USOO5418243A United States Patent 19 11 Patent Number: 5,418,243 Angerbauer et al. 45 Date of Patent: May 23, 1995

54 SUBSTITUTED 4-PHENYL-PYRIDONES 4,215,126 7/1980. Durant et al...... 514/345 AND 4-PHENYL-3-ALKOXYPYRIDNES 4,684,477 8/1987 Sugimori et al. ... 546/290 4,916,239 4/1990 Treiber ...... 549/292 75 Inventors: Rolf Angerbauer; Peter Fey; Walter 4,988,711 1/1991 Angerbauer et al. ... 514/326 Hibsch, all of Wuppertal; Thomas 5,032,602 7/1991 Fey et al...... 54/345

Philipps, Cologne; Hilmar Bischoff, 5,064,841 11/1991 Angerbauer et al. ... 514/336 Wuppertal; Hans-Peter Krause, 5,138,090 8/1992 Fey et al...... 560/59 Schwelm; Jörg Peterson-von Gehr, Bochum; Delf Schmidt, Wuppertal, FOREIGN PATENT DOCUMENTS all of Germany 0373423 6/1990 European Pat. Off. . 73 Assignee: Bayer Aktiengesellschaft, OTHER PUBLICATIONS Leverkusen, Germany J. Med. Chem., 1990, vol. 33, pp. 52-60; “Synthesis and 21) Appl. No.: 166,775 Biological Activity of New HGM-CoA Reductase 22 Filed: Dec. 14, 1993 Inhibitors ... ', G. Beck. Primary Examiner-C. Warren Ivy (30) Foreign Application Priority Data Assistant Examiner-A. A. Owens Dec. 21, 1992 DE Germany ...... 4243 278.2 Attorney, Agent, or Firm-Sprung, Horn, Kramer & Jun. 28, 1993 DE Germany ...... 43 21421.5 Woods 511 Int. Cl...... A61K 31/44; C07D 213/64 57 ABSTRACT 52 U.S. C...... 514/345; 546/24; 546/290; 514/89 Substituted 4-phenyl-pyridones and 4-phenyl-2-alkox 58 Field of Search ...... 546/290, 24; 514/345, ypyridines are prepared by reducing corresponding 514/89 4-phenyl-pyridone and 4-phenyl-2-alkoxypyridine de rivatives. The substituted 4-phenyl-pyridones and 4 56) References Cited phenyl-2-alkoxypyridines can be employed as active U.S. PATENT DOCUMENTS compounds in medicaments, in particular for the treat 4,083,983 4/1978 Durant et al...... 514/345 ment of hyperlipoproteinaemia. 4,154,838 5/1979 Durant et al...... 514/345 4,156,727 5/1979 Durant et al...... 514/345 8 Claims, No Drawings 5,418,243 1. 2 R9 and R10 are identical or different and denote SUBSTITUTED 4-PHENYL-PYRDONES AND straight-chain or branched alkyl having up to 4-PHENY L-3-ALKOXYPYRONES 8 carbon atoms, or phenyl, or R6 and R7 together form a radical of the formula The invention relates to substituted 4-phenyl-pyri 5 dones and 4-phenyl-2-alkoxypyridines, processes for H3C CH3, their preparation, and their use in medicaments. It is known that lactone derivatives isolated from fungal cultures are inhibitors of 3-hydroxy-3-methyl R represents phenyl which is optionally substituted glutaryl coenzyme A reductase (HMG-CoA reductase) 10 up to 2 times by identical or different halogen, Mevinolin, EP22478; U.S. Pat. No. 4,231,938. trifluoromethyl, methoxy, phenoxy or straight It is additionally known that pyridine-substituted chain or branched alkyl having up to 8 carbon dihydroxyheptenoic acids are inhibitors of HMG-CoA atOInS, reductase EP 325 130; EP307342, EP306929). 15 R has the abovementioned meaning of R3 and is The present invention relates to substituted 4-phenyl identical to or different from this, or represents pyridones and 4-phenyl-2-alkoxypyridines of the gen hydrogen, cyano, carboxyl or straight-chain or eral formula (I) branched alkoxycarbonyl having up to 8 carbon atoms, or represents straight-chain or branched 20 alkyl having up to 8 carbon atoms, which is option R4 (Ia) ally substituted by halogen, hydroxyl, by straight RS 21 R3 chain or branched alkoxy having up to 8 carbon atoms, or by a group of the formula -O-(CH 2)-R1 or -O-CO-R12, in which o? N R2 25 a denotes a number 0 or 1, Rll denotes phenyl or benzyl, each of which is k optionally substituted up to 2 times in the aro matic system by identical or different halogen, R4 (Ib) trifluoromethyl, cyano, nitro or straight-chain or RS 21 R3 30 branched alkyl having up to 6 carbon atoms, R12 has the abovementioned meaning of R1 and is Sa identical to or different from this, or denotes R1O N R2 straight-chain or branched alkyl having up to 8 carbon atoms, in which 35 O R represents straight-chain or branched alkyl having R represents a radical of the formula -CH up to 8 carbon atoms, =N-O-R13, in which R represents cycloalkyl having 3 to 7 carbon atoms, R13 has the abovementioned meaning of R12 and is or represents straight-chain or branched alkyl hav identical to or different from this. ing up to 8 carbon atoms, Depending on the side chains mentioned under R R3 represents a radical of the formula and/or R, the compounds according to the invention in each case have 1 or 2 asymmetric carbon atoms, to which the radicals -OR6 and -OR7 are bonded. They R6O OR7 (a) can therefore exist in various stereochemical forms. 45 The invention relates both to the individual isomers --N-N (CH2)2-OR, and to their mixtures. Depending on the relative posi tion of the radicals -OR/-OR7, the substances ac O OR7 (b) cording to the invention can thus be present in the ery -X-P (CH2)2-OR, thro configuration or in the threo configuration. OR6 50 This will be illustrated by way of example for the substituents R/Rs having the meaning a) as follows: R6O ORT (c) -N-N-cho o OR6 OR7 55 ------nor and OR7 (d) erythro form OR6 oR7

OH N-N- OR8 threo form in which Two enantiomers existin turn in each case both of the X denotes the group -CH2-CH2-, -CH= substances in the threo and in the erythro configuration. CH- or -C=C-, and 65 The erythro forms are preferred in each case. R6, R7 and R8 are identical or different and denote Moreover, on account of the double bond hydrogen or a radical of the formula-CO-9 or (X=-CH=CH-), the substances according to the -COOR10, in which invention can be present in the Econfiguration or the Z 5,418,243 3 4. configuration. Those compounds which have the E having up to 6 carbon atoms, or which is substi configuration are preferred. tuted by a group of the formula -O-(CH In addition, the radicals (subst. (c) are in 2)-R or -O-CO-R12, in which each case in equilibrium with the corresponding hy a denotes a number 0 or 1, and droxypyrans (subst. (d)). 5 R11 denotes phenyl or benzyl, each of which is optionally substituted in the aromatic system by OR7 fluorine, chlorine, bromine, trifluoromethyl, cy ano, nitro or straight-chain or branched alkyl having up to 4 carbon atoms, R6O OR7 G 10 R12 has the abovementioned meaning of R and is --N-N-cho <-- O OH identical to or different from this, or denotes straight-chain or branched alkyl having up to 6 Preferred compounds of the general formula (I) are carbon atoms, those in which O R represents straight-chain or branched alkyl having 15 Rs represents a radical of the formula -CH up to 6 carbon atoms, =N-O-R13, in which R2 represents cyclopropyl, cyclopentyl or cyclo R13 has the abovementioned meaning of R12 and is hexyl, or represents straight-chain or branched identical to or different from this. alkyl having up to 6 carbon atoms, Particularly preferred compounds of the general for R represents a radical of the formula 20 mula (I) are those in which R1 represents straight-chain or branched alkyl having up to 4 carbon atoms, R6O OR7 R2 represents cyclopropyl or represents straight --> -sci-or 25 chain or branched alkyl having up to 4 carbon atOnS, OR7 R3 represents a radical of the formula -x- (CH2)2-OR3, OR6 30 R6O OR7 R6O OR7 -N-sch-on' - x-N-N-cho d R6O OR7 OR7 35 -N-N-CHO o OR7

-X O OH 40 in which -X O OH X denotes the group -CH2-CH2-, -CH= CH- or -C=C-, in which R6, R7 and R8 are identical or different and denote X notes the group CH2-CH2- or -CH= hydrogen or a radical of the formula -CO-R9 45 or -COO-R10, in which R6, R7 and R8 are identical or different and denote R°and R10 are identical or different and denote hydrogen or a radical of the formula-CO-9, in straight-chain or branched alkyl having up to 6 which carbon atoms, or phenyl, 50 R9 denote straight-chain or branched alkyl hav O ing up to 4 carbon atoms, R6 and R7 together form a radical of the formula R represents phenyl which is optionally substituted by fluorine, trifluoromethyl or by straight-chain or H3C CH3, branched alkyl having up to 4 carbon atoms, >< 55 R has the abovementioned meaning of R3 and is identical to or different from this, or represents R represents phenyl which is optionally substituted hydrogen or represents straight-chain or branched up to 2 times by identical or different fluorine, alkyl having up to 4 carbon atoms, which is option chorine, bromine, trifluoromethyl or straight-chain ally substituted by hydroxyl or by straight-chain or or branched alkyl having up to 6 carbon atoms, 60 branched alkoxy having up to 4 carbon atoms. R has the abovementioned meaning of R3 and is Very particularly preferred compounds of the gen identical to or different from this, or represents eral formula (I) are those in which hydrogen, cyano, carboxyl or straight-chain or R represents straight-chain or branched alkyl having branched alkoxycarbonyl having up to 6 carbon up to 4 carbon atoms, atoms, or represents straight-chain or branched 65 R2 represents cyclopropyl or represents straight alkyl having up to 6 carbon atoms, which is option chain or branched alkyl having up to 4 carbon ally substituted by fluorine, chlorine, bromine, hy atoms, droxyl or by straight-chain or branched alkoxy R3 represents a radical of the formula 5,418,243 5 6 group, the ethene group (X=-CH=CH-) or the OH OH ethine group (X=-C=C-) is hydrogenated step wise according to customary methods and, if ap -N1-cis-on propriate, the isomers are separated. in which The process according to the invention can be illus X denotes the group -CH2-CH2- or -CH trated by way of example by the following reaction CH-, equation: R represents phenyl which is optionally substituted by fluorine, and 10 R has the abovementioned meaning of R3 or repre sents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl or alkoxy having up to four carbon CO2CH3 atOS. 15 disobutyl Especially preferred compounds of the general for mula (I) according to the invention are those in which hydride G R represents methyl and THF/-78 C. R3 represents the radical of the formula 20

OH OH

OH '-- 25 A process for the preparation of the compounds of the general formula (I) according to the invention has additionally been found, which is characterized in that pyridones or 2-alkoxypyridines of the general formula 30 (II) R4 (IIa) In general, suitable solvents for the reduction are the customary organic solvents. Ethers such as , or dioxane are preferred. Tetra r 35 hydrofuran is particularly preferred. O N R2 or Suitable reducing agents are complex metal hydrides, R such as, for example, lithium , so 40 dium cyanoborohydride, aluminium hydride, R4 (IIb) disobutylaluminium hydride or sodium bis-(2-methox yethoxy)-dihydroaluminate. Diisobutylaluminium hy dride is preferred. In general, the reducing agent is employed in an Rio 1 N 1 R2 45 amount from 4 mol to 10 mol, preferably from 4 mol to 5 mol, relative to 1 mol of the compounds of the general in which formula (II). R, R2 and Rhave the meaning indicated and In general, the reduction proceeds in a temperature D represents a radical of the formula 50 range from -78 C. to --50 C., preferably from -78 C. to 0 C., particularly preferably at -78 C., in each OR6 OR7 case depending on the choice of the reducing agent and solvent. -N-N- COR1 or In general, the reduction proceeds at normal pres OR7 55 sure, but it is also possible to work at elevated or re duced pressure. -x- COR14 The cyclization of the to give the corre OR6 sponding hydroxy-pyrans is in general carried out at room temperature or by heating in inert organic sol in which 60 A, B, R6 and R7 have the meaning indicated vents, if appropriate in the presence of molecular sieve. R represents C1-C6-alkyl and Suitable solvents in this case are hydrocarbons such E either also has the abovementioned meaning of D as benzene, toluene, xylene, mineral oil fractions, or or the abovementioned meaning of R, tetralin or diglyme or triglyme. Benzene, toluene or are reduced in inert solvents, under a protective 65 xylene is preferably employed. It is also possible to gas atmosphere, if appropriate via the aldehyde employ mixtures of the solvents mentioned. Hydrocar step, using reducing agents, and in the case in bons, in particular toluene, in the presence of molecular which -X- represents the -CH2-CH2 sieve are particularly preferably used. 5,418,243 7 8 The cyclization is in general carried out in a tempera also possible to employ mixtures of the solvents men ture range from -40 C. to +100° C., preferably from tioned. -25 C. to --50° C. The reduction of the ketone group to the hydroxy The hydrogenation of the double bond is carried out group is particularly preferably carried out under con by customary methods using hydrogen in the presence ditions in which the other functional groups, such as, of noble metal catalysts, such as, for example, Pd/C, for example, the alkoxycarbonyl group, are not Pt/C or Raney nickel in one of the abovementioned changed. Particularly suitable for this is the use of so solvents, preferably in such as, for example, dium borohydride as a reducing agent, in the presence methanol, ethanol or propanol, in a temperature range of triethylborane in inert solvents such as, preferably, from -20° C. to -100° C., preferably from 0° C. to 10 ethers. +50 C., at normal pressure or elevated pressure. The reduction is in general carried out in a tempera The reduction of the triple or double bond is option ture range from -80 C. to +30 C., preferably from ally also carried out during the abovementioned reduc -78 C. to O' C. - tion of the group. The process according to the invention is in general The compounds of the general formula (II) in which 15 carried out at normal pressure. However, it is also possi D and/or E represent the radical of the formula ble to carry out the process at reduced pressure or at elevated pressure (e.g. in a range from 0.5 to 5 bar). OR6 OR7 In general, the reducing agent is employed in an 4. amount of from 1 to 2 mol, preferably from 1 to 1.5 mol, x-N-N- COR relative to 1 mol of the keto compound. Under the abovementioned reaction conditions, the are prepared by reducing ketones of the general formu carbonyl group is in general reduced to the hydroxy lae IIIa and b group without reduction of the double bond to the single bond taking place. OH O (IIIa) The ketones IIIa and b employed as starting sub I COOR 14 stances are prepared by reacting aldehydes of the for R4 mulae IVa and b

Fea 30 (IVa)

O N R2 k (IIIb) 35

(IVb)

in which R to R and R1 have the abovementioned meaning 45 and, if appropriate, separating isomers. The reduction can be carried out using the customary reducing agents, preferably using those which are suit in which able for the reduction of ketones to hydroxy com R1 to Rhave the meaning indicated, pounds. Particularly suitable in this case is reduction SO in inert solvents with acetoacetic of the general using metal hydrides or complex metal hydrides in inert formula V solvents, if appropriate in the presence of a trialkylbo rane. Preferably, the reduction is carried out using com plex metal hydrides such as, for example, lithium boro hydride, , potassium borohydride, 55 H3C-C-CH2-COOR14 Zinc borohydride, lithium trialkylborohydrides, sodium trialkylborohydrides, sodium cyanoborohydride or lith in which ium aluminium hydride. The reduction is very particu R1 has the meaning indicated, larly preferably carried out using sodium borohydride, in the presence of bases. in the presence of triethylborane. Possible bases in this case are the customary strongly Suitable solvents in this case are the customary or basic compounds. These preferably include organoli ganic solvents which do not change under the reaction thium compounds such as, for example, n-butyllithium, conditions. These preferably include ethers such as, for sec-butyllithium, tert-butyllithium or phenyllithium or example, diethyl ether, dioxane, tetrahydrofuran or amides such as, for example, lithium diisopropylamide, dimethoxyethane, or halogenohydrocarbons such as, 65 Sodium amide or potassium amide, or lithium hexame for example, dichloromethane, trichloromethane, tetra thyldisilylmide, or alkali metal hydrides such as sodium chloromethane or 1,2-dichloroethane or hydrocarbons hydride or potassium hydride. It is also possible to em such as, for example, benzene, toluene or xylene. It is ploy mixtures of the bases mentioned. n-Butyllithium or 5,418,243 10 or a mixture thereof is particularly preferably employed. perature to -70' C., depending on the reducing agent Additions of metal halides such as e.g. magnesium used. The reduction is preferably carried out using chloride, zinc chloride or zinc bromide are possibly disobutylaluminium hydride in tetrahydrofuran in a advantageous. The addition of zinc halides is particu temperature range from -78 C. to room temperature. larly preferred. The hydroxymethyl compounds are oxidized to the Suitable solvents in this case are the customary or aldehydes (XIII) in the second step 2 according to ganic solvents which do not change under the reaction customary methods. The oxidation can be carried out, conditions. These preferably include ethers such as for example, using pyridinium chlorochromate, if ap diethyl ether, tetrahydrofuran, dioxane or dimethoxy 10 propriate in the presence of aluminium oxide, in inert ethane, or hydrocarbons such as benzene, toluene, xy solvents such as chlorohydrocarbons, preferably meth lene, cyclohexane, hexane or mineral oil fractions. It is also possible to employ mixtures of the solvents men ylene chloride, in a temperature range from 0°C. to 60 tioned. Ethers such as diethyl ether or tetrahydrofuran C., preferably at room temperature, or else using trifluo are particularly preferred. roacetic acid/dimethyl sulphoxide according to the In general, the reaction is carried outin a temperature 15 customary methods of Swern oxidation. The aldehydes range from -80 C. to +50 C., preferably from -20 (VIIb) are reacted to give the aldehydes (IVb) in the C. to room temperature. third step 3) using diethyl 2-(cyclohexylamino)-vinyl In general, the process is carried out at normal pres phosphonate in the presence of sodium hydride in inert sure, but it is also possible to carry out the process at reduced pressure or at elevated pressure, e.g. in a range 20 solvents such as ethers, for example diethyl ether, tetra from 0.5 to 5 bar. hydrofuran or dioxane, preferably in tetrahydrofuran, When carrying out the process, the acetoacetic acid in a temperature range from -20° C. to -40°C., pref ester is in general employed in an amount from 1 to 2 erably from -5°C. to room temperature. mol, preferably from 1 to 1.5 mol, relative to 1 mol of The compounds of the formula (VIa, b) employed as the aldehyde. 25 starting substances in this process are new. They are The acetoacetic acid esters of the formula (V) em possibly obtained in scheme B, shown by way of exam ployed as starting substances are known or can be pre ple for the alkoxy-dihydropyridines (IXb), by oxidation pared by known methods. of 3,4-dihydropyridines. The oxidation of the dihy Acetoacetic acid esters for the process according to the invention which may be mentioned are, for exam 30 dropyridines (IXb) to the pyridines (VIb), in which R ple: methyl acetoacetate, ethyl acetoacetate, propyl has the abovementioned meaning, can be carried out, acetoacetate, isopropyl acetoacetate. for example, using chromium oxide or sodium nitrite in The preparation of the aldehydes of the general for glacial acetic acid in a temperature range from -20°C. mula IVa or b employed as starting substances will be to -- 150 C., using nitric acid in aqueous suspension or illustrated in the following by way of example for the 35 using cerium salts, such as, for example, ammonium compounds of the type (IVb). cerium nitrate, in a solvent mixture of acetonitrile and A) water. Preferably, acetonitrile and water are reacted with ammonium cerium nitrate in the mixture. R4 R4 A) FNe1 COOalkyl Ele CH2OH R4 R4 (B) Ro1 N 1R2 >Ro1SN 1R22 e. F-Nea COOR14 FNe1 COOR14 45

(VIb) N. RlO N R2 -GRio N R2 (IXb) (VIb) R4 50 The 3,4-dihydropyridines of the general formula E 21 CHO E (IXa, b) employed in this process as starting substances 2TeleV. R1O Sa N R2 Perlo In general, they are obtained by reaction of suitably 55 substituted af3-unsaturated carboxylic acid esters of the (VIIIb) (IVb) general formula (X) and appropriately substituted B amino-a?s-unsaturated carboxylic acid esters of the In this process, according to scheme A compounds of general formula (XI) and subsequent alkylation. the formula VIb are reduced to the hydroxymethyl The process can be carried out without solvent or in compounds in the first step 1 in inert solvents such as 60 ethers, for example, diethyl ether, tetrahydrofuran or a high-boiling solvent such as, for example, ethylene dioxane, preferably tetrahydrofuran, using metal hy glycol, either under basic conditions using alkali metal drides as reducing agents, for example lithium alumin alkoxides, such as, for example sodium methoxide or ium hydride, sodium cyanoborohydride, sodium alu potassium methoxide at room temperature to +200 C. minium hydride, diisobutylaluminium hydride or so 65 or in glacial acetic acid at room temperature. Reaction dium bis-(2-methoxyethoxy)-dihydroaluminate, in tem with alkali metal alkoxides at --140' C. is preferred. perature ranges from -70° C. to -100° C., preferably The reaction can be illustrated by the following reac from -70 C. to room temperature, or from room tem tion equation: 5,418,243 11 12 Suitable solvents in this case are in particular alcohols R4 C such as methanol, ethanol or propanol, preferably etha nol. The reduction can be carried out using the customary reducing agents, preferably using those which are suit E 2 r able for the reduction of ketones to hydroxy con o1 YOR 14 e R2 pounds. Particularly suitable in this case is reduction (I) (XI) using metal hydrides or complex metal hydrides in inert R4 solvents, if appropriate in the presence of a trialkylbo 10 rane. Reduction is preferably carried out using complex metal hydrides such as, for example, lithium borohy dride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylborohydride or lith O N rR2 ium aluminium hydride. Reduction is very particularly H (XII) 15 preferably carried out using sodium borohydride, in the presence of triethylborane. The reduction in general proceeds in a temperature range from -78° C. to +50 C., preferably from -78 C. to +25° C. and at normal pressure. R4 r R4 20 The compounds of the general formula (III) are mostly new, but can be prepared in analogy to known E COOR14 E COOR 14 methods (cf. DE 38 17298 A; U.S. Pat. No. 5,091,378. In the case of the enantiomerically pure compounds 2 of the general formula (I), either the corresponding o1N R2 Rio 1 SN R2 25 enantiomerically pure esters of the general formula (II) k (IXa) (IXb) are employed, which can be obtained according to published processes by reaction of the racemic products The alkylation is in general carried out using alkyl or with enantiomerically pure amines to give the corre benzyl halides in the presence of a base such as, for sponding diastereomeric amide mixtures, subsequent 30 separation by chromatography or crystallization into example, potassium carbonate, sodium hydride or an the individual diastereomers and final hydrolysis (cf. acid halide. The O-alkyl or O-acyl derivatives can be German Offendegungsschrift 4040026) or by separating prepared in the presence of a base such as imidazole, the racemic end products by customary chromato pyridine or triethylamine. graphic methods. In the case in which D and/or E represents the radi 35 The substituted 4-phenyl-pyridones and 4-phenyl-2- cal of the formula alkoxypyridines according to the invention and their isomeric forms have useful pharmacological properties OR7 which are superior in comparison to the prior art, in particular they are highly active inhibitors in vivo of -Xa- -N- COR1 3-hydroxy3-methyl-glutaryl coenzyme A (HMG-CoA) OR6 reductase and, as a result of this, inhibitors of choles terol biosynthesis. They can therefore be employed for the compounds are mostly new. the treatment of hyperlipoproteinaemia or arterioscle However, they can be prepared in analogy to the rosis. The active compounds according to the invention process described above, by reducing, starting from the 45 additionally cause a decrease in the cholesterol content compounds of the general formulae in the blood. The pharmacological action of the substances ac cording to the invention was determined in the follow R4 R4 ing test: L 21 M L 21 M Biological test for HMG-CoA reductase inhibitors Cholesterol is synthesized in the mammal body from Sa acetate units. In order to measure hepatic cholesterol O N R2 RO N R2 biosynthesis in vivo, radiolabelled C-acetate was ad ministered to the animals and the content of 14C-choles k 55 terol was later determined in the liver. The substances to be investigated were tested for in which inhibition of hepatic cholesterol biosynthesis in vivo on R, R2 and R have the abovementioned meaning, male Wistar rats having a body weight between 140 and L and/or M represent the radical of the formula 160 g. For this purpose, the rats were weighed 18 h before oral administration of the substances, divided O into groups of 6 animals (control group without sub stance loading of 8 animals) and fasted. The substances -X-P-CH2C-CH2-COR14 to be investigated were suspended in aqueous 0.75% OR6 strength tragacanth suspension using an Ultra-Turrax 65 immediately before administration. Administration of in which the tragacanth suspension (control animals) or the sub -X-, R6 and R1 have the meaning indicated and stances suspended in tragacanth was carried out by represents C1-C6-alkyl. means of a stomach tube. The animals were injected 5,418,243 13 14 intraperitoneally with C-acetate (12.5 uCi/animal) 2h after oral substance administration. STARTING COMPOUNDS A further 2 h later (4 h after substance administra tion), the animals were sacrificed and bled out by cut EXAMPLE ting the throat. The abdominal cavity was then opened 5 and aliversample of about 700 mg was removed for the Ethyl 3-amino-4-methyl-pent-2-en-oate determination of the 14 C-cholesterol synthesized from C-acetate. The cholesterol was extracted by a modifi cation of the method of Duncan et al. (J. Chromatogr. EtOOC 162 (1979) 281-292). The liver sample was homoge O nized in a glass Potter in isopropanol. After shaking and Subsequent centrifugation, the supernatant was treated with alcoholic KOH and the cholesterol-ester was hy drolyzed. After hydrolysis, the total cholesterol was extracted by shaking with heptane and the supernatant 15 was evaporated. The residue was taken up in isopropa 10.8g of p-toluenesulphonic acidx4 H2O are added nol, transferred to scintillation tubes and made up with to 500 g (3.16 mol) of ethyl isobutyrylacetate in 1,500 ml LSC cocktail. The C-cholesterol synthesized from C-acetate in the liver was measured in the liquid scin of toluene p.a., the mixture is saturated with ammonia tillation counter. The hepatic 14C-cholesterol content of 20 gas while stirring at room temperature and allowed to the animals treated only with tragacanth was used as a control. The inhibitory activity of the substances is stand overnight. It is then heated under reflux in a water indicated in % of the synthesized hepatic 14C-choles separator and ammonia gas is continuously introduced terol content of the tragacanth control animals until the calculated amount of water has separated (47 (=100%). 25 TABLE 1. ml of water after reflux for 8 hours). The mixture is Acute inhibition of C-cholesterol allowed to cool overnight, and the precipitate which biosynthesis in vivo in the rat liver has deposited is filtered off with suction and washed Dose which inhibits hepatic 30 C-cholesterol with toluene. The combined toluene phases are washed synthesis by 50% Ex. No. (ug/kg of body weight p.o.) several times with water, dried using sodium sulphate, 8 concentrated in vacuo and distilled in a high vacuum. II 8 35 B.p.: 82-85 C/1 mm Hg, Yield: 315 g (63.4% of The present invention also includes pharmaceutical theory, about 90% strength). preparations which, in addition to inert, non-toxic, pharmaceutically acceptable auxiliaries and excipients, EXAMPLE 2 contain one or more compounds of the general formula 40 (I), or which consist of one or more active compounds Methyl 1-carbomethoxy-2-(4-fluorophenyl)-propenoate of the formula (I), and processes for the production of these preparations. The active compounds of the formula () should be present in these preparations in a concentration from 0.1 45 to 99.5% by weight, preferably from 0.5 to 95% by weight of the total mixture. In addition to the active compounds of the formula (I), the pharmaceutical preparations can also contain other pharmaceutical active compounds. SO O The abovementioned pharmaceutical preparations can be prepared in a customary manner according to H3CO 21 known methods, for example using the auxiliary(ies) or excipient(s). H3CO S O In general, it has proven advantageous to administer 55 the active compound(s) of the formula (I) in total amounts from about 0.1 g/kg to about 100 g/kg, 229 ml (2 mol) of dimethyl malonate, 223 ml (2 mol) preferably in total amounts of about 1 g/kg to 50 of 4-fluorobenzaldehyde, 40 ml of piperidine and 103 ml pig/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the of glacial acetic acid are heated under reflux in a water desired result. separator overnight in 1.51 of cyclohexane. After cool However, it may sometimes be advantageous to de ing to room temperature, the mixture is taken up in part from the amounts mentioned, namely depending on the type and body weight of the subject to be treated, ethyl acetate, washed with water, dried using sodium on individual behaviour towards the medicament, the 65 sulphate and distilled. nature and severity of the disease, the type of prepara tion and administration, and the time or interval at B.p.: 135 C-140 C. (1 mm) Yield: 342.9 g (72% of which administration takes place. theory). 5,418,243 15 16 EXAMPLE 3 EXAMPLE 5 3-Methyl 5-ethyl 3-Methyl 5-ethyl 4-(4-fluorophenyl)-6-isopropyl-2-methoxy-pyridine-3,5- 3,4-dihydro-4-(4-fluorophenyl)-6-isopropyl-(1H)-pyrid- 5 dicarboxylate 2-one-3,5-dicarboxylate

10

15

20 11.3 g (31 mmol) of the compound of Example 4, 1.2 114.3 g (0.48 mol) of methyl 1-carbo-methoxy-2-(4- g (50 mmol) of sodium hydride and 4 ml (62 mmol) of methyl iodide are heated at 80 C. for 2 h in 50 ml of fluorophenyl)-propenoate, 75.4 g (0.48 mol) of ethyl dimethylformamide, and the mixture is poured into 500 3-amino-4-methyl-pent-2-en-oate, 1 g of sodium meth 25 ml of water at room temperature and extracted three oxide and 5 ml of ethanol were stirred at a bath tempera times with 150 ml of ether. The combined organic pha ture of 140 C. for 60 h and the product was recrystal ses are washed with water and dried using sodium sul lized from ethanol. phate. After distilling off the solvent in vacuo, 11.1 g are obtained. B.p.: 124° C. Yield: 115.4 g (66% of theory). 30 Crude yield: 95.2% of theory Melting point: 83° C. EXAMPLE 4 EXAMPLE 6 3-Methyl 5-ethyl Ethyl 4-(4-fluorophenyl)-6-isopropyl-(1H)-pyrid-2-one-3,5- 35 4-(4-fluorophenyl)-3-hydroxymethyl-6-isopropyl-2- dicarboxylate methoxy-pyridine-5-carboxylate

F

45

1.48 g (3.95 mmol) of the compound from Example 5 10.8 g (30 mmol) of the compound from Example 3 are dissolved in 30 ml of toluene, the solution is cooled to -78° C. under nitrogen and 6.6 ml (10 mmol) of a 1.5 and 3.9 g (39 mmol) of chromium trioxide were heated molar solution of diisobutylaluminium hydride in tolu under reflux in 100 ml of glacial acetic acid, a further 2 55 ene are added dropwise at this temperature. The cool g (20 mmol) of chromium trioxide were added after 2 h ing bath is removed and the mixture is stirred at room and the mixture was heated under reflux overnight. The temperature for 2 h. After hydrolysis using 20% strength aqueous potassium sodium tartrate solution, solvent was distilled off, the residue was dissolved in the organic phase is separated off, the aqueous phase is dilute hydrochloric acid, the solution was washed with washed three times with toluene, and the combined ether, and the combined ether phases were washed with organic phases are washed with saturated sodium chlo water, aqueous sodium hydrogen carbonate solution ride solution and dried using sodium sulphate. and water, dried using sodium sulphate and chromato After distilling off the solvent in vacuo, 1.52 g of oil 65 are obtained, which is chromatographed on silica gel graphed on silica gel 70-230 mesh using ethyl acetate/- (ethyl acetate/petroleum ether 1:5). petroleum ether 1:1. Yield: 520 mg (38% of theory) and 310 mg (21%) of Yield: 5.5 g (51% of theory). Melting point: 178 C. starting product. 5,418,243 17 18 EXAMPLE 7 EXAMPLE 9 4-(4-Fluorophenyl)-6-isopropyl-2-methoxy-3-methox Ethyl ymethyl-pyridine-5-carbaldehyde 4-(4-fluorophenyl)-6-isopropyl-3-methoxymethyl-2- 5 methoxy-pyridine-5-carboxylate

O

5

568 mg (2.64 mmol) of pyridinium chlorochromate 20 are added to a solution of 0.7 g (2.2 mmol) of the com pound from Example 8 in 120 ml of methylene chloride, the mixture is stirred overnight at room temperature, 520 mg (1.5 mmol) of the compound from Example 6 filtered off with suction through kieselguhr and washed with 200 ml of methylene chloride, filtered off with are stirred at room temperature for 4h in 42 mg (1.75 25 suction through silica gel, washed with 200 ml of meth mol) of sodium hydride and 0.3 ml (4.5 mmol) of methyl ylene chloride and dried using sodium sulphate, and 670 mg of oil are obtained after removal of the solvent in a iodide in 4 ml of dimethylformamide. The reaction rotary evaporator. mixture is poured into ice-water, washed three times Yield: 96% of theory. 30 with ether, and the combined ether phases are washed EXAMPLE 10 with water and saturated solution and (E)-3-(4-(4-Fluorophenyl)-6-isopropyl-2-methoxy-3- dried using sodium sulphate. After removal of the sol methoxymethyl-pyridin-5-yl)-prop-2-enal vent in a rotary evaporator 520 mg of oil are obtained. 35

F Yield: 100% of theory. EXAMPLE 8 4-(4 -Fluorophenyl)-5-hydroxymethyl-6-isopropyl-2- methoxy-3-methoxy-methylpyridine

45

804 (3.1 mmol) of diethyl 2-(cyclohexylamino)-vinyl phosphate dissolved in 6 ml of dry tetrahydrofuran are 50 added dropwise under nitrogen to a suspension of 59mg (2.5 mmol) of sodium hydride in 6 ml of dry tetrahydro furan at -5° C. After 30 min, 0.65 g (2.05 mmol) of the compound from Example 9 in 15 ml of dry tetrahydro furan is added dropwise at the same temperature and 55 the mixture is heated to reflux for 30 min. After cooling to room temperature, the mixture is added to 200 ml of ice-cold water and extracted three times using 100 ml of ethyl acetate each time. The combined organic phases 1.19 g (3.5 mmol) of the compound from Example 7 are washed with saturated sodium chloride solution and 60 dried over sodium sulphate. After concentration in were reduced with 5.2 m (7.7 mmol) of a 1.5 molar vacuo, the residue is taken up in 5 ml of toluene, treated solution of diisobutylaluminium hydride in toluene anal with a solution of 0.9 g (7 mmol) of oxalic acid dihy drate in 12 ml of water and heated to reflux for 90 min. ogously to Example 6. After chromatography on silica After cooling to room temperature, the phases are sepa gel (ethyl acetate/petroleum ether 1:5), 730 mg of solid 65 rated, and the organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate are obtained. and concentrated in vacuo. The residue is dissolved in Yield: 66% of theory Melting Point: methylene chloride and filtered through silica gel. 5,418,243 19 20 Yield: 560 mg of solid (79.6% of theory). acetate each time, the combined organic phases are EXAMPLE 1.1 washed once each with 10% strength potassium iodide Methyl solution, 10% strength sodium thiosulphate solution, (E)-7-4-(4-fluorophenyl)-6-isopropyl-2-methoxy-3- 5 saturated sodium hydrogen carbonate solution and Satu methoxy-methyl-pyridin-5-yl)-5-hydroxy-3-oxo-hept-6- rated sodium chloride solution, dried over sodium sul enOate phate and concentrated in vacuo. The residue is chro matographed on a column (100 g of silica gel 230-400 mesh, ethyl acetate/petroleum ether 1:2). 10 Yield: 350 mg of oil (47.6% of theory). EXAMPLE 13 Ethyl 3-(tert-butyldimethylsilyloxymethyl)-4-(4-fluoro 15 phenyl)-6-isopropyl-2-methoxy-pyridine-5-carboxylate

F 0.35 ml (3.3 mmol) of methyl acetoacetate are added 20 dropwise under nitrogen to a suspension of 80 mg (3.4 mmol) of sodium hydride in 3 ml of dry tetrahydrofuran at -5° C. After 15 min, 2.3 ml (3.3 mmol) of 15% strength butyllithium in n-hexane and 3.3 ml (3.3 mmol) H. of a 1 molar zinc chloride solution in ether are added 25 (Ho-c-i-o-Hi-c 21 COOC2H5 dropwise at the same temperature and the mixture is CH3 stirred for 15 min. 530 mg (1.5 mmol) of the compound Sa from Example 10 dissolved in 8 ml of dry tetrahydrofu H3CO N ran are then added dropwise and the mixture is stirred at -5 C. for 30 min. The reaction solution is cautiously diluted with 100 ml of saturated aqueous ammonium 30 304 mg (2 mmol) of tert-butylidimethylsilyl chloride, chloride solution and the mixture is extracted three times with 100 ml of ether each time. The combined 262 mg (4 mmol) of imidazole and 0.05 g of 4-dime organic phases are washed twice with saturated sodium thylaminopyridine are added at room temperature to a hydrogen carbonate solution and once with saturated solution of 600 mg (1.8 mmol) of the compound from sodium chloride solution, dried over sodium sulphate 35 Example 6 in 20 ml of dimethylformamide. The mixture and concentrated in vacuo. is stirred overnight at room temperature, treated with Crude yield: 760 mg (100% of theory). 200 ml of water and adjusted to pH 3 using 1N hydro chloric acid. The mixture is extracted three times using EXAMPLE 12 100 ml of ether each time, and the combined organic Methyl 40 erythro-(E)-7-4-(4-fluorophenyl)-6-isopropyl-2- phases are washed once with saturated sodium chloride methoxy-3-methoxymethyl-pyridin-5-yl)-3,5-dihy solution, dried over magnesium sulphate and concen droxy-hept-6-enoate trated in vacuo. The residue is chromatographed on a column (150 g of silica gel, 70-230 mesh, d4 cm, using 45 ethyl acetate/petroleum ether 1:9). Yield: 700 mg (87% of theory). EXAMPLE 14 Methyl 50 erythro-(E)-7-3-tert-butyldimethylsilyloxymethyl-4-(4- fluorophenyl)-6-isopropyl-2-methoxy-pyridin-5-yl)-3,5- dihydroxy-hept-6-enoate

55 1.9 ml (1.9 mmol) of 1M triethylborane solution in tetrahydrofuran are added at room temperature to a solution of 730 mg (1.6 mmol) of the compound from Example 11 in 13 ml of dry tetrahydrofuran, air is passed through the solution for 5 min and it is cooled to 60 an internal temperature of -30 C. 72 mg (1.9 mmol) of sodium borohydride and, slowly, 1.3 ml of methanol are added, the mixture is stirred at -30 C. for 30 min and then treated with a mixture of 5 ml of 30% strength hydrogen peroxide and 11 ml of water. The tempera- 65 ture is allowed to rise to 0 C. during the course of this Starting from Example 13, the title compound was and the mixture is stirred for a further 30 min. The prepared analogously to the procedures of Examples mixture is extracted three times with 70 ml of ethyl 8-12. 5,418,243 21 22 EXAMPLE 15 EXAMPLE II Methyl 3S,5S-(+)-(E)-7-4-(4-Fluorophenyl)-3-hydroxymethy erythro-(E)-7-4-(4-fluorophenyl)-3-hydroxymethyl-6- l-6-isopropyl-2-methoxy-pyrid-5- isopropyl-2-methoxy-pyridin-5-yl)-3,5-dihydroxy-hept 5 -yl)-hept-6-ene-1,3,5-triol 6-enoate

F

10

15

100 mg (0.18 mmol) of the compound from Example 20 Preparation is carried out analogously to Example I 14 are stirred at room temperature overnight in a solu starting from 3R,5S-(+)-methyl (E)-7-4-(4-fluoro tion of 1 ml of 1N hydrochloric acid and 9 ml of metha phenyl)-3-hydroxymethyl-6-isopropyl-2-methoxy nol. After concentration, the residue is taken up using pyrid-5-yl-3,5-dihydroxy-hept-6-enoate. methylene chloride, washed with saturated sodium hy 1H NMR (CDCl3): 8=1.25 (d, 6H); 1.42 (m, 2H); 1.63 drogen carbonate solution, dried and filtered through 25 (m,2H); 3.28 (sept. 1H); 3.82 (m,2H); 4.01 (m, 1H); 4.06 silica gel (ethyl acetate/petroleum ether 1:1). (s, 3H); 427 (m, 1H); 4.35 (d, 2H); 5.23 (dd, 1H); 6.22 (d, Yield: 46 mg (57% of theory) Melting point: 1H); 7.0–7.2 (m, 4H) ppm. We claim: PREPARATION EXAMPLES 1. Substituted 4-phenyl-pyridones and 4-phenyl-2- EXAMPLE I 30 alkoxypyridines of the general formula 3S,5S-(+)-(E)-7-4-(4-Fluorophenyl)-6-isopropyl-2- methoxy-3-methoxymethyl-pyrid-5-yl)-hept-6-ene R4 (Ia) 1,3,5-triol R5 21 R3 35

o1 N R2 k R4 (Ib) R5 21 R3

S. 45 RO N R2 in which R represents straight-chain or branched alkyl having 3.92 g (8.5 mmol) of 3R,5S-(+)-methyl (E)-7-4-(4- up to 8 carbon atoms, fluorophenyl)-6-isopropyl-2-methoxy-3-methoxymeth R2 represents cycloalkyl having 3 to 7 carbon atoms, yl-pyrid-5-yl-3,5-dihydroxy-hept-6-enoate are dis 50 or represents straight-chain or branched alkyl hav solved in 100 ml of absolute THF under argon. 35.8 ml ing up to 8 carbon atoms, (43 mmol) of a 1.2M. diisobutylaluminium hydride solu R3 represents a radical of the formula tion (in toluene) are added dropwise at -78° C. After 12 h at -30° C., the reaction solution is allowed to 55 R6O OR7 (a) come to 0 C. and 150 ml of water are cautiously added. The mixture is then extracted three times with 200 ml of -x-Scio-or ethyl acetate each time. The organic phase is washed with saturated NaCl solution, dried using Na2SO4 and R6O OR7 (c) concentrated in a rotary evaporator. The desired prod 60 --N-N- CHO or uct is obtained after chromatography on silica gel 60 (25-40, eluent ethyl acetate/petroleum ether 7:3). OR7 (d) Yield: 1.54 g (42% of theory) 1H NMR (CDCl3): 8=1.22 (m, 6H); 1.43 (m, 2H); 1.62 (m, 2H); 3.22 (s, 3H); 65 3.25 (sept. 1H); 3.84 (m, 2H); 4.01 (s, 3H); 4.04 (m, 1H); 4.06 (s, 2H); 4.28 (m, 1H); 5.22 (dd, 1H); 6.25 (d, 1H); -X O OH 7.0–7.2 (m, 4H) ppm. 5,418,243 23 24 in which R6, R7 and R8 are identical or different and denote X denotes the group -CH2-CH2-, -CH=CH hydrogen or a radical of the formula -CO-R or or -C=C-, and -COO-R10, in which R9, R7 and R8 are identical or different and denote R9 and R10 are identical or different and denote hydrogen or a radical of the formula -CO-R9 or 5 straight-chain or branched alkyl having up to 6 -COOR10, in which carbon atoms, or phenyl, R9 and R10 are identical or different and denote O straight-chain or branched alkyl having up to 8 R6 and R7 together form a radical of the formula carbon atoms, or phenyl, O O H3C CH3, R6 and R7 together form a radical of the formula

H3C CH3, R“represents phenyl which is optionally substituted up to 2 times by identical or different fluorine, 15 chorine, bromine, trifluoromethyl or straight-chain R represents phenyl which is optionally substituted or branched alkyl having up to 6 carbon atoms, up to 2 times by identical or different halogen, Rs has the abovementioned meaning of R and is trifluoromethyl, methoxy, phenoxy or straight identical to or different from this, or represents chain or branched alkyl having up to 8 carbon 20 hydrogen, cyano, carboxyl or straight-chain or atoms, branched alkoxycarbonyl having up to 6 carbon R has the abovementioned meaning of R3 and is atoms, or represents straight-chain or branched identical to or different from this, or represents alkyl having up to 6 carbon atoms, which is option hydrogen, cyano, carboxyl or straight-chain or ally substituted by fluorine, chlorine, bromine, hy branched alkoxycarbonyl having up to 8 carbon 25 droxyl or by straight-chain or branched alkoxy atoms, or represents straight-chain or branched having up to 6 carbon atoms, or which is substi alkyl having up to 8 carbon atoms, which is option tuted by a group of the formula -O-(CH ally substituted by halogen, hydroxyl, by straight 2)-R11 or -O-CO-R12, in which a denotes a number 0 or 1, and chain or branched alkoxy having up to 8 carbon R11 denotes phenyl or benzyl, each of which is atoms, or by a group of the formula -O-(CH 30 optionally substituted in the aromatic system by 2)-R11 or -O-CO-R12, in which fluorine, chlorine, bromine, trifluoromethyl, cy a denotes a number 0 or 1, ano, nitro or straight-chain or branched alkyl Rll denotes phenyl or benzyl, each of which is having up to 4 carbon atoms, optionally substituted up to 2 times in the aro R12 has the abovementioned meaning of R and is matic system by identical or different halogen, 35 identical to or different from this, or denotes trifluoromethyl, cyano, nitro or straight-chain or straight-chain or branched alkyl having up to 6 branched alkyl having up to 6 carbon atoms, carbon atoms, R12 has the abovementioned meaning of R11 and is O identical to or different from this, or denotes R5 represents a radical of the formula -CH straight-chain or branched alkyl having up to 8 =N-O-R13, in which carbon atoms, or R13 has the abovementioned meaning of R12 and is R represents a radical of the formula -CH identical to or different from this. =N-O-R13, in which 3. Substituted 4-phenyl-pyridones and 4-phenyl-2- R13 has the abovementioned meaning of R12 and is alkoxypyridines according to claim 1, in which identical to or different from this. 45 R represents straight-chain or branched alkyl having 2. Substituted 4-phenyl-pyridones and 4-phenyl-2- up to 4 carbon atoms, alkoxypyridines according to claim 1, in which R2 represents cyclopropyl or represents straight R represents straight-chain or branched alkyl having chain or branched alkyl having up to 4 carbon up to 6 carbon atoms, atoms, R2 represents cyclopropyl, cyclopentyl or cyclo 50 R3 represents a radical of the formula hexyl, or represents straight-chain or branched alkyl having up to 6 carbon atoms, R3 represents a radical of the formula R6O OR7 55 -x-N-Scho-o. R6O. OR7 -N-> (CH2)2-OR8, OR7 OR7 R6O OR7 -X 1N-N- CHO Ot -X O OH R6O OR7 in which -X 1N-N- CHO Ot -X O OH X denotes the group -CH2-CH2- or -CH= 65 CH-, in which R6, R7 and R8 are identical or different and denote X denotes the group -CH2-CH2-, -CH=CH hydrogen or a radical of the formula -CO-R', in which 5,418,243 25 26 R9 denotes straight-chain or branched alkyl hav ing up to 4 carbon atoms, R represents phenyl which is optionally substituted by fluorine, trifluoromethyl or by straight-chain or branched alkyl having up to 4 carbon atoms, R has the abovementioned meaning of R3 and is identical to or different from this, or represents hydrogen or represents straight-chain or branched alkyl having up to 4 carbon atoms, which is option O ally substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms. 4. Substituted 4-phenyl-pyridones and 4-phenyl-2- alkoxypyridines according to claim 1, in which 15 6. A compound according to claim 1 wherein such R represents straight-chain or branched alkyl having compound is 3S,5S-(+)-(E)-7-4-(4-fluorophenyl)-3- up to 4 carbon atoms, hydroxymethyl-6-isopropyl-2-methoxypyrid-5-yl)- R2 represents cyclopropyl or represents straight hept-6-ene-1,3,5-triol of the formula chain or branched alkyl having up to 4 carbon atOnS, R3 represents a radical of the formula 20 F

OH OH --N-N (CH2)2-OH 25 in which X denotes the group -CH2-CH2- or -CH= CH-, R represents phenyl which is optionally substituted 30 by fluorine, and Rs has the abovementioned meaning of R3 or repre sents straight-chain or branched alkyl having up to 7. A composition for the treatment of hyperlipo proteinae and arteriosclerosis comprising an amount 4 carbon atoms, which is optionally substituted by 35 effective therefor of a compound according to claim 1 hydroxyl or alkoxy having up to four carbon and a pharmacologically acceptable diluent. atOnS. 8. The method of treating hyperlipoproteinaemia and 5. A compound according to claim 1 wherein such arteriosclerosis in a patient in need thereof which com compound is 3S,5S-(-)-(E)-7-4-(4-fluorophenyl)-6-iso prises administering to such patient an amount effective propyl-2-methoxy-3-methoxymethylpyrid-5-yl)-hept therefor of a compound according to claim 1. 6-ene-1,3,5triol of the formula k k is k . It

45

50

55

65