine, chlorine, bromine, cyano, nitro, Hydroxy, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms or amino-substituted η,

Trialkylsilyl having up to 8 carbon atoms in the entire alkyl moiety, tetrahydropyranyl or 2,5-dioxo-tetrahydropyrryl,

- Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, which in turn may be substituted by fluorine, chlorine, bromine, cyano, nitro or amino, or

a group of the formula-COR ⁷ in which R ^{7 is} straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or a group of the formula -NR ¹ R ² , R ^{5 is} hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms en which is optionally substituted by hydroxy, phenyl, fluorine, chlorine, bromine or cyano,

- phenyl, naphthyl, pyrryl, pyrimidyl, pyridyl, pyrrolidinyl or morpholino, which in turn may be substituted by fluorine, chlorine, bromine, amino, hydroxy, nitro or cyano, or

- a group of the formula-NR ¹ R ² OdCr-OR ⁴ means, n- a number 0 or 2, R ⁶ - represents straight-chain or branched alkyl having up to 8 carbon atoms, by fluorine, chlorine, bromine, hydroxyl, phenyl or may be substituted by a group of formula NR ¹ R ² ,

- phenyl, which may be substituted by fluorine, chlorine, bromine, hydroxyl, cyano, nitro or amino, or

- a group of the formula -NR ¹ R ² , if η is the number 2, or

D and E are the same or different and

- represent a group of the formula NR'R ^ -OR ⁴ or -COR ⁵ , in which R ¹ , R ² , R ⁴ and R ^{5 have} the abovementioned meaning,

or D or E together with B form a 5- to 7-membered, saturated or unsaturated ring, optionally substituted by

straight chain or branched alkyl of up to 6 carbon atoms or phenyl, G - represents an oxygen or a sulfur atom, X - represents a group of the formula -CH ₂ -CH ₂ - or -CH = CH- and R - represents a group of the formula

> 8

R ⁸ \ ^ ⁴ X ^ ^C

stands,

-CH-CH ₇ -C-CHo-COOR ⁹ or

worm R ⁸ - hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms

R ^{9 is} hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or benzyl, or

- phenyl or a cation means, or

D - represents the group of the formula X-R in which

X and R have the abovementioned meaning and their salts.

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

A - represents oxiranyl, pyridyl, pyrimidyl, quinolyl or isoquinolyl which is optionally identical or different by fluorine, chlorine, trifluoromethyl, straight-chain or branched alkyl, alkylthio, alkylsulfonyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, phenyl, Phenylthio, phenylsulfonyl or substituted by a group of formula NR ¹ R ² ,

wherein R ¹ and R ^{2 are the} same or different and

Hydrogen, phenyl, phenylsulfonyl, straight-chain or branched alkyl or alkylsulfonyl having up to 4 carbon atoms, benzyl or benzylsulfonyl,

A group of the formula -COR ³ , in which R ³ denotes straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms or phenyl,

R ¹ and R ² preferably form, alone with the nitrogen atom, a 5- to 7-membered ring which may be substituted by straight-chain or branched alkyl having up to 4 carbon atoms,

is phenyl, which is optionally substituted identically or differently up to 3 times by straight-chain or branched alkyl, alkylthio, alkylsulfonyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, which are in turn denoted by hydroxy, methoxy, ethoxy, propoxy, phenyl or by a Group of the form el-N R ¹ R ² may be substituted, or by phenyl, phenyloxy, fluorine, chlorine, nitro, cyano, trifluoromethyl, benzyl oxy or a group of the formula -NR ¹ R ^{2 is} substituted, wherein R ¹ and R ^{2 have} the meaning given above,

represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

is straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by fluorine, chlorine, cyano, azido, alkoxy having up to 6 carbon atoms, phenyl or phenoxy, which in turn by fluorine, chlorine, cyano, straight-chain or branched alkyl or Alkoxy having up to 4 carbon atoms or substituted by a group of the formula -NR ¹ R ² OdCr-COR ³ ,

- is phenyl which is substituted by fluorine, chlorine, nitro, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms or amino,

D and E are the same or different and have the abovementioned meaning of A and are identical or different, or

- stand for hydrogen, nitro or cyano,

- represent cyclopropyl, cyclopentyl or cyclohexyl,

- represent straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms or imino, which is optionally substituted by fluorine, chlorine, azido, 2,5-dioxo-tetrahydropyrryl, phenyl, pyrrolidinyl, morpholino or morpholino-N-oxide, or are substituted by a group of formula NR ¹ R ² , -OR ⁴ , -COR ⁵ or -S (O) _n -R ⁶ , wherein R ¹ and R ^{2 have} the meaning given above, R ⁴ - hydrogen or

G X R

straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxy, dimethyl-tert-butylsilyl, fluorine, chlorine or by phenyl, which in turn may be substituted by fluorine, chlorine, hydroxyl or amino,

Trialkylsilyl having up to 6 carbon atoms in the entire alkyl moiety, tetrahydropyranyl or 2,5-dioxo-tetrahydropyrryl,

- Cyclopropyl, cyclopentyl, cyclohexyl or phenyl, or

- a group of the formula-COR ⁷ means, in which

R ⁷ - straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or a group of the formula el -NR ¹ R ²

means

R ⁵ - is hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, optionally

is substituted by hydroxy, phenyl, fluorine or chlorine,

- phenyl, pyrryl, pyrrolidinyl or morpholino, or

a group of the formula-NR ¹ R ² or -OR ⁴ means that η is a number 0 or ² ,

R ^{6 represents} straight-chain or branched alkyl having up to 6 carbon atoms, which may be substituted by fluorine, chlorine, hydroxyl, phenyl or by a group of the formula -NR ¹ R ² ,

Phenyl, which may be substituted by fluorine, chlorine, hydroxyl, cyano, nitro or amino,

- a group of the formula -NR ¹ R ² , if η is the number 2, or

and E are the same or different and

- stand for a group of formula-NR ¹ R ² , -OR ⁴ or-COR ⁵ , wherein R ¹ , R ² , R ⁴ and R ^{5 have} the meaning given above, or

or E together form with B a 5- to 7-membered, saturated or unsaturated ring optionally substituted by methyl, ethyl, propyl, isopropyl, butyl, tert. Butyl or phenyl is substituted,

- represents an oxygen or sulfur atom,

- for a group-CH = CH- and

- for a group of the formula

-CH-CH ₂ -C-CH ₂ -COOR ⁹

or

OH

OH

stands ,

R ^{8 is} hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert. Butyl means and

R ⁹ - hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. Butyl or benzyl, or - means a sodium, potassium, calcium, magnesium or ammonium ion or

D - represents a group of the formula X-R, wherein

X and R have the abovementioned meaning and their salts.

The substituted 2-pyridones and pyrid-2-thiones of the general formula (I) according to the invention have several asymmetric carbon atoms and can therefore exist in different stereochemical forms. Both the individual isomers as

also their mixtures are the subject of the invention.

Depending on the meaning of the group X or of the radical R, different stereoisomers result, which are described in more detail below

should be explained:

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:

(II) E-form

(IH) Z-shape

(A, B, D, E, G and R are as defined above).

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

b) If the rest of R is a group of the formula

OH

OH

Thus, the compounds of general formula (I) have at least two asymmetric carbon atoms, namely the two carbon atoms to which the hydroxy groups are attached. Depending on the relative position of these hydroxy groups to one another, the compounds of the invention in the erythro-Konfigu ration (IV) oderinderthreo configuration (V) can be present.

I is CH-CH ₂ -C-CH ₂ -COOR

^{0H 0H}

Erythro-form (IV)

¹ CH-CH ₂ -C-CH ₂ -COOR

OH OH

Threo form (V)

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

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

c) If the rest of R is a group of the formula

thus, the substituted 2-pyridones and pyrid-2-thiones have at least two asymmetric carbon atoms, namely the carbon atom to which the hydroxy group is bonded and the carbon atom on which the radical of the formula

B A

is bound. Depending on the position of the hydroxy group to the free valence on the lactone ring, the substituted 2-pyridones and pyrid-2-thiones may be present as cis-lactones (VI) or as trans-lactones (VII).

cis-lactone (VI)

trans-lactone (VII)

In turn, both the cis-lactone and the trans-lactone have two isomers, namely the 4R, 6R isomers or the 4S, 6S isomers (cis-lactone) and the 4R, 6S isomers or 4S, 6R -lsomere (trans-lactone). Preferred isomers are the trans-lactones. Particularly preferred here is the 4R, 6S isomer (trans) and the 4R, 6S-4S, 6R racemate. For example, the following isomeric forms of the substituted 2-pyridones and pyrid-2-thiones may be mentioned:

он он

CH-CH ^ -CR ⁸ -CH ₇ -COOR ⁹

он

CH-CH ₂ -CR ⁸ -CH ₂ -COOR ⁹

ОН ОН

CH-CH, -CR ⁸ -CHO-COOR ⁹

ОН CH-CH ₂ -CR ⁸ -CH ₂ -COOR ⁹

он

CH-CH ₂ -CR ⁸ -CH ₂ -COOR ⁹

ОН

CH-CH ₂ -CR ⁸ -CH ₂ -COOR ⁹

ОН

CH-CH ₂ -CR ⁸ -CH ₂ -COOR ⁹

ОН

CH-CH ₂ -CR ⁸ -CH ₂ -COOR ⁹

In addition, a process for the preparation of the substituted 2-pyridones and pyrid-2-thiones of the general formula (I) B A

in which

A, B, D, E, G, X and R have the abovementioned meaning, which is characterized in that ketones of the general formula (VIII)

CH = CH-CH-CH ₂ -C -CH ₂ -COOr

10

(VIII)

он

in which

A, B, D, E and G are as defined above,

R ^{10 is} alkyl,

reduced,

in the case of the preparation of the acids, saponifying the esters, in the case of the preparation of the lactones cyclizing the carboxylic acids, in the case of preparing the salts, saponifying either the esters or the lactones, in the case of preparation of the ethylene compounds (X = -CH ₂ -CH ₂ - ) the ethene compounds (X = -CH = CH-) are hydrogenated by customary methods,

and optionally isomers.

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

CH ₂ COOCH ₃

он

reduction

ОН

CH ₂ COOCH ₃

он

COO ⁰ Na ⁰

 ОН

Сус1і S ierung |

ОН

ОН

COOH

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 boronanate, potassium borohydride, zinc borohydride, lithium trialkylborohydrides, sodium trialkylhydridoboranates, 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 xyxlol. It is also possible to use mixtures of said solvents.

The reduction of the ketone group to the hydroxy group is particularly preferably carried out under conditions in which the other functional groups, such as, for example, 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 of -80 ⁰ C to +30 ⁰ C, preferably from - 78 ° C to 0 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 m of oil, preferably from 1 to 1.5 mol, based on the tolter 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.

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

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

OH

R ^c

OH

(Ic)

in which

A, B, D, E, G and R ⁸ are as defined above.

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

X-CH-CHo-C-CHO-COOR

I i

10

OH

OH

(Id)

in which

A, B, D, E, G and R ⁸ are as defined above,

R ^{10 is} -alkyl.

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

R ⁸

X-CH-CHo-C-CHO-COO "

I i

OH OH

(Ie)

in which,

A, B, D, E, G and R ⁸ are as defined above,

M ^{n + is} a cation, where η indicates the valency.

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

BALI (If)

in which

A, B, D, E, G and R ⁸ are as defined above.

For the preparation of the carboxylic acids of the general formula (Ic) according to the invention, the carboxylic acid esters of the general formula (Id) or the lactones of the general formula (If) are generally saponified by customary methods.

The saponification is generally carried out by treating the esters or lactones in inert solvents with customary bases, which generally initially the salts of the general formula (I e) arise, which then in a second step by treatment with acid in the free acids of the general formula (Ic) can be converted.

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

Suitable solvents for the saponification are water or the usual organic solvents for saponification. These include, preferably, alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or 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 said solvents.

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

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

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

In carrying out the reaction, in the first step, the salts of the compounds (I e) according to the invention are formed as intermediates which can be isolated. The acids (Ic) according to the invention are obtained by treating the salts (Ie) with customary inorganic acids. These preferably include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. In the production of the carboxylic acids (Ic), it has proven to be advantageous in this case to acidify the basic reaction mixture of the saponification in a second step without isolating the salts. The acids can then be isolated in the usual way.

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

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

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

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

In addition, the cyclization is also carried out in inert organic solvents, with the aid of cyclizing or dehydrating agents. As dehydrating agents preferably carbodiimides are used here. Preferred carbodiimides are N, N'-dicyclohexylcarbodiimide paratoluenesulfonate, N-cyclohexyl-N '- [2- (N "-methylmorpholinium) ethyl] carbodiimide or N- (3-dimethylamino-inopropyl) -N'-ethylcarbodiimide-Hyd smelled I orid used.

Suitable solvents here are the customary organic solvents. These include preferably ethers such as diethyl ether, tetrahydrofuran or dioxane, or chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride, or hydrocarbons such as benzene, toluene, xylene or petroleum fractions. Particularly preferred are chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride, or hydrocarbons such as benzene, toluene, xylene, or petroleum fractions. Very 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 of 0 ⁰ C to +80 ⁰ C, preferably from + 1O ⁰ C to +50 ⁰ C.

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

The separation of the isomers into the stereoisomerically uniform constituents is generally carried out by customary methods, as described, for example, by E * L. ENeI, Stereochemistry of Carbon Compounds, McGraw Hill, 1962. The separation of the isomers at the stage of the racemic esters is preferred here. Particularly preferred is the racemic mixture dertrans-lactones (VII) by treating with either D - (+) - or L - (-) - a-methylbenzylamine by conventional methods in the diastereomeric Dihydroxyamide (Ig)

ОН

CH-

CH ₂ -CONH-CH-C ₆ H ₅

(Ig)

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

OH OH

COOCH ₃

erythro racemate

CH-

+ H ₂ N-CH-C ₆ H ₅

он

CH ₂ -CO-NH-CH-C ₆ H ₅

Di astereomerengemisch

1) diastereorraine separation

2) verse

3) lactonization

CH-

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.

BA I!

(VIII)

OH

in which A, B, D, E, G and R ^{10 have} the abovementioned meaning, which is characterized in that aldehydes of the general formula (IX) _t

in which A, B, D, E and G have the abovementioned meaning, in inert solvents with acetoacetic ester of the general formula (X).

H ₃ CC-CH ₂ -COOR ¹⁰

in which R ^{10 has} the meaning given above, in the presence of bases.

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

H ₃ CC-CH ₂ -COOCH ₃

base

CH ₂ COOCH ₃

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

Possibly additives of metal halides such. As magnesium chloride, zinc chloride or zinc bromide advantageous. Particularly preferred is the addition of zinc halides.

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 petroleum 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 ° C, preferably from -20 ⁰ C ⁰ C to room temperature is performed.

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, for. B. in a range of 0.5 to 5 bar.

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

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

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

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

The preparation of the aldehydes of the general formula (IX) used as starting materials will be explained below by way of example for the 2-pyridones of the type (I a).

COOR

11

Cl]

CH ₂ OH

(XI)

(XII)

CHO

[3]

A H

'CHO

(XIII)

(IX)

In this case, according to Scheme A, 2-pyridones of the formula (XI) in which R ^{11 is} an alkyl radical having up to 4 carbon atoms, in the first step [1] in inert solvents such as ethers, for example diethyl ether, tetrahydrofuran or dioxane, preferably tetrahydrofuran, -dihydroaluminate using metal hydrides as reducing agent, for example lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, diisobutylaluminum hydride or sodium bis (2-methoxyethoxy), in temperature ranges from -70 ⁰ C to + 100 ° C, preferably from -70 ⁰ C to room temperature, and reduced from room temperature to +70 ⁰ C depending on the reducing agent used to hydroxymethyl (XII). Preferably, the reduction is carried out with diisobutylaluminum hydride in tetrahydrofuran in a temperature range from -78 ^C C to room temperature. The hydroxymethyl compounds (XII) are oxidized in the second step [2] by conventional methods to the aldehydes (XIII). The oxidation can be carried out, for example, with pyridinium chlorochromate, if appropriate in the presence of aluminum oxide, in inert solvents such as chlorinated hydrocarbons, preferably methylene chloride, in a temperature range from 0 ^° C. to 60 ^° C., preferably at room temperature, or else with trifluoroacetic acid / dimethyl sulfoxide according to customary methods the Swern oxidation are carried out. The aldehydes (xIiL) are in the third step [3] using diethyl 2- (cyclohexylamino) -vinylphosphonate in the presence of sodium hydride in inert solvents such as ethers, for example diethyl ether, tetrahydrofuran or dioxane, preferably in tetrahydrofuran, in a temperature range of -20 ⁰ C to + 40 ⁰ C, preferably from -5 ° C to room temperature, converted to the aldehydes (IX).

The pyridones of the formula (XI) used here as starting materials are new. They are generally obtained according to Scheme B by oxidation of 3,4-dihydropyrid-2-ones (XIV). The oxidation of the dihydropyridones (XIV) to the pyridones (XI) in which R ¹ 'has the abovementioned meaning, for example, with chromium oxide or sodium nitrite in glacial acetic acid in a temperature range from -20 ⁰ C to +150 ⁰ C, with nitric acid in aqueous suspension or with cerium salts, such as ammonium cerium nitrate, in a solvent mixture of acetonitrile and water. Preferably, ammonium nitrate in the mixture converts acetonitrile and water.

COOR

11

D '

COOR ¹¹

(XIV)

(XI)

The 3,4-dihydropyrid-2-ones of the general formula (XIV) used here as starting materials are new.

They are generally obtained by reacting appropriately substituted .alpha.,. Beta.-unsaturated carboxylic acid esters of the general formula (XV) ## STR4 ## in which A, B, D and R ^{11 have} the abovementioned meaning, and correspondingly substituted .beta.-amino-a, ßunsaturated carboxylic acid esters of the general Formula (XVI).

The process can be carried out neat or in a high-boiling solvent such as ethylene glycol either basic with alkali metal alkoxides, such as sodium or potassium at room temperature to +200 ⁰ C or in glacial acetic acid at room temperature. The reaction with alkali metal alkoxides is preferably from ⁰ to +140 C.

The reaction can be explained by the following formula scheme:

) 11

OR

(XV)

(XVI)

(XIV)

The compounds of the general formula (I) in which A, B, D, E, X and R have the abovementioned meaning and G is sulfur can be prepared from the 2-pyridones of the general formula (XI) in which A denotes , B, D and E have the abovementioned meaning, if appropriate by methods known from the literature (AY Guttsait et al., Khim. Geterotsikl. Soedin 1987, 9, 1233-1237).

The pyridones (XI) prepared by oxidation as described above from the dihydropyridones (XIV) may be prepared by suitable reducing agents such as lithium aluminum hydride, diisobutylaluminum hydride or sodium bis (2-methoxyethoxy) dihydroaluminate in inert solvents such as, for example Tetrahydrofuran or toluene, are reduced to the pyridones (XVIII).

The pyridones (XVIII) can be converted to the pyridones (XIX) by known methods, for example by reaction with an alkyl or benzyl halide in the presence of a base such as sodium hydride or, for example, by reaction with a trialkylsilyl halide or an acid halide in the presence of a base such as Imidazole, pyridine or triethylamine. The hydroxy group of the pyridones (XVIII) can be converted by known methods into a leaving group, for. Example by reaction with Trifluormethansulfonsäureanhydrid, thionyl chloride or methanesulfonyl chloride in the presence of a base. The leaving group can then be replaced by known methods against nucleophiles.

A A

11

0OC

COOR ¹¹

COOR

COOR

(XVIII)

(XIX)

The radicals A, B, E, R ⁴ and R "of the formulas (XVII), (XVIII) and (XIX) have the abovementioned meaning.

By reaction of the pyridones (XVIII) or (XVII), whose radicals A, B and R ^{11 have} the abovementioned meaning and E is hydrogen, alkyl or benzyl halides in the presence of a base such as potassium carbonate, sodium hydride or an acid halide in the presence a base such as imidazole, pyridine or triethylamine, the N-alkyl or N-acyl derivatives can be prepared.

The compounds of the general formula (I) according to the invention have valuable pharmacological properties and can be used in medicaments. In particular, they are inhibitors of S-hydroxy-S-methyl-glutaryl-coenzyme A (HMG-CoA) reductase and, consequently, inhibitors of cholesterol biosynthesis. They can therefore be used for the treatment of hyperlipoproteinemia, lipoproteinemia or arteriosclerosis. The active compounds according to the invention also cause a reduction in the cholesterol content in the blood.

The enzyme activity determination was modified according to G.C. Ness et al., Archives of Biochemistry and Biophysics 197, 493-499

(1979). Male ricot rats (body weight 300-40g) were treated for 11 days with Altromin powder feed supplemented with 40g cholestyramine / kg diet. After decapitation the animals were taken from the liver and placed on ice. The livers were minced and ground in the Potter-Elvejem homogenizer 3 times in 3 volumes of 0.1M sucrose, 0.05M KCl,

0.04m ^ HyPhosphat, 0.03m ethylenediaminotraacetic acid, 0.002m dithiothreitol (SPE) buffer pH7.2, homogenized.

It was then centrifuged for 15 minutes at 15,000g and the sediment discarded. The supernatant was sedimented at 100,000 g for 75 minutes. The pellet is taken up in ¹ A volume of SPE buffer, homogenized again and then again centrifuged for 60 minutes at 100,000 g. The pellet is taken up with 5 times its volume SPE buffer, homogenized and frozen at -78 ° C and stored (= enzyme solution).

For testing, the test compounds (or mevinolin as reference substance) were dissolved in dimethylformamide with the addition of 5% by volume of 1 N NaOH and used in the enzyme assay with different concentrations of olefin. The test was started after 20 minutes of pre-incubation of the compounds with the enzyme at 37 ⁰ C. The assay was 0.380 ml and contained 4μΜοΙ glucose-6-phosphate, 1.1 mg bovine serum albumin, 2.1μΜοΙ dithiothreitol, 0.35μΜοΙ NADP, 1 unit glucose-6-phosphate dehydrogenase, 35μΜοΙ K _x H _y phosphate pH 7.2, 20μΙ enzyme preparation and 56nMol 3-hydroxy-3-methyl-glutaryl coenzyme A (glutaryl-3- ^& C) lOOOOOdpm.

After incubation for 60 minutes at 37 ° C, the mixture was centrifuged and 600μΙ of the supernatant applied to a 0.7 cm χ 4cm filled with a 5-chloride anion exchanger (100-200mesh) column. It was distilled with 2ml. Rinse water and pass plus wash water with 3 ml of Aquasol and count in the LKB scintillation counter. IC ₅₀ values were determined by order of percentage inhibition against the concentration of the compound as assayed by intrapolation. To determine the relative inhibitory potency, the IC ₅₀ value of the reference substance mevinolin was set as 1 and compared with the simultaneously determined IC ₅₀ value of the test compound.

Measurement of cholesterol biosynthesis after administration of HMG-CoA reductase inhibitors.

Male rats (about 180g) receive the test substance in 10ml / kg 0.75% tragant solution 16h after food withdrawal. The control group receives only the vehicle. At various times after substance application, the animals receive 20 μ Ci ' ⁴ C-acetate per animal intraperitoneally. At different times after the ¹⁴ C-Acetatinjektion the animals are killed, the livers taken and determined after extraction and subsequent radioactivity measurement of cholesterol synthesis.

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

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

Examples of adjuvants 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), carriers, e.g. Ground natural minerals (eg kaolins, clays, talc, chalk), ground synthetic minerals (eg highly disperse silicic acid, silicates), sugars (eg, cane, milk and dextrose), emulsifying agents (eg polyoxyethylene fatty acid Esters, polyoxyethylene fatty alcohol ethers, alkylsulfonates and arylsulfonates), dispersants (eg lignin-sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg

Magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application is carried out in a customary manner, preferably orally, parenterally, perlingually or intravenously. In the case of oral administration, of course, apart from the abovementioned excipients, tablets may 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 to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight to achieve effective results when given intravenously, for oral administration the dosage is about 0, 01 to 20 mg / kg, preferably 0.1 to 10 mg / kg of body weight.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on the body weight or the type of 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.

Embodiments Production Examples

example 1

3-Amino-4-methyl-pent-2-en-acid ethyl ester

БѢООС

To 500 g (3.16 mol) of ethyl isobutyrylacetate in 1500 ml of toluene p. A. 10.8 g of p-toluenesulfonic acid χ 4H ₂ O, the mixture was saturated with stirring at room temperature with ammonia gas and allowed to stand overnight. The mixture is then heated under reflux at the water separator and continuously introduced ammonia gas until the calculated amount of water is separated (after 8 hours of reflux, 47 ml of water). It is allowed to cool overnight, the precipitate is filtered off with suction and washed with toluene. The combined toluene phases are washed several times with water, dried with sodium sulfate, concentrated in vacuo and distilled under high vacuum.

Bp .: 82-85 ° C / 1 torr.

Yield: 315 g (63.4% of theory, approx. 90%),

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.13 (d, 6H); 1.25 (t, 3H); 2.32 (sept, 1H); 4.12 (q, 2H); 4.56 (s, 1H).

Example 2

1-carbomethoxy-2- (4-fluorophenyl) propenoate

229 ml (2 mol) of dimethyl malonate, 223 ml (2 mol) of 4-fluorobenzaldehyde, 40 ml of piperidine and 103 ml of glacial acetic acid are refluxed in 1.51 of cyclohexane over a water separator overnight. After cooling to room temperature, it is taken up in ethyl acetate, washed with water, dried with sodium sulfate and distilled.

Spd .: 135 ° C-140 ° C (1mm)

Yield: 342.9 g (72% of theory)

¹ H-NMR (CDCl ₃ ): 5 (ppm) = 3.85 (s, 6H); 7.0-7.5 (m, 4H); 7.7 (s, 1H).

Example 3

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

114.3 g (0.48 mol) of methyl 1-carbomethoxy-2- (4-fluorophenyl) -propenoate, 75.4 g (0.48 mol) of ethyl S-amino-1-methyl-p-p-acid, 1 g of sodium methylate and 5 ml of ethanol were stirred for 60 h at 140 ° C bath temperature and recrystallized from ethanol

 Mp .: 124 ° C

Yield: 115.4 g (66% of theory)

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.1-1.3 (m, 9H); 3.55 (d, 1H); 3.75 (s, 3H); 4.1 (q, 2H); 4.2 (sept., 1H); 4.65 (d, 1H); 6.9-7.2

(m, 4H); 7.7 (s, 1H)

Example 4

4- (4-Fluorophenyl) -6-isopropyl- (1H) -pyrid-2-one-3,5-dicarboxylic acid 3-methyl-5-ethyl ester

H ₃ CO

10.8 g (30 mmol) of the compound from Example 3 and 3.9 g (39 mmol) of chromium trioxide were refluxed in 100 ml of glacial acetic acid, after 2 h another 2 g (20 mmol) of chromium trioxide were added and the mixture was refluxed overnight. The solvent

was distilled off, the residue was dissolved in dilute hydrochloric acid, washed with ether, the combined ether phases washed with water, aqueous sodium bicarbonate solution and water, dried with sodium sulfate and chromatographed on silica gel 70-230mesh with ethyl acetate / petroleum ether 1: 1.

Yield: 5.5 g (51% of theory)

¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.9 (tr, 3 H); 1.4 (d, 6H); 3.15 (sept., 1H); 3.6 (s, 3H); 3.9 (q, 2H); 7.0-7.3 (m, 4H); 12.2 (s, 1H).

Example 5

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

H ₃ CO

11.3 g (31 mmol) of the compound from Example 4,1,2 g (50 mmol) of sodium hydride and 4 ml (62 mmol) ethyl iodine id M are heated in 50 ml dimethylformamide for 2 h at 80 ⁰ C, the mixture is stirred at room temperature poured into 500 ml of water and extracted three times with 150 ml of ether. The combined organic phases are washed with water and dried with sodium sulfate.

After distilling off the solvent in vacuo, 11.1 g.

Crude yield: 95.2% of theory

¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.95 (tr, 3 H); 1.3 (d, 6H); 3.15 (sept., 1H); 3.6 (s, 3H); 4.0 (q, 2H); 4.05 (s, 3H); 7.0-7.3 (m, 4H).

Example 6

4- (4-fluorophenyl) -3-hydroxymethyl-6-isopropyl-1-methyl-pyrid-2-on-5-carboxylate

1.48 g (3.95 mmol) of the compound from Example 5 are dissolved in 30 ml of toluene, cooled to -78 ° C. under nitrogen, and at this temperature 6.6 ml (10 mmol) of a 1.5 molar solution of diisobutylaluminum hydride in toluene are added dropwise , Remove the cooling bath and stir for 2 h at room temperature. After hydrolysis with 20% aqueous potassium sodium tartrate solution, the organic phase is separated, the aqueous phase washed three times with toluene, the combined organic phases washed with saturated sodium chloride solution and dried with sodium sulfate.

After distilling off the solvent in vacuo, 1.52 g of oil, which is chromatographed over silica gel (ethyl acetate / petroleum ether 1: 5).

Yield: 520 mg (38% of theory) and 310 mg (21%) of starting material.

¹ H NMR (CDCl ₃ ) ^ (PPm) = 0.95 (tr, 3H); 1,3 (d, 6H); 2,3 (tr, 1H); 3.1 (sept. 1H); 3.95 (q, 2H); 4.05 (s, 3H); 4.4 (d, 2H);

7.0-7.3 (m, 4H).

Example 7

Ethyl 4- (4-fluorophenyl) -6-isopropyl-3-methoxymethyl-1-methyl-pyrid-2-one-5-carboxylate F

520 mg (1.5 mmol) of the compound from Example 6 are stirred with 42 mg (1.75 mmol) of sodium hydride and 0.3 ml (4.5 mmol) of methyl iodide in 4 ml of dimethylformamide for 4 h at room temperature. The reaction mixture is poured onto ice water, washed three times with ether, the combined ether phases washed with water and saturated sodium chloride solution and dried with sodium sulfate. After removal of the solvent on a rotary evaporator gives 520 mg of oil. Yield: 100% of theory

¹ H NMR (CDCl ₃ ) ^ (PPm) = 0.95 (tr, 3H); 1,3 (d, 6H); 3.1 (sept., 1H); 3.25 (s, 3H); 3.95 (q, 2H); 4.05 (s, 3H); 4.1 (s, 2H);

7.0-7.3 (m, 4H).

Example 8

4- (4-fluorophenyl) -5-hydroxymethyl-6-isopropyl-3-methoxymethyl-1-methyl-pyrid-2-one

1.19 g (3.5 mmol) of the compound from Example 7 were reduced analogously to Example 6 with 5.2 ml (7.7 mmol) of a 1.5 molar solution of diisobutylaluminum hydride in toluene. Chromatography on silica gel (ethyl acetate / petroleum ether 1: 5) gives 730 mg of solid.

Yield: 66% of theory

¹ H-NMR (CDCI ₃₎ ^ (ppm) = 1.2 (tr, 1 H); 1.3 (d, 6H); 3.2 (s, 3H); 3.4 (sept., 1H); 4.05 (2 s, 5 H); 4.35 (d, 2H); 7.1-7.3 (m, 4H).

Example 9

4- (4-fluorophenyl) -6-isopropyl-3-methoxymethyl-1-methyl-pyrid-2-on-5-carbaldehyde

To a solution of 0.7 g (2.2 mmol) of the compound from Example 8 in 120 ml of methylene chloride is added 568 mg (2.64 mmol) of pyridinium chlorochromate, stirred overnight at room temperature, filtered off with suction through kieselguhr, washed with 200 ml of methylene chloride, filtered through silica gel After washing with 200 ml of methylene chloride, dried with sodium sulfate and after removal of the solvent on a rotary evaporator 670 mg of oil.

Yield: 96% of theory

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.3 (d, 6H); 3.25 (s, 3H); 4.0 (sec -1 H); 4.08 (s, 2H); 4.10 (s, 3H); 7.1-7.3 (m, 4H); 9.7 (s, 1 H).

Example 10

(E) -3- [4- (4-fluorophenyl) -6-isopropyl-3-methoxymethyl-i-methyl-pyrid-2-on-5-yl] -prop-2-enal

Under nitrogen is added dropwise to a suspension of 59 mg (2.5 mmol) of sodium hydride in 6 ml of dry tetrahydrofuran at -5 ° C 804 mg (3.1 mmol) of diethyl ^ -fcyclohexylaminoJ-vinylphosphonate dissolved in 6 ml of dry tetrahydrofuran. After 30 min, 0.65 g (2.05 mmol) of the compound from Example 9 in 15 ml of dry tetrahydrofuran are added dropwise at the same temperature and heated to reflux for 30 min. 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 sodium sulfate. After concentration in vacuo, the residue is taken up in 5 ml of toluene, treated with a solution of 0.9 g (7 mm oil) of oxalic acid dihydrate in 12 ml of water and heated to reflux for 90 min. After cooling to room temperature, the phases are separated, the organic phase washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in methylene chloride and filtered through silica gel

 Yield: 560 mg solid (79.6% of theory)

¹ H NMR (CDCl ₃ ): δ (ppm) = 1.3 (d, 6H); 3.25 (s, 3H); 3.35 (sept, 1H); 4.05 (s, 5H); 5.9 (dd, 1H); 7.05-7.3 (m, 5H); 9.35

(D, 1H).

Example 11

Methyl (E) -7- [4- (4-fluorophenyl) -6-isopropyl-3-methoxy-methyl-1-methyl-pyrid-2-on-5-yl] -5-hydroxy-3-oxo- hept-6-enoate

Under nitrogen is added dropwise to a suspension of 80 mg (3.4 mmol) of sodium hydride in 3 ml of dry tetrahydrofuran at -5 ⁰ C 0.35 ml (3.3 mmol) of methyl acetoacetate. After 15 minutes, 2.3 ml (3.3 mmol) of 15% strength butyllithium in η-hexane and 3.3 ml (3.3 mmol) of a 1 molar solution of zinc chloride in ether are added dropwise at the same temperature and stirred for 15 min. Subsequently, 530 mg (1.5 mmol) of the compound from Example 10 dissolved in 8 ml of dry tetrahydrofuran are added dropwise and stirred at -5 ° C for 30 min. The reaction solution is carefully diluted with 100 ml of saturated aqueous ammonium chloride solution 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 sodium sulfate and concentrated in vacuo

 Crude yield: 760mg (100% of theory)

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.25 (m, 6H); 2.45 (m, 2H), 3.2 (m, 4H); 3.4 (s, 2H), 3.75 (s, 3H); 4.0 (s, 3H); 4.05 (s, 2H);

4.45 (m, 1H); 5.2 (dd, 1H); 6.3 (d, 1H); 7.0-7.2 (m, 4H).

Example 12

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

To a solution of 730 mg (1.6 mmol) of the compound from Example 11 in 13 ml of dry tetrahydrofuran is added at room temperature 1.9 ml (1.9 mmol) of 1 MTriethylboran solution in tetrahydrofuran, passing air through the solution for 5 min and cooled to -30 ⁰ C internal temperature. There are added 72 mg (1.9 mmol) of sodium borohydride and slowly 1.3 ml of methanol, stirred for 30 min at -30 ⁰ C and then treated with a mixture of 5ml of 30% hydrogen peroxide and 11 ml of water. The temperature is allowed to rise to 0 ° C and stirred for 30 minutes after. The mixture is extracted three times with 70 ml of ethyl acetate, the combined organic phases are washed once each with 10% potassium iodide solution, 10% sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on a column (100 g silica gel 230-400 mesh, ethyl acetate / petroleum ether 1: 2)

 Yield: 350 mg of oil (47.6% of theory)

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.25 (m, 6H); 1.45 (m, 2H); 2.4 (m, 2H); 3.2 (s, 3H); 3.28 (sept., 1H); 3.75 (s, 3H); 4.0 (s, 3H);

4.05 (s, 2H); 4.1 (m, 1H); 4.25 (m, 1H); 5.2 (dd, 1H); 6.25 (d, 1H); 7.0-7.2 (m, 4H).

Example 13

4- (4-Fluorophenyl) -3-hydroxymethyl-6-isopropyl- (1H) -pyrid-2-one-5-carboxylic acid ethyl ester

7.02g (19.45mmol) of the compound of Example 4 were refluxed with 1.17g (29.2mmol) of lithium aluminum hydride in 100ml of tetrahydrofuran for 2 hours, hydrolyzed with 20% aqueous potassium-sodium tartrate solution under ice-cooling and washed with ether. The combined ether phases are washed with water, dried with sodium sulfate and, after removal of the solvent, purified by chromatography on silica gel (methylene chloride / methanol 20: 1). Yield: 1.09 g (16.8% of theory)

¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.9 (tr, 3H); 1.4 (d, 6H); 3.15 (sept., 1H); 3.9 (q, 2H); 4.05 (tr, 1H); 4.4 (d, 2H); 7.05-7.3 (m, 4H);

12.4 (s, 1H).

Example 14

1,6-diisopropyl-4- (4-fluorophenyl) -3-hydroxymethyl-pyrid-2-on-5-carboxylate

1.6 g (4.8 mmol) of the compound from Example 13.1.7 ml (17.3 mmol) of 2-iodopropane and 2.3 g of potassium carbonate are refluxed for 5 h in 30 ml of acetone, after filtration and removal of the solvent the residue taken up in methylene chloride, washed with water, dried with sodium sulfate and chromatographed on silica gel (methylene chloride / methanol 40: 1). Yield: 1.14 g (63% of theory)

¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.95 (tr, 3H); 1,3 (d, 6H); 1.45 (d, 6H); 2.5 (tr, 1H); 3.1 (sept., 1H); 3.95 (q, 4H); 4.35 (d, 2H);

5.5 (sept., 1H); 7.0-7.3 (m, 4H).

Example 15

1,6-diisopropyl-4- (4-fluorophenyl) -3-methoxymethyl-pyrid-2-on-5-carboxylate

H ₃ CO

Starting from 1.1 g (2.93 mmol) of the compound from Example 14.1.1 ml (17.6 mmol) of methyl iodide and 155 mg (6.45 mmol) of sodium hydride, 1.04 g of oil are obtained analogously to Example 7. Rohausbeut: 91% of theory

¹ H NMR (CDCl ₃ ) ^ (PPm) = 0.95 (tr, 3H); 1.25 (d, 6H); 1.4 (d, 6H); 3.1 (sept., 1H); 3.25 (s, 3H); 3.95 (q, 2H); 4.1 (s, 2H);

5.45 (sept., 1H); 7.0-7.4 (m, 4H).

Example 16

1,6-diisopropyl-4- (4-fluorophenyl) -5-hydroxymethyl-3-methoxymethyl-pyrid-2-one

Starting from 1.02 g (2.57 mmol) of the compound from Example 15, 680 mg of the title compound are obtained analogously to Example 8. Yield: 76.2% of theory

¹ H NMR (CDCl ₃ ) Io (PPm) = 1.15 (tr, 1 H); 1,3 (d, 6H); 1.4 (d, 6H); 3.2 (s, 3H); 3.4 (sept., 1H); 4.05 (s, 2H); 4.35 (d, 2H);

5.4 (sept., 1H); 7.05-7.3 (m, 4H).

Example 17

1,6-diisopropyl-4- (4-fluorophenyl) -3-methoxymethyl-pyrid-2-on-3-carbaldehyde

Starting from 680 mg (1.96 mmol) of the compound of Example 16, 620 mg of the title compound are obtained analogously to Example 9. Yield; 91.6% of the theory

¹ H NMR (CDCl ₃ ) Io (PPm) = 1.25 (d, 6H); 1.45 (d, 6H); 3.25 (s, 3H); 4.0 (sept, 1H); 4.05 (s, 2H); 5.5 (sept., 1H);

7.1-7.3 (m, 4H), 9.65 (s, 1H).

Example 18

(E) -3- [1,6-diisopropyl-4- (4-fluorophenyl) -3-methoxymethyl-pyrid-2-on-5-yl] -prop-2-enal

Starting from 620 mg (1.8 mmol) of the compound of Example 17, 550 mg of the titer compound are obtained analogously to Example 10. Yield: 82.5% of theory

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.25 (d, 6H), 1.40 (d, 6H); 3.2 (s, 3H); 3.30 (m, 1H); 4.05 (s, 2H); 5.45 (m, 1H); 5.85 (dd, 1H);

7.0-7.2 (m, 5H).

Example 19

Methyl (E) -7- [1,6-diisopropyl-4- (4-fluorophenyl) -3-methoxymethyl-pyrid-2-on-5-yl] -5-hydroxy-3-oxo-hept-6- enoate

OCH

Starting from 520 mg (1.4 mmol) of the compound from Example 18, 1.11 g of crude product are obtained analogously to Example 11. Crude yield: 100% of theory

¹ H NMR (CDCl ₃ ) IO (PPm) = 1.15-1.45 (m, 12H); 2.4 (m, 2H); 3.25 (m, 4H); 3.45 (s, 2H); 3.75 (s, 3H); 4.05 (s, 2H);

4.5 (m, 1H); 5.2 (dd, 1H); 5.4 (m, 1H); 6.3 (d, 1H); 7.0-7.2 (m, 4H).

Example 20

Methyl erythro- (E) -7- [1,6-diisopropyl-4- (4-fluorophenyl) -3-methoxymethyl-pyrid-2-on-5-yl] -3,5-dihydroxy-hept-6- enoate

OH OH O

H ₃ CO

OCH ^

Starting from 1.05 g (2.16 mmol) of the compound of Example 19, 240 mg of oil are obtained analogously to Example 12. Yield: 22.7% of theory

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.1-1.5 (m, 14H); 2.40 (m, 2H); 3.25 (m, 4H); 3.75 (s, 3H); 4.05 (m, 3H); 4.30 (m, 1H);

5.15 (dd, 1H); 5.40 (m, 1H, 6.25 (d, 1H); 6.95-7.2 (m, 4H).

Example 21

3,5-dihydroxymethyl-4- (4-fluorophenyl) -6-isopropyl-1-methyl-pyrid-2-one

Starting from 3.0 g (8 mmol) of the compound of Example 5 and 26.6 ml (40 mmol) of a 1.5 m solution of diisobutylaluminum hydride in toluene, the title compound is obtained in the same way as in Example 6. Crude yield: 100% of theory

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.20 (tr, 1 H); 1.35 (d, 6H); 2.40 (tr, 1H); 3.45 (m, 1H); 4.05 (s, 3H); 4.30 (d, 2H); 4.35 (d, 1H);

7.1-7.3 (m, 4H).

Example 22

4- (4-fluorophenyl) -6-isopropyl-1-methyl-pyrid-2-one-3,5-dicarbaldehyde

CH ₃

Starting from 2.60 g (8.5 mmol) of the compound from Example 21, 2.13 g of the title compound are obtained analogously to Example 9.

Yield: 83.3% of theory

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.35 (d, 6H); 4.0 (m, 1H); 4.2 (s, 3H); 7.15-7.3 (m, 4H); 9.65 (s, 1H); 9.95 (s, 1H).

Example 23

(E, E) -3,3- [4- (4-fluorophenyl) -6-isopropyl-1-methyl-pyrid-2-one-3,5-diyl] -diprop-2-enal

Starting from 2.13 g (7.1 mmol) of the compound of Example 22, 2.70 g of crude product are obtained analogously to Example 10.

Yield: 100% of theory

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.30 (d, 6H); 3.30 (m, 1H); 4.15 (s, 3H); 5.95 (dd, 1H); 7.0-7.25 (m, 5H); 9.3-9.4 (m, 2H).

Example 24

3,5-di- [methyl (E) -hydroxy-3-oxo-hept-6-enoate-7-yl] -4- (4-fluorophenyl) -6-isopropyl-1-methyl-pyrid-2- on

OCH

CH-

Starting from 0.31 g (0.88 mmol) of the compound of Example 23, 1.04 g of crude product are obtained analogously to Example 11. Yield: 100% of theory

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.1-1.4 (m, 6H); 2.3-2.7 (m, 4H); 3.2 (m, 1H); 3.45 (m, 4H); 3.75 (m, 6H); 4.05 (s, 3H);

4.5 (m, 2H); 5.2 (m, 2H); 6.2 (m, 2H) 6.8-7.2 (m, 4H).

Example 25

3,5-di- [methyl-erythro- (E) -3,5-dihydroxy-hept-6-enoate-7-yl] -4- (4-fluorophenyl) -6-isopropyl-1-methyl-pyrid- 2-one

H ₃ CO

OCH

Analogously to Example 12, starting from 1.04 g (0.88 mmol) of the compound of Example 24 after chromatography on silica gel (ethyl acetate / petroleum ether 1: 1) 74 mg

 Yield: 14.3% of theory

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.25 (m, 6H); 1.6 (m, 4H); 2.45 (m, 4H); 3.30 (m, 1H); 3.75 (2s, 6H); 4.05 (s, 3H); 4.15 (m, 2H);

4.30 (m, 2H); 5.25 (dd, 2H); 6.2 (m, 2H); 6.95-7.15 (m, 4H).

Example 26

3-benzyloxymethyl-4- (4-fluorophenyl) -6-isopropyl-1-methyl-pyrid-2-one-5-carboxylate

OEt

Starting from 630 mg (1.9 mmol) of the compound from Example 6 and 720 mg of benzyl bromide, the title compound is obtained analogously to Example 7

 Yield: - 92.2% of theory

¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.9 (t, 3H); 1,3 (d, 6H); 3.05 (sept., 1H); 3.95 (q, 2H); 4.03 (s, 3H); 4.2 (s, 2H); 4.4 (s, 2H);

7.0-7.4 (m, 9H).

Example 27

3-benzyloxymethyl-4- (4-fluorophenyl) -5-hydroxymethyl-6-isopropyl-1-methyl-pyrid-2-one

Starting from 700 mg (1.7 mmol) of the compound from Example 26, 520 mg of the title compound are obtained analogously to the procedure for Example 8.

Yield: 77.4% of theory

¹ H NMR (CDCl ₃ ) ^ (PPm) = 1.32 (d, 6H); 3.4 (sept., 1H); 4.02 (s, 3H); 4.15 (s, 2H); 4.3 (s, 2H); 4.38 (s, 2H); 7.0-7.4 (m, 9H).

Example 28

3-benzyloxymethyl-4- (4-fluorophenyl) -6-isopropyl-1-methyl-pyrid-2-on-5-carbaldehyde

Starting from 500 mg (1.3 mmol) of the compound of Example 27, 400 mg of the title compound are obtained analogously to Example 9.

Yield: 78.3% of theory

¹ H-NMR (CDCl ₃ VO (ppm) = 1.25 (d, 6H), 4.0 (sept, 1H),. 4.08 (s, 3H), 4.15 (s, 2H); 4.4 (s, 2H); 7.0-7.4 (m, 9H); 9.65 (s, 1H).

Example 29

(E) -3- [3-benzyloxymethyl-4- (4-fluorophenyl) -6-isopropyl-1-methyl-pyrid-2-on-5-yl] -prop-2-enal

Starting from 380 mg (0.97 mmol) of the compound from Example 28, 400 mg of the title compound are obtained analogously to the procedure for Example 10

 Yield: 78.3% of theory

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.28 (d, 6H); 3.32 (sept., 1H); 4.03 (s, 3H); 4.15 (s, 2H); 4.38 (s, 2H); 5.88 (dd, 1H);

7.0-7.4 (m, 10H), 9.35 (d, 1H).

Example 30

Methyl (E) -7- [3-benzyloxymethyl-4- (4-fluorophenyl) -6-isopropyl-1-methyl-pyrid-2-on-5-yl] -5-hydroxy-3-oxo-hept- 6-enoate

OCH

Starting from 400 mg (0.76 mmol) of the compound of Example 29, 70 mg of the title compound are obtained analogously to Example 11. Yield: 20.9% of theory

¹ H-NMR (CDCl ₃ ) ^ (PPm) = 1.25 (m, 6H); 2.45 (m, 2H); 3.22 (m, 1H); 3.41 (s, 2H); 3.72 (s, 3H); 4.0 (s, 3H); 4.15 (s, 2H);

4.4 (s, 2H); 4.48 (m, 1H); 5.18 (dd, 1H); 6.28 (d, 1H); 7.0-7.4 (m, 9H).

Example 31

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

Starting from 70 mg (0.13 mmol) of the compound of Example 30, 42 mg of the title compound are obtained as an oil, analogously to Example 12.

Yield: 60.2% of theory

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.1-1.5 (m, 8H); 2.4 (m, 2H); 3.25 (sept., 1H); 3.72 (s, 3H), 4.02 (s, 3H), 4.08 (m, 1H);

4.15 (s, 2H); 4.3 (m, 1H); 4.42 (s, 2H); 5.2 (dd, 1H); 6.26 (d, 1H); 7.0-7.4 (m, 9H).

Example 32

3- (tert-butyldimethylsilyloxymethyl-4- (4-fluorophenyl) -6-isopropyl-1-methyl-pyrid-2-one-5-carboxylate

CH-

CH-

COOCoH

о-

СИ-

304 mg (2 mmol) of tert-butyldimethylsilyl chloride, 262 mg (4 mmol) of imidazole and 0.05 g of 4-dimethylaminopyridine are added at room temperature to a solution of 600 mg (1.8 mmol) of the compound from Example 6 in 20 ml of dimethylformamide. It is stirred overnight at room temperature, treated with 200 ml of water and adjusted with 1 N hydrochloric acid and pH3. The mixture is extracted three times with 100 ml of ether, the combined organic phases washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column (150 g of silica gel, 70-230 mesh, 0 4 cm, with ethyl acetate / petroleum ether 1: 9)

 Yield: 700 mg (87% of theory)

¹ H-NMR (CDCl ₃ ): δ = 0.0 (s, 6H); 0.85 (s, 9H); 0.95 (t, 3H); 1.3 (d, 6H); 3.1 (m, 1H); 3.95 (q, 2H); 4.0 (s, 2H);

4.35 (s, 3H); 7.05 (m, 2H); 7.35 (m, 2H) ppm.

Example 33

Methyl erythro- (E) -7- [3-tert-butyldimethylsilyloxy-methyl-4- (4-fluorophenyl) -6-isopropyl-1-methyl-pyrid-2-on-5-yl] -5-dihydroxy hept-6-enoate

(H ₃ C) ₃ C-Si-OH ₂ C

OCH

Starting from Example 32, the title compound was prepared analogously to the instructions of Examples 8-12. ¹ H-NMR (CDCl ₃₎ ^ = 0.0 (s, 6H); 0.9 (s, 9H); 1.25 (m, 6H); 1.5 (m, 2H); 2.45 (m, 2H); 2.8 (m, 1H); 3.3 (m, 1H);

3.6 (m, 1H); 3.75 (s, 3H); 4.0 (s, 3H); 4.1 (m, 1H); 4.3 (m, 3H); 5.2 (dd, 1H); 6.3 (d, 1H);

7.0-7.3 (m, 4H) ppm.

Example 34

Methyl erythro- (E) -7- [4- (4-fluorophenyl-3-hydroxymethyl-6-isopropyl-1-1-methylpyrid-2-on-5-yl] -3,5-dihydroxy -hept-6-en oat

OCH

100 mg (0.18 mmol) of the compound from Example 33 are stirred in a solution of 1 ml of 1 N hydrochloric acid and 9 ml of methanol overnight at room temperature. After concentration, it is taken up in methylene chloride, washed with saturated sodium bicarbonate solution, dried and filtered through silica gel (ethyl acetate / petroleum ether 1: 1). Yield: 46 mg (57% of theory) ¹ H-NMR (CDCl ₃ ): δ = 1.2 (m, 6H); 1.4 (m, 2H); 2.4 (m, 2H); 3.4 (m, 1H); 3.3 (m, 1H); 3.55 (m, 1H); 3.7 (s, 3H);

4.05 (s, 3H); 4.1 (m, 1H); 4.35 (m, 3H); 5.2 (dd, 1H); 6.3 (d, 1H); 7.0-7.2 (m, 4H) ppm.

100 mg (0.18 mmol) of the compound from Example 33 are stirred in a solution of 1 ml of 1 N hydrochloric acid and 9 ml of methanol overnight at room temperature. After concentration, it is taken up in methylene chloride, washed with saturated sodium bicarbonate solution, dried and filtered through silica gel (ethyl acetate / petroleum ether 1: 1). Yield: 46 mg (57% of theory) ¹ H-NMR (CDCl ₃ ): δ = 1.2 (m, 6H); 1.4 (m, 2H); 2.4 (m, 2H); 3.4 (m, 1H); 3.3 (m, 1H); 3.55 (m, 1H); 3.7 (s, 3H);

4.05 (s, 3H); 4.1 (m, 1H); 4.35 (m, 3H); 5.2 (dd, 1H); 6.3 (d, 1H); 7.0-7.2 (m, 4H) ppm.

Example 35

i-Carbo-methoxy-2-phenyl-propenoic acid methyl ester

Analogously to Example 2, the title compound was obtained from benzaldehyde and dimethyl malonate.

Yield: 97.3% of theory

Bp: 131 ° C / 12mm

¹ H-NMR (CDCl ₃ ): δ = 3.75 (s, 6H); 7.4 (m, 5H); 7.8 (s, 1H) ppm.

Example 36

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

OH OH O

H ₃ CO

OCH

Starting from Example 35, the title compound was obtained analogously to the instructions of Examples 3-12. ¹ H NMR (CDCl ₃ ): δ = 1.2 (m, 6H); 1.4 (m, 2H); 2.4 (m, 2H); 2.6 (s, 1H); 3.2 (s, 3H); 3.25 (m, 1H); 3.5 (m, 1H);

3.7 (s, 3H); 4.0 (s, 3H); 4.1 (s, 2H); 4.05 (m, 1H); 4.25 (m, 1H); 5.2 (dd, 1H); 6.3 (d, 1H);

7.1-7.5 (m, 5H) ppm.

Example 37

S-Amino-S-cyclopropyl-propanoic acid-ethyl ester

EtO

Analogously to Example 1, the title compound was obtained from cyclopropyl-carbonyl-acetic acid ethyl ester. Bp .: 63 ° C / 0.3mbar Yield: 24% of theory

Example 38

Methyl erythro-Fel ^ -ie-cyclopropyl ^ -i ^ fluorphenyD-S-methoxymethyl-i-methyl-pyrid ^ -on-S-yll-S.B-dihydroxy-hept-e-enoate

OCH ^

Starting from Example 37, the title compound was prepared in analogy to the specifications of Examples 3-12. Ή-NMR (CDCl ₃ ): δ = 0.95 (m, 2H); 1.15 (m, 2H); 1.35 (m, 2H); 2.25 (m, 1H); 2.45 (m, 2H); 2.75 (s, 1H); 3.2 (s, 3H);

3.5 (s, 1H); 3.7 (s, 3H); 3.95 (s, 3H); 4.05 (s, 2H); 4.1 (m, 1H); 4.3 (m, 1H); 5.5 (dd, 1H);

6.3 (d, 1H); 7.0-7.2 (m, 4H) ppm.

In analogy to the procedure for Example 5, the corresponding N-alkyl derivatives were prepared by alkylation with ethyl iodide, benzyl bromide id and 4-M et hoxybenzy Ich lorid, which in turn analogy to the provisions of Examples 6-12 to the examples listed below 39, 40 and 41 have been implemented.

Example 39

Methyl erythro- (E) -7- [1-ethyl-4- (4-fluorophenyl) -6-isopropyl-3-methoxymethyl-pyrid-2-on-5-yl] -3,5-dihydroxy-hept- 6-enoate

OCH

CH-

¹ H-NIVIR (CDCI ₃ ): δ

CH-

= 1.2 (m, 6H), 1.4 (m, 5H), 2.45 (m, 2H), 2.7 (s, 1H); 3.2 (s, 3H); 3.25 (m, 1H); 3.5 (s, 1H); 3.7 (s, 3H); 4.05 (m, 3H); 4.3 (m, 1H); 4.5 (q, 2H); 5.2 (dd, 1H); 6.25 (d, 1H); 7.0-7.2 (m, 4H) ppm.

Example 40

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

OH O

H ₃ CO

OCH

¹ H-NMR (CDCl ₃ ) IO

= 1.2 (m, 6H); 1.45 (m, 2H); 2.4 (m, 2H); 2,3 (s, 1H); 3.2 (s, 3H); 3.25 (m, 1H); 3.5 (s, 1H); 3.7 (s, 3H); 4.05 (m, 3H); 4.25 (m, 1H); 5.2 (dd, 1H); 5.5 (s, 2H); 6.25 (d, 1H); 7.0-7.5 (m, 9H) ppm.

Example 41

Methyl erythro- (E) -7- [4- (4-fluorophenyl) -6-isopropyl-3-methoxymethyl-1- (4-methoxyphenyl) pyrid-2-on-5-yl] -3,5- dihydroxyhept-6-enoate

H ₃ CO

OCH

¹ H-NMR (CDCl ₃ ): δ

1,2 (m, 6H); 1.45 (m, 2H); 2.4 (m, 2H); 2.7 (s, 1H); 3.2 (s, 3H); 3.25 (m, 1H); 3.5 (s, 1H); 3.7 (s, 3H), 3.8 (s, 3H), 4.1 (m, 3H), 4.3 (m, 1H), 5.2 (dd, 1H), 5.45 (s , 2H); 6.25 (d, 1H); 6.8-7.5 (m, 8H) ppm.

Example 42

Ethyl 3,4-dihydro-4- (4-fluorophenyl) -6-isopropyl- (1H) -pyrid-2-one-5-carboxylate

OC ₂ H ₅

20.0 g (55 mm oil) of the compound from Example 3 and 3.3 g of sodium chloride were stirred for 2.5 h at 180 ^° C. in 55 ml of dimethyl sulfoxide and 2.5 ml of water and, after cooling, added to ice-water. The precipitated solid was filtered off and recrystallized from ethanol.

M .: 119-12O ⁰ C

Yield: 12.6 g (75% of theory)

Example 43

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

OCH

Starting from Example 42, the title compound was obtained analogously to the instructions of Examples 4, 5 and 8-12. ¹ H-NMR (CDCl ₃ ) IO = 1.2 (d, 6H), 1.5 (m, 2H), 2.45 (m, 2H), 3.0 (s, 1H), 3.3 ( m, 1H); 3.6 (s, 1H); 3.7 (s, 3H);

3.95 (s, 3H); 4.1 (m, 1H); 4.4 (m, 1H); 5.25 (dd, 1H); 6.45 (m, 2H); 7.0-7.3 (m, 4H) ppm.

example

The serum cholesterol-lowering effect of the compounds of the invention on the blood cholesterol levels of dogs was found 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. given. The feed was also throughout the experimental period, i. Cholestyramine (4g / 100g diet) is added as bile acid sequestrant before, during and after the application period of the substance to be tested.

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

Claims (1)

in which A - represents a 3- to 7-membered heterocycle which may contain up to 4 heteroatoms selected from sulfur, oxygen or nitrogen and optionally up to 5 times the same or different from halo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, straight-chain or branched alkyl, alkylthio , Alkylsulfonyl, alkoxy or alkoxy carbonyl each having up to 8 carbon atoms, is substituted by aryl, arylthio or arylsulfonyl having 6 to 10 carbon atoms or by a group of the formula -NR ¹ R ² ,
wherein
R ¹ and R ^{2 are the} same or different Hydrogen, aryl or arylsulfonyl having 6 to 10 carbon atoms, straight-chain or branched alkyl or alkylsulfonyl having up to 8 carbon atoms, the last-mentioned radicals being optionally substituted by aryl having 6 to 10 carbon atoms, a group of the formula COR ³
wherein R ³ straight-chain or branched alkyl or alkoxy having up to 8 carbon atoms or Phenyl means, or R ¹ and R ² together with the nitrogen atom form a 5- to 7-membered ring which may be substituted by straight-chain or branched alkyl having up to 8 carbon atoms, - represents aryl having 6 to 10 carbon atoms, which is optionally substituted up to 5 times, identically or differently, by straight-chain or branched alkyl, alkylthio, alkylsulphonyl, alkoxy or alkoxycarbonyl having in each case up to 10 carbon atoms which in turn are hydroxyl, alkoxy having up to 6 carbon atoms , Phenyl or by a group of the formula -NR ¹ R ² SUbStItuItTsSInIn, or by aryl, aryloxy, arylthio or arylsulfonyl having 6 to 10 carbon atoms, or by halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, benzyloxy or a group of Formula -NR ¹ R ^{2 is} substituted, wherein R ¹ and R ^{2 have} the abovementioned meaning,
B - represents cycloalkyl having 3 to 8 carbon atoms, - represents straight-chain or branched alkyl having up to 12 carbon atoms, which may be halogen, cyano, azido, trifluoromethyl, trifluoromethyl, trifluoromethylsulfonyl, alkoxy having up to 10 carbon atoms, aryl, aryloxy or arylthio having from 6 to 10 carbon atoms or substituted by a 5-membered heterocycle having up to 4 heteroatoms selected from the group consisting of sulfur, oxygen or nitrogen, this and the Aryl radicals optionally up to 3 times the same or different by halogen, cyano, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, alkoxy , Alkylthio or alkylsulfonyl each having up to 8 carbon atoms, or substituted by a group of the formula -NR ¹ R ² or -COR ³ wherein R ¹ , R ² and R ^{3 have} the abovementioned meaning, - is aryl having 6 to 10 carbon atoms, which is optionally monosubstituted or disubstituted by halogen, cyano, nitro, trifluoromethyl, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having up to 8 carbon atoms or amino, each up to 3 times, D and E are the same or different and have the abovementioned meaning of A and are the same or different therefrom, or - stand for hydrogen, nitro or cyano, - represent cycloalkyl having 3 to 8 carbon atoms, - represent straight-chain or branched alkyl or alkenyl each having up to 12 carbon atoms or imino, optionally substituted by halogen, azido, 2,5-dioxo-tetrahydropyrryl, aryl having 6 to 10 carbon atoms, by a 5- to 7-membered heterocycle having up to 4 heteroatoms from Series of nitrogen, oxygen or sulfur and the corresponding N-oxides or by a group of the formula -NR ¹ R ² , -OR ⁴ , -COR ⁵ or S (O) _n -R ^{6 are} substituted, wherein R ¹ and R ^{2 have} the abovementioned meaning, R ⁴ -hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by hydroxy, trialkylsilyl having up to 10 carbon atoms in the entire alkyl portion, halogen or aryl having 6 to 10 carbon atoms, which in turn by halogen, cyano, nitro, hydroxy, straight chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 8 carbon atoms or amino may be substituted, Trialkylsilyl having up to 10 carbon atoms in the entire alkyl moiety, tetrahydropyranyl or 2,5-dioxo-tetrahydro-pyrryl, Cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms, which may be substituted in its entirety by halogen, cyano, nitro or amino, or a group of the formula -COR ⁷ means
wherein R ^{7 is} straight or branched alkyl of up to 8 carbon atoms, aryl of 6 to 10 carbon atoms or group NR ¹ R ² , R ^{5 is} hydrogen or straight or branched alkyl of up to 10 carbon atoms optionally substituted by hydroxy, phenyl, halogen or cyano substituted, -aryl having 6 to 10 carbon atoms or a 5-to 7-membered heterocycle having up to 4 heteroatoms selected from the group consisting of sulfur, nitrogen or oxygen, which in turn may be substituted by halogen, amino, hydroxy, nitro or cyano, or a group of the formula-NR ¹ R ² or -OR ⁴ means
η-a number 0,1 or 2 means R ^{6 represents} straight-chain or branched alkyl having up to 10 carbon atoms, which may be substituted by halogen, hydroxy, phenyl or a group of the formula -ΝR ¹ R ² η may mean -aryl having 6 to 10 carbon atoms which is represented by halogen, hydroxy , Cyano, nitro or amino, or a group of formula NR ¹ R ² , if η is the number 2, or
D and E are the same or different and For a group of Formula NR ¹ R ² , OR ⁴ or COR ⁵
wherein R ¹ , R ² , R ⁴ and R ^{5 have} the abovementioned meaning, or D or E together with legs form a 5- to 7-membered saturated or unsaturated ring which is optionally substituted by straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, G - represents an oxygen or sulfur atom,
X - represents a group of the formula CH ₂ -CH ₂ - or -CH = CH-, and R - represents a group of the formula I HO -CH-CHo-C-CHo-COOR ⁹ or ^^ v " ⁰ , I ² IT OH OH wherein R ^{8 is} hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms R ^{9 is} hydrogen or straight or branched chain alkyl having up to 10 carbon atoms, which may be substituted by phenyl, or -aryl having from 6 to 10 carbon atoms or a cation, or D - stands for the group XR,
wherein X and R have the abovementioned meaning and their salts, characterized in that ketones of the general formula (VIII)