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 aldehyde 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.