KR0149634B1 - Lactones prepared from 7-substituted 3,5-dihydroxyhept-6-ynoic acid derivatives, a process for the preparation thereof and pharmaceutical compositions containing them - Google Patents

Abstract

The present invention relates to lactones prepared from 7-substituted derivatives of 3,5-dihydroxyhept-6-phosphoric acid of formula (2), methods for their preparation, and pharmaceutical products comprising the same.

Formula 2

In Chemical Formula 2,

R is

a) chemical formula Radicals where X = YZ is a group of formula CR ³ = CR ⁴ -CR ⁵ , wherein R ³ is hydrogen, R ⁴ is isopropyl, tert-butyl, phenyl or 4-fluorophenyl, R ⁵ is hydrogen), R ¹ is isopropyl, R ² is 4-fluorophenyl, or

X = YZ is a group of formula N = CR ⁴ -CR ⁵ , wherein R ⁴ is isopropyl, tert-butyl, phenyl or 4-fluorophenyl, R ⁵ is hydrogen, and R ¹ is isopropyl Or cyclopropyl, R ² is 4-fluorophenyl, or

X = YZ is a group of formula N = N—CR ⁵ , wherein R ⁵ is phenyl or 4-fluorophenyl, R ¹ is isopropyl, R ² is 4-fluorophenyl, or

X = YZ is a group of the formula N = CR ⁴ -N wherein R ⁴ is isopropyl, tert-butyl, phenyl or 4-fluorophenyl, R ¹ is isopropyl and R ² is fluoro Phenyl;

b) chemical formula Radicals where R ⁶ is isopropyl, R ⁷ is 4-fluorophenyl, UVW is a group of the general formula C-NR ⁹ -CR ⁸ , wherein R ⁸ is hydrogen and R ⁹ is isopropyl or Phenyl)] or

c) chemical formula Is a radical of which AB is a group of formula C = C, R ¹¹ is isopropyl and R ¹² and R ¹³ are 4-fluorophenyl or 4-fluoro-3-methylphenyl.

Description

Lactone prepared from 7-substituted derivatives of 3,5-dihydroxyhept-6-phosphate, preparation method thereof and pharmaceutical product comprising the same

The conversion of 3-hydroxy-3-methylglutaric acid (HMG) to mevalonic acid forms a major step in the biosynthesis of cholesterol. This step is catalyzed by the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). A number of compounds have been described that inhibit the activity of HMG-CoA reductase. In most cases, these compounds are derivatives of 3,5-dihydroxyheptanoic acid and 3,5-dihydroxyhept-6E-enoic acid, and of 3,5-dihydroxy-6-oxo-hexanoic acid. Derivatives (see, eg, Drugs of the Future 12, 437 (1987)), which are substituted with sterically necessary sterically radicals at position 7 or on an oxygen atom. Examples of suitable hodgeophilic sub-structures described are those of the natural substance Compactin [A.B. Brown et al., J. Chem. Soc. Perkin Trans 1, 15 1976, 1165] and mebinoline [A.W. Alberts et al., Proc. Natl. Sci. U.S.A. 77, 3957 (1980)] hexahydro naphthyl radical, substituted phenyl nucleus [see, eg, G.E. Stokker et al., J. Med. Chem. 29, 170 (1986)], heteroaromatic radicals [see, for example, Drugs of the Future 12, 437 (1987), EP-A 0,221,025], or other triple substituted ethylene groups [see, for example, For example, E. Baader et al., Tetrahedron Lett, 29, 929 (1988).

The degree and pattern of substitution of the agonistic radicals is critically important for the biological activity of the HMG-CoA reductase inhibitor. The value of IC ₅₀ ≦ 1 × 10 ⁻⁸ mol / liter for enzyme inhibition can be reached by suitable substitution of the hodgephilic radical.

Little is known about the inhibitory effect on 7-substituted 3,5-dihydroxyhept-6-phosphate derivatives and their HMG-CoA reductase. Only one known example, 7-phenyl-substituted derivatives, is described in GE Stokker et al., J. Med. Chem. 28, 346 (1985). However, enzyme inhibition by this compound is weak (IC ₅₀ ≫1 x 10 ^-6 mol / liter), and also identically substituted 3,5-dihydroxyheptanoic acid and 3,5-dihydroxy hept-6E- It is significantly lower than enzymatic inhibition of enic acid.

In contrast to these results, the formula (I) and 3,5-dihydroxy-hept-6-phosphoric acid derivative of formula (II) of the present invention, a) HMG-CoA is a potent inhibitor of the reductase (IC ₅₀ ≤ 1 x 10 ^{- 8} moles / liter), b) has the same or greater inhibitory effect as that of the 3,5-dihydroxyhept-6E-enoic acid derivative, correspondingly identically substituted at position 7.

Accordingly, the present invention relates to 7-substituted 3,5-dihydroxyhept-6-phosphate and its derivatives of formula (1), and to the corresponding lactones of formula (2).

In Chemical Formulas 1 and 2,

R is

a) chemical formula Radicals wherein R ¹ and R ² independently of one another are straight or branched chain alkyl or alkenyl radicals having up to 6 carbon atoms, saturated or double unsaturated cyclic hydrocarbon radicals having 3 to 6 carbon atoms, or unsubstituted or straight chains having up to 4 carbon atoms Or a phenyl radical substituted with one to three identical or different radicals selected from the group consisting of branched alkyl, halogen, alkoxy having up to 4 carbon atoms and hydroxyl,

X = YZ is a group of the general formula CR ³ = CR ⁴ -CR ⁵ , N = CR ⁴ -CR ⁵ , N = N-CR ⁵ , or N = CR ⁴ -N,

R ³ , R ⁴ and R ⁵ are independently of each other hydrogen, straight or branched chain alkyl or alkenyl radicals having 6 or less carbon atoms or saturated or double unsaturated cyclic hydrocarbon radicals having 3 to 6 carbon atoms, or unsubstituted or straight chains having 4 or less carbon atoms Phenyl radicals substituted with one to three identical or different radicals selected from the group consisting of branched alkyl, halogen, alkoxy having up to 4 carbon atoms, and hydroxyl;

b) chemical formula Radicals of which R ⁶ and R ⁷ are independently of each other a straight or branched chain alkyl or alkenyl radical having 6 or less carbon atoms, a saturated or double unsaturated cyclic hydrocarbon radical having 3 to 6 carbon atoms, or an unsubstituted or straight chain having 4 or less carbon atoms Or a phenyl radical substituted with one to three identical or different radicals selected from the group consisting of branched alkyl, halogen and alkoxy having up to 4 carbon atoms,

UVW is represented by general formula C-NR ⁹ -CR ⁸ , CO-CR ⁸ , CS-CR ⁸ , -C-NR ⁹ -N, CON (= CNO), CSN (= CNS), N-CR ¹⁰ = CR ⁸ , NN = CR ⁸ or N-CR ¹⁰ = N,

R ⁸ is hydrogen, straight or branched chain alkyl or alkenyl radical having 6 or less carbon atoms, saturated or double unsaturated cyclic hydrocarbon radical having 3 to 6 carbon atoms, or unsubstituted or straight chain or branched chain alkyl having 4 or less carbon atoms, halogen, 1 to C A phenyl radical substituted with 1 to 3 same or different radicals selected from the group consisting of alkoxy and hydroxyl of 4,

R ⁹ and R ¹⁰ independently of one another are straight or branched chain alkyl or alkenyl radicals having up to 6 carbon atoms, saturated or double unsaturated cyclic hydrocarbon radicals having 3 to 6 carbon atoms, or unsubstituted or straight chain or branched chain alkyl having up to 4 carbon atoms, halogen And 1 to 3 identical or different radicals selected from the group consisting of alkoxy of up to 4 carbon atoms) or

c) chemical formula Radicals where AB is a group of the formula CH-CH or C = C, and R ¹¹ , R ¹² and R ¹³ independently of one another are straight or branched chain alkyl or alkenyl radicals having up to 20 carbon atoms, saturated with 3 to 6 carbon atoms Or a double unsaturated cyclic hydrocarbon radical, unsubstituted or substituted with 1 to 3 radicals selected from the group consisting of straight or branched chain alkyl of up to 4 carbon atoms, alkoxy and halogen of up to 4 carbon atoms, and

R ⁰ is hydrogen, a straight or branched chain alkyl radical having up to 6 carbon atoms, an alkali metal or ammonium.

Preferred substituents R include:

a) R ¹ is a straight or branched chain alkyl radical having 4 or less carbon atoms or a cycloalkyl radical having 3 to 6 carbon atoms,

R ² is a phenyl radical which is unsubstituted or substituted with 1 to 3 identical or different radicals selected from the group consisting of C ₁ -C ₁ -alkyl, fluorine, chlorine, alkoxy having 1 to 4 carbon atoms and hydroxyl,

X = YZ is a group of the formula CR ³ = CR ⁴ -CR ⁵ , N = CR ⁴ -CR ⁵ , N = N-CR ⁵ or N = CR ⁴ -N,

R ³ and R ⁵ independently of one another are hydrogen, a straight or branched chain alkyl radical having 4 or less carbon atoms, a cycloalkyl radical having 3 to 6 carbon atoms, or unsubstituted or C ₁ -C ₄ -alkyl, fluorine, chlorine, having 1 to C atoms A phenyl radical substituted with 1 to 3 same or different radicals selected from the group consisting of alkoxy and hydroxyl of 4,

R ⁴ is a straight or branched chain alkyl radical having 4 or less carbon atoms, a cycloalkyl radical having 3 to 6 carbon atoms, or an unsubstituted or substituted C ₁ -C ₄ -alkyl, fluorine, chlorine, alkoxy having 1 to 4 carbon atoms and hydroxyl group Is a phenyl radical substituted with one to three identical or different radicals selected from Radicals;

b) R ⁶ is a straight or branched chain alkyl radical having 4 or less carbon atoms or a cycloalkyl radical having 3 to 6 carbon atoms,

R ⁷ is unsubstituted or substituted with 1 to 3 identical or different radicals selected from the group consisting of C ₁ -C ₄ -alkyl, fluorine, chlorine, alkoxy having 1 to 4 carbon atoms and hydroxyl,

UVW is a group of the general formula C-NR ⁹ -CR ⁸ ,

R ⁸ is 1 to 3 identical or selected from hydrogen, straight or branched chain alkyl radicals of up to 4 carbon atoms, cycloalkyl radicals of 3 to 6 carbon atoms, or unsubstituted or C ₁ -C ₄ -alkyl, fluorine and chlorine; Phenyl radicals substituted with different radicals,

R ⁹ is a straight or branched chain alkyl radical having 4 or less carbon atoms, a cycloalkyl radical having 3 to 6 carbon atoms, or 1 to 3 identical or different radicals selected from the group consisting of unsubstituted or C ₁ -C ₄ -alkyl, fluorine and chlorine; Is a phenyl radical substituted with Radicals; And

c) A-B is a group of the formula CH-CH or C = C,

R ¹¹ is a straight or branched chain alkyl radical having 6 or less carbon atoms or a cycloalkyl radical having 3 to 6 carbon atoms,

R ¹² and R ¹³ independently of one another are straight or branched chain alkyl radicals of up to 6 carbon atoms, cycloalkyl radicals of 3 to 6 carbon atoms, unsubstituted or C ₁ -C ₄ -alkyl, halogen, alkoxy and hydroxide of 1 to 4 carbon atoms Formula is a phenyl radical substituted with one to three identical or different radicals selected from the group consisting of yarns Has radicals.

Preferred radicals R ⁰ include hydrogen, straight or branched chain alkyl radicals having up to 4 carbon atoms, sodium and potassium.

Particularly preferred radicals R include:

a) X = YZ is a group of formula CR ³ = CR ⁴ -CR ⁵ , wherein R ³ is hydrogen, R ⁴ is isopropyl, tert-butyl, phenyl or 4-fluorophenyl, R ⁵ Is hydrogen),

R ¹ is isopropyl,

R ² is 4-fluorophenyl,

X = YZ is a group of the general formula N = CR ⁴ -CR ⁵ , wherein R ⁴ is isopropyl, tert-butyl, phenyl or 4-fluorophenyl, and R ⁵ is hydrogen;

R ¹ is isopropyl or cyclopropyl,

R ² is 4-fluorophenyl,

X = YZ is a group of the formula N = N—CR ⁵ , wherein R ⁵ is phenyl or 4-fluorophenyl,

R ¹ is isopropyl,

R ² is 4-fluorophenyl, or

X = YZ is a group of the general formula N = CR ⁴ -N wherein R ⁴ is isopropyl, tert-butyl, phenyl or 4-fluorophenyl,

R ¹ is isopropyl,

R ² is fluorophenyl Radicals,

b) R ⁶ is isopropyl,

R ⁷ is 4-fluorophenyl,

UVW is a group of formula C-NR ⁹ -CR ⁸ wherein R ⁸ is hydrogen and R ⁹ is isopropyl or phenyl Radicals; And

c) A-B is a group of formula C = C,

R ¹¹ is isopropyl,

R ¹² and R ¹³ are 4-fluorophenyl or 4-fluoro-3-methylphenyl Has radicals.

Particularly preferred radicals R ⁰ are hydrogen, methyl, ethyl, tert-butyl, sodium and potassium.

The present invention relates to pure enantiomers with absolute coordination 3R / 5S, and racemates of formula (1) and mixtures thereof, namely racemates and pure enantiomers with absolute coordination 3RS / 5RS.

The present invention also relates to racemates of formula (2) derived from the stereoisomer dihydroxycarboxylic acid derivatives of formula (I) mentioned above and to pure enantiomers. In particular, they are racemates with absolute coordination 4RS / 6SR and pure enantiomers with absolute coordination 4R / 6S.

In addition, the present invention

a) converting the aldehyde of formula 3 to the corresponding hydroxy keto ester of formula 4,

b) converting the hydroxy keto ester of formula 4 to the corresponding 3,5-dihydroxy compound of formula 1 and optionally hydrolyzing the obtained compound to a compound of formula 1 wherein R ⁰ is an alkali metal, If desired, therefrom free acid (R ⁰ = hydrogen) is released, and if desired, the free acid is converted to a compound of formula 1 as defined in formula 1 except that R ⁰ is hydrogen,

c) a process for the preparation of compounds of formulas (1) and (2), characterized in that the obtained compounds of formula (1) are optionally converted to lactones of formula (2).

Formula 1

Formula 2

In Chemical Formulas 1 to 4,

R is as defined in Formula 1,

R ⁰ is alkyl having 1 to 6 carbon atoms.

Examples of different modification processes for the conversion of the compound of formula 3 to the compound of formula 4 according to the conditions and needs are as follows:

1. The racemic compound of formula 4 is produced by reaction at -78 ° C to room temperature in a solvent of divalent anion of aldehyde of formula 3 and acetoacetic ester (for example, THF). The divalent anion of acetoacetic ester is -40 in an ethereal solvent, preferably diethyl ether, THF or dimethoxyethane with various bases, preferably sodium hydride, n-butyllithium and lithium diisopropyl amide (LDA). It may be prepared at ℃ to room temperature.

2. Enolates and solvents (eg THF) of achiral acetic acid esters (eg methyl, ethyl or propyl esters) prepared in ethereal solvents (eg THF) with strong bases (eg metal amides, preferably LDA) The racemic compound of formula 5 is produced by reaction with an aldehyde of formula 3 at -78 to 0 ° C.

In Chemical Formula 5,

R ¹⁴ is an achiral acid protecting group (eg methyl, ethyl or propyl group). The racemic compound of formula 4 is produced by reaction with another acetester enolate at -78 to 30 ° C in a solvent such as THF.

3. The optically active adduct of formula 5 by reaction of the aldehyde of formula 3 with the enolate of the optically active acetester, preferably lithium or magnesium enoleate, at -78 to 0 ° C. in a solvent such as THF Is generated. In this case, R ¹⁴ is a suitable optically active acid protecting group which determines the coordination at C-3. See R. Devant, U. Mahler and M. Braun, Chem. Ber. 121, 397 (1988)], the groups preferably used in this case are those which generate 3R configuration. Group, which is prepared from L-(+)-mandelic acid. However, other optically active groups are also suitable. The optically active compound of formula (5) obtained is reacted directly with achiral acet ester enolate to produce the optically active compound of formula (4), or first by transesterification to an alkyl ester of formula (5), preferably methyl ester And then converted to the compound of formula 4 by modification process 2.

The conversion of the compound of formula 4 to the compound of formula 1 is described in, for example, K. Naraska, HC Pai, Chem. Lett. 1980, 1415 or KM Chen, KG Gunderson, GE Hardtmann, K. Prasad, O. Repic and MJ Shapiro, Chem. Lett. 1978, 1923]. First, the compound of formula 4 is reacted with trialkyl- or alkoxydialkylborane, preferably triethyl- or methoxydiethyl borane, and then, where appropriate, methanol is added to reduce at -78 to 0 ° C. Compounds of formula (I) having the specific relative coordination (3R ^* , 5S ^* ) in C-3 and C-5 are obtained by this method.

Salts and acids of compounds of formula 1 are obtained by conventional known methods.

Lactone of formula (2) removes water from the dihydroxy carboxylic acid of formula (R ⁰ = H) by addition of p-toluenesulfonic acid in known methods per se, for example, from room temperature to reflux temperature in benzene, hexane or toluene. Or remove the water from the dihydroxy carboxyl ester of formula 1 (R ⁰ = methyl, ethyl or tert-butyl) by addition of a strong acid (eg trifluoroacetic acid) in dichloromethane at room temperature to reflux. To obtain similarly.

The racemic compounds of formulas (1) and (2) can be separated into pure enantiomers by known racemate cleavage methods.

R is as defined for Formula 1 and the aldehyde of Formula 3 used as starting material in the process according to the invention is obtained, for example, as described in Scheme 1.

Suitable aldehydes of formula (6), wherein R is as defined for formula (1), can be prepared analogously to the methods known from or described in the literature.

X = YZ is CR ³ = CR ⁴ -CR ⁵ Aldehydes with R radicals of: GE Stokker et al., J. Med. Chem. 29, 170 (1986).

X = YZ is N = CR ⁴ -CR ⁵ or N = CR ⁴ -N Aldehydes of the general formula 6 having an R radical of: Published Federal Publication No. 38 23 045 (corresponding to EP-A 0,307,342; corresponding to US Patent Application No. 07/216458) (corresponding alcohol R-CH ₂ OH And aldehydes of formula 3 can be prepared by known methods, for example by oxidation with pyridinium chlorochromate.

X = YZ is N = N-CR ⁵ Aldehyde of formula 6: having R radical of: German Patent Application No. P 38 00 785.1 (corresponds to US Patent Application No. 07/294096).

Formula UVW is C-NR ⁹ -CR ⁸ Aldehydes of the general formula 6 having an R radical of: German Patent Application Publication No. 37 22 806 (EP-A 0,300,249; corresponding to US Patent Application No. 216,423).

Formula UVW is CO-CR ⁸ , CS-CR ⁸ or N-CR ¹⁰ = CR ⁸ Aldehydes of formula 6: with R radical of EP-A 0,221,025.

Formula wherein UVW is C-NR ¹⁰ -N or NN = CR Aldehydes of formula 6: having R radicals of: WO 86/00307

Formula wherein UVW is N-CR = N Aldehydes of formula 6: having R radicals of: WO 86/07054

Formula where UVW is CON or CSN Aldehydes of the general formula 6: having R radicals of: JP 3,621,372 and references cited therein (the corresponding alcohols R-CH ₂ OH are described, from which the aldehydes of the formula 6 are known Prepared by oxidation).

Chemical formula Aldehydes of the general formula 6 having an R radical of: German Patent Publication No. 37 22 807 (corresponding to EP-A 03 06 649; US Patent Application No. 07 / 216,331).

Aldehydes of the formula (6) are described, for example, in E. J. Corey and P. L. Fuchs, Tetrahedron Lett. Similar to the method described in 1972, 3769, the corresponding gem-dibromoolefin of formula 7 is prepared and then reacted with n-butyllithium and carbon dioxide to convert to the carboxylic acid of formula 8.

The carboxyl esters of formula (9) wherein R ¹⁵ is an alkyl radical, preferably a methyl or ethyl radical, are prepared by esterification in a manner known per se. The latter is reduced to alcohols of formula 10 by known methods, for example metal hydrides such as LiAlH ₄ , diisobutylaluminum hydride or beadide. The aldehyde of formula 3 is then produced by known methods, for example by oxidation with pyridinium chlorochromate.

It is advantageous to protect the phenolic hydroxyl groups in a suitable way for the synthesis of the compounds of the formulas (1) and (2) with the phenolic hydroxyl groups. Starting from the aldehyde of formula (3) having a protected phenolic hydroxyl group, first, a compound of formula (1) or (2) having a similarly protected phenolic hydroxyl group is prepared, which is then used to free free phenolic hydroxyl groups. Is converted to the compound of formula (I) or (II). Suitable protecting groups for this purpose, for example alkyl ethers or silyl ethers, and suitable methods for the selective introduction and removal thereof are described in, for example, TW Greene: Protective Groups in Organic Synthesis, Wiley Sons, New York 1981 is commonly known.

In addition to the compounds described in the Examples, the following compounds can be prepared by the process according to the invention.

Tert-butyl

Tert-butyl

Tert-butyl hept-6-inoate,

Tert-butyl

Tert-butyl hept-6-inoate,

Tert-butyl 7- (2-cyclopropyl-6- (2,2-dimethyl ethyl) -4- (4-fluorophenyl) pyridin-3-yl) -3R, 5S-dihydroxy hept-6- Innoate,

Tert-butyl inoate,

Tert-butyl

Tert-butyl 7- (6- (2,2-dimethylethyl) -4- (4-fluorophenyl) -2- (1-methylethyl) pyrimidin-3-yl) -3R, 5S-dihydro Hydroxy hept-6-inoate,

Tert-butyl

salt

salt

Sodium hept-6-inoate,

Sodium 7- (2,6-bis- (1-methylethyl) -4- (4-fluorophenyl) -pyridin-3-yl) -3R, 5S-dihydroxyhept-6-inoate sodium inoate ,

Sodium 7- (2-cyclopropyl-6- (2,2-dimethylethyl) -4- (4-fluorophenyl) pyridin-3-yl) -3R, 5S-dihydroxyhept-6-inoate,

salt

salt

Sodium hept-6-inoate,

salt

Hydro-2H-pyran-2-one,

6S- (2- (2,4-bis- (4-fluorophenyl) -6- (1-methyl ethyl) phenyl) -ethynyl-4R-hydroxy-3,4,5,6-tetrahydro- 2H-pyran-2-one,

Hydro-2H-pyran-2-one,

5,6-tetrahydro-2H-pyran-2-one,

Hydro-2H-pyran-2-one,

5,6-tetrahydro-2H-pyran-2-one and

Biological test system:

1. HMG-CoA Reductase Activity in Enzyme Preparation

HMG-CoA reductase activity is measured on dissolved enzyme preparations from liver microsomes of rats induced with clestriamine ( ^R Cuemid) after changing the day / night rhythm. (Sm R) ¹⁴ C-MHG-CoA is used as the substrate and the concentration of NADPH is maintained by the regeneration system during incubation. Column eluting separates the ¹⁴ C-mevalonate from the substrate and other products (eg, ¹⁴ C-HMG) while measuring the elution profile of each sample to be measured. ³ H-Mevalonate is not always included because it is intended to measure relative data on inhibitory effects. In each test series, the mixture containing the enzyme-free control, the enzyme-containing normal mixture (= 100%) and the product added at the final concentrations of ^10-5 to ^10-9 M are treated together. Each individual value is formed as an average of three corresponding samples. The significance of the difference between the mean values of the product-free and product-containing samples is evaluated by t-test.

Using the method described above, for example, the following HMG-CoA reductase inhibition value for the compound according to the present invention is obtained [IC ₅₀ / mol / L determines the molar concentration of compound per liter required for 50% inhibition. Is indicated.

In this way, the IC ₅₀ value obtained for the compound of Formula 1 is obtained from the same (substituted IC ₅₀ reference value) for enzyme inhibition by the same substituted 3,5-dihydroxyhept-6E-enoic acid derivative (reference compound). Compare. Exponential IC ₅₀ reference value / IC ₅₀ indicates relative activity.

Specific values obtained are, for example, those listed in Table 1.

2. Inhibition (suppression or inhibition) of HMG-CoA reductase in cell culture medium of HEP-G2 cells

Monolayers of HEP-G2 cells in lipoprotein-free nutrient medium are preincubated with appropriate concentrations of test substance for a defined time (e.g., 1 hour) and labeled precursors, such as sodium ¹⁴ C-acetate, are added. The culture is then continued (eg for 3 hours). After addition of the internal standard ( ³ H-cholesterol), the cell aliquots are alkali hydrolyzed. Fat from the hydrolyzed cells is extracted with chloroform / methanol. After the addition of carrier cholesterol, separated after the fat and the mixture was applied to thin-layer chromatography for separation and visualizing the cholesterol bands with iodine vapor, by the amount of cholesterol produced from the ¹⁴ C- ¹⁴ to C- precursor sinti Photography Measure The cellular protein in the cell aliquot is measured to allow the calculation of the amount of ¹⁴ C-cholesterol produced per unit time per mg of cellular protein. The inhibitory effect of certain test products on cholesterol biosynthesis by HEP-G2 cell cultures was calculated as described above, with ¹⁴ C-cholesterol produced per mg of cellular protein and unit time in cultures treated in the same manner without the test substance. Is revealed in comparison with the amount of.

Testing of Substances for Inhibition of Cholesterol Biosynthesis in Consistent Cell Cultures (monolayer) of HEP-G2 Cells

8. Results

¹⁴ C-cholesterol (nmol) / cell (mg) compared to solvent control

Using the method described above, for example, the following cholesterol biosynthesis (in HEP-G2 cells) inhibition of the compound according to the present invention is obtained (IC ₅₀ / mol is the compound concentration that inhibits cholesterol biosynthesis by about 50%). . IC ₅₀ values are determined for the compounds according to the invention and for the same substituted 3,5-dihydroxyhept-6E-enoic acid derivatives (IC ₅₀ reference values). Index IC ₅₀ Reference / IC ₅₀ indicates the relative activity of the compounds according to the invention. Thus, for example, the compound of Example 8a (R = a; X = YZ = N = CR ⁴ -C ⁵ , R ¹ = iC ₃ H ₇ , R ² = 4-FC ₆ H ₄ , R ⁴ = C _{For 6} H ₅ , R ⁵ = H), based on similar hept-6E-enoic acid derivatives, an IC ₅₀ value of ⁹ × 10 ⁻⁹ mol / L is determined, which is a relative activity of 2.67 (Compare, Table 1, see Compound / German Publication No. 38 23 045, Example 11e). Compounds of Example 9e (R = a; X = YZ ⁴ = N = CR ⁴ -N; R ¹ = iC ₃ H ₇ , R ² = 4-FC ₁ H ₄ , R ⁴ = 4-C ₆ H ₄ ) Inhibits cholesterol biosynthesis with an IC ₅₀ of 1.1 x 10 ^-8 mol / l. This corresponds to a relative activity of 1.6 based on similar hept-6E-enoic acid derivatives.

Compounds of formulas (1) and (2) are distinguished by potent inhibition of HMG-CoA reductase, the rate determining enzyme of cholesterol biosynthesis.

The enzyme HMG-CoA reductase is widely distributed in nature. This catalyzes the production of mevalonic acid from HMG-CoA. This reaction is the central stage of cholesterol biosynthesis. J.R. Sabine in CRC Series in Enzyme Biology: 3-hydroxy-3-methylglutaryl-coenzyme A reduc ase, CRC Press Inc., Boca Raten, Florida 1983 (ISBN O-849-36551-1).

High cholesterol concentrations are thought to be associated with many diseases, such as coronary heart disease or atherosclerosis. This is why lowering elevated cholesterol levels is the purpose of the prophylaxis and treatment of these types of diseases.

One approach to this is characterized by inhibiting or reducing endogenous cholesterol biosynthesis. Inhibitors of HMG-CoA reductase block cholesterol biosynthesis at an early stage.

Thus, the compounds of formulas (1) and (2) are suitable as a therapeutic agent for hypolipidemia and for the treatment and prevention of changes to atherosclerosis.

The present invention therefore also relates to pharmaceutical products and medicaments based on these compounds, in particular their use as agents for treating hypolipidemia and as a preventive agent for the change to atherosclerosis.

The compounds of the formulas (1) and (2) are used as an antihypertensive agent or an atherosclerosis agent in an oral dosage of 3 to 2500 mg, preferably 10 to 500 mg. In addition, such daily dose may be divided into two to four single doses, if necessary, or may be administered in the form of a depot. Dosage regimens may depend on the constitution, age, weight, sex and medical condition of the patient.

Further cholesterol-lowering effects can be achieved by co-administration of the compounds according to the invention with substances which bind bile acids, such as anion exchange resins. The secretion of bile acids promotes new synthesis and thus increases the destruction of cholesterol. M.S. Brown, P.T. Koranen and J.C. Goldstein, Science 212, 628 (1981); M.S. Brown, J.C. Goldstein, Spektrum der Wissenschaft 1985, 1, 96].

The compounds of formula 1 or 2 according to the invention can be used in the form of δ-lactones, as free acids, in the form of their physiologically acceptable inorganic or organic salts, or as esters. Acids and salts or esters may be in the form of their aqueous solutions or suspensions, or pharmacologically acceptable organic solvents such as monohydric or polyhydric alcohols such as ethanol, ethylene glycol or glycerol, triacetin, alcohol / acetaldehyde diacetal mixtures. , Oils such as sunflower oil or fish liver oil, ethers such as diethylene glycol dimethyl ether, or other polyethers such as polyethylene glycol, or other pharmacologically acceptable polymeric vehicles such as poly Vinylpyrrolidone) in dissolved or suspended form, or in the form of a solid dosage form.

Solid formulations which may be administered orally and which may contain conventional adjuvants are preferred for the compounds of formulas (1) and (2). These are prepared by conventional methods.

Particularly suitable formulations for oral use are tablets, coated tablets or capsules. Dosage units preferably contain 10 to 500 mg of active substance.

Compounds of formulas (3) and (4) are novel and valuable intermediates for the preparation of compounds of formula (I). Accordingly, the present invention also relates to these compounds and methods for their preparation.

Note: Unless otherwise noted, NMR spectra are recorded in CDCl ₃ containing TMS as an internal standard. The following abbreviations are used to classify NMR signals: s = single line, d = double line, t = triple line, q = quartet, h = single line, m = multiline. Melting point is not a corrected value.

The following abbreviations are used for substituents.

i = iso, t = class 3, c = cyclo

Example 1

Conventional Preparation of Compounds of Formula 7

Example 1a

1,1-dibromo-2- (4- (4-fluorophenyl) -2- (1-methylethyl) -6-phenylpyridin-3-yl) ethene (R = a; X = YZ = N = C (C ₆ H ₅ ) -CH, R ¹ = iC ₃ H ₇ , R ² = 4-FC ₄ H ₄ )

5.2 g (80 mmol) of activated Zn powder and 21.0 g (80 mmol) of triphenylphosphine are added to a solution of 26.5 g (80 mmol) of carbon tetrabromide in 500 ml of dichloromethane. After the suspension was stirred for 30 hours at room temperature, a solution of 12.8 g (40 mmol) of 4- (4-fluorophenyl) -2- (1-methylethyl) -6-phenylpyridine-3-aldehyde in 400 ml of dichloromethane was added. Add. The reaction mixture is refluxed for 48 hours and filtered. The solid component is washed with 400 ml of dichloromethane, the filtrates are collected and shaken with water and extracted, MgSO₄ Dry over phase and evaporate. The residue is purified by chromatography to give 13.0 g (68%) of the title compound.

Melting point: 116-118 ° C

¹ H NMR: δ = 1.4 (d, J = 7Hz, 6H), 3.2 (h, J = 7Hz, 1H), 7.1 (m, 2H), 7.3-7.5 (m, 6H), 7.5 (s, 1H) , 8.1 (m, 2 H).

Examples 1b-1m

The compounds listed in Tables 2a to 2b are obtained similarly to Example 1a.

Example 2

Conventional Preparation of Compounds of Formula 9

Example 2a

Methyl X = YZ = N = C (C ₆ H ₅ ) -CH, R ¹ = iC ₃ H ₇ , R ² = 4F-C ₆ H ₄ , R ¹⁵ = CH ₃ )

A) 3- (4- (4-fluorophenyl) -2- (1-methylethyl) -6-phenyl-pyridin-3-yl) prop-2-phosphate

30.3 ml (48.4 mmol) of a 1.6 M solution of n-butyllithium in hexane was added to 1,1-dibromo-2- (4- (4-fluorophenyl) -2- (1-methylethyl)-in 70 ml of THF. To a solution of 11.5 g (24.2 mmol) of 6-phenylpyridin-3-yl) ethene (Example 1a) was added dropwise at -70 ° C. The resulting solution is stirred at -70 ° C for 1 hour and at room temperature for 1 hour, then cooled to -60 ° C. After adding 10.7 g (242 mmol) of crushed dry ice, the reaction mixture was slowly brought to room temperature, hydrolyzed on ice-water, acidified with dilute hydrochloric acid and extracted several times with ether. The combined organic phases are washed with saturated NaCl solution, dried over MgSO ₄ and evaporated. The residue is 11.0 g of the title compound which is reacted further without purification. For analysis, a small amount of crude product is purified on silica gel (dichloromethane / methanol 9: 1).

Melting Point: 152-153 ° C

NMR: δ = 1.4 (m, 7H), 3.7 (h, J = 7 Hz), 7.2 (m, 2H), 7.4-7.6 (m, 6H), 8.2 (m, 2H).

MS m / e = 360 (M ⁺ + H) C ₂₃ H ₁₈ FNO ₂

B) Methyl 3- (4- (4-fluorophenyl) -2- (1-methylethyl) -6-phenyl pyridin-3-yl) prop-2-inoate

11.0 g of crude 3- (4- (4-fluorophenyl) -2- (1-methylethyl) -6-phenylpyridin-3-yl) prop-2-phosphate was dissolved in 400 ml of diethyl ether and reacted. Ethereal diazomethane solution is added in small portions until complete according to this TLC. After evaporating off the solvent, the remaining crude ester is purified by column chromatography (silica gel; cyclohexane / dichloromethane 1: 1). The title compound is obtained in a yield of 8.85 g, corresponding to 98%, based on the dibromide used.

Melting point: 118-120 ° C

NMR: δ = 1.4 (d, J = 7Hz, 6H), 3.7 (h, J = 7Hz, 1H), 3.8 (s, 3H), 7.0-7.8 (m, 8H), 8.2 (m, 2H)

MS: m / e = 374 (M ⁺ + H) C ₂₄ H ₂₀ FNO ₂

Examples 2b to 2m

The compounds listed in Tables 3a to 3d are obtained similarly to Example 2a.

Example 3

Conventional Methods for Making Compounds of Formula 10

Example 3a

3- (4- (4-fluorophenyl) -2- (1-methylethyl) -6-phenylpyridin-3-yl) prop-2-yn-1-ol (R = a; X = YZ = N = C (C ₆ H ₅ ) -CH, R ¹ = iC ₃ H ₇ , R ² = 4-FC ₆ H ₄ )

49 ml (58.6 mmol) of a 1.2 M DIBAH solution in toluene were added dropwise at 0 ° C. to a solution of 8.80 g (23.6 mmol) of methyl 2a in 100 ml of toluene at 0 ° C. and the mixture was stirred at 0-20 ° C. until the reaction was complete ( 1.5 hours) Check by TLC. Pour into 100 ml of ethyl acetate and stir the mixture for another 30 minutes, then pour into 100 ml of saturated NaCl solution, acidify with dilute hydrochloric acid until the aluminum salt is dissolved, and extract by shaking several times with ethyl acetate. The combined organic extracts are washed with saturated NaHCO ₃ solution and water, dried over MgSO ₄ and evaporated. The residue is purified by chromatography (silica gel; cyclo hexane / dichloromethane 1: 1). 7.14 g (88%) of the title compound are obtained.

Melting Point: 119-121 ° C

NMR: δ = 1.4 (d, J = 7Hz, 6H), 1.6 (s, 1H), 3.6 (h, J = 7Hz, 1H), 4.5 (s, 2H), 7.0-7.7 (m, 8H), 8.2 (m, 2 H).

MS: m / e = 346 (M ⁺ + H) C ₂₃ H ₂₀ FNO

Examples 3b to 3m

The compounds listed in Tables 4a to 4d are obtained similarly to Example 3a.

Example 4

Conventional Preparation of Compounds of Formula 3

Example 4a

3- (4- (4-fluorophenyl) -2- (1-methylethyl) -6-phenylpyridin-3-yl) prop-2-ynal (R = a; X = YZ = N = C ( C ₆ H ₅ ) -CH, R ¹ = iC ₃ H ₇ , R ² = 4-FC ₆ H ₄ )

3- (4- (4-fluorophenyl) -2- (1-methylethyl) -6-phenylpyridin-3-yl) prop-2-yn-1-ol in 150 ml of dichloromethane (Example 3a) A solution of 7.14 g (20.7 mmol) and 6.68 g (31.0 mmol) pyridinium chlorochromate is stirred at room temperature. The progress of the reaction is checked by TLC. All starting materials react after 3 hours. The reaction solution is filtered through a silica gel layer and evaporated. The residue is column chromatographed (silica gel; cyclohexane / ethyl acetate 20: 1) to give 6.4 g (90%) of the title compound.

NMR: δ = 1.4 (d, J = 7Hz, 6H), 3.8 (h, J = 7Hz, 1H), 7.2 (m, 2H), 7.4-7.6 (m, 6H), 8.2 (m, 2H), 9.7 (s, 1 H).

MS: m / e = 344 (M ⁺ + H) C ₂₃ H ₁₈ FNO

Examples 4b-4m

The compounds listed in Tables 5a to 5b are obtained similarly to Example 4a.

Example 5

Conventional Preparation of Compounds of Formula 6

Example 5a

Methyl X = YZ = N = C (C ₆ H ₅ ) -CH, R ¹ = iC ₃ H ₇ , R ² = 4-FC ₆ H ₄ , R ⁰ = CH ₃ )

26 ml (42 mmol) of 1.6 M n-butyllithium in hexane are added dropwise at 0 ° C. to a solution of 4.84 g (47.9 mmol) of diisopropylamine in 50 ml of THF. After stirring the solution for 30 minutes, 1.57 g (13.6 mmol) of methyl acetoacetate are added dropwise by cooling to -78 ° C. After the addition is complete, the resulting solution is stirred at 0 ° C. for 15 minutes and cooled to −78 ° C. again. Then 1.3 g of 3- (4- (4-fluorophenyl) -2- (1-methylethyl) -6-phenylpyridin-3-yl) prop-2-ynal (Example 4a) in 30 ml of THF ( 9.0 mmol) is added dropwise. The reaction mixture is stirred for 2 h at −78 ° C., acidified with 1M hydrochloric acid and extracted several times with ether. The combined organic phases are washed with NaHCO ₃ solution and water, dried over MgSO ₄ and evaporated. The residue is purified by chromatography to give 2.09 g (50%) of the title compound.

NMR: δ = 1.4 (d, J = 7Hz, 6H), 2.8 (d, J = 6Hz, 1H), 2.9 (dd, J = 18Hz, 4Hz, 1H), 3.0 (dd, J = 18Hz, 6Hz, 1H ), 3.5 (s, 2H), 3.7 (h, J = 7 Hz, 1H), 3.8 (s, 3H), 5.0 (m, 1H), 7.2 (m, 2H), 7.4-7.7 (m, 6H), 8.1 (m, 2 H).

MS: m / e = 460 (M ⁺ H) C ₂₈ H ₂₆ FNO ₄

Examples 5b-5m

The compounds listed in Tables 6a-6d are obtained similarly to Examples 5a.

Example 6

Conventional Preparation of Compounds of Formula 1

Example 6a

Methyl X = YZ = N = C (C ₆ H ₅ ) -CH, R ¹ = iC ₃ H ₇ , R ² = 4-FC ₆ H ₄ , R ⁰ = CH ₃ )

6.75 ml of a 1M solution of triethylborane in THF is diluted with 40 ml of THF and 10 ml of methanol is added dropwise at 0 ° C. The resulting solution is stirred at 0 ° C. for 1 hour and cooled to −78 ° C. After dropwise addition of a solution of 2.07 g (4.5 mmol) keto ester (Example 5a) in a small amount of THF, the mixture is stirred at -78 ° C for 30 minutes. 340 mg (9.0 mmol) of sodium borohydride are then added and the resulting mixture is stirred for an additional 3 hours at -78 ° C. For workup, the reaction mixture is diluted with ethyl acetate, poured into saturated ammonium chloride solution and extracted several times with ethyl acetate. The organic phase is dried (MgSO ₄ ) and concentrated to remove the boric esters and the residue is taken up in methanol and evaporated three times each. The remaining crude product is purified by column chromatography (cyclohexane / ethyl acetate 4: 1). The yield of pure title compound is 1.45 g (70%).

Melting point: 134 ℃

NMR δ: 1.4 (d, J = 7 Hz, 6H), 1.8 (m, 1H), 2.0 (m, 1H), 2.4-2.6 (m, 3H), 2.7 (d, J = 3 Hz, 1H), 3.4 ( d, J = 2H, 1H), 3.4 (s, 3H), 4.2 (m, 1H), 5.3 (m, 1H), 7.2 (m, 2H), 7.4-7.6 (m, 6H), 8.1 (m, 2H)

MS: m / e = 462 (M ⁺ + H) C ₂₈ H ₂₈ FNO ₄

Examples 6b-6m

The compounds listed in Tables 7a-7e are obtained similarly to Examples 6a.

Example 7

Conventional Preparation of Compounds of Formula 1

Example 7a

Sodium X = YZ = N = C (C ₆ H ₅ ) -CH, R ¹ = iC ₃ H ₇ , R ² = 4-FC ₆ H ₄ R ⁰ = Na)

Methyl 6a) 1.40 g (3.02 mmol) is dissolved in 40 ml of anhydrous ethanol, and 3 ml (30 mmol) of 1 M sodium hydroxide solution are added. The reaction mixture is stirred at room temperature and checked by TLC. Starting material is no longer detected after 2 hours. The solvent is evaporated off, toluene is added to the solid residue and evaporated again. The residue after drying under high vacuum is 1.47 g (100%) of the title compound in the form of white crystals.

¹ H NMR (D ₂ O): 1.1 (d, J = 7Hz, 6H), 1.6 (m, 1H), 1.8 (m, 1H), 2.1 (dd, J = 15Hz, 9Hz, 1H), 2.3 (dd , J = 15Hz, 3Hz, 1H), 3.4 (h, J = 7Hz, 1H), 3.9 (m, 1H), 4.4 (dd, J = 6Hz, 6Hz, 1H), 6.5 (s, 1H), 6.7- 6.9 (m, 7 H), 7.3 (m, 2 H).

Examples 7b-7m

The compounds listed in Tables 8a-8d are obtained similarly to Example 7a.

Example 8

Conventional Preparation of Compounds of Formula 2

Example 8a

X = YZ = N = C (C ₆ H ₅ ) -CH, R ¹ = iC ₃ H ₇ , R ² = 4-FC ₆ H ₄ )

3.3 ml (3.3 mmol) of 1 M hydrochloric acid are added to a solution of 1.40 g (2.85 mmol) of sodium 7a) in 50 ml of water. The suspension obtained is extracted several times with ethyl acetate. The combined organic layers were washed several times with saturated NaCl solution, dried over MgSO ₄ and evaporated to dry the remaining resin under high vacuum and then placed in 20 ml of dry THF and cooled in ice with 0.32 g (3.14 mmol) of triethylamine Add. After 10 minutes, 0.31 g (2.85 mmol) of methyl chloroformate is added dropwise and the resulting solution is stirred at 0 ° C. The progress of the reaction is checked by TLC. After 2 hours, the mixture is poured into water and extracted by shaking several times with ether. The combined organic extracts are washed with water and saturated NaCl solution, dried over MgSO ₄ and evaporated. The residue is purified by chromatography (silica gel; cyclohexane / ethyl acetate 2: 1) to give 0.95 g (78%) of the title compound.

Melting point: 161 ℃

¹ H NMR: 1.4 (d, J = 7 Hz, 6H), 1.9 (s, 1H), 2.1 (m, 2H), 2.5 (dd, J = 18 Hz, 6 Hz, 1H), 2.7 (dd, J = 18 Hz, 6 Hz, 1H), 3.7 (h, J = 7 Hz, 1H), 4.3 (m, 1H), 5.5 (dd, J = 6 Hz, 5 Hz, 1H), 7.2 (m, 2H), 7.4-7.6 (m, 6H ), 8.1 (m, 2H)

MS: m / e = 430 (M ⁺ + H) C ₂₇ H ₂₄ FNO ₃

Examples 8b-8m

The listed compounds of Tables 9a-9f are obtained similarly to Example 8a.

Claims (3)

Lactone of formula (2). Formula 2 In Chemical Formula 2, R is a) chemical formula Radicals where X = YZ is a group of formula CR ³ = CR ⁴ -CR ⁵ , wherein R ³ is hydrogen, R ⁴ is isopropyl, tert-butyl, phenyl or 4-fluorophenyl, R ⁵ is hydrogen, R ¹ is isopropyl, R ² is 4-fluorophenyl, or X = YZ is a group of the formula N = CR ⁴ -CR ⁵ , wherein R ⁴ is isopropyl, tertiary- Butyl, phenyl or 4-fluorophenyl, R ⁵ is hydrogen), R ¹ is isopropyl or cyclopropyl, R ² is 4-fluorophenyl or X = YZ is represented by the formula N = N-CR ⁵ Is a group of wherein R ⁵ is phenyl or 4-fluorophenyl, R ¹ is isopropyl, R ² is 4-fluorophenyl, or X = YZ is a group of formula N = CR ⁴ -N Wherein R ⁴ is isopropyl, tert-butyl, phenyl or 4-fluorophenyl), R ¹ is isopropyl and R ² is fluorophenyl], b) chemical formula Radicals where R ⁶ is isopropyl, R ⁷ is 4-fluorophenyl, UVW is a group of the general formula C-NR ⁹ -CR ⁸ , wherein R ⁸ is hydrogen and R ⁹ is isopropyl or Phenyl)] or c) chemical formula Is a radical of which AB is a group of formula C = C, R ¹¹ is isopropyl and R ¹² and R ¹³ are 4-fluorophenyl or 4-fluoro-3-methylphenyl. A process for preparing the compound of formula (2) as claimed in claim 1, characterized by converting the compound of formula (1) to lactone of formula (2). Formula 1 Formula 2 In Chemical Formulas 1 and 2, R is In Chemical Formula 2, R is a) chemical formula Radicals where X = YZ is a group of formula CR ³ = CR ⁴ -CR ⁵ , wherein R ³ is hydrogen, R ⁴ is isopropyl, tert-butyl, phenyl or 4-fluorophenyl, R ⁵ is hydrogen, R ¹ is isopropyl, R ² is 4-fluorophenyl, or X = YZ is a group of the formula N = CR ⁴ -CR ⁵ , wherein R ⁴ is isopropyl, tertiary- Butyl, phenyl or 4-fluorophenyl, R ⁵ is hydrogen), R ¹ is isopropyl or cyclopropyl, R ² is 4-fluorophenyl or X = YZ is represented by the formula N = N-CR ⁵ Is a group of wherein R ⁵ is phenyl or 4-fluorophenyl, R ¹ is isopropyl, R ² is 4-fluorophenyl, or X = YZ is a group of formula N = CR ⁴ -N Wherein R ⁴ is isopropyl, tert-butyl, phenyl or 4-fluorophenyl), R ¹ is isopropyl and R ² is fluorophenyl], b) chemical formula Radicals where R ⁶ is isopropyl, R ⁷ is 4-fluorophenyl, UVW is a group of the general formula C-NR ⁹ -CR ⁸ , wherein R ⁸ is hydrogen and R ⁹ is isopropyl or Phenyl)] or c) chemical formula Radicals, wherein AB is a group of formula C = C, R ¹¹ is isopropyl, R ¹² and R ¹³ are 4-fluorophenyl or 4-fluoro-3-methylphenyl, R ⁰ is hydrogen, methyl, ethyl, tert-butyl, sodium or potassium. A pharmaceutical product containing a compound as claimed in claim 1 for preventing and treating hypercholesterolemia.