DE3530798A1 - 6-Phenoxymethyl-4-hydroxytetrahydropyran-2-ones, processes for their preparation, their use as medicaments, pharmaceutical preparations and intermediates - Google Patents

Abstract

6-Phenoxymethyl-4-hydroxytetrahydropyran-2-ones of the formula I <IMAGE> in which R<1>, R<2>, R<3>, R<4> and R<5> have the meanings indicated, and the corresponding open-chain dihydroxycarboxylic acids, their pharmacologically tolerable salts and esters, processes for the preparation of these compounds, their use as medicaments, and pharmaceutical preparations are described. In addition, novel intermediates for the preparation of the compounds of the formula I are described.

Description

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) catalyzes the formation of mevalonic acid from 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA). This reaction plays a central role in the biosynthesis of cholesterol. Derivatives of 3-hydroxy-3-methyl-glutaric acid (HMG) and mevalonic acid have been described as inhibitors of cholesterol biosynthesis (MR Boots et al., J. Pharm. Sci. 69, 306 (1980), FM Singer et al., Proc. Soc. Exper. Biol. Med. 102, 270 (1959), H. Feres, Tetrahedron Lett. 24, 3769 (1983)). 3-Hydroxy-3-methyl-glutaric acid itself shows significant cholesterol-lowering effects in rats and in human experiments (Z. Beg, Experientia 23, 380 (1967), ibid 24, 15 (1968), PJ Lupien et al., Lancet 1978, 1, 283). It has now been found that 6-phenoxymethyl-4-hydroxytetrahydropyran-2-one of the general formula I or the corresponding dihydroxycarboxylic acids, their salts and esters are inhibitors of HMG-CoA reductase. The invention therefore relates to new 6-phenoxymethyl-4-hydroxytetrahydropyran-2-ones of the general formula I. wherein
R ¹ and R ^{5 are the} same or different and a) hydrogen or halogen, b) cycloalkyl having 4-8 C atoms or a phenyl radical which can be substituted 1 to 3 times in the nucleus with halogen, trifluoromethyl and / or alkyl or alkoxy each having 1-4 carbon atoms or c) a straight-chain or branched alkyl radical having 1 to 18 carbon atoms or a straight-chain or branched alkenyl radical having 2 to 18 carbon atoms, the alkyl or alkenyl radicals themselves being substituted 1-3 times can be with

α) straight-chain or branched alkoxy radicals with up to 10 carbon atoms or cycloalkoxy radicals with 3 to 7 carbon atoms or straight-chain or branched alkenyloxy or Alkynyloxy radicals with 3 to 6 carbon atoms,

β) halogen, hydroxy, cycloalkyl with 3-7 C atoms, unsubstituted phenyl, α or β thienyl radicals, or phenyl, α or β-thienyl radicals, which in turn is substituted 1 to 3 times in the core are with halogen, trifluoromethyl and / or alkyl or alkoxy with 1-4 C atoms,

γ) unsubstituted phenoxy, benzyloxy, α or β-thienyloxy radicals, or phenoxy, benzyloxy, α- or β-thienyloxy radicals, which in turn in the core are 1 to 3 times substituted with Halogen, trifluoromethyl and / or alkyl or Alkoxy with 1 to 4 carbon atoms,

δ) of the group where R ⁶ denotes: a straight-chain or branched alkyl or alkenyl radical having up to 8 carbon atoms, or a cycloalkyl or cycloalkenyl radical each having 3-8 C atoms, or an unsubstituted phenyl radical or a phenyl radical, which in turn has a core of 1- to 3- is substituted with halogen, trifluoromethyl and / or alkyl or alkoxy with 1-4 C atoms, or a 3-pyridyl radical,

R ² and R ^{4 are the} same or different and are hydrogen, alkyl with 1-4 C atoms, halogen or alkoxy with 1-4 C atoms, and

R ^{3 is} hydrogen, alkyl or alkenyl with up to 4 C atoms, halogen or alkoxy with 1-4 C atoms, and the corresponding open-chain dihydroxycarboxylic acids, their pharmacologically acceptable salts with bases and their pharmacologically acceptable esters.

The substituents preferably have the following meanings:
R ¹ and R ⁵ , both the same or different:
a) hydrogen or halogen,
b) cycloalkyl with 5 to 6 carbon atoms phenyl, which can be substituted 1-3 times in the nucleus with halogen, trifluoromethyl and / or alkyl or alkoxy, each with 1-4 carbon atoms, or
c) 1. straight-chain or branched alkyl or alkenyl having up to 12 carbon atoms, it being possible for the alkyl or alkenyl radical in turn to be substituted 1-2 times with phenyl radicals which in turn may be substituted 1 to 3 times with halogen in the nucleus, Trifluoromethyl and / or alkyl or alkoxy with 1-4 C atoms,
2. straight chain, with substituted alkyl of the formula where n = 1 to 3 and R ^{6 is} a straight-chain or branched alkyl or alkenyl radical having up to 8 carbon atoms, a cycloalkyl radical having 5 to 6 carbon atoms, or a phenyl radical, which in turn can be substituted 1-3 times in the nucleus can with halogen, trifluoromethyl and / or alkyl or alkoxy with 1 to 4 carbon atoms,
3. straight-chain alkyl of the formula substituted by OR ⁷

- (CH ₂ ) _n OR ⁷ ,

in which n = 1 to 3 and R ^{7 is} hydrogen or a straight-chain or branched alkyl or alkenyl radical having up to 8 carbon atoms, a cycloalkyl radical having 5 to 6 carbon atoms, or a phenyl radical or benzyl radical, which in turn is 1- in the aromatic nucleus 3 times can be substituted with halogen, trifluoromethyl and / or alkyl or alkoxy with 1 to 4 carbon atoms,
R ² and R ^{4 are} hydrogen,
R ^{3 is} hydrogen, methyl, ethyl, propyl, 1-propenyl, allyl fluorine or chlorine.

The substituents particularly preferably mean:
R ¹ and R ⁵ , where R ¹ and R ^{5 are the} same or different:
1) hydrogen, methyl, ethyl, propyl, allyl, 1- propenyl, isopropenyl, isopropyl, cyclopentyl, cyclohexyl, or
2) the group with n = 1-3, where R ⁶ means: methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl, phenyl or in the core 1- to 3-fold substituted phenyl with halogen, methyl or methoxy, or
3) the group - (CH ₂ ) _n OR ⁷ , with n = 1 to 3, where R ⁷ means: hydrogen, methyl, straight-chain or branched alkyl or alkenyl with 3-5 carbon atoms, cyclopentyl, cyclohexyl; Phenyl or benzyl, where the aromatic nuclei can be substituted 1-3 times with fluorine, chlorine, methyl, methoxy, or
4) an alkyl group of the formula

- (CH ₂ ) _n CHR ⁸ R ⁹

wherein n = 0 to 2 and R ⁸ and R ^{9 are the} same or different and are hydrogen, methyl, ethyl, propyl, allyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclohexyl, cyclopentyl, benzyl or Phenyl, where the aromatic nuclei can be substituted 1 to 3 times with fluorine, chlorine, methyl or methoxy.
R ² and R ^{4 are} hydrogen
R ^{3 is} hydrogen, methyl, chlorine, fluorine

As pharmacologically acceptable salts of dihydroxycarboxylic acids, which have the formula VII wherein R ¹ to R ^{5 have} the meanings given for formula I, alkali metal salts or ammonium salts may be mentioned; pharmaceutically acceptable esters are e.g. B. alkyl esters with 1 to 4 carbon atoms, phenyl ester, benzyl ester or 2,3-dihydroxypropyl ester.

The invention relates to the enantiomers with the in general Formula I specified absolute configuration 4R, 6S, the open-chain dihydroxycarboxylic acids VII, whose esters and salts are those specified in the general formula VII have absolute configuration 3R, 5S.

The invention further relates to a process for the preparation of the compounds of general formula I, which is characterized in that:
a) appropriately substituted phenols of the formula II, wherein R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meanings given, with the chiral iodide of the formula III wherein R ^{10 is} a protective group stable against bases and weak acids, e.g. B. the t-butyldiphenylsilyl group (t-BuPh ₂ Si),
into the ethers of formula IV wherein R ¹ to R ^{5 have} the meanings given for formula I and R ^{10 have} the meanings given for formula III
b) the ethers of the formula IV to the corresponding hemiacetals of the formula V. wherein R ¹ to R ⁵ and R ^{10 have} the meanings given for formulas I and III, hydrolyzed,
c) the hemiacetals of formula V to the corresponding lactones of formula VI wherein R ¹ to R ^{5 have} the meanings given for formula I and R ¹⁰ for formula III, oxidized and
d) the protected hydroxylactones of the formula VI in the 6-phenoxymethyl-4-hydroxytetrahydropyran-2-ones of the formula I. transferred, optionally converting the compounds of the formula I obtained into the corresponding open-chain dihydroxycarboxylic acids, their salts or their esters, optionally converting salts or esters into the free dihydroxycarboxylic acids or optionally converting the free carboxylic acids into the salts or esters.

The etherification of compounds of the formula II with compounds of the formula III to compounds of the general Formula IV takes place e.g. B. in a solvent in the presence a base, preferably using dimethyl sulfoxide of potassium carbonate at 50-80 ° C.

The hydrolysis of acetals IV to semi-acetals V is appropriately carried out under aqueous acidic conditions, preferably with acetic acid in tetrahydrofuran / water mixtures, or with hydrochloric acid in THF / water or trifluoroacetic acid at 0-80 ° C.

The conversion of the hemiacetals V into the lactones VI is included Performed using an oxidizing agent, preferably with chromium trioxide in pyridine / methylene chloride.

The cleavage of the t-butyldiphenylsilyl group to the free Hydroxylactones I is preferred in acetonitrile aqueous hydrogen fluoride at 40-60 ° C or with tetrabutylammonium fluoride in glacial acetic acid / THF at room temperature or slightly elevated temperature.

The hydroxalactones I are optionally with aqueous alkali with the help of a solvent, for example Alcohol of tetrahydrofuran in the usual way in the Transferred alkali salts, from which the acid let free acids be preserved. The ammonium salts are with corresponding amines from the free acids in generally known Way get. The free acid esters can from these themselves, from the corresponding alkali salts or obtained from lactones I by customary known methods will.

If the individual reaction products are not already sufficient  pure form so that they can be used for the following Reaction step can be used, a Purification using crystallization, column or high pressure liquid chromatography.

If the iodide of formula III is not a pure enantiomer is present, mixtures of the enantiomeric end products arise, which are separated by common procedures can be.

The chiral iodide III can, for example, according to a known Procedure (J.R. Falck, Tetrahedron Lett 23, 4305 (1982)) from tri-O-acetyl-D-glucal.

Insofar as the phenols II used as starting material are not described in the literature, they can be prepared in analogy to known processes (Houben-Weyl, Methods of Organic Chemistry, Volume VI / 1 c. 1976). A preferred process for the preparation of phenols II which have the general formulas XVII, XVIII and XIX given in formula 1, where the radicals R ¹ - R ^{4 have} the meaning given above, starts from appropriately substituted phenols X (formula 1). These are converted into the corresponding allyl ether XI, preferably with allyl bromide in acetone or dimethylformamide at elevated temperature using a suitable base, for. As potassium carbonate, the allyl ethers XI are rearranged at elevated temperature in the corresponding allylphenols XII, in many cases without solvent but also optionally using diethylaniline as solvent. The phenols XII thus obtained are protected on the OH group. The benzyl group is suitable as a protective group (Z), but also others such as, for. B. THP can be used. The protected allylphenols XIII are preferably hydroborated with diborane or 9-borabicyclo (3.3.1) nonane (9-BBN) in tetrahydrofuran to give the alcohols XV ( n = 3). The aldehydes XIV are from the protected phenols XIII with oxidizing agents such. B. NaIO ₄ / OsO ₄ or ozone either obtained directly or obtained by glycol cleavage of the 1,2-diols obtainable from XIII. Reduction of the aldehydes XIV, preferably with sodium hydride, leads to the alcohols XV ( n = 2). The alcohols of the formula XV ( n = 2 or 3) are optionally converted into a reactive derivative, preferably tosylate, mesylate or iodide and with appropriate phenols or alcohols in the presence of a base, preferably potassium carbonate, in suitable solvents, for. B. etherified dimethyl sulfoxide or dimethylformamide (compounds of formula XVII according to the formula, but protected). Alternatively, the alcohols XV ( n = 2, 3) can be reacted with suitable alkyl halides, for example in dimethylformamide using sodium hydride as base to the protected ethers corresponding to XVII. After the protective group Z has been removed, the phenols XVII are obtained. Acylation of the alcohols XV with a reactive derivative of a carboxylic acid by generally customary methods leads to phenols of the formula XVIII after the protective group Z has been split off. The action of suitable Grignard reagents on the aldehydes XIV leads to the alcohols XVI. These alcohols are converted into the phenols of the formula XIX (R ⁹ = H) by generally known processes. The alcohols XVI can be converted into the corresponding ketones using oxidizing agents and then converted into the phenols XIX (R ⁸ , R ⁹ ≠ H) by renewed action of a Grignard reagent and according to generally known processes. For phenols XIX with n = 0, it is expedient to start from appropriate benzaldehydes, benzoic esters or aromatic ketones.

Formula scheme 1

In addition to the compounds described in the examples, the following compounds can be prepared by the processes according to the invention:
6 (S) {2- [3- (4-fluorophenoxy) propyl] -4-methyl-6-propylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [3- (4-fluorophenoxy) propyl] -4-fluoro-6-propylphenoxymethyl} -3,4,5,6-tetrahydro-4- (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [3- (4-chlorophenoxy) propyl] -4-fluoro-6-propyleneoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {3- (4-methylphenoxy) propyl] -4-fluoro-6-propylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [3- (4-fluorophenoxy) propyl] -4-chloro-6-propylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2,6-bis- [3- (4-fluorophenoxy) propyl] -4-methylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2,6-bis- [3- (4-methylphenoxy) propyl] -4-methylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [3- (2,4,6-trimethylphenoxy) propyl] -6-allyl-4-methylphenoxymethyl} -3,4,5,6-tetrahydro-4- (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [3- (2,4,6-trimethylphenoxy) propyl] -6-propyl-4methylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [3- (4-fluorophenoxy) propyl] -4-chloro-6-cyclopentylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [3- (4-Methylphenoxy) propyl] -4-chloro-6-cyclopentylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [3- (4-fluorophenoxy (propyl) -4-methyl-6-cyclopentylphenoxymethyl} -3,4,5,6-tetrahydro-4- (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [2- (4-fluorophenyl (ethyl] -4-methyl-6-cyclopentylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [2- (4-methylphenyl) ethyl] -4-methyl-6-cyclopentylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [2- (4-chlorophenyl) ethyl] -4,6-dimethylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [2- (4-fluorophenyl) ethyl] -4-methyl-6-propylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [2- (4-fluorophenoxy) ethyl] -4,6, -dimethylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [2- (4-methylphenoxy) ethyl] -4,6-dimethylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [2,2-bis (4-methylphenyl) ethyl] -4,6-dimethylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - [2- (4-methylbenzyl) -4,6-dimethylphenoxymethyl] -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - [2- (4-methylphenoxymethyl] -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - [2- (4-fluorobenzyl) -6-methylphenoxymethyl] -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - [2-bis- (4-methylphenyl) methyl-4,6-dimethylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - [2-bis- (4-methylphenyl) methyl-6-methylphenoxymethyl] -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - [2-bis- (4-fluorophenyl) methyl-6-methylphenoxymethyl] -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - [2- [1- (4-fluorophenyl-3-methylbutyl] -4,6-dimethylphenoxymethyl] -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [1- (4-fluorophenyl) 2-methylpropyl] -4,6-dimethylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - (2-cyclohexylmethyl-4,6-dimethylphenoxymethyl) -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - [2- (1-Cyclohexyl-1-methyl) ethyl-4,6-dimethylphenoxymethyl] -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [1- (4-fluorophenyl) -1-methyl] ethyl-4,6-dimethylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [1- (4-fluorophenyl) -3-methylbutyl] -6-cyclopentylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - {2- [1- (4-fluorophenyl) -1-methylethyl] -6-cyclopentylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - (2-cyclohexylmethyl-6-cyclopentyl) phenoxymethyl) -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) - [2- (3,4,5-trimethoxybenzyl) -6-cyclopentylphenoxymethyl] -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) [2- (4-fluorophenyl) -6-cyclopentylphenoxymethyl] -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) [2- (2-cyclohexylethyl) -4,6-dimethylphenoxymethyl] -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) {2- [2,2-bis (4-fluorophenyl) ethyl] -6-cyclopentylphenoxymethyl} -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one
6 (S) [2- (3,4,5-trimethoxybenzyl) -4,6-dimethylphenoxymethyl] -3,4,5,6-tetrahydro-4 (R) -
hydroxy-2H-pyran-2-one

The enzyme HMG-CoA reductase is widespread in nature. It catalyzes the formation of mevalonic acid from HMG-CoA. This reaction is a key step in cholesterol biosynthesis (I.R. Sabine, 3-hydroxy-3-methylglutaryl Coenzyme A Reductase, CRC Press, 1983). High cholesterol are associated with a number of diseases such as B. coronary artery disease or atheroaclerosis related brought. Therefore, lowering cholesterol levels for the prevention and treatment of such diseases a therapeutic Target. One starting point is inhibition or Decrease in endogenous cholesterol synthesis. Inhibitors of HMG-CoA reductase block cholesterol biosynthesis at an early stage. They are therefore suitable for prevention and treatment of diseases caused by an increased Cholesterol levels are caused. A reduction or Decrease in endogenous synthesis leads to an increased Absorption of cholesterol from the plasma into the cells. A additional effect can be given by simultaneous administration Achieve bile acid binding substances such as anion exchangers. The increased bile acid excretion leads to an increased New synthesis and thus an increased cholesterol reduction (M. S. Brown, P. T. Kovanen, J. L. Goldstein, Science 212, 628 (1981): M. S. Brown, J. L. Goldstein Spectrum of Science 1985 (1), 96). The compounds of the invention are inhibitors of HMG-CoA reductase. You are suitable therefore to inhibit or reduce cholesterol biosynthesis and thus for the prevention or treatment of Diseases caused by high cholesterol especially coronary artery disease, atherorsclerosis, Hypercholesterolemia, hyperlipoproteinemia and similar diseases.

The invention therefore also relates to pharmaceutical preparations based on the compounds of formula I or the corresponding Dihydroxycarboxylic acids, their salts and esters, and the use of these compounds as pharmaceuticals, in particular to treat hypercholesterolemia.  

The compounds of the formula I or the corresponding acids, Salts or esters come in different dosage forms administered, preferably orally in the form of tablets, Capsules or liquids. The daily dose is moving depending on body weight and constitution of the patient in the area from 3 mg to 2500 mg, but preferably in the dose range 10-500 mg.

The compounds of the invention can be used as lactones general formula I, in the form of the free acids VII or in Form of pharmaceutically acceptable salts or esters for use come, dissolved or suspended in pharmacological harmless organic solvents such as one or polyhydric alcohols such as B. ethanol or glycerin, in triacetin, oils such as B. sunflower oil or cod liver oil, Ethers such as B. diethylene glycol dimethyl ether or Polyethers such as B. polyethylene glycol or in the presence other pharmacologically acceptable polymer carriers such as e.g. B. polyvinyl pyrrolidone or other pharmaceutically acceptable Additives such as starch, cyclodextrin or polysaccharides. The compounds of the invention can also be combined with additives that bind bile acids, especially non-toxic, basic anion exchange resins, the bile acids in a non-absorbable form bind in the gastrointestinal tract. The salts of dihydroxycarboxylic acids can also be processed as an aqueous solution will.

The compounds of formulas IV-VI are new and z. B. valuable Intermediates for the production of connections of formula I. The invention therefore also relates to the compounds of the formulas IV, V and VI and methods for their Manufacturing.  

The HMG-CoA reductase activity was determined in the following test systems certainly: 1) Inhibition of HMG-CoA reductase activity on solubilized Enzyme preparations from rat liver microsomes

The HMG-CoA reductase activity was measured on solubilized enzyme preparations from liver microsomes of rats, which were induced with cholestyramine (®Cuemid) after switching in the day-night rhythm. (S, R) ¹⁴ C-HMG-CoA was used as substrate, the concentration of NADPH was maintained during the incubation by a regenerating system. ¹⁴ C-Mevalonate was separated from the substrate and other products (e.g. ¹⁴ C-HMG) by column elution, the elution profile of each individual sample being determined. The ³ H-mevalonate was never carried because the determination is a relative statement of the inhibitory effect. In a series of tests, the enzyme-free control, the enzyme-containing normal batch (= 100%) and those with preparation additives were treated together. Each individual value was averaged from 3 parallel samples. The significance of the mean differences between specimen-free and specimen-containing samples was assessed after the t-test.

According to the method described above, z. B. the following inhibitory values for HMG-CoA reductase are determined:

2) Suppression or inhibition of HMG-CoA reductase in Cell cultures of fibroblasts

Monolayers of fibroblasts (L cells) in lipoprotein-free nutrient medium were incubated with appropriate concentrations of the test substances for a certain time (for example 3 hours), then the HMG-CoA reductase activity of the cells, modified according to Chang et al. (J. Biol. Chem. 256, 6174 (1981)). For this, the cell extracts were incubated with D, L [ ³ H] -HMG-CoA and the product [ ³ H] -mavalonate formed from the cells under the action of the existing HMG-CoA reductase activity after cyclization to [ ³ H] -evalonolactone by thin-layer chromatography separated from the starting product and, using an internal standard of [ ¹⁴ C] -evalonate, the amount of the [ ³ H] -evalonate formed in the unit of time, based on the amount of cell protein, was determined. The HMG-CoA reductase activity of the cell culture found with the addition of a certain concentration of a test preparation was related as a percentage to that of an identical treatment without test preparation, but the same solvent concentration.

Biological test results:

Under the condition of a three-hour incubation period of confluent L cells in the lipoprotein-free nutrient medium with the investigated compounds, the following molar concentration of the test preparations required for 50% inhibition of HMG-CoA reductase activity (IC ₅₀ ) was determined: Preparation of the starting compounds of the formula II

Example 1:

2-allyl-4,6-dimethylphenol (1) (Formula Scheme 1, XII)

150 g (1.23 mol) of 2,4-dimethylphenol, 330 g (2.4 mol) of potassium carbonate and 180 g (1.5 mol) of allyl bromide were stirred under reflux in 900 ml of acetone for 20 h. After cooling, the precipitate was filtered off and washed with acetone. The filtrate was concentrated in vacuo and the residue was partitioned between petroleum ether and 2N sodium hydroxide solution. The organic phase was washed three times with 2N sodium hydroxide solution and twice with water. Drying with magnesium sulfate, concentration in vacuo and distillation gave 178.7 g (1.08 mol, 88%) of 2,4-dimethylphenyl allyl ether, bp. 86 ° C./7 torr. The allyl ether was heated to 210 ° C. for 3 hours with no solvent. Distillation gave 165.4 g (1.02 mol. 94%) of 2-allyl-4,6-dimethylphenol (1) bp. 96-100 ° C / 8 torr. ¹ H-NMR (CDCl ₃ , 60MHz): δ = 2.2 (S, 6 H, methyl-H), 3.3 (d, 2H, -CH ₂ -), 4.6 (s, 1 H, -OH), 4.8-6.2 (m, 3 H, olefinic H), 6.7 (m, 2 H, aromatic H).

Example 2:

2-allyl-4,6-dimethylphenylbenzylether (2) (Formula Scheme 1, XIII)

76.15 g (0.47 mol) of 2-allyl-4,6-dimethylphenol, 130 g (0.94 mol) of potassium carbonate and 65.5 g (0.52 mol) of benzyl chloride were refluxed in 1 l of acetone for 20 h heated. After 20 hours, a further 26 g of potassium carbonate and 13 g of benzyl chloride were added. It was suction filtered and the filtrate was concentrated in vacuo and taken up in toluene. The organic phase was washed twice with 2N sodium hydroxide solution and twice with water. Drying with magnesium sulfate, stripping off the solvent and distillation gave 109.8 g (0.44 mol, 85%) of benzyl ether 2, b.p .: 147-153 ° C / 0.2 torr. ¹ H-NMR (CDCl ₃ , 60 MHz): δ = 2.2 (s, 6 H, methyl-H), 3.4 (d, 2 H, allyl.-CH ₂ -), 4.7 (s , 2 H, benzyl.-CH ₂ -), 4.8-6.2 (m, 3 H, olefinic H), 6.8 (s, 2 H, aromatic H), 7.0-7.4 ( m, 5 H, aromatic H).

In analogy to Example 1, the allylphenols 3,5,7,10, 13 and 15 obtained and in analogy to Example 2 as benzyl ether 4,6,8,11,14 and 16 protected.  

Table 1

(the formulas correspond to formulas X, XII and XIII of formula 1)

Table 1 continued

Example 17:

3- (2-benzyloxy-3,5-dimethylphenyl) propan-1-ol (17) (Formula scheme 1, XV)

108.5 g (0.43 mol) of 2-allyl-4,6-dimethylphenylbenzyl ether (Example 2) were in 250 ml of dry tetrahydrofuran under an argon atmosphere with 0.76 g (0.258 mol) of sodium borohydride transferred. Within 5 minutes, with stirring 32.5 g (0.258 mol) of dimethyl sulfate were added dropwise. The reaction mixture warmed up to approx. 40 ° C. It was left for 4 hours Stir at 35-40 ° C. Then were careful at 5 ° C 43 ml of water and then 320 ml of 14N aqueous Sodium hydroxide solution added dropwise. Finally, were under cooling 65 ml 35 percent (0.75 mol) of hydrogen peroxide solution was added dropwise and stirred for 30 min. The reaction mixture was poured into toluene and four times with ice water and twice washed with saturated aqueous sodium chloride solution. Dry with magnesium sulfate and concentrate in vacuo 110.4 g of a light yellow oil. Prep. HPLC on silica gel (Cyclohexane / ethyl acetate = 5: 1) gave 89.16 g (0.33 Mol. 76%) alcohol as a light yellow oil.

¹ H-NMR (CDCl ₃ , 60 MHz): δ = 1.8 (m, 2H, -CH ₂ -), 2.2 (d, 6H, methyl-H), 2.7 (t, 2H, Ar -CH ₂ -), 3.4 (t, 2H, -CH ₂ O-), 4.8 (s, 2H, benzyl. -CH ₂ -) 6.8 (s. 2H, aromatic H), 7, 0-7.4 (m, 5H, aromatic H).

Example 18:

3- {2-benzyloxy-3- [3- (4-fluorophenoxy) propyl] -4-chloro} propan-1-ol (18) (Formula 1, XV)

72.6 ml of a 0.5 m 9-BBN solution (35 mmol) in tetrahydrofuran were placed in 50 ml of dry tetrahydrofuran. At room temp. 9.5 g (23.1 mmol) of allyl compound became Example 11 added dropwise and stirred for 30 min. Then was  Heated under reflux for 1 h. After cooling, they were consecutively carefully 14 ml of ethanol, 23 ml of 2N aqueous NaOH (46 mmol) and finally 6.1 ml (59 mmol) 30 percent. Hydrogen peroxide solution. The mixture was allowed to reflux for 1 hour Cook. The reaction mixture was poured into toluene. The organic phase was three times with ice water and once washed with saturated aqueous sodium chloride solution. Dry with magnesium sulfate, concentrate in vacuo and Chromatography on silica gel (cyclohexane / ethyl acetate = 5: 1) gave 9.0 g (21 mmol, 91%) alcohol 18

¹ H-NMR (CDCl ₃ , 60 MHz): δ = 1.4-2.5 (m, 4 H, -CH ₂ -), 2.5-3.0 (m, 4 H, Ar-CH ₂ -), 3.5 and 3.8 (each t, each 2H, -OCH ₂ -), 4.8 (s, 2H, benzyl, -CH ₂ -), 6.6-7.5 (m, 11H , aromatic H).

In analogy to Examples 17 and 18, those in Table 2 alcohols listed.

Table 2: (see formula 1, XV)

Example 24:

2- [3- (4-fluorophenoxy) propyl] -4,6-dimethylphenol (24) (Formula scheme 1, XVII)

1. 43.5 g (162 mmol) of 17 were dissolved in 160 ml of methylene chloride and 160 ml of pyridine, and 37 g (194 mmol) of p-toluenesulfonic acid chloride were added in portions with cooling. They were left at room temp. come. After 18 h the solvent was removed in vacuo and the residue was taken up in toluene and washed twice with water and twice with saturated aqueous sodium hydrogen carbonate solution and finally with saturated aqueous sodium chloride solution. Drying with magnesium sulfate, stripping off the solvent and chromatography on silica gel (CH ₂ C1 ₂ ) gave 51 g (120 mmol, 74%) tosylate 17a as a colorless oil.

2. 51 g (120 mmol) tosylate (17a) were mixed with 90 g (600 mmol) Sodium iodide in 900 ml of acetone heated under reflux for 4 h. You sucked off the insoluble. The filtrate was in vacuo concentrated and the residue taken up in toluene. The organic phase was washed once with water, twice with 2 percent aqueous sodium bisulfite solution and once with saturated aqueous sodium hydrogen carbonate solution washed. Drying with magnesium sulfate, peeling off the Solvent in vacuo and chromatography on silica gel (cyclohexane / ethyl acetate = 92: 8) gave 40.6 g (107 mmol, 89%) iodide 17b as a colorless oil.

3. 9.62 g (86 mmol) of 4-fluorophenol was added with 23.7 g (172 mmol) potassium carbonate in 75 ml of dimethyl sulfoxide submitted. 21.8 g (57.3 mmol) of iodide 17b were added and heated to 50 ° C for 4 h. The reaction mixture was partitioned between ether and water. The watery Phase extracted again with ether. The United Ether phases were washed once with water and over Magnesium sulfate dried. Remove the solvent  in vacuum and chromatography on silica gel (cyclohexane / ethyl acetate = 9: 1) gave 20.5 g (56.3 mmol), 98%) 4-fluorophenyl ester.

4. 20.5 g (56.3 mmol) of 4-fluorophenyl ether was added to 200 ml Methanol with 1 g Pd / C (10%) at room temp. and normal pressure hydrated. After chromatography, 13.3 g were obtained (48.5 mmol, 86%) 2- [3- (4-fluorophenoxy) propyl] -4,6-dimethylphenol (24).

MS: 274 (M⁺)
¹ H-NMR (CDCl ₃ , 60 MHz): δ = 1.8 - 2.3 (s and m, 8H, methyl-H, -CH ₂ -), 2.8 (t, 2H, Ar-CH ₂ -), 3.9 (t, 2H, OCH ₂ -), 5.1 (s, 1H, OH), 6.7-7.2 (m, 6H, aromatic H).

Example 25:

2- [2- (4-fluorophenoxyethyl] -4,6-dimethyl phenol (25)

In analogy to Example 24, Example 38 became Tosylate obtained according to reaction 21.1 and directly in Dimethylformamide using 1.05 equivalents Potassium carbonate at 150 ° C, reacted with 4-fluorophenol. Cleavage of the protective group according to 24.4 gave phenol 25.

MS: 260 (M⁺)
¹ H NMR (CDCl ₃ , 60 MHz): δ = 225 (s, 6H, -CH ₃ ), 3.06 (t, 2H, Ar-CH ₂ -), 4.20 (t, 2H, -CH ₂ O) ), 6.50 (2, 1H, OH), 6.67-7.00 (m, 6H, aromatic H)

In analogy to Example 24, those listed in Table 3 were Phenols. The benzyl group is split off was used for chloroaromatics with the addition of acetic acid carried out.

Table 3: (see Formula Scheme 1, XVII)

Table 3 continued

Example 32:

2- [3- (4-fluorophenoxy) propyl] -4-chloro-6- (3-pivaloyloxypropyl) phenylbenzyl ether (32) (see formula scheme 1, XVIII, protected)

9 g (21 mmol) of alcohol 18 were dissolved in 90 ml of methylene chloride and 90 ml triethylamine dissolved and with 3.4 g (28 mmol) Pivaloyl chloride stirred overnight. The mixture was on Ice / conc. Poured hydrochloric acid and the organic phase once with 2N hydrochloric acid and once with saturated aqueous sodium bicarbonate solution washed. Drying with magnesium sulfate, Stripping off the solvent and chromatography on silica gel (cyclohexane / ethyl acetate = 5: 1) gave 5.12 g (10 mmol, 48%) pivaloyester 32.

¹ H-NMR (CDCl ₃ , 60 MHz): δ = 1.2 (s, 9H, methyl-H), 1.7-2.3 (m, 4H, -CH ₂ -), 2.5-3 , 0 (m, 4H, Ar-CH ₂ -), 3.7-4.3 (m, 4H, -OCH ₂ -), 4.8 (see 2H, benzyl.-CH ₂ -), 6, 5-6.6 (m, 11H, aromatic H).

Example 33:

2- [3- (4-fluorophenoxy) propyl] -4-chloro-6- (3-pivaloyloxypropyl) phenol (33) (see Formula Scheme 1, XVIII)

5.1 g (10 mmol) of pivaloyl ester were dissolved in 200 ml of ethyl acetate and 20 ml glacial acetic acid with 500 mg palladium hydrogenated on carbon (10%) at room temperature and normal pressure. Chromatography on silica gel gave 3.7 g (8.8 mmol, 87%) phenol 33.

Mp: 78 ° C

MS: 422 (M⁺), 320  

The examples were analogous to Examples 32 and 33 34-36 manufactured.

Example 34:

2- [3- (4-fluorophenoxy) propyl] -4-methyl-6- (3-pivaloyloxypropyl) phenol, MS: 402 (M⁺), 300, starting from 22.

Example 35:

4,6-Dimethyl-2- (3-pivaloyloxypropyl) phenol, MS: 264 (M⁺) 162, starting from 17.

Example 36:

4,6-Dimethyl-2- [2 (R, S) -pivaloxypropyl] phenol, MS: 264 (M⁺), 162, starting from 4,6-dimethyl-2- [2 (R, S) -privaloyloxypropyl] phenylbenzyl ether, which is used in the preparation of 17 occurs.  

Example 37:

2- (2-benzyloxy-3,5-dimethylphenyl) acetaldehyde (37) (see formula 1, XIV)

1. 205 g (0.81 mol) of 2-allyl-4,6-dimethylphenylbenzylether (Example 2) and 147 g (1.25 mol) of N-methylmorpholine-N-oxide were placed in 1000 ml of acetone and 750 ml of water and mixed with 200 mg (0.79 mmol) of osmium tetroxide were added. The mixture was stirred at room temperature for 20 h, 5 g of sodium pyrosulfite were added and saturated with sodium chloride. The acetone was largely removed in vacuo and the residue extracted with ethyl acetate. The combined ethyl acetate phases were washed once with aqueous NaCl / HCl and once with aqueous NaCl / KHCO ₃ solution. Drying with magnesium sulfate, stripping off the solvent in vacuo and bulb tube distillation (170-180 ° C, 0.1 Torr) gave 114.8 g (0.40 mol, 50%) diol. Rf (silica gel. Ethyl acetate / methylene chloride = 1: 1): 0.35.

2. 0.3 g (29.0 mmol) diol and 14.5 g (67.8 mmol) Sodium periodate was dissolved in 50 ml of tetrahydrofuran and 10 ml of water at 20-25 ° C with cooling for 30 min. It was diluted with water and extracted with Ether. The combined ether phases were once with Water and once with potassium hydrogen carbonate solution washed. Dry with magnesium sulfate and peel off of the solvent gave after adding toluene and rotating again and drying on the oil pump 7.1 g (28 mmol, 96%) 2- (2-benzyloxy-3,5-dimethylacetaldehyde (37).

¹ H NMR (CCl ₄ , 60 MHz): δ = 2.1 (s, 6H, -CH ₃ ), 3.4 (d, 2H, -CH ₂ -), 4.6 (s, 2H, -CH ₂ ), 6.6 and 6.8 (each see 1H each, aromatic H), 7.2 ("s", 5H, aromatic H), 9.2 (t, 1H, -CHO)

Example 38:

2- (2-benzyloxy-3,5-dimethylphenyl) ethanol (38) (see formula 1, XV)

7.7 g (30.3 mmol) of aldehyde 37 were in 50 ml of methanol dissolved and 0.9 g (23.8 mmol) of sodium borohydride in Ice water dissolved in dropwise at 15 ° C. After 30 min was acidified while cooling with dilute acetic acid, with 100 ml of saturated aqueous sodium chloride solution stirred and extracted with ether. The United Ether phases were washed once with saturated aqueous Washed sodium bicarbonate solution. Drying with Magnesium sulfate, removal of the solvent in the Vacuum and Kugelrohr distillation (140 ° C / 0.05 Torr) resulted 6.9 g (27.0 mmol, 89%) alcohol 38.

¹ H NMR (CCl ₄ , 60 MHz): δ = 2.2 (s, 6H, -CH ₃ ), 2.7 (t, 2H, -CH ₂ -), 3.6 (t, 2H, -CH ₂ -), 4.7 (s, 2H, benzyl CH ₂ ), 6.7 (s, 2H, aromatic H), 7.2 (m, 5H, aromatic H).

Example 39:

4,6-dimethyl-2- [2- (4-fluorophenyl) ethyl] phenol (39) (see formula 1, XIX)

1. To a Grignard solution in ether from 2.7 g (111 mmol) Magnesium and 19 g (108 mmol) 4-fluorobromobenzene 18.4 g (72 mmol) of aldehyde were added at room temperature 37 added dropwise in ether and stirred at room temperature for 2 h. While cooling with ice, 4N acetic acid hydrolyzed, and extracted with ether. The United Ether phases were washed once with water and once with saturated potassium hydrogen carbonate solution washed. Dry with magnesium sulfate and peel off of the solvent in vacuo gave after crystallization from cyclohexane 18.4 g (52.6 mmol, 73%)

2- (benzyloxy-3,5-dimethyl-phenyl) -1- (4-fluorophenyl) ethanol

Mp: 74 ° C.  

2. 7 g (20 mmol) alcohol according to stage 1., 2.55 g (25 mmol) Acetic anhydride and 2.4 g (30.3 mmol) pyridine were 2 h heated on the steam bath. Toluene was added and distilled off in vacuo at 50 ° C. The residue was taken up in ether and twice with 2N hydrochloric acid once with saturated aqueous potassium hydrogen carbonate solution washed. Drying with Magnesium sulfate and removal of the solvent in the Vacuum gave 7.7 g (19.6 mmol, 98%) 1-acetoxy-2- (benzyloxy-3,5-dimethylphenyl) -1- (4-fluorophenyl) ethane

3. 18.4 g (46.9 mmol) of acetate according to stage 2 were hydrogenated in methanol with 3 g of palladium on carbon (10%) with the addition of 4 g of sodium acetate for 6 h at room temperature and normal pressure. When the uptake of hydrogen had ended, the mixture was filtered off with suction, the filtrate was concentrated, the residue was taken up in ether and the ethereal solution was washed once with water. Drying with magnesium sulfate, concentration in vacuo gave crystallization from cyclohexane 6.6 g (27 mmol), 57%) phenol 39.
Mp: 70-72 ° C
¹ H NMR (CCl ₄ , 60 MHz): δ = 2.2 ("s", 6H, -CH ₃ ), 2.8 ("s", 4H, -CH ₂ -), 4.1 (s, 1H, OH ), 6.5-7.2 (m, 6H, aromatic H)
MS: 244 (M⁺)

Example 40:

4,6-dimethyl-2- [2- (4-methylphenyl) ethyl] phenol (40)

In analogy to Example 39, Example 40 was obtained.  

Example 41:

4,6-dimethyl-2- [2,2-bis (4-fluorophenyl) ethyl] phenol (41) (see formula 1, XIX)

1. To 4.75 g (37.4 mmol) of oxalyl chloride in 10 ml Methylene chloride was added dropwise at -65 ° C to 5.8 g (74.2 mmol) dimethyl sulfoxide in 10 ml methylene chloride. Man allowed to stir at this temperature for 30 min and dripped then 9.5 g (27.1 mmol) of alcohol according to Example 39, step 1 in 20 ml of methylene chloride and allowed to stir at -65 ° C for 30 min. Subsequently 15 g (148 mmol) of triethylamine were added dropwise. It was washed twice with water, with Dried magnesium sulfate and the solvent in Vacuum removed. The residue was treated with cyclohexane recrystallized. 8 g (23 mmol, 85%) were obtained 2- (benzyloxy-3,5-dimethyl) -1- (4-fluorophenyl) ethan-1-one (56)

Mp: 99 ° C.

¹ H-NMR (CCl ₄ , 60 MHz): δ = 2.2 ("d", 6H, -CH ₃ ), 4.0 (s, 2H, -CH ₂ -), 4.7 (s, 2H, OCH ₂ -), 6.6-7.9 (m, 11H, aromatic H)

2. 6.4 g (34 mmol) of 1,2-dibromoethane became 0.85 g (35 mmol) of magnesium dropped into diethyl ether and 1 h heated under reflux. With a syringe Solution to a Grignard solution from 0.85 g (35 mmol) Magnesium and 6 g (34.3 mmol) 4-fluorobromobenzene in Dropped diethyl ether. Then 6.8 g (19.5 mmol) ketone according to step 1 was added dropwise in ether and 4 h heated under reflux. It was hydrolyzed with ice / HCl, extracted three times with ether, washed the combined Ether phases once with saturated aqueous Sodium bicarbonate solution and dried with Magnesium sulfate. Removing the solvent in the Vacuum and recrystallization from cyclohexane resulted 7.3 g (16.4 mmol, 84%) alcohol

Mp: 119-120 ° C  

3. 7.0 alcohol according to level 2 was in toluene with a catalytic Amount of p-toluenesulfonic acid in a water separator for 1 h cooked. Then the solution was used once saturated aqueous sodium hydrogen carbonate solution washed and evaporated. The residue was with Palladium on carbon (10%) in methanol at room temperature and hydrogenated normal pressure. Usual workup. Kugelrohr distillation: 150-160 ° C, 0.05 torr.

¹ H-NMR (CDCl ₃ , 60 MHz): δ = 2.16 ("d", 6H, CH ₃ ), 3.25 (d, 2H, -CH ₂ -), 4.17 (s, 1H, -OH), 4.30 (t, 1H, methine-H), 6.42-7.33 (m, 1OH, aromatic H).

MS: 338 (M⁺)

Example 42:

4,6-Dimethyl-2- [2- (4-fluorophenyl) -2-isobutylethyl] phenol (42)

Analogously to Example 41, Example 42 was obtained. In place of the Grignard compound, i-butyllithium was used reacted with ketone according to Example 41, stage 1.

¹ H-NMR (CDCl ₃ , 60 MHz): δ = 0.66-1.0 (m, 6H, -CH ₃ ), 1.2-1.8 (m, 3H, -CH ₂ - and methine-H), 2.17 ("s" , 6H, -CH ₃ ), 2.6-3.1 (m, 3H, -CH ₂ - and methine-H), 4.1 (s, 1H, OH), 6.4-7.2 (m, 6H, aromatic H)

MS; 300 (M⁺)

Example 43-45:

Examples 43 and 44 were obtained in analogy to Examples 41 and 42, starting from 4,6-dimethyl-2- (4-fluorobenzoyl) phenol (cf. Houben-Weyl, Methods of Organic Chemistry, Volume 7 / 2a, 1973). 45 was obtained by reduction of the phenol mentioned above with sodium borohydride and subsequent hydrogenolysis.
43: 4,6-dimethyl-2- [bis- (4-fluorophenyl) methyl] phenol
44: 4,6-dimethyl-2- [1- (4-fluorophenyl) ethyl] phenol
45: 4,6-Dimethyl-2- [4-fluorobenzyl) phenol
Preparation of the starting compound of formula III

Example 46:

4 (R) - (t-butyldiphenylsilyloxy) -2 (R, S) -methoxy-6 (S) - (4- methylphenylsulfonyloxymethyl) -3,4,5,6-tetrahydro-2H-pyran (46)

(Tetrahedron Lett. 23, 4305 (1982))

60 g (150 mmol) alcohol 4 (R) - (t-butyldiphenylsilyloxy) -2 (R, S) -methoxy-6 (S) -hydroxymethyl-3,4,5,6-tetrahydro-2H-pyran (Tetrahedron Lett 23, 4305 (1982)) were dissolved in 240 ml of dry methylene chloride and 240 ml of dry pyridine, and 56 g (293 mmol) of p-toluenesulfonic acid chloride were added in portions at room temperature. The mixture was allowed to stir at room temperature for 3 hours. The solvent was largely stripped off in vacuo and the residue was partitioned between toluene and water. The organic phase was washed twice with water and twice with saturated aqueous sodium hydrogen carbonate solution and once with saturated aqueous sodium chloride solution. Drying with magnesium sulfate, removal of the solvent in vacuo (to remove the pyridine completely, the residue was mixed twice with toluene and concentrated again) and chromatography on silica gel (CH ₂ Cl ₂ ) gave 79 g (142 mmol, 95%) tosylate 46 as colorless oil.

(TLC: chloroform / ethyl acetate = 9: 1, Rf = 0.63)

Example 47, (III):

4 (R) - (t-butyldiphenylsilyloxy) -6 (S) -iodomethyl-2 (R, S) -methoxy- 3,4,5,6-tetrahydro-2H) pyran (47)

(Tetrahedron Lett. 23, 4305 (1982))

79 g (142 mmol) of tosylate 46 were mixed in dry acetone 43 g (286 mmol) sodium iodide heated under reflux. Until complete The reaction was additionally an additional 107 g (713 mmol) of sodium iodide added, TLC control (chloroform).  

The solvent was largely removed in vacuo and the residue was partitioned between water and ether. The ether phase was washed successively twice with water, once with a little sodium bisulfite solution and once with saturated sodium hydrogen carbonate solution. Drying with magnesium sulfate, stripping off the solvent in vacuo and chromatography on silica gel (toluene) gave 68 g (134 mmol, 94%) iodide 47 (III) as a colorless oil.
Manufacture of end products
Implementation of compounds of the formulas II + III to compounds of the formula IV

Example 48 a:

6 (S) - {4,6-Dimethyl-2- [3- (4-fluorophenoxy) propyl] phenoxymethyl} - 3,4,5,6-tetrahydro-2 (R, S) -methoxy-4 (R) - (t-butyldiphenylsilyloxy) -2H-pyran (48a)

14.5 g (53 mmol) phenol 24 and 14.6 g (105 mmol) potassium carbonate were placed in 100 ml of dimethyl sulfoxide and with 18 g (35 mmol) of iodide 47 in 200 ml of dimethyl sulfoxide transferred. After 10 h at 60 ° C with water and ether added and the aqueous phase again with ether extracted. The combined ether phases were once with Washed water. Dry with magnesium sulfate and peel off the solvent gave after chromatography on silica gel (Cyclohexane / ethyl acetate = 9: 1) 18.3 g (28 mmol, 80%) Alkylation product 48a.

MS: C ₄₀ H ₄₉ FO ₅ Si, 656 (M⁺).
¹ H-NMR (CDCl ₃ , 60 MHz): δ = 1.1 (s, 9H, t-Bu), 2.3 ("d", 6H, -CH ₃ ), 3.5 (s, 3H, OCH ₃ ), 3.7-5.1 (m, 7H, methine-H and -OCH ₂ -), 6.7 - 7.8 (m, 16H, aromatic H).

In analogy to Example 48a, the corresponding Phenols and the iodide 47 those listed in Table 4  Examples 48b-48aa obtained.

Table 4

Implementation of compounds of formula IV to compounds Formula V

Example 49a

6 (S) - {4,6-Dimethyl-2- [3- (4-fluorophenoxy) propyl] phenoxymethyl} - 3,4,5,6-tetrahydro-2 (R, S) -hydroxy-4 (R) - (t-butyldiphenylsilyloxy) -2H-pyran (49a)

1.4 g (2.13 mmol) of alkylation product 48a was added in 75 ml Tetrahydrofuran, 75 ml water and 105 ml glacial acetic acid for 18 h kept between 70 and 80 ° C. The solvent was removed in vacuo and the residue for removal Existing acetic acid residues mixed with toluene and again rotated in. Chromatography on silica gel (cyclohexane / ethyl acetate = 8: 2) gave 950 mg (1.48 mmol, 70%) hydrolysis product 49a.

MS: C ₃₉ H ₄₇ FO ₄ Si, 642 (M⁺). 624 (M⁺-H ₂ O)

TLC: Rf = 0.18 (cyclohexane / ethyl acetate = 5: 1).

In analogy to Example 49a, Examples 48b-48c Examples 49b-49e49e listed in Table 5 were obtained.

Conversion of compounds of formula V to compounds of formula VI

Example 50a

6 (S) - {4,6-Dimethyl-2- [3- (4-fluorophenoxy) propyl] phenoxymethyl} - 3,4,5,6-tetrahydro-4 (R) - (t-butyldiphenylsilyloxy) -2H-pyran-2-one (50a)

9.66 g (96.6 mmol) of chromium trioxide was dried in 250 ml Methylene chloride submitted and at room temp. 15.3 g (193.3 mmol) of pyridine was added dropwise. The mixture was left at room temperature for 20 minutes.  stir and then drip at room temp. 6.2 g (9.66 mmol) Hydrolysis product 49a in 250 ml of methylene chloride. To 30 min at room temp. was diluted with methylene chloride, Aspirated over Celite and the residue thoroughly with Washed out methylene chloride. The filtrate was in vacuo concentrated and the residue with cyclohexane / ethyl acetate = 1: 1 recorded and suctioned off again through Celite. Constrict in vacuum and chromatography on silica gel cyclohexane / ethyl acetate = 8: 2) gave 5.34 g (8.34 mmol, 86%) Lactone 50a.

MS: C ₃₉ H ₄₅ FO ₅ Si, 640 (M⁺)
¹ H-NMR (CDCl ₃ , 60 MHz): δ = 1.1 (s, 9H, t-Bu), 1.8-2.9 (m, 14H, -CH ₃ and -CH ₂ -), 3 , 9 (m, 4H, -OH ₂ -), 4.4 and 5.1 (each m, each 1H, methine-H), 6.7-7.8 (m, 16H, aromatic H)

Analogously to Example 50a, Examples 50b-50a listed in Table 5 were prepared from Examples 49b-49a.
Implementation of compounds of formula VI to compounds of formula I.

Example 51a

6 (S) - {4,6-Dimethyl-2- [3, (4-fluorophenoxy) propyl] phenoxymethyl} - 3,4,5,6-tetrahydro-4 (R) -hydroxy-2H-pyran-2-one (51a)

950 mg (1.48 mmol) of silyl compounds 50a were at room temperature. submitted in 60 ml of tetrahydrofuran and with 355 mg (5.92 mmol) glacial acetic acid was added. Then 1.4 g (4.44 mmol) tetrabutylammonium fluoride trihydrate added. After 16 h room temp. the solvent was largely removed and the residue was partitioned between ether and water. The aqueous phase was extracted with ether. The combined ether phases were washed once with water. Dry with magnesium sulfate, remove the solvent in vacuo and chromatography on silica gel (cyclohexane / ethyl acetate  = 1: 1) gave 470 mg (1.17 mmol, 79%) hydroxylactone 51a.

MS: C ₂₃ H ₂₇ FO ₅ , 402 (M⁺), 384 (M⁺-H ₂ O).
¹ H-NMR (CDCl ₃ , 270 MHz): δ = 1.82 (broad, 1H, OH), 2.00-2.20 (m, 4H, methylene-H), 2.25 and 2.27 ( each s, each 3H, -CH ₃ ), 2.68-2.83 (m, 4H, Ar-CH ₂ and -CH ₂ CO), 3.88-4.01 (m, 4H, -OH ₂ ) , 4.50 and 5.00 (each m, each 1H, methine-H), 6.80-7.10 (m, 6H, aromatic H).

In analogy to Example 51a, 50b-50aa in the Examples 51b-51aa listed in Table 5 were obtained.  

Table 5: characteristic data ( ¹ H-NMR in CDCl ₃ , δ; TLC on silica gel, Rf)

Example 52 1:

3 (R), 5 (S) -dihydroxy-6- {4-chloro-2- [3- (4-fluorophenoxy) propyl] phenoxy} hexanoic acid sodium salt (52 1)

200 mg (0.49 mmol) of lactone 51 1 in 15 ml of tetrahydrofuran were mixed with 4.6 ml of 0.1 N aqueous sodium hydroxide solution (0.46 mmol). After 1h at room temp. the solvent was stripped off in vacuo and toluene was added to the residue several times and evaporated. Crystallization with diisopropyl ether gave 175 mg (0.39 mmol, 80%) sodium salt 52 1.
Mp: 215 ° C (dec.)
¹ H-NMR (270 MHz, D ₂ O): δ = 1.75, 2.00, 2.35 and 2.78 (each m, each 2H, methylene-H), 3.80-4.20 ( m, 6H, -OCH ₂ - and methine-H), 6.80-7.25 (m, 7H, aromatic H).

In analogy to Example 52 1, the corresponding sodium salts from the hydroxyl actones 51 a-51aa (Table 5) produced. In some cases, tetrahydrofuran was substituted Methanol used as a solvent.

Claims (10)

1. 6-phenoxymethyl-4-hydroxytetrahydropyran-2-one of the general formula I wherein
R ¹ and R ^{5 are the} same or different and a) hydrogen or halogen, b) cycloalkyl having 4-8 C atoms or a phenyl radical which can be substituted 1 to 3 times in the nucleus with halogen, trifluoromethyl and / or alkyl or alkoxy each having 1-4 carbon atoms or c) a straight-chain or branched alkyl radical having 1 to 18 carbon atoms or a straight-chain or branched alkenyl radical having 2 to 18 carbon atoms, the alkyl or alkenyl radicals themselves being substituted 1-3 times can be with

• α) straight-chain or branched alkoxy radicals having up to 10 carbon atoms or cycloalkoxy radicals having 3 to 7 carbon atoms or straight-chain or branched alkenyloxy or alkynyloxy radicals having 3 to 6 carbon atoms.
• β) halogen, hydroxy, cycloalkyl with 3-7 C atoms, unsubstituted phenyl, α or β-thienyl radicals, or phenyl, α or β-thienyl radicals, which in turn are in the nucleus 1- to 3-fold substituted with Halogen, trifluoromethyl and / or alkyl or alkoxy with 1-4 C atoms.
• γ) unsubstituted phenoxy, benzyloxy, α- or β-thienyloxy radicals, or phenoxy, benzyloxy, α- or β-thienyloxy radicals, which in turn are 1 to 3 times substituted in the nucleus with halogen, trifluoromethyl and / or alkyl or alkoxy with 1 to 4 carbon atoms,
• γ) of the group where R ⁶ means:
  a straight-chain or branched alkyl or alkenyl radical having up to 8 carbon atoms, or a cycloalkyl or cycloalkenyl radical each having 3-8 C atoms, or an unsubstituted phenyl radical or a phenyl radical which in turn is in the nucleus 1 to 3 times substituted by halogen , Trifluoromethyl and / or alkyl or alkoxy with 1-4 C atoms, or a 3-pyridyl radical,

R ² and R ^{4 are the} same or different and are hydrogen, alkyl with 1-4 C atoms, halogen or alkoxy with 1-4 C atoms, and
R ^{3 is} hydrogen, alkyl or alkenyl with up to 4 C atoms, halogen or alkoxy with 1-4 C atoms,
and the corresponding open-chain dihydroxycarboxylic acids, their pharmacologically acceptable salts with bases and their pharmacologically acceptable esters. 2. Compounds according to claim 1, characterized in that in formula I.
R ¹ and R ^{5 are} both the same or different and
a) hydrogen or halogen,
b) cycloalkyl with 5 to 6 carbon atoms, phenyl, which can be substituted 1-3 times in the nucleus with halogen, trifluoromethyl and / or alkyl or alkoxy, each with 1-4 carbon atoms, or
c) 1. straight-chain or branched alkyl or alkenyl having up to 12 carbon atoms, it being possible for the alkyl or alkenyl radical in turn to be substituted 1-2 times with phenyl radicals which in turn may be substituted 1 to 3 times with halogen in the nucleus, Trifluoromethyl and / or alkyl or alkoxy with 1-4 C atoms,
2. straight-chain alkyl of the formula substituted with O-COR ⁶ where n = 1 to 3 and R ^{6 is} a straight-chain or branched alkyl or alkenyl radical having up to 8 carbon atoms, a cycloalkyl radical having 5 to 6 carbon atoms, or a phenyl radical, which in turn can be substituted 1-3 times in the nucleus can with halogen, trifluoromethyl and / or alkyl or alkoxy with 1 to 4 carbon atoms,
3. straight-chain alkyl substituted by OR ^{7 of} the formula - (CH ₂ ) _n OR ⁷ , in which n = 1 to 3 and R ^{7 is} hydrogen or a straight-chain or branched alkyl or alkenyl radical having up to 8 C atoms, a cycloalkyl radical having 5 to 6 carbon atoms, or a phenyl radical or benzyl radical, which in turn can be substituted 1-3 times in the aromatic nucleus with halogen, trifluoromethyl and / or alkyl or alkoxy with 1 to 4 carbon atoms
R ² and R ^{4 are} hydrogen and
R ^{3 is} hydrogen, methyl, ethyl, propyl, 1-propenyl, allyl fluorine or chlorine. 3. Compounds according to claim 1, characterized in that in formula I.
R ¹ and R ^{5 are the} same or different and
1) hydrogen, methyl, ethyl, propyl, allyl, 1- propenyl, isopropenyl, isopropyl, cyclopentyl, cyclohexyl, or
2) the group with n = 1-3, where R ⁶ means: methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl, phenyl or phenyl which is substituted 1 to 3 times with halogen, methyl in the nucleus or methoxy, or
3) the group - (CH ₂ ) _n OR ⁷ , with n = 1 to 3, where R ⁷ means: hydrogen, methyl, straight-chain or branched alkyl or alkenyl with 3-5 carbon atoms, cyclopentyl, cyclohexyl; Phenyl or benzyl, where the aromatic nuclei can be substituted 1-3 times with fluorine, chlorine, methyl, methoxy, or
4) an alkyl group of the formula - (CH ₂ ) _n CHR ⁸ R ⁹ in which n = 0 to 2 and R ⁸ and R ^{9 are} identical or different and are hydrogen, methyl, ethyl, propyl, allyl, i-propyl, n - Butyl, i-butyl, t-butyl, cyclohexyl, cyclopentyl, benzyl or phenyl, where the aromatic nuclei can be 1 to 3 times substituted by fluorine, chlorine, methyl or methoxy.
R ² and R ^{4 are} hydrogen and
R ^{3 is} hydrogen, methyl, chlorine, fluorine. 4. A process for the preparation of the compounds according to claim 1, characterized in that
a) appropriately substituted phenols of the formula II, wherein R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meanings given, with the chiral iodide of the formula III in which R ¹⁰ denotes a protective group stable against bases and weak acids,
into the ethers of formula IV wherein R ¹ to R ^{5 have} the meanings given for formula I and R ^{10 have} the meanings given for formula III
b) the ethers of the formula IV to the corresponding hemiacetals of the formula V. wherein R ¹ to R ⁵ and R ^{10 have} the meanings given for formulas I and III, hydrolyzed,
c) the hemiacetals of formula V to the corresponding lactones of formula VI wherein R ¹ to R ^{5 have} the meanings given for formula I and R ¹⁰ for formula III, oxidized and
d) the protected hydroxylactones of the formula VI in the 6-phenoxymethyl-4-hydroxytetrahydropyran-2-ones of the formula I. transferred, optionally the compounds of formula I obtained into the corresponding open-chain dihydroxycarboxylic acids of formula VII their salts or their esters are converted, any salts or esters obtained are converted into the free dihydroxycarboxylic acids or if appropriate the free carboxylic acids are converted into the salts or esters. 5. Pharmaceutical preparations containing a compound according to Claim 1. 6. Use of a compound according to claim 1 for prophylaxis and therapy of hypercholesterolemia 7. Ether of formula IV wherein R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meanings given for formula I and R ¹⁰ for formula III 8. Semi-acetals of formula V wherein R ¹ to R ⁵ and R ^{10 have} the meanings given for formula I and III. 9. Lactones of the formula VI wherein R ¹ to R ^{5 have} the meanings given for formula I and R ¹⁰ for formula III.