DE4321421A1 - Substituted 4-phenyl-pyridones and 4-phenyl-2-alkoxypyridines - Google Patents

Description

The invention relates to substituted 4-phenyl-pyridones and 4-phenyl-2-alkoxy pyridines, processes for their preparation, and their use in medicaments.

It is known that isolated from fungal cultures lactone derivatives inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase) [Mevinolin, EP 22478; U.S. 4,231,938].

In addition, it is known that pyridine-substituted dihydroxyheptenoic inhibitors HMG-CoA reductase are [EP 325 130; EP 307342; EP 306929].

The present invention now relates to substituted 4-phenyl-pyridones and Phenyl-2-alkoxypyridines of the general formula (I)

in which
R ^{1 represents} straight-chain or branched alkyl having up to 8 carbon atoms,
R ^{2 is} cycloalkyl having 3 to 7 carbon atoms, or is straight-chain or branched alkyl having up to 8 carbon atoms,
R ^{3 is} a radical of the formula

stands in which
X is the group -CH ₂ -CH ₂ -, CH = CH- or -C≡C-, and
R ⁶ , R ⁷ and R ^{8 are the} same or different and are hydrogen or a radical of the formula -CO-R ⁹ or -COOR ¹⁰ , in which
R ⁹ and R ^{10 are the} same or different and are straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, or
R ⁶ and R ⁷ together form a radical of the formula

form,
R ^{4 is} phenyl which is optionally monosubstituted or disubstituted by identical or different halogen, trifluoromethyl, methoxy, phenoxy or straight-chain or branched alkyl having up to 8 carbon atoms,
R ^{5 has} the abovementioned meaning of R ³ and is identical or different, or
is hydrogen, cyano, carboxy or straight-chain or branched alkoxycarbonyl having up to 8 carbon atoms, or
represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by halogen, hydroxy, by straight-chain or branched alkoxy having up to 8 carbon atoms, or by a group of the formula -O- (CH ₂ ) _a -R ¹¹ or -O -CO-R ^{12 is} substituted, in which
a is a number 0 or 1,
R ^{11 is} phenyl or benzyl, which are optionally substituted in aromatics up to 2-fold, identically or differently, by halogen, trifluoromethyl, cyano, nitro or by straight-chain or branched alkyl having up to 6 carbon atoms,
R ^{12 has} the abovementioned meaning of R ¹¹ and is identical or different, or
straight-chain or branched alkyl having up to 8 carbon atoms, or
R ^{5 is} a radical of the formula -CH = NOR ¹³ , in which
R ^{13 has} the abovementioned meaning of R ¹² and is identical or different with this.

The compounds according to the invention each have, depending on the side chains listed under R ³ and / or R ⁵ , 1 or 2 asymmetric carbon atoms to which the radicals -OR ⁶ and -OR ^{7 are} bonded. They can therefore exist in different stereochemical forms.

The invention relates to both the individual isomers and their mixtures. Thus, the substances according to the invention can be present in the erythro configuration or in the threo configuration, depending on the relative position of the radicals -OR ⁶ / -OR ⁷ .

This should be exemplified for the substituent R ³ / R ⁵ with the meaning a) as follows:

Both of the fabrics in the threo and erythro configuration exist again in each case two enantiomers.

Preference is given in each case to the erythro forms.

In addition, the substances of the invention due to the double bond (X = -CH = CH-) in the E configuration or the Z configuration. Preferred are those compounds which are E-configured.

In addition, the aldehyde radicals (Subst. (C)) in each case in equilibrium with the corresponding hydroxypyrans (Subst. (d)).

Preference is given to compounds of the general formula (I) in which
R ^{1 represents} straight-chain or branched alkyl having up to 6 carbon atoms,
R ^{2 is} cyclopropyl, cyclopentyl or cyclohexyl, or
represents straight-chain or branched alkyl having up to 6 carbon atoms,
R ^{3 is} a radical of the formula

stands in which
X is the group -CH ₂ -CH ₂ -, CH = CH- or -C≡C-,
R ⁶ , R ⁷ and R ^{8 are the} same or different and are hydrogen or a radical of the formula -CO-R ⁹ or -COO-R ¹⁰ , wherein
R ⁹ and R ^{10 are the} same or different and denote straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,
or R ⁶ and R ⁷ together form a radical of the formula

form,
R ^{4 is} phenyl which is optionally monosubstituted or differently substituted by fluorine, chlorine, bromine, trifluoromethyl or by straight-chain or branched alkyl having up to 6 carbon atoms,
R ^{5 has} the abovementioned meaning of R ³ and is identical or different, or
is hydrogen, cyano, carboxy or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or
represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, hydroxyl or by straight-chain or branched alkoxy having up to 6 carbon atoms, or by a group of the formula -O- (CH ₂ ) _a -R ¹¹ or -O-CO-R ^{12 is} substituted, wherein
a is a number 0 or 1, and
R ^{11 is} phenyl or benzyl which are optionally substituted in aromatics by fluorine, chlorine, bromine, trifluoromethyl, cyano, nitro or by straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{12 has} the abovementioned meaning of R ¹¹ and is identical or different, or
is straight-chain or branched alkyl having up to 6 carbon atoms, or R ^{5 is} a radical of the formula -CH = NOR ¹³ , in which
R ^{13 has} the abovementioned meaning of R ¹² and is identical or different with this.

Particular preference is given to compounds of the general formula (I) in which
R ^{1 represents} straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{2 is} cyclopropyl or straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{3 is} a radical of the formula

stands in which
X is the group -CH ₂ -CH ₂ - or CH = CH-,
R ⁶ , R ⁷ and R ^{8 are the} same or different and are hydrogen or a radical of the formula -CO-R ⁹ , wherein
R ^{9 is} straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{4 is} phenyl which is optionally substituted by fluorine, trifluoromethyl or by straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{5 has} the abovementioned meaning of R ³ and is identical or different, or
for hydrogen or
is straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxy or by straight-chain or branched alkoxy having up to 4 carbon atoms.

Very particular preference is given to compounds of the general formula (I) in which
R ^{1 represents} straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{2 is} cyclopropyl or straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{3 is} a radical of the formula

stands, where
X is the group -CH ₂ -CH ₂ - or -CH = CH-,
R ^{4 is} phenyl which is optionally substituted by fluorine, and
R ^{5 has} the abovementioned meaning of R ³ or represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxy or alkoxy having up to four carbon atoms.

Particular preference is given to the compounds of the general formula (I) according to the invention, in which
R ^{1 is} methyl and
R ³ for the rest of the formula

stands.

In addition, a process for the preparation of the compounds according to the invention of the general formula (I) was found, which is characterized in that
Pyridones or 2-alkoxypyridines of the general formula (II)

R ¹ , R ² and R ^{4 have} the meaning given and
D is a radical of the formula

stands in which
A, B, R ⁶ and R ^{7 have} the meaning given
R ^{14 is} C ₁ -C ₆ alkyl and
E is also either as defined above for D or has the abovementioned meaning of R ⁵ ,
in inert solvents, under a protective gas atmosphere, optionally via the stage of the aldehyde, reduced with reducing agents,
and in the event that -X- is the -CH ₂ -CH ₂ group, the ethene group (X = -CH = CH-) or the ether group (X = -C≡C-) hydrogenated stepwise by conventional methods, and optionally separating the isomers.

The process of the invention can be exemplified by the following equation be explained:

Suitable solvents for the reduction are generally the usual organic solvents. Preference is given to ethers, such as diethyl ether, tetrahydrofuran or dioxane. Particularly preferred is tetrahydrofuran.

Suitable reducing agents are complex metal hydrides, such as Lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, Diisobutylaluminum hydride or sodium bis (2-methoxyethoxy) dihydroaluminate. Preference is given to diisobutylaluminum hydride.

The reducing agent is generally used in an amount of 4 mol to 10 mol, preferably from 4 mol to 5 mol, based on 1 mol of the compounds of general formula (II) used.

The reduction generally proceeds in a temperature range from -78 ° C to + 50 ° C, preferably from -78 ° C to 0 ° C, more preferably at -78 ° C, each in Dependence on the choice of reducing agent and solvent.

The reduction generally proceeds at atmospheric pressure, but it is also possible to work at elevated or reduced pressure.  

The cyclization of the aldehydes to the corresponding hydroxy-pyrans occurs in general at room temperature or by heating in inert organic Solvents, if appropriate in the presence of molecular sieve.

Suitable solvents include hydrocarbons such as benzene, toluene, xylene, Petroleum fractions, or tetralin or diglyme or triglyme. To be favoured Benzene, toluene or xylene used. It is also possible mixtures of to use mentioned solvent. Particularly preferably used Hydrocarbons, especially toluene, in the presence of molecular sieve.

The cyclization is generally in a temperature range from -40 ° C to + 100 ° C, preferably from -25 ° C to + 50 ° C.

The hydrogenation of the double bond is carried out by conventional methods with hydrogen in the presence of noble metal catalysts such as Pd / C, Pt / C or Raney nickel in one of the solvents listed above, preferably in Alko get such as methanol, ethanol or propanol, in a temperature range from -20 ° C to + 100 ° C, preferably from 0 ° C to + 50 ° C, at atmospheric pressure or Overpressure.

Optionally, the reduction of the triple or double bond also occurs at the above-mentioned reduction of the ester group.

The compounds of the general formula (II) in which D and / or E is the radical the formula

are produced by
Ketones of general formulas IIIa, b

in which
R ¹ to R ⁴ and R ^{14 have} the meaning indicated reduced and optionally isomers.

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, durchge be led. Particularly suitable here is the reduction with metal hydrides or complex metal hydrides in inert solvents, optionally in the presence a trialkylborane. Preference is given to reduction with complex metal hydrides such as lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, Lithium trialkyl hydridoborates, sodium trialkyl hydridoborates, sodium cyano-trihydrido-boranate or lithium aluminum hydride. Very special It is preferred that the reduction with sodium borohydride, in the presence of Triethylborane performed.

Suitable solvents here are the customary organic solvents which are 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, trichloro  methane, carbon tetrachloride, 1,2-dichloroethane or hydrocarbons as in For example, benzene, toluene or xylene. It is also possible mixtures of to use mentioned solvent.

Particularly preferred is the reduction of the ketone group to the hydroxy group Conditions in which the remaining functional groups such as For example, the alkoxycarbonyl group can not be changed. Especially for this suitable is the use of sodium borohydride as a reducing agent, in Presence of triethylborane in inert solvents such as preferably ethers.

The reduction is generally carried out in a temperature range from -80 ° C to + 30 ° C, preferably from -78 ° C to 0 ° C.

The inventive method is generally carried out at atmospheric pressure leads. But it is also possible, the process at reduced pressure or at overpressure (eg in a range of 0.5 to 5 bar).

In general, the reducing agent will be in an amount of 1 to 2 moles before to 1 to 1.5 mol, based on 1 mol of the keto compound used.

Among the above-mentioned reaction compounds, the car Bonyl group reduced to the hydroxy group, without reduction of the double binding to the single bond.

The ketones IIIa, b used as starting materials are prepared by Aldehydes of the formulas IVa, b

in which
R ¹ to R ^{4 have} the meaning given in inert solvents with acetoacetic esters of the general formula V

in which
R ^{14 has} the meaning given in the presence of bases.

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

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 are do not change under the reaction conditions. These include preferably ethers such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, or coals hydrogens such as benzene, toluene, xylene, cyclohexane, hexane or petroleum fractions. It is also possible to use mixtures of said solvents. Especially Preference is given to using ethers, such as diethyl ether or tetrahydrofuran.

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

The process is generally carried out at atmospheric pressure, but it is possible to carry out the process at reduced pressure or at overpressure, z. In a range of 0.5 to 5 bar.

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

The acetoacetic esters of the formula (V) used as starting materials are known or can be prepared by known methods.

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 used as starting materials of the general Formula IVa, b is given below by way of example for the compounds of type (IVb) be explained.

Here are compounds of formula VIb in the first step according to Scheme A. [1] in inert solvents such as ethers, for example diethyl ether, tetrahydrofuran or dioxane, preferably tetrahydrofuran, with metal hydrides as reduction medium, for example lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, diisobutylaluminum hydride or sodium bis (2-methoxy ethoxy) dihydroaluminate, in temperature ranges from -70 ° C to + 100 ° C, before preferably from -70 ° C to room temperature, or from room temperature to + 70 ° C each reduced by reducing agent used to the hydroxymethyl compounds. Preferably, the reduction with diisobutylaluminum hydride in tetrahydro furan in a temperature range of -78 ° C to room temperature. The Hydroxymethyl compounds in the second step [2] according to customary Methods for the aldehydes (XIII) oxidized. The oxidation can, for example, with Pyridinium chlorochromate, optionally in the presence of alumina, in  inert solvents such as chlorinated hydrocarbons, preferably methylene chloride, in a temperature range from 0 ° C to 60 ° C, preferably at room temperature be carried out with trifluoroacetic acid / dimethyl sulfoxide according to the usual methods of Swern oxidation are performed. The aldehydes (VIIb) in the third step [3] with diethyl 2- (cyclohexylamino) -vinylphosphonat in 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 ° C to + 40 ° C, preferably from -5 ° C to room temperature converted to the aldehydes (IVb).

The compounds of the formula (VIa, b) used here as starting materials are new. They are possibly obtained in Scheme B by way of example for the alkoxy-dihydropyridines (IXb) shown by oxidation of 3,4-dihydropyridines. The oxidation of the dihydropyridines (IXb) to the pyridines (VIb), in which R ^{14 has} the meaning given above, can, for example, with chromium oxide or sodium nitrite in ice cracked in a temperature range from -20 ° C to + 150 ° C, with nitric acid in aqueous Suspension or with cerium salts, such as ammonium cerium nitrate, in a mixed solvent of acetonitrile and water are performed. Preferably, ammonium nitrate in the mixture converts acetonitrile and water.

The case used as starting materials 3,4-dihydropyridines of the general Formula (IXa, b) are new.

They are generally obtained by reaction of suitably substituted α, β-unge saturated carboxylic acid ester of the general formula (X) and correspondingly substi tuted β-amino-α, β-unsaturated carboxylic acid esters of the general formula (XI) and subsequent alkylation.

The process can be carried out in bulk or in a high boiling solvent such as For example, ethylene glycol either basic with alkali metal such as For example, sodium or potassium methoxide at room temperature to + 200 ° C. or in glacial acetic acid at room temperature. Preferably, the Reaction with alkali metal alkoxides at + 140 ° C.

The reaction can be explained by the following formula scheme:

The alkylation is generally carried out with alkyl or benzyl halides in Presence of a base such as potassium carbonate, sodium hydride or an acid halide in the presence of a base such as imidazole, pyridine or Triethylamine, the O-alkyl or O-acyl derivatives can be prepared.

In the case that D and / or E is the radical of the formula

stands are the connections mostly new.

However, they can be prepared in analogy to the method described above are obtained by starting from the compounds of the general formulas

in which
R ¹ , R ² and R ^{4 have} the abovementioned meaning
L and / or M for the rest of the formula

stand in which
-X-, and R ⁶ and R ^{4 have} the meaning given, and
R ^{14 is} C ₁ -C ₆ alkyl, reduced.

Suitable solvents in this case are, in particular, alcohols, such as methanol, Ethanol or propanol, preferably ethanol.

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, durchge be led. Particularly suitable here is the reduction with metal hydrides or complex metal hydrides in inert solvents, optionally in the presence a trialkylborane. Preference is given to reduction with complex metal hydrides such as lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, Lithium trialkylhydrido-boranate or lithium aluminum hydride performed. All particularly preferred is reduction with sodium borohydride in the presence of Triethylborane performed.

The reduction generally proceeds in a temperature range from -78 ° C to + 50 ° C, preferably from -78 ° C to + 25 ° C and atmospheric pressure.

The compounds of the general formula (III) are largely new, but can be described in Be prepared analogously to known methods [see. DE 38 17 298 A; US 50 91 378].  

In the case of the enantiomerically pure compounds of general formula (I) either the corresponding enantiomerically pure esters of the general formula (II) used according to published procedures by reaction of racemic Products with enantiomerically pure amines to the corresponding diastereomers Amide mixtures, followed by separation by chromatography or Crystallization into the individual diastereomers and final hydrolysis to be obtained [cf. DOS 40 40 026] or by the racemic End products separated by conventional chromatographic methods.

The substituted 4-phenyl-pyridones and 4-phenyl-2-alkoxy according to the invention pyridines and their isomeric forms have valuable, compared to the state superior pharmacological properties, in particular they are in vivo highly potent inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A. (HGM-CoA) reductase and, as a result, inhibitors of cholesterol biosynthesis. They can therefore be used to treat hyperlipoproteinemia or arteriosclerosis be used. The active compounds according to the invention also cause a Lowering the cholesterol content in the blood.

The pharmacological action of the substances according to the invention were in the following Test determines:

Biological test for HMGCoA reductase inhibitors

Cholesterol is built up in the mammalian organism from acetate units. To measure the hepatic cholesterol biosynthesis in vivo, the animals radioactively labeled ¹⁴ C-acetate was applied and later determined the content of ¹⁴ C-cholesterol in the liver.

The substances to be tested were tested for inhibition of hepatic cholesterol biosynthesis in vivo on male Wistar rats with a body weight between 140 and 160 g. The rats were weighed for this purpose 18 h before the oral administration of the substances, divided into groups of 6 animals (control group without substance burden 8 animals) and fasted. The substances to be examined were suspended directly before administration in aqueous 0.75% tragacanth suspension with an Ultra-Turrax the application tion of Traganthsuspension (control animals) or suspended in tragacanth substances by means of a gavage. 2 hours after the oral administration of the substance, ¹⁴ C-acetate (12.5 μCi / animal) was intraperitoneally injected into the animals.

Another 2 h later (4 h after substance administration), the animals were killed by throat cutting and bled. Subsequently, the abdominal cavity was opened and a liver sample of about 700 mg was taken for the determination of ¹⁴ C-acetate synthesized from ¹⁴ C-cholesterol. The extraction of cholesterol was modified according to Duncan et al. (J. Chromatogr. 162 (1979) 281-292). The liver sample was homogenized in a glasspotter in isopropanol. After shaking and subsequent centrifugation, the supernatant was treated with alcoholic KOH and the cholesterol ester saponified. After saponification, the total cholesterol was shaken out with heptane and the supernatant was evaporated. The residue was taken up in isopropanol, transferred to scintillation vials and made up with LSC cocktail. The ¹⁴ C-cholesterol synthesized from ¹⁴ C-acetate in the liver was measured in the liquid scintillation counter. The hepatic ¹⁴ C-cholesterol content, which served only traganth-treated animals served as a control. The inhibitory activity of the substances is given in% of the synthesized hepatic ¹⁴ C-cholesterol content of tragacanth control animals (= 100%).

Acute inhibition of ¹⁴ C-cholesterol biosynthesis in vivo in rat liver Example no. Dose that inhibits hepatic ¹⁴ C cholesterol synthesis by 50% (μg / kg bw po) I 8th II 8th

The present invention also includes pharmaceutical preparations which in addition to inert, non-toxic, pharmaceutically suitable excipients and carriers contain one or more compounds of general formula (I), or from one or more active compounds of the formula (I), as well as methods for Preparation of these preparations.

The active compounds of the formula (I) are intended in these preparations in a concentration from 0.1 to 99.5 wt .-%, preferably from 0.5 to 95 wt .-% of the total mixture to be available.

In addition to the active compounds of the formula (I), the pharmaceutical preparations also contain other active pharmaceutical ingredients.

The above-listed pharmaceutical preparations can be prepared in the usual way are prepared by known methods, for example with the or Auxiliaries or carriers.

In general, it has proved to be advantageous, the active substance (s) of the Formula (I) in total amounts of about 0.1 μg / kg to about 100 μg / kg, preferably in Total amounts from about 1 μg / kg to 50 μg / kg body weight per 24 hours, optionally in the form of several individual doses to achieve the desired To give results.  

However, it may be advantageous, of the quantities mentioned depending on the type and body weight of the treated object, from individual behavior to the drug, the Type and severity of the disease, the method of preparation and application, as well the time or interval at which the administration takes place.  

starting compounds example 1 3-Amino-4-methyl-pent-2-en-acid ethyl ester

To 500 g (3.16 mol) of ethyl isobutyrylacetate in 1500 ml of toluene pA are added 10.8 g of p-toluenesulfonic acid × 4 H ₂ O, the mixture with stirring at room temperature saturated with ammonia gas and allowed to stand overnight. At closing, the water is heated under reflux and ammonia gas is introduced continuously until the calculated amount of water is deposited (after 8 hours of reflux, 47 ml of water). It is allowed to cool overnight, filtered off with suction from the precipitate and washed with toluene. The combined toluene phases are washed 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, about 90% pure).

Example 2 1-carbomethoxy-2- (4-fluorophenyl) propenoic acid-methylester

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 1.5 l of cyclohexane over a water separator. After cooling to room temperature, it is taken up in ethyl acetate, washed with water, dried with sodium sulfate and distilled.
Bp .: 135 ° C-140 ° C (1 mm)
Yield: 342.9 g (72% of theory)

Example 3 3,4-dihydro-4- (4-fluorophenyl) -6-isopropyl- (1H) -pyrid-2-one-3,5-dicarb-oic 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 3-amino-4-methyl-pent-2-one Acid ethyl ester, 1 g of sodium methoxide 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)

Example 4 4- (4-fluorophenyl) -6-isopropyl- (1H) -pyrid-2-one-3,5-dicarboxylic acid 3-me-thyl-5-ethyl ester

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 refluxed overnight heated. 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 70-230 mesh with ethyl acetate / petroleum ether 1: 1.
Yield: 5.5 g (51% of theory)
Melting point: 178 ° C

Example 5 4- (4-fluorophenyl) -6-isopropyl-2-methoxy-pyridine-3,5-dicarboxylic acid-3 - methyl-5- ethyl ester

11.3 g (31 mmol) of the compound from Example 4, 1.2 g (50 mmol) of sodium hydride and 4 ml (62 mmol) of methyl iodide are heated in 50 ml of dimethylformamide for 2 h at 80 ° C, the mixture is allowed to stand at room temperature Poured 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 by means of in vacuo, 11.1 g.
Crude yield: 95.2% of theory
Melting point: 83 ° C

Example 6 4- (4-fluorophenyl) -3-hydroxymethyl-6-isopropyl-2-methoxy-pyridin-5-ca-rbonsäure ethyl ester

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

Example 7 4- (4-fluorophenyl) -3-isopropyl-3-methoxymethyl-2-methoxy-pyridin-5-ca-rbonsäure ethyl ester

520 mg (1.5 mmol) of the compound from Example 6 are stirred in 42 mg (1.75 mol) 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.

Example 8 4- (4-fluorophenyl) -3-hydroxymethyl-6-isopropyl-2-methoxy-3-methoxy-me thyl- pyridine

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.
Melting point:

Example 9 4- (4-fluorophenyl) -6-isopropyl-2-methoxy-3-methoxy-pyridin-5-carbalde-hyd

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 Methylene chloride after, sucks over silica gel, washed with 200 ml of methylene chloride, dried with sodium sulfate and replaced after removal of the solvent on a rotary evaporator 670 mg of oil.
Yield: 96% of theory.

Example 10 (E) -3- [4- (4-fluorophenyl) -6-isopropyl-2-methoxy-3-methoxymethyl-pyrid-in-5-yl] prop-2-enal

Under nitrogen is added dropwise to a suspension of 59 mg (2.5 mmol) Sodium hydride in 6 ml dry tetrahydrofuran at -5 ° C 804 mg (3.1 mmol) Diethyl 2- (cyclohexylamino) vinyl phosphonate dissolved in 6 ml of dry Tetra hydrofuran. After 30 min. At the same temperature, 0.65 g (2.05 mmol) of the Added dropwise from Example 9 in 15 ml of dry tetrahydrofuran and Heated to reflux for 30 min. After cooling to room temperature, the An Set in 200 ml of ice-cold water and three times with 100 ml of ethyl acetate extracted. The combined organic phases are washed with saturated sodium washed chloride solution and dried over sodium sulfate. After concentration in the Vacuum the residue is taken up in 5 ml of toluene, with a solution of 0.9 g (7 mmol) of oxalic acid dihydrate in 12 ml of water and 90 min to Reflux heated. After cooling to room temperature, the phases are separated, the organic phase washed with saturated sodium chloride solution, over Dried sodium sulfate and concentrated in vacuo. The residue is in Methlen Dissolved chloride and filtered through silica gel.

Yield: 560 mg of solid (79.6% of theory).

Example 11 Methyl (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2-methoxy-3-methoxy-meth-yl-pyridin- 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 ° C 0.35 ml (3.3 mmol) of methyl acetoacetate. After 15 min, 2.3 ml (3.3 mmol) of 15% butyl lithium in n-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: 760 mg (100% of theory).

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 M triethylborane solution in tetrahydrofuran, passed through air for 5 min the solution and cooled to -30 ° 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 ° C and then treated with a mixture of 5 ml of 30% hydrogen peroxide and 11 ml of water. The temperature is allowed to rise to 0 ° C and stirred for 30 min 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, 10% sodium thiosulfate, 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 of silica gel 230 -400 mesh, ethyl acetate / petroleum ether 1: 2).
Yield: 350 mg of oil (47.6% of theory).

Example 13 3- (tert-butyldimethylsilyloxymethyl-4- (4-fluorophenyl) -6-isopropyl-2 - methoxy pyridine-5-carboxylate

To a solution of 600 mg (1.8 mmol) of the compound from Example 6 in 20 ml of dimethylformamide is added at room temperature 304 mg (2 mmol) of tert-butyldi methylsilylchlorid, 262 mg (4 mmol) of imidazole and 0.05 g of 4- dimethylaminopyridine. It is stirred overnight at room temperature, mixed with 200 ml of water and adjusted to pH 3 with 1 N hydrochloric acid. 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, Ø 4 cm, with ethyl acetate / petroleum ether 1: 9).
Yield: 700 mg (87% of theory).

Example 14 Methyl erythro- (E) -7- [3-tert-butyldimethylsilyloxy-methyl-4 (4-fluoro-phenyl) -6- isopropyl-2-methoxy-pyridin-5-yl] -5-dihydroxy-hept-6-enoate

Starting from Example 13 was analogous to the provisions of Examples 8-12 the Title compound prepared.

Example 15 Methyl erythro- (E) -7- [4- (4-fluoromethyl-3-hydroxymethyl) -6-isopropyl - 2-methoxy pyridin-5-yl] -5-dihydroxy-hept-6-enoate

100 mg (0.18 mmol) of the compound from Example 14 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)
Melting point:

PREPARATION Example I 3S, 5S - (+) - (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2-methoxy-3-methoxyme thyl- pyrid-5-yl] hept-6-en-1,3,5-triol

3.92 g (8.5 mmol) of 3R, 5S - (+) - methyl (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2-methoxy-3-methoxymethyl-pyrid-5 -yl] -3,5-dihydroxy-hept-6-enoate are dissolved under argon in 100 ml of absolute THF. At -78 ° C., 35.8 ml (43 mmol) of a 1.2 M diisobutylaluminum hydride solution (in toluene) are added dropwise. After 12 h at -30 ° C, the reaction solution is allowed to come to 0 ° C and carefully added to 150 ml of water. Then it is extracted 3 times with 200 ml of ethyl acetate each time. The organic phase is washed with saturated NaCl solution, dried with Na ₂ SO ₄ ge and concentrated on a rotary evaporator. After chromatography on silica gel 60 (25-40 μ, eluent ethyl acetate / petroleum ether 7/3) to obtain the desired product.
Yield: 1.54 g (42% of theory)
¹ H-NMR (CDCl _3): δ = 1.22 (m, 6H); 1.43 (m, 2H); 1.62 (m, 2H); 3.22 (s, 3H); 3.25 (sept. 1H); 3.84 (m, 2H); 4.01 (s, 3H); 4.04 (m, 1H); 4.06 (S; 2H); 4.28 (m, 1H); 5.22 (dd, 1H); 6.25 (d, 1H); 7.0-7.2 (m, 4H) ppm.

Example II 3S, 5S - (+) - (E) -7- [4- (4-fluorophenyl) -3-hydroxymethyl-6-isopropyl-2-met hoxy-pyrid- 5-yl] hept-6-en-1,3,5-triol

The preparation is carried out analogously to Example 1 from 3R, 5S - (+) - methyl (E) -7- [4- (4-fluoro phenyl) -3-hydroxymethyl-6-isopropyl-2-methoxy-pyrid-5-yl] -3,5-dihydr oxy-hept- 6-enoate.

¹ H-NMR (CDCl _3): δ = 1.25 (d, 6H); 1.42 (m, 2H); 1.63 (m, 2H); 3.28 (sept. 1H); 3.82 (m, 2H); 4.01 (m, 1H); 4.06 (s, 3H); 4.27 (m, 1H); 4.35 (d, 2H); 5.23 (dd, 1H); 6.22 (d, 1H); 7.0-7.2 (m, 4H) ppm.

Claims (9)

1. Substituted 4-phenyl-pyridones and 4-phenyl-2-alkoxypyridines of the general mean of my formula in which
R ^{1 represents} straight-chain or branched alkyl having up to 8 carbon atoms,
R ^{2 is} cycloalkyl having 3 to 7 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms,
R ^{3 is} a radical of the formula stands in which
X is the group -CH ₂ -CH ₂ -, CH = CH- or -C≡C-, and
R ⁶ , R ⁷ and R ^{8 are the} same or different and are hydrogen or a radical of the formula -CO-R ⁹ or -COOR ¹⁰ , in which
R ⁹ and R ^{10 are the} same or different and are straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, or
R ⁶ and R ⁷ together form a radical of the formula form,
R ^{4 is} phenyl which is optionally monosubstituted or disubstituted by identical or different halogen, trifluoromethyl, methoxy, phenoxy or straight-chain or branched alkyl having up to 8 carbon atoms,
R ^{5 has} the abovementioned meaning of R ³ and is identical or different, or
is hydrogen, cyano, carboxy or straight-chain or branched alkoxycarbonyl having up to 8 carbon atoms, or
represents straight-chain or branched alkyl having up to 8 carbon atoms, optionally atoms by halogen, hydroxy, by straight-chain or branched alkoxy having up to 8 carbon atoms, or by a group of the formula -O- (CH ₂ ) aR ¹¹ or -O -CO-R ^{12 is} substituted, in which
a is a number 0 or 1,
R ^{11 is} phenyl or benzyl, which are optionally substituted in aromatics up to twice the same or different by halogen, tri fluoromethyl, cyano, nitro or by straight-chain or branched alkyl having up to 6 carbon atoms,
R ^{12 has} the abovementioned meaning of R ¹¹ and is identical or different, or
straight-chain or branched alkyl having up to 8 carbon atoms, or
R ^{5 is} a radical of the formula -CH = NOR ¹³ , in which
R ^{13 has} the abovementioned meaning of R ¹² and is identical or different with this. 2. Substituted 4-phenyl-pyridones and 4-phenyl-2-alkoxypyridines according to claim 1, wherein
R ^{1 represents} straight-chain or branched alkyl having up to 6 carbon atoms,
R ^{2 is} cyclopropyl, cyclopentyl or cyclohexyl, or represents straight-chain or branched alkyl having up to 6 carbon atoms,
R ^{3 is} a radical of the formula stands in which
X is the group -CH ₂ -CH ₂ -, CH = CH- or -C≡C-, R ⁶ , R ⁷ and R ^{8 are} identical or different and are hydrogen or a radical of the formula -CO-R ⁹ or -COO R ^{10 is} where
R ⁹ and R ^{10 are the} same or different and are straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, or
R ⁶ and R ⁷ together form a radical of the formula form,
R ^{4 is} phenyl which is optionally monosubstituted or differently substituted by fluorine, chlorine, bromine, trifluoromethyl or by straight-chain or branched alkyl having up to 6 carbon atoms,
R ^{5 has} the abovementioned meaning of R ³ and is identical or different, or
is hydrogen, cyano, carboxy or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or
represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, hydroxyl or by straight-chain or branched alkoxy having up to 6 carbon atoms, or by a group of the formula -O- (CH ₂ ) _a -R ¹¹ or -O-CO-R ^{12 is} substituted, wherein
a is a number 0 or 1, and
R ^{11 is} phenyl or benzyl which are optionally substituted in aromatics by fluorine, chlorine, bromine, trifluoromethyl, cyano, nitro or by straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{12 has} the abovementioned meaning of R ¹¹ and is identical or different, or
straight-chain or branched alkyl having up to 6 carbon atoms, or
R ^{5 is} a radical of the formula -CH = NOR ¹³ , in which
R ^{13 has} the abovementioned meaning of R ¹² and is identical or different with this
3. Substituted 4-phenyl-pyridones according to claim 1 wherein
R ^{1 represents} straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{2 is} cyclopropyl or straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{3 is} a radical of the formula stands in which
X is the group -CH ₂ -CH ₂ - or CH = CH-, R ⁶ , R ⁷ and R ^{8 are} identical or different and denote hydrogen or a radical of the formula -CO-R ⁹ , in which
R ⁹ denotes straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{4 is} phenyl which is optionally substituted by fluorine, trifluoromethyl or by straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{5 has} the abovementioned meaning of R ³ and is identical or different, or
for hydrogen or
represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxy or by straight-chain or branched alkoxy having up to 4 carbon atoms. 4. Substituted 4-phenyl-pyridones according to claim 1 wherein
R ^{1 represents} straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{2 is} cyclopropyl or straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{3 is} a radical of the formula stands, where
X is the group -CH ₂ -CH ₂ - or -CH = CH-,
R ^{4 is} phenyl which is optionally substituted by fluorine, and
R ^{5 has} the abovementioned meaning of R ³ or
represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxy or alkoxy having up to four carbon atoms. 5. Substituted 4-phenyl-pyridones according to claim 1 for therapeutic Application. 6. A process for the preparation of substituted 4-phenyl-pyridones according to claim 1, characterized in that R ¹ , R ² and R ^{4 have} the meaning given and
D is a radical of the formula stands in which
A, B, R ⁶ and R ^{7 have} the meaning given
R ^{14 is} C ₁ -C ₆ alkyl and
E is also either as defined above for D or has the abovementioned meaning of R ⁵ ,
in inert solvents, under a protective gas atmosphere, optionally via the stage of the aldehyde, reduced with reducing agents,
and in the event that -X- is the -CH ₂ -CH ₂ group, the ethene group (X = -CH = CH-) or the ether group (X = -C≡C-) hydrogenated stepwise by conventional methods, and optionally separating the isomers. 7. Medicaments containing at least one substituted 4-phenyl-pyridone or 4-phenyl-2-alkoxypyridine according to claim 1.   8. Medicament according to claim 1 for the treatment of hyperlipoproteinemia. 9. A process for the preparation of medicaments according to claim 7 characterized ge indicates that the substituted 4-phenyl-pyridones or 4-phenyl- 2-alkoxypyridines optionally with the aid of customary auxiliaries and carriers converted into a suitable application form. 10. Use of substituted 4-phenyl-pyridones and 4-phenyl-2-alkoxy pyridines for the manufacture of medicaments.